Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

18. Acute Leukemias

Olga Frankfurt and Martin S. Tallman

I. GENERAL FEATURES OF ACUTE LEUKEMIAS

The acute leukemias are a heterogeneous group of disorders characterized by clonal proliferation and abnormal differentiation of neoplastic hematopoietic progenitor cells. Accumulation of immature hematopoietic cells, or blasts, in the bone marrow and peripheral blood ultimately leads to inhibition of normal hematopoiesis. If left untreated, acute leukemias are rapidly fatal.

Over the last 40 years, significant therapeutic advances have been made and many patients can now be cured of their disease. The general treatment approach for most patients with acute leukemia includes eradication of the leukemic clone with intensive systemic chemotherapy, followed by some form of consolidation and, in certain cases, maintenance therapy. Despite this strategy, most patients under the age of 55 and the vast majority of older adults die from their disease.

Numerous questions regarding optimal therapeutic strategies for patients with acute leukemia remain unanswered. Hence, all patients with acute leukemia should be considered candidates for clinical trials and treated in centers where appropriate intensive and comprehensive care can be provided.

A. Epidemiology

The incidence of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is 2.7 and 1.5 per 100,000 of the population, respectively, and is slightly higher in males than in females. Sixty percent of patients with ALL are children, with a peak incidence in the first 5 years of life. The second peak emerges after the age of 60 years. The incidence of AML rises exponentially after the age of 40 years with the median age of disease presentation at 68 years. The median age of patients diagnosed with acute promyelocytic leukemia (APL), a distinct subtype of AML, is 40 years, and the incidence of the disease does not increase with advanced age. While in general the incidence of acute leukemias is slightly higher in the populations of European descent, the incidence of APL may be higher among patients of Hispanic origin.

B. Etiology and risk factors of acute leukemias

Although the association of the acute leukemias with various infectious, genetic, environmental, and socioeconomic factors has been evaluated extensively, the etiology remains obscure in most cases.

1. Infection. There is a strong association between Epstein-Barr virus, a DNA virus causing infectious mononucleosis, and Burkitt lymphoma/leukemia.

2. Genetic factors have been implicated in the pathogenesis of acute leukemia based on epidemiologic studies, showing the 25% increased risk of ALL within 1 year in a monozygotic twin of an affected infant. There is also a fourfold increase in risk of developing leukemia in dizygotic siblings. The risk of developing acute leukemia is significantly higher in patients with Down and Klinefelter syndromes, and conditions with excessive chromosome fragility such as Fan-coni anemia, ataxia telangiectasia, and Bloom syndrome.

3. Exposures to chemotherapy and radiation significantly increase the risk of developing acute leukemias. AML with chromosome 5 and/or 7 abnormality has been reported to occur 2 to 9 years after therapy with alkylating agents. Topoisomerase inhibitors have been linked to the development of AML and ALL with 11q23 aberration, characteristically 1 to 3 years after the exposure. An increased incidence of acute leukemias has been reported after radiation exposure such as atomic bomb explosion, the Chernobyl accident, and therapeutic radiation. Increased incidence of leukemia has been linked to the exposure to gasoline, benzene, tobacco, diesel, motor exhaust, and electromagnetic fields.

C. Clinical and laboratory features

Clinical and laboratory features of acute leukemias and their associated signs and symptoms are shown in Table 18.1.

D. Diagnosis, classification, and prognostic features in acute leukemias

The acute leukemias are divided into AML and ALL, based on the morphologic, immunohistochemical, and immunophenotypic characteristics of the stem cell of origin. Although the peripheral blood smear may be highly suggestive of the diagnosis, examination of the bone marrow aspirate and core biopsy is essential to confirm the diagnosis and to determine the extent of the disease. Cytogenetic analysis and molecular studies may aid in establishing an accurate diagnosis, estimate prognosis, and guide therapy.

1. AML classification. Currently, two pathologic classifications are used to define AML. The morphology-based French-American-British (FAB) classification, devised in 1976, utilizes cytochemical stains and, more recently, immunophenotyping by flow cytometry to differentiate myeloid from lymphoid blasts (Tables 18.2 and 18.3). According to FAB classification, eight subcategories of AML are established based on the type of the cell involved and the degree of differentiation (Table 18.4). A more recent World Health Organization (WHO) classification created in 1999 and updated in 2008 generated 17 subclassifications of AML, based on presence of dysplasia, chromosomal translocations, and molecular markers (see Table 18.4). Additional changes included the decrease of the diagnostic threshold to 20% blasts (from the original classification of 30%, hence eliminating the refractory anemia with excess blasts transformation category of myelodys-plastic syndrome [MDS]) and the diagnosis of AML regardless of the percent of marrow blasts in marrows with evidence of abnormal hematopoiesis and clonal cytogenetic abnormalities such as t(8;21), t(15;17), and t(16;16) or inv(16).

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2. Prognostic factors in AML. Prognostic factors in AML could be viewed as patient-related characteristics (age, performance status [PS]) and leukemic clone–related characteristics. Advanced age is an adverse prognostic factor. Even after accounting for risk factors such as cytogenetics, molecular genetics, presence of antecedent hematologic disorder, and PS, older patients have worse outcome than younger patients: 40% to 60% complete response (CR) rates, and only 5% to 16% are alive at 5 years.

However, chronologic age alone should not be the only determinant of whether patients should receive potentially curative chemotherapy because age is not the most important prognostic factor for either treatment-related mortality (TRM) or resistance to therapy (see Section IV.G.1).

AML-related prognostic characteristics include WBC count at presentation, presence of antecedent hematologic disorder, prior exposure to the cytotoxic therapy, as well as cytogenetic and molecular changes. In fact, cytogenetic and molecular genetic changes in leukemia cells at diagnosis are the most important prognostic characteristic for predicting the rate of remission, relapse, and overall survival (OS). Younger adult patients are commonly separated into three risk groups: favorable, intermediate, or adverse (Table 18.5).

Based on the recent analysis of 1213 patients with AML treated on Cancer and Leukemia Group B (CALGB) protocols, the 5-year survival for patients with favorable, intermediate, and poor-risk cytogenetics was 55%, 24%, and 5%, respectively.

Complex karyotype, defined by the presence of three or more (in some studies five or more) chromosomal abnormalities, occurs in 10% to 12% of patients and is associated with very poor outcome. Monosomal karyotype, a recently proposed cytogenetic category, has a particularly poor survival (5-year OS of 4%). It is defined by presence of a single monosomy (excluding isolated loss of X and Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding core binding factor [CBF] AML).

Cytogenetically normal (CN)-AML patients harboring internal tandem duplication (ITD) of the FLT-3 gene have an inferior outcome compared to those without FLT-3-ITD. In the recent series, 5-year survival of patients with a normal karyotype and the presence of FLT3 mutations was 20% compared to that of 42% for patients with normal karyotype without FLT3 mutation. In a clinical trial, the information regarding FLT3 status is unlikely to change the initial therapy; however, this may change, as FLT3 inhibitors become part of the armamentarium of agents active against AML.

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In several, but not all, studies, presence of nucleophosmin (NPM) mutation (and the absence of a FLT3 ITD mutation) in CN-AML confers an improved outcome with higher CR, relapse-free survival (RFS), and event-free survival (EFS) rates. NPM1+/ FLT3— genotype demonstrate rates of CR and OS similar to those of the CBF leukemias.

Double mutation (biallelic) in the CCAAThenhancer binding protein alpha (CEBPA) gene in CN-AML patients predicts a favorable outcome. It remains to be established whether presence of FLT3 negates the positive effect of CEBPA Among the cytogenetically favorable CBF-AML, presence of the c-KIT mutation exerts a negative influence of outcome in retrospective studies. Internal tandem duplication of the MLL gene has also been associated with poor prognosis in patients with normal karyotype.

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3. ALL classification. The diagnosis and classification of ALL is based on cell morphology, immunohistochemistry, as well as immunophenotypic and cytogenetic features. Marrow involvement of more than 25% lymphoblasts is used to differentiate ALL from lymphoblastic lymphoma, in which the preponderance of tumor bulk is in nodal structures. Approximately 70% to 75% of adult ALL cases are of precursor B-cell origin; 20% to 25% are of T-cell origin (Tables 18.6 and 18.7).

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4. Prognostic factors in ALL. Although modern intensive chemotherapy regimens have abolished multiple prognostic factors identified in the past, several biologic and clinical features of ALL still predict response to therapy, remission duration, disease-free survival (DFS), and help to determine the intensity of the induction and postremission therapy. Similar to the patients with AML, the outcome of therapy for patients with ALL worsens with increasing age. In multivariate analysis, age over 60 years is associated with a particularly poor prognosis, with shorter remission durations and worse survival. Presenting WBC of greater than 30,000/(µL is an adverse prognostic factor predicting shorter remission durations that pertains more to precursor B-lineage ALL. (Treshold WBC greater than 100,000/(µL may be important for T-cell ALL.) The time required to achieve CR (more than 4 weeks) following induction chemotherapy has been demonstrated to be an adverse prognostic factor in several, but not all, clinical trials. A report from the GIMEMA ALL group demonstrated that response (defined as peripheral blast count of 0 to 1000/(µL on day 10) to 7 days of initial prednisone treatment prior to induction was prognostic in predicting disease outcome in adult patients with ALL. A recently published study demonstrated that presence of minimal residual disease (MRD), defined as greater than or equal to a 10−4reduction in the leukemic cell burden detected at diagnosis at weeks 16 to 22 (detected by leukemia-specific reverse transcription [RT]-polymerase chain reaction [PCR] probes), was a very strong predictor of relapse.

Similar to AML, cytogenetic abnormalities are one of the most important factors predicting outcome in ALL. Approximately half of the patients with ALL have cytogenetic abnormalities, which usually take the form of translocation rather than deletion, as seen more commonly in AML. The landmark International ALL trial (UKALLXII/ Eastern Cooperative Oncology Group [ECOG] E2993) conducted by the Medical Research Council (MRC; now the National Cancer Research Institute) in the United Kingdom and the ECOG in the United States identified in a very large number of patients the incidence and clinical associations of more than 20 specific cytogenetic abnormalities. The t(4;11), t(8;14), complex karyotype (five or more abnormalities), and hypodiploid/near triploidy abnormalities all were associated with a poorer EFS and OS compared to patients with other abnormalities. Other adverse cytogenetic abnormalities include t(9;22), t(1:19), 9p21, and 11q23. Alternatively, patients with high hyperdiploidy or a del(9p) were associated with an improved outcome.

E. Acute leukemias of ambiguous lineage

With the expansion of immunophenotyping panels, use of electron microscopy, and gene rearrangement studies for the characterization of acute leukemia, increasing degrees of infidelity of myeloid and lymphoid markers is demonstrated. Cases in which differentiation between AML and ALL is difficult are described by the WHO as “acute leukemia of ambiguous lineage” and comprise those cases that show no evidence of lineage differentiation (i.e., acute undifferentiated leukemia [AUL]) or those with blasts thaThexpress markers of more than one lineage (mixed phenotype acute leukemia [MPAL]; see Table 18.4). AUL often expresses human leukocyte antigen (HLA)-DR, CD34, and/or CD38, but by definition lacks lineage-specific markers. MPAL can either contain a distinct blast population of different lineages, one blast population with markers of different lineages on the same cell, or a combination of both.

II. INITIAL SUPPORT

Once the diagnosis of acute leukemia has been established, the next 24 to 48 hours are spent preparing the patient for the initiation of cytotoxic chemotherapy. The following issues need to be addressed in almost all individuals facing induction chemotherapy.

A. Hyperleukocytosis, leukostasis, and leukapheresis

Hyperleukocytosis, defined as an absolute blast count of more than 100,000/µL, predisposes to rheologic problems and is associated with increased induction mortality in AML. Leukostasis, manifesting as cerebral and cardiopulmonary dysfunction due to vascular obstruction and/or vessel wall necrosis with hemorrhage, occurs almosThexclusively in AML and represents an oncologic emergency. Given the increased risk of early death with hyperleukocytosis, steps to rapidly reduce the blast counts should be undertaken as soon as the diagnosis is made. In the hemodynamically stable patient, leukapheresis is the most rapid way to lower the blast count; however, no impact on long-term outcome has been shown. With very high blast counts (more than 200,000/µL), decreasing the blast count by 50% may have to be the initial goal because mathematic modeling suggests that prolonged leukapheresis after a “3-L exchange” does not significantly decrease the blast count further. Leukapheresis may be repeated daily. Systemic chemotherapy should be initiated immediately after emergent leukapheresis or if leukapheresis cannot be performed. Hydroxyurea 3 to 5 g/m2/day split into three doses daily until WBC are less than 10,000 to 20,000/(µL is commonly used. In patients presenting with hyperleukocytosis, an allopurinol dose of 600 mg twice a day is well tolerated for the first 2 days, followed by 300 mg twice a day for 2 to 3 days. Emergent cranial radiation for hyperleukocytosis and cranial nerve palsies (or other severe neurologic deficit) is another treatment modality that may be used.

Blood transfusions in the anemic patient with hyperleukocytosis should be undertaken with great care as an aggressive packed red blood cell transfusion in such patients may precipitate symptoms of hyperviscosity. Unless the patient has symptoms due to anemia, a packed cell volume (hematocrit) of 20% to 25% is a reasonable goal.

B. Hydration and correction of electrolyte imbalance

Dehydration needs to be corrected and adequate urine output maintained to prevent renal failure due to the deposition of cellular breakdown products resulting from the tumor lysis syndrome. In the absence of cardiac disease, normal saline with or without 5% dextrose (D5W) is infused to maintain the urine output at more than 100 mL/h. The concomitant use of loop diuretics may be necessary in patients with congestive heart failure.

A variety of electrolyte abnormalities, such as hypocalcemia, hyperphosphatemia, and hyperkalemia, may occur in patients with acute leukemia. Hypocalcemia may cause potentially lethal cardiac (ventricular arrhythmias, heart block) and neurologic (hallucination, seizures, coma) complications. In an asymptomatic patient with laboratory evidence of hypocalcemia and hy-perphosphatemia, calcium replacement is not recommended as it may precipitate metastatic calcifications. However, in a patient with symptomatic hypocalcemia, calcium gluconate may be carefully administered to correct the clinical symptoms. Hyperkalemia, defined by a potassium level of greater than 6 mmol/L, caused by massive cellular degradation, may precipitate significant neuromuscular (muscle weakness, cramps, paresthesias) and potentially life-threatening cardiac (asystole, ventricular tachycardia, and ventricular fibrillation) abnormalities. Patients should be treated with oral sodium-potassium exchange resin, such as sodium polystyrene 15 to 30 g every 6 hours and/or combined glucose/insulin therapy.

Serum electrolytes, uric acid, phosphorus, calcium, and crea-tinine should be monitored several times a day, depending on the severity of the clinical condition and degree of metabolic abnormality. Early hemodialysis may be required in patients who develop oliguric renal failure or recalcitranThelectrolyte disturbances. The electrocardiogram should be obtained and cardiac rhythm monitored while these abnormalities are corrected.

C. Prevention of uric acid nephropathy

Hyperuricemia is common at presentation and may also occur with the tumor lysis caused by chemotherapy. Allopurinol is the mainstay of prevention of uric acid nephropathy. The usual initial adult dose is 300 mg (150 mg/m2) twice per day for 2 to 3 days, which is then decreased to 300 mg once a day. Allopurinol should be stopped after 10 to 14 days to lessen the risk of rash and hepatic dysfunction. If chemotherapy needs to be initiated urgently, al-lopurinol at a dose of 600 mg twice per day is well tolerated for 1 to 2 days. With the advent of allopurinol, the role of urine al-kalinization has become less clear. Although urine alkalinization increases uric acid solubility, it decreases the solubility of urinary phosphates and may promote phosphate deposition in patients susceptible to the tumor lysis syndrome (e.g., B-cell ALL and T-cell lymphoblastic leukemia). A commonly employed method of urine alkalinization is to hydrate the patient with D5W to which two syringes of sodium bicarbonate (44 mEq of NaHCO3 per syringe) have been added per liter.

Rasburicase, a recombinant urate oxidase, is a safe and effective alternative to allopurinol. Although the recommended dose of rasburicase is 0.15 to 0.2 mg/kg/day for 5 days, at our institution an excellent control of hyperuricemia was achieved with a lower dose of 3 mg/day. Administration of 3 mg of rasburicase to 18 patients with hyperuricemia secondary to leukemia/lymphoma resulted in the normalization of the uric acid in 11 patients with just a single dose of rasburicase, in 6 patients with two doses, and in 1 patient with three doses.

D. Correction of coagulopathy

Hemostatic defect secondary to thrombocytopenia may be potentiated by the presence of consumption coagulopathy (disseminated intravascular coagulation [DIC]). Life-threatening bleeding complications are particularly common in patients with APL due to the presence of DIC and primary fibrinolysis (see APL management, Section VII). Lysozyme released from monoblasts in M4 and M5 subtypes of AML may trigger a clotting cascade leading to consumption coagulopathy. In ALL, therapy with L-asparaginase (L-Asp) may lead to DIC. Additionally, sepsis may contribute to coagulopathy in newly diagnosed patients with acute leukemias. Frequent monitoring of coagulation parameters and adequate replacement with cryoprecipitate or fresh frozen plasma products in appropriate patients is critical.

E. Blood product support (see Chapter 28)

Most patients with acute leukemia present with evidence of bone marrow failure. Symptomatic anemia, hemoglobin less than 8 g/dL, thrombocytopenia less than 10,000/µL, as well as signs of bleeding, must be corrected. The threshold below which platelet transfusion is needed may be higher (e.g., 20,000/µL) if conditions known to increase the risk of bleeding such as severe mucositis, fever, anemia, and coagulopathy are present. Blood products should be leukoreduced to decrease the risk of febrile nonhemolytic transfusion reaction; alloimmunization to HLAs, which may lead to subsequent refractoriness to platelet transfusion; and transmission of cytomegalovirus (CMV). Additionally, blood products should be gamma irradiated to reduce the risk of transfusion-related graft-versus-host disease (GVHD). Patients who are potential candidates for stem cell transplant (SCT) should be screened for CMV and receive CMV-negative blood until CMV status is determined.

F. HLA typing

Patients who are candidates for SCT should be HLA typed prior to the initiation of therapy because chemotherapy-induced severe myelosuppression will not leave enough lymphocytes for HLA typing. However, occasionally an inadequate number of circulating lymphocytes and the presence of blast cells preclude the ability to carry out HLA typing prior to initial therapy. HLA-matched platelet transfusions may need to be administered to patients who develop alloimmunization and become refractory to pooled or single-donor platelets.

G. Fever or infection (see Chapter 27)

Patients frequently have a fever or an infection at initial diagnosis. The cardinal rule is that all patients with acute leukemia and fever are presumed to have an infection until proved otherwise. Given the additional myelosuppressive and immunosuppressive effects of chemotherapy, severe infections should be treated aggressively before initiating chemotherapy. However, the antibiotic treatment frequently needs to be administered concurrently with induction chemotherapy. Patients with acute leukemia need a careful physical examination daily. There should be close attention toward potential sites of infection, including the fundi, sinuses, oral cavity, intertriginous areas, perineum (attempts are made to avoid internal rectal examination during neutropenia), and catheter sites. A dental consultation at the time of diagnosis is often useful.

H. Vascular access

Because of the need for several sites of venous access for at least 1 month, a multiple-lumen implantable catheter (e.g., Hickman catheter or peripherally inserted central catheter line) must be placed as soon as possible (except in patients suspected to have APL). An implantable port is not recommended for patients with leukemia because there is higher risk of infection and hematoma at the access site. Because of the coagulopathy in patients with APL, the placement of a long indwelling catheter is avoided altogether if at all possible and certainly until the coagulopathy has been completely corrected and the patient is in a CR. A risk of life-threatening bleeding in patients with APL is presenTheven when most or all of the routine coagulation studies are normal.

I. Suppression of menses

A serum human chorionic gonadotropin (β-hCG) assay (pregnancy test) should be done in all premenopausal women prior to initiation of chemotherapy. It may be desirable to prevent menses during chemotherapy to avoid the severe menorrhagia due to the thrombocytopenia. Medroxyprogesterone (Provera) 10 mg twice per day may be started 5 to 7 days before the expected starting time of the next menstrual period. It may be increased to 10 mg three times per day or higher if breakthrough bleeding occurs. Medroxyprogesterone acetate IM (Depo-Provera) is contraindicated in the thrombocytopenic and neutropenic patient.

J. Birth control and fertility

Given the potential teratogenic effects of cytotoxic chemotherapy, appropriate measures for preventing conception must be addressed with women of reproductive age undergoing chemotherapy. Although there are no clear data linking chemotherapy in the male partner to teratogenic effects in the fetus, it is prudent to suggest that appropriate birth control measures be undertaken in this situation as well.

Late effects of chemotherapy, such as infertility, need to be considered in younger patients. Sperm cryopreservation should be offered to men of reproductive age prior to initiation of chemotherapy.

Gonadal function in women seems to be less affected by cytotoxic chemotherapy. Cryopreservation offertilized eggs is currently available, while cryopreservation of unfertilized eggs may be conducted on the investigational basis.

K. Psychosocial support

Patients with acute leukemia are usually previously healthy individuals who have suddenly had to accept the possibility of their own imminent mortality. Intensive psychological and spiritual support by the healthcare team, family, and religious leaders is critical for maintaining the patient's sense of well-being.

III. THERAPEUTIC PRINCIPLES AND APPROACH TO THERAPY OF ACUTE LEUKEMIA

A. Therapeutic aim

The goals of chemotherapy are to eradicate the leukemic clone and re-establish normal hematopoiesis in the bone marrow. Long-term survival is seen only in patients in whom a CR is attained. Although leukemia therapy is toxic and infection is the major cause of death during therapy, the median survival time of untreated (or unresponsive) acute leukemia is 2 to 3 months, and most untreated patients die of bone marrow failure and its complications. The doses of chemotherapy are never reduced because of cytopenia, because lowered doses still produce the unwanted side effects (further marrow suppression) without having as great a potential for eradicating the leukemic clone and ultimately improving marrow function.

B. Forms of chemotherapy and response criteria

1. Induction chemotherapy is initial intensive chemotherapy given in an attempt to eradicate the leukemic clone and to induce a CR. The term complete response depicts patients who achieve recovery of normal peripheral blood counts with recovery of bone marrow cellularity, including the presence of less than 5% blast cells, in the absence of extramedullary disease. The aim of induction chemotherapy is to reduce the leukemia cell population by several logs from the clinically evident total body tumor burden of 1012 leukemia cells (about 1 kg), commonly seen at diagnosis, to below the cytologically detectable level of 109 cells. It is important to note that because achievement of initial CR represents only a 3- to 6-log leukemia cell reduction, a substantial leukemia cell burden persists, and patients usually relapse within months if further therapy is not administered. Induction therapy is typically initiated as soon as diagnostic work-up has been completed, as there retrospective data suggesting that treatment outcome might be adversely impacted when treatment is delayed by more than 5 days from the diagnosis.

2. Postremission chemotherapy is administered subsequently to achievement of a CR in a further attempt to eradicate the residual, but often undetectable, leukemic clone. In a younger patient population, considering the relatively high rate of CR after the induction, future advances are likely to be made through improved postremission therapy. Patients older than 60 years tend to achieve suboptimal CR rates of 40% to 60% and poor 5-year OS of approximately 10%, and should be enrolled in investigational protocols aimed at improving induction and consolidation therapy.

bull Consolidation therapy involves repeated courses of the same drugs at similar or higher doses as those used to induce the remission, which are given soon after the remission has been achieved (2 to 3 weeks after the recovery of blood counts). Consolidation often requires further hospitalization.

bull Maintenance therapy pertains primarily to ALL and includes low doses of drugs designed to be administered on an outpatient basis for up to 2 years. In AML, this strategy applies only to APL.

3. The definition of response is based ontheperipheralblood counts and the status of the recovered bone marrow. If the marrow is hypoplastic, it is imperative to repeat the bone marrow biopsy to document remission on recovery.

bull CR is the return of the complete blood count to a “normal” absolute neutrophil count (ANC) of more than 1500/(µL and to a platelet count of more than 100,000/(µL in conjunction with a normal bone marrow (i.e., normal cellularity, less than 5% blasts or promyelocytes and promonocytes, an absence of obvious leukemic cells, and absence of extramedullary disease). Presence of minimal residual disease (MRD) as determined by flow cytometry or PCR analysis is a predictor of the relapse. Relapse rates range from 0% in patients with a reduction to less than 10−4 leukemic cells detected at the completion of the induction (compared to leukemia cell burden at diagnosis) to 14% in those with 10−3 to 10−4 to 89% in patients with 1% residual disease.

bull Partial response is the persistence of morphologically identifiable residual leukemia (5% to 15% leukemic cells in the bone marrow).

IV. THERAPY FOR ADULT AML (OTHER THAN APL)

The day that induction chemotherapy is started is arbitrarily called day 1. Bone marrow aspiration and biopsy are typically repeated on day 14. If the bone marrow is severely hypoplastic with fewer than 5% residual blasts or if the bone marrow is aplastic, no further chemotherapy is given, and the patient is supported until bone marrow recovery occurs (usually 1 to 3 weeks more). A bone marrow examination is repeated 2 weeks later (about days 26 to 28). Once a CR has been documented, the potential benefit of further consolidation therapy should be determined on an individual basis.

A. Induction therapy

Factors that influence the choice of the initial chemotherapeutic agents include the patient's age, cardiac function, and PS. An age of 60 years has traditionally been considered a cut-off point to recommending induction chemotherapy due to higher prevalence of unfavorable cytogenetics, antecedent myelodysplasia, expression of multidrug resistant protein, as well as frequency and severity of comorbid conditions affecting the ability to tolerate intensive chemotherapy. The initial drug doses outlined below are based on the presence of normal hepatic and renal function and do not require modification for depressed (or elevated) peripheral blood counts.

1. “3 + 7.” During the last 35 years, a series of clinical trials have identified an induction regimen of 3 days of anthracycline (daunorubicin [DNR] 60 to 90 mg/m2/day, idarubicin 10 to 12 mg/m2/day, or mitoxantrone, and anthracenedione, 12 mg/m2/day) and 7 days of cytarabine (Ara-C) 100 to 200 mg/m2, which is considered standard (Table 18.8). With such regimens, the anticipated rate of CR in younger patients (younger than 55 to 60 years) is 60% to 80%. No other intervention has been convincingly demonstrated to be better. Several randomized trials have compared DNR at 45 to 60 mg/m2 with idarubicin, mitoxantrone, aclarubicin, and amsacrine; with respect to OS, none of the agents appeared to be superior to DNR at the equivalent doses. In younger patients, idarubicin, which attains a higher intracellular drug concentration, was shown to induce higher remission rates, longer response duration, and improved OS. In older adults, however, a randomized trial showed no benefit of one anthracycline/anthracenedione over the other. In a recently published randomized clinical trial, a higher dose of DNR (90 mg/m2/day) resulted in a higher rate of CR (70.6 versus 57.3, p 0.001) and improved OS (23.7 versus 15.7 months, p = 0.003) as compared with a lower (than standard) dose (45 mg/m2/day). Although 60 mg/m2/day was never formally compared to 90 mg/m2/day, doses thaThexceed 45 mg/m2/day for induction are now considered standard. Several nuances will require further clarification, particularly in patients older than 50 years; for example, those with unfavorable cytogenetic profile, FLT3-ITD+ and MLL-PTD mutation did not benefit from the higher doses of DNR.

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2. Cytarabine dose intensification. The merit of cytarabine dose intensification has been explored in several clinical trials. Based on the results, the rate of CR was not affected by the administration of high-dose cytarabine (HDAC) compared to the standard dose.

In a Southwest Oncology Group (SWOG) study, patients received DNR (45 m/m2 for 3 days) and were randomized to receive either standard-dose cytarabine (SDAC) (200 mg/m2 continuous infusion for 7 days) or HDAC (2 g/m2 every 12 hours for 6 days for a total dose of 24 g/m2). The CR rates were equivalent. Subsequently, complete responders in the HDAC arm were given another HDAC plus DNR cycle for consolidation, whereas complete responders in the SDAC group were randomized to receive two additional courses of SDAC plus DNR or one course of HDAC plus DNR. With the median follow-up of 51 months, survival was not significantly better in the HDAC arm. However, the RFS was somewhat better following the HDAC induction compared to those with SDAC induction (33% versus 21% for the younger group and 21% versus 9% for the older group).

In conclusion, induction therapy with HDAC plus DNR is associated with greater toxicity than SDAC plus DNR, but without improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increases the toxicity but not survival or DFS. Hence, the use of HDAC induction outside the clinical trial is not recommended.

3. Other regimens. Many permutations to the standard “7 + 3” regimen have been studied over the years in attempts to improve the CR rate of induction therapy and prolong survival. The addition of other agents such as 6-thioguanine and etoposide (3 + 7 + 3) to the “7 + 3” regimen have improved the CR rate and response duration in some studies, but these regimens produce increased toxicity without improvement in OS. The SWOG trial comparing a combination of SDAC and DNR with mito-xantrone and etoposide in patients older than 55 years showed similar CR rates (43% versus 34%) and therapy-related toxicity (16% versus 22%), respectively. Furthermore, the risk of secondary acute leukemia from topoisomerase inhibitors needs to be considered in patients who are potentially long-term survivors. HDAC has been examined through a protocol that contained a second induction course on day 16 of TAD (6-thioguanine, cytarabine, and DNR) or HAM (HDAC plus mitoxantrone) for double induction (TAD-TAD versus TAD-HAM). CR and OS rates were similar in these two treatment groups. However, TAD-HAM was associated with a higher CR rates (65% versus 49%) and 5-year survival (25% versus 18%) in the unfavorable subgroup of patients defined by lactate dehydrogenase (LDH) higher than 700 U/L, greater than 40% blasts in the day 16 bone marrow, and unfavorable cytogenetics.

Addition of modulators of multidrug resistance did not provide additional benefits. Sensitization ofleukemic cells to chemotherapy with hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF), have brought conflicting results, with most studies demonstrating lack of benefits; hence, it is not recommended in the absence of the clinical trial. Addition of gemtuzumab ozogamicin (GO) to conventional chemotherapy did not improve CR rates or DFS. As a consequence, the U.S. Food and Drug Administration (FDA) accelerated approval from 2000 has been withdrawn and drug availability limited to currently treated patients or trials conducted through an investigational new drug application only.

The use of an anthracycline or an anthracenedione is contraindicated in patients with severe underlying cardiac disease, particularly if the patient has had a recent myocardial infarction or has an ejection fraction of less than 50%. The choice of therapy in this situation is HDAC, although the optimum dose and schedule of HDAC therapy are not known (i.e., number of doses, dosage, infusion rate; see Table 18.8).

B. Residual disease

Patients who have residual disease at day 28 should be considered primary treatment failures and have alternative therapy initiated. If a significant response has been demonstrated at the day 10 to 14 marrow examination (greater than 50% to 60% reduction in leukemic infiltration) but residual leukemia persists, a second course of similar chemotherapy is given (or an alternative regimen such as HDAC). Patients with significant involvement of leukemia on day 10 to 14 (less than 40% to 50% leukemic reduction) should receive an alternative chemotherapy regimen. There is no dose modification for the second course based on blood cell counts. The doses of drugs may be decreased for the second cycle if the total dose of anthracycline would be cardiotoxic or hepatic dysfunction attributed to the chemotherapy develops.

C. Common HDAC toxicities

Neurotoxicity (cerebellar dysfunction, somnolence) occurs more frequently in older patients and as the number of doses of HDAC increases. Renal and hepatic dysfunction contributes to the development of neurotoxicity. One- to two-hour infusions are generally recommended as opposed to the original infusion rate over two to three hours, as the neurotoxicity appears to be decreased with shorter infusion times.

Reducing the dose of cytarabine in the face of renal dysfunction may decrease the risk of neurotoxicity. The following schema has been suggested to decrease neurotoxicity in the face of renal dysfunction. For a baseline serum creatinine level of 1.5 to 1.9 mg/dL or an increase in serum creatinine of 0.5 to 1.2 mg/dL from baseline, reduce the cytarabine to 1 g/m2 per dose. For a baseline serum creatinine of more than 2 mg/dL or an increase of serum creatinine of greater than 1.2 mg/dL from baseline, reduce the cytarabine dose to 100 mg/m2/day.

Because cytarabine is secreted in tears, ulcerative keratitis can be prevented by instilling eye drops (saline, methylcellulose, or steroid) every 4 hours while awake and Lacri-Lube ophthalmic ointment (Allergan, Inc., Irvine, CA) at bedtime, starting at the time HDAC is initiated and continuing for 2 to 3 days after the last dose of HDAC.

D. Postremission therapy

Despite attaining a CR, the majority of patients with AML relapse, necessitating further therapy aimed at eradication of the residual yet undetected leukemic clone. There are three general treatment strategies for postremission therapy: consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT), or allogeneic (allo-) HSCT. Although the optimum postremission strategy remains to be defined, almost all younger adults with AML benefit from further therapy. The type of postremission therapy should be determined based on prognostic factors, particularly age, cytogenetic, and molecular genetic findings at diagnosis. Patients with AML in first CR should be considered candidates for investigational protocols examining postremission therapy options. For patients who cannot be enrolled in protocol studies, the approach to postinduction therapy used as a guide at North-western University is shown in Table 18.9. Consolidation should be initiated when the peripheral blood counts have returned to normal (ANC more than 1500/μL and platelet count more than 100,000/μL), marrow cellularity is normal, infections have resolved, and mucositis has cleared.

Current data suggest that HDAC offers a distinct advantage over SDAC consolidation in patients younger than 55 to 60 years of age. A landmark study conducted by CALGB demonstrated that four cycles of HDAC (3 g/m2 every 12 hours on days 1,3, and 5) are superior to four courses of intermediate cytarabine (400 mg/m2 continuous intravenously (IV) on days 1 to 5) or SDAC (100 mg/m2 continuous IV on days 1 to 5). More than 40% to 50% of patients will be in a continuous CR 5 years after consolidation with HDAC. The beneficial effect of cytarabine dose intensification, however, was restricted to patients with CBF-AML and, to a lesser extent, to patients with CN-AML, whereas outcome of patients with other cytogenetic abnormalities was not affected by the cytarabine dose.

The addition of other agents such as DNR or amsacrine to HDAC consolidation therapy failed to show improvements in long-term outcomes.

1. Favorable-risk AML. Postremission therapy with three to four cycles of HDAC or other intensive cytotoxic regimen is considered standard for younger adults with CBF-AML, NPM1+/ FLT3TTD−, and double-mutated CEBPA (see Table 18.9). A retrospective study conducted by CALGB demonstrated that three or more cycles of HDAC (cumulative dose: 54 to 72 g/m2) are superior to a single cycle (18 g/m2); however, in a joint collaboration between the M.D. Anderson Cancer Center, SWOG, and ECOG, reporting a large number of patients with CBF-AML, the outcome even among patients treated with HDAC or any post-remission therapy was not as favorable as previously reported in earlier series with many fewer patients. Neither auto- nor allo-HSCT showed advantage over consolidation therapy in first remission.

However, several subsets of CBF-AML, such as t(8;21) with high WBC, CBF-AML with c-kit mutation, or persistence of MRD, do poorly with the conventional therapy and may benefit from the allo-HSCT.

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2. Intermediate-risk AML. Long-term survival for patients presenting with intermediate cytogenetics is 40% to 45%. For patients younger than age 60, with the intermediate cytogenetics in general and CN-AML with unfavorable molecular markers (lack of mutated NPM1, double CEBPA, as well as presence of FLT3-ITD mutation), data (although not all prospective) support the use of allo-HSCT. The largest collection of prospective cohort data in this subgroup by the MRC documented superior 3-year relapse rates of18% for allo-HSCT, 35% for auto-HSCT, and 55% for chemotherapy consolidation, and 3-year survival rates of 65%, 56%, and 48%, respectively. The U.S. Intergroup Study did not demonstrate advantage for allo-HSCT, although analysis was based on a much smaller cohort of patients. The optimal timing of allo-HSCT is yet to be established, although retrospective data collected from the Center for Blood and Marrow Transplant Research demonstrated lack of additional benefit from receiving consolidation chemotherapy prior to matched-sibling HSCT in first CR. In other words, patients in postinduction CR may proceed immediately to allo-HSCT.

Auto-HSCT has been studied in this subgroup of patients but has not been shown to represent an advantage over consolidation chemotherapy alone in randomized studies conducted during the last decade.

3. Adverse-risk AML. Despite the CR rates of up to 60%, this group of patients with AML has a 5-year OS of11% (ranging from 3% to 20%) depending on the specific cytogenetic abnormality at diagnosis (e.g., 4% of patients with monosomal karyotype are alive at 4 years). The U.S. Intergroup Study demonstrated a significant long-term survival advantage for patients with unfavorable cytogenetics who received allo-HSCT for consolidation as compared to auto-HSCT or conventional chemotherapy. Although the total number of patients analyzed in this and similar trials has been small, matched-sibling allo-HSCT likely represents the therapy with the best potential to prevent relapse. Data from the European Organisation for Research and Treatment of Cancer GIMEMA AML-10 trial and from three consecutive studies of the Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) group demonstrated an advantage of the allo-HSCT among younger patients with adverse cytogenetics. The outcome after allo-HSCT from fully matched unrelated donor (MUD), based on molecular high-resolution HLA typing, appear to be similar to that of allo-HSCT from matched siblings. The Center for International Blood and Marrow Transplant Research reported a long-term survival probability of 30% for patients with AML with adverse cytogenetics transplanted in first CR from MUD.

Given the dismal outcome of high-risk AML patients treated with the conventional therapy, allo-HSCT from either matched related or unrelated donors in first CR is considered a reasonable treatment option.

E. Primary refractory AML

Several studies have shown that lack of early blast clearance or lack of response to the first induction cycle are major predictors for poor survival, and conventional therapy offers almost no chance of cure for these patients. Even with the allo-HSCT, the most aggressive approach available, the rates of relapse and mortality are high, yielding OS of 20% to 30%. Alternative conditioning regimens are being studied in this setting. Patients with induction failure, who are noTheligible for allo-HSCT, should be considered for clinical trial evaluating novel agents.

F. Relapsed AML

1. Prognostic factors. A significant number of patients with AML who achieve a remission will ultimately relapse. Unfortunately, the prognosis of patients with relapsed disease is poor and treatment options remain unsatisfactory. The long-term survival depends on the ability to achieve a remission and receive consolidation with allo-HSCT. Initial remission duration, cytogenetics, and age determine which therapeutic approach should be undertaken: curative, palliative, or in the context of a clinical trial (Table 18.10).

2. Interventions on relapse include intensive chemotherapy with conventional agents, investigational therapies on a clinical trial including the immunoconjugate agent GO, palliative intent chemotherapy, or best supportive care. Individuals who relapsed after allo-HSCT may be eligible for immunosuppression withdrawal and/or donor lymphocyte infusions as an immunologic maneuver to generate a graft-versus-leukemia (GVL) effect.

a. Standard chemotherapy. The selection of conventional salvage therapy, the optimal dose of cytarabine, and the benefits of the addition of an anthracychne or other agents all remain important unanswered questions. HDAC (2 to 3 g/m2 for 8 to 12 doses) paired with mitoxantrone, etoposide, methotrexate (MTX), and fludarabine have produced short-lived (4 to 6 month) CRs in 40% to 60% of patients with relapsed AML. A randomized trial conducted by SWOG failed to demonstrate a significant benefit to the addition of mitoxantrone to cytarabine 3 g/m2 every 12 hours for six doses. The German AML Cooperative Group trial compared cytarabine 3 g/m2 versus cytarabine 1 g/m2administered twice daily on days 1,2,8, and 9 in patients younger than 60 years of age. All patients received mitoxantrone. There was no substantial difference in CR rate or median OS. Thus, dose-intense cytarabine should probably be viewed as an essential component of a conventional salvage program, buThescalation to 3 g/m2 is probably not justified given the increased toxicity. There appears to be no value to adding standard-dose anthracyclines. However, there are multiple single-arm trials using escalated doses of anthracyclines that may present a reasonable alternative. A combination of topotecan and cytarabine induced CR in 35% to 70% of patients with AML and high-risk MDS. Nucleoside analogs, such as cladribine and fludarabine, showed activity in pediatric and adult AML. A recent study reported a 61% CR rate and 7-month CR duration in patients with AML treated with a combination of fludarabine, Ara-C, G-CSF, and idarubicin.

(1) “7 + 3.” Up to half of patients who undergo induction with the “7 + 3” regimen respond to a repeat course of “7 + 3.” Patients who relapse within 6 to 12 months of the last chemotherapy are unlikely to respond to the same regimen again. Thus, a different regimen should be considered.

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(2) HDAC regimens. Fifty to seventy percent of patients respond to HDAC. Although HDAC combination regimens may have a slightly higher response rate, their increased toxicity may not make them significantly better than single-agent HDAC. Patients who relapse within 6 to 12 months of HDAC intensification are unlikely to have a significant response to further HDAC. The doses given for the HDAC are those originally described for each regimen. Options include the following:

bull HDAC plus anthracycline

bull HDAC 3 g/m2 IV infusion over 2 hours every 12 hours on days 1 to 4, plus

bull Mitoxantrone 10 mg/m2/day IV on days 2 to 5 or 2 to 6.

bull Cyclophosphamide, topotecan, and cytarabine

bull Cyclophosphamide 500 mg/m2 IV every 12 hours on days 1 to 3, and

bull Topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and

bull Cytarabine 2 g/m2 IV over 4 hours daily for 5 days on days 2 to 6.

bull Mitoxantrone, etoposide, and cytarabine (MEC) may produce significant gastrointestinal and cardiac toxicity. It is not recommended for patients older than 60 years of age or those with borderline cardiac function. A variation of MEC currently used by the ECOG is as follows:

bull Etoposide 40 mg/m2/day IV infusion over 1 hour on days 1 to 5, followed immediately by

bull Cytarabine 1 g/m2/day IV infusion over 1 hour on days 1 to 5, and

bull Mitoxantrone 4 mg/m2/day IV on days 1 to 5, given after completion of HDAC each day.

bull Fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA)

bull Fludarabine 30 mg/m2/day IV over 30 minutes on days 1 to 5, and

bull Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and

bull Idarubicin 10 mg/m2/day on days 1 to 3, and

bull G-CSF 5 (μg/kg subcutaneously (SC) 24 hours after the completion of chemotherapy and until neutrophil regeneration.

bull Fludarabine, cytarabine, idarubicin, plus GO

bull Fludarabine 25 mg/m2/day IV over 30 minutes on days 1 to 5, and

bull Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and

bull Idarubicin 10 mg/m2/day on days 1 to 3, and

bull GO 3 mg/m2 on day 6 (if available)

bull G-CSF 5 (μg/kg SC 24 hours after the completion of chemotherapy as medically indicated.

(3) Non-HDAC regimens

bull Etoposide 100 mg/m2/day IV on days 1 to 5 and mitoxantrone 10 mg/m2/day IV on days 1 to 5 represents an active and well-tolerated combination that is commonly used for relapsed or refractory leukemia.

bull High-dose etoposide 70 mg/m2/h continuous IV infusion for 60 hours and high-dose cyclophosphamide 50 mg/kg (1850 mg/m2)/day IV infusion over 2 hours on days 1 to 4 is a highly toxic but active regimen that does not require bone marrow support. It is active against HDAC-resistant AML (30% CR). This regimen may be useful for young patients who are good candidates for allo-HSCT while waiting for an unrelated donor search to be completed. This regimen may also be associated with substantial toxicity.

b. Salvage consolidation with HSCT. Allo-HSCT is the preferred consolidation therapy once salvage remission has been achieved. The source of the stem cells include HLA identical sibling, MUD, umbilical cord (UCB) unit (typically use two), or a haploidentical donor. HSCT with reduced-intensity conditioning (RIC) regimen is associated with increased risk of relapse compared to that of standard conditioning regimen and is being evaluated prospectively. If allo-HSCT is not possible, auto-HSCT could be considered. Although retrospective studies in selected patients demonstrate a 20% to 50% probability of long-term survival, it is often impossible to collect leukemia-free stem cells at this phase of the disease.

Patients who sustain a relapse after allo-HSCT can be managed with withdrawal of immunoprophylaxis with or without donor lymphocyte infusions. Such interventions would not be possible in patients who already suffer from GVHD. Transplant recipients who relapse a year or longer after undergoing HSCT may be offered a second HSCT.

c. Investigational strategies and novel agents. Improved understanding of the molecular pathogenesis ofAML has led to the development of molecularly targeted approaches. However, as the AML phenotype (aside from APL) results from multiple genetic/epigenetic lesions affecting differentiation, proliferation, and apoptosis, it is likely thaTheradication of the leukemic clone will require a combination of multiple agents.

(1) Several FLT3 inhibitors demonstrated in vitro cytotoxicity in leukemic cells. Although first-generating of FLT-3 inhibitors showed minimal activity in patients with AML, some of the newer ones are active as a single agent and are currently investigated in combination with chemotherapy in salvage as well as in front-line settings.

(2) Hypomethylating agents. 5-azacitidine (5-Aza) and decitabine have received FDA approval for patients with MDS. Approximately a third of patients (n = 113) participating in clinical trials demonstrating survival advantage of 5-Aza were classified as having AML by current WHO criteria (20% to 30% of bone marrow blasts). Among those patients, 2-year OS was 50% in the 5-Aza arm compared with 16% in the conventional treatment regimen arm.

(3) Clofarabine. In phase I/II studies, a novel nucleoside analog clofarabine induced a 16% CR rate in patients with relapsed AML. When clofarabine was combined with cytarabine, the overall response rate was 32%, with a CR rate of 22%. When clofarabine was administered to previously untreated older patients with AML, the CR was 60%. Randomized clinical trials comparing a combination of clofarabine and cytarabine with “7 + 3” are ongoing.

d. Central nervous system (CNS) prophylaxis may be considered in patients at high risk of CNS recurrence such as patients with WBC greater than 50,000/µL or those with myelomonocytic (FAB M4) or monocytic (FAB M5) differentiation. Patients treated with HDAC (greater than 7.2 g/m2) do not require intrathecal (IT) therapy as they achieve therapeutic drug level in the cerebrospinal fluid (CSF). If required, IT therapy with MTX 12 mg or Ara-C 30 mg is used. For patients with CNS involvement (uncommon on presentation), chemotherapy should be administered via Ommaya catheter together with 30 mg of hydrocortisone.

G. AML in older adults

1. Background. AML is a disease of older adults, as the median age of diagnosis is 68 years. Despite the refinements in supportive care and chemotherapy programs, the long-term survival rates have improved little over the last 35 years for patients over age 55. Standard remission-induction and postremission therapy results in median DFS of 10 months and rare long-term survival. Because of the effects of comorbid disease and age on normal physiology, older adults are less able to withstand the inherent toxicity of induction chemotherapy than young adults. There are also intrinsic differences in the biology of older adults with AML: a higher percentage of the leukemic cells express Pgp at diagnosis (71% versus 35% in younger patients) and existence of an overt or covert antecedent hematologic disorder that predisposes to drug resistance. Moreover, AML in older adults is associated with a greater number of high-risk cytogenetic abnormalities (i.e., abnormalities of chromosomes 5 and 7 and complex karyotypes). As reported by the MRC, the favorable cytogenetic risk group was less common in patients over age 55 (7% versus 26% in patients younger than 55), while complex karyotypes were more common (13% versus 6%). Furthermore, patients over age 55 with complex karyotype predicted a poor outcome with OS of 2% at 5 years. The MRC recognized a predictive hierarchical cytogenetic classification for older adults similar to previous analysis for younger patients, although 5-year OS for favorable cytogenetic group patients over age 55 was 34% compared with 65% for younger patients (and 13% and 41%, respectively, for intermediate cytogenetic risk).

The decision to forgo therapy in an older patient with AML should not be made a priori based solely on age; rather, the decision to treat or not to treat should be based on more substantive factors such as the presence of comorbid disease, PS before diagnosis, quality of life before diagnosis, and projected long-term survival. Studies suggest that remission-induction chemotherapy provides better quality of life and longer survival compared to supportive care only.

2. Induction therapy. Older patients with excellent PS and a lack of comorbidities may expect a CR rate of 50% and mortality under 15% from the standard induction therapy. Patients with similar PS but adverse cytogenetics may expect CR rates of only 20% to 30% and dismal long-term survival.

Although attenuated doses of “7 + 3” have been recommended in the past, full-dose therapy is now generally recommended in older adults without significant comorbidities, in part owing to improvements in supportive care. In fact, the AML Study Group (AMLSG) has been using 60 mg/m2 of DNR in the elderly patient population without unexpected morbidity and mortality and recently, HOVON-SAKK/AMLSG demonstrated that the dose of 90 mg/m2was safe in patients up to 65 years of age.

Continuous attempts have been made to improve the efficacy of this regimen by varying the doses of Ara-C; comparing one anthracycline or anthracenedione with another; combining with other chemotherapeutic agents; using growth factors as priming agents; or as supportive care. Improved CR rates in many of the phase II studies were not confirmed in the randomized phase III trials.

Although karyotype may be unknown at diagnosis, delays in initiating therapy may not be harmful in older patients, thus allowing an individual approach to care.

bull Standard “7 + 3”: Cytarabine 100 mg/m2/day or 200 mg/m2/ day IV continuous infusion on days 1 to 7, and either

    bull DNR 60 to 90 mg/m2/day for 3 days or

    bull Idarubicin 8 to 12 mg/m2/day IV bolus on days 1 to 5.

bull Modified HDAC decreases the cytarabine dose to try to diminish the neurotoxicity that is dose-limiting in older adults. Modified HDAC is generally believed to be more toxic than the “7 + 3” regimen. We do not routinely recommend the use of HDAC for induction in older patients given the lack of data to support a higher CR rate and the significantly increased morbidity and mortality associated with HDAC during the induction period. In selected older patients with excellent PS and a decreased ejection fraction, one can consider using modified HDAC. Although the optimum dose and schedule are not known, 1.5 to 2 g/m2 IV over 2 hours every 12 hours for 8 to 12 doses is commonly used.

For older patients with suboptimal PS and several comorbidities and organ dysfunctions, low-dose cytarabine (20 mg twice a day SC for 10 days) was demonstrated to be superior in terms of OS compared to that of hydroxyurea in a randomized trial. However, the magnitude of improvement was not so dramatic to make hydroxyurea and supportive care an unreasonable option. Even with this low-intensity therapy, the 30-day mortality was 26% and patients with adverse cytogenetics did not derive any benefit at all. Any discussion regarding therapeutic intervention should refer to the observation that 74% of older patients estimated their chance of cure with “7 + 3” to be 50% or more, whereas 85% of their physicians estimated this chance to be less than 10%. Considering the poor outcome of older patients with AML with standard therapy, serious consideration ought to be given to the enrollment of patients in clinical trials evaluating novel agents.

3. Postremission therapy. Older patients may tolerate one or two cycles of lower doses of HDAC (1.5 g/m2 every 12 hours on days 1, 3, and 5) than is usually given for younger adults, although a beneficial impact of HDAC consolidation chemotherapy on long-term outcome is not proven. The CALGB trial of varying doses of cytarabine (100 mg/m2/day, 400 mg/m2/day, and 3 g/m2) reported similar 5-year DFS and OS within each arm (each less than 15% and 8%, respectively). Other reports have demonstrated that prolonged consolidation courses (over four cycles) will likely not benefit long-term outcomes. Recent data suggest that CBF-AML and NPM1+/FLT3/ITD-AML patients may benefit from dose escalation of consolidation. A recently published randomized clinical trial compared four cycles of GO postinduction therapy (6 mg/m2 every 4 weeks) with observation in older patients with AML. There were no significant differences between the groups with regard to rate of relapse, nonrelapse mortality, and OS and DFS at 5 years (17% versus 16%). Novel therapeutic approaches are needed. Current strategies include incorporation of less intensive therapy, such as incorporation of agents such as GO, FTIs, and bcl-2 antisense oligonucleotides into consolidation (and induction) therapy. Auto-HSCT may be considered for fit patients, although, as in younger patients, the exact integration of this therapy is not known. RIC allo-HSCTs have allowed allo-HSCT in older patients, but this modality should still be considered experimental in this setting. Current treatment options include the following:

bull HDAC 1.5 g/m2 IV infusion over 3 hours every 12 hours on days 1, 3, and 5 (better tolerated) for one course (with careful attention to cerebellar toxicity and to renal function; if either is noted to be apparent, HDAC should be immediately discontinued).

bull Cytarabine 100 mg/m2/day for 5 days per course.

  However, there are not definitive data showing that postremission therapy benefits older adults.

4. Other therapeutic approaches

a. Gemtuzumab ozogomycin(GO), a recombinant humanized monoclonal anti-CD33 antibody conjugated to a highly potent anti-tumor antibiotic calicheamicin, was approved by the FDA for the treatment of patients older than 60 years with CD33+ AML in first relapse who are not candidates for cytotoxic therapy. The majority of AML blast cells (80% to 90%) express the CD33 surface antigen, while pluripotent hematopoietic stem cells/tissues and nonhematopoietic cells do not. After administration, GO is believed to be internalized into lysosomes, where the calicheamicin dissociates form the antibody, migrates to the nucleus, and causes double-stranded DNA breaks. With the FDA withdrawal of prior “accelerated” approval and removal from the market, it will be available only on clinical trial.

GO has been administered at a dose of 9 mg/m2 as a 2-hour IV infusion on days 1 and 15. Leukoreduction with leukapheresis or hydroxyurea to lower the WBC below30,000/(µL prior to GO therapy is recommended. No dose adjustments for anemia or thrombocytopenia should be made. Benadryl may be administered prior to infusion. Acetaminophen has the potential to contribute to hepatotoxicity (increased free radicals) and theoretically should be avoided.

GO was voluntarily removed from the market and is not readily available in routine clinical practice.

b. Reduced intensity conditioning (RIC) (mini)-HSCT. Older adults are increasingly offered an option of undergoing nonmyeloablative or mini-HSCT as a postremission therapy. Although most of the studies evaluating mini-HSCT are limited to a single institution experience, they show feasibility of this potentially curative approach in the older patient population. A retrospective study from the Cooperative German Transplant Study Group of 368 patients demonstrated that survival is comparable between patients receiving stem cells from the sibling donor or MUD.

c. Other investigational therapies include FLT-3 inhibitors, clofarabine, cloretazine, azacitidine/decitabine with histone deacetylase inhibitors or GO, or chemotherapy with GO.

V. THERAPY-RELATED AML

A. Background

Therapy-related AML (t-AML) is a recognized clinical syndrome occurring after exposure to cytotoxic and/or radiation therapy. AML that develops after the exposure to the alkylating agent is characterized by the cytogenetic abnormalities involving chromosomes 5 and/or 7, a long latency (7 to 10 years), and, frequently, an antecedent MDS. Patients who develop AML following exposure to topoisomerase II inhibitors have a rearrangement of chromosome 11q23 (MLL) or 21q22 (RUNX1), a relatively short latency period (2 to 3 years), and myelomonocytic or monocytic differentiation. High-dose chemotherapy with auto-HSCT has been increasingly implicated in the pathogenesis of secondary leukemias. In one study, the estimated cumulative probability of developing therapy-related MDS or AML was approximately 8.6% ± 2.1% at 6 years among 612 patients undergoing high-dose chemotherapy and HSCT for Hodgkin lymphoma and non-Hodgkin lymphoma. The most important risk factor appears to be large cumulative doses of alkylating agents. However, patient age and previous radiotherapy, particularly total-body irradiation as part of the conditioning regimen, are additional risk factors.

B. Therapy

Although up to 50% of patients with t-AML may achieve a CR with chemotherapy, the median remission duration is approximately 5 months. Therapeutic options include supportive care, “7 + 3,” HDAC, or other chemotherapy regimens. Amonafide, a topoisomerase II inhibitor, has shown promising activity in patients with AML, particularly AML arising on the background of MDS, and is being evaluated in combination with Ara-C in clinical trials.

Younger patients with t-AML should be considered for allo-HSCT in first remission. Nonmyeloablative allo-HSCT is under investigation for those who are not eligible to undergo standard HSCT. The European Group for Blood and Marrow Transplantation Registry reported 35% 3-year OS in 65 patients with t-AML treated with auto-HSCT.

The main considerations for patients with t-AML include the status of primary malignancy, the patient's PS, age, and the leukemic karyotype. All patients should be treated on a clinical trial if at all possible, and those eligible should be transplanted.

VI. AML DURING PREGNANCY

The outcomes of both the mother and the fetus must be considered when discussing the therapeutic options for a pregnant woman who develops AML. Pregnancy does not appear to alter the course of AML, with more than 75% of patients achieving a CR after standard chemotherapy. Therapeutic abortion must be considered if AML develops during the first trimester. If therapeutic abortion is not an option or if AML develops during the second or third trimester, induction chemotherapy may be undertaken. Although there is a slightly increased risk of premature labor and fetal death, in most cases “7 + 3” appears to be well tolerated by both the patient and the fetus. Idarubicin is more lipophilic, favoring an increased placental transfer and had a higher DNA affinity, compared to other anthracyclines; hence, DNR should be offered instead.

VII. ACUTE PROMYELOCYTE LEUKEMIA (APL)

APL is a distinct subtype of AML, designated M3 by the FAB classification. It accounts for 10% to 15% of cases of adult AML in the general population and perhaps 20% to 25% of AML cases in Latin America. The median age at presentation (40 years) is significantly lower than that of patients diagnosed with other AML subtypes (68 years). Due to the remarkable sensitivity of APL to anthracyclines, all-trans-retinoic acid (ATRA), and arsenic trioxide (ATO; As2O3), it has become the most curable acute leukemia in adults, with cure rates exceeding 80% with contemporary therapeutic strategies.

A. Cytogenetic abnormalities and prognostic factors

The characteristic molecular genetic abnormality in APL is a balanced reciprocal translocation between the gene for retinoic acid receptor α (RARα) located on chromosome 17 and the gene for promyelocytic leukemia (PML) located in chromosome 15, resulting in two hybrid gene products: PML-RARα and RARα-PML. PML-RARα fusion protein, detectable by the PCR technique, is essential for the diagnosis and identification of MRD. Four alternative chromosomal translocations have been identified (PLZF-RARα, NPM-RARα, NuMA-RARα, and STAT5b-RARα). Prognostic factors are listed in Table 18.11.

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B. Management of coagulopathy in APL

Coagulopathy, a peculiar presenting feature of APL, must be managed aggressively at the suspicion of APL diagnosis, as it results in a high rate of spontaneous and potentially fatal hemorrhage. Pooled data through the late 1980s suggested that under the best of circumstances with cytotoxic induction chemotherapy, 5% of APL patients would die of CNS hemorrhage within the first 24 hours of hospitalization and another 20% to 25% would die of CNS hemorrhage during induction chemotherapy. With intensive supportive care and the introduction of ATRA therapy, the most recent studies suggest that less than 5% of patients will die of hemorrhage during induction chemotherapy, while overall induction mortality in APL remains approximately 10% reported in clinical trials (likely higher when all patients are considered). Regardless of clinical manifestations, essentially all patients with APL have laboratory features of DIC. Table 18.12 outlines the general management plan to minimize complications of the coagulopathy in APL.

C. APL therapy (Table 18.13)

Based on cumulative experience of multiple cooperative groups, therapy for APL should include simultaneous administration of ATRA and anthracycline-based chemotherapy for induction and consolidation and a combination of ATRA and chemotherapy for maintenance (particularly for high-risk subgroups of patients). ATRA a vitamin A derivative, is able to induce a high rate (85%) of short-lived clinical remissions by promoting cell maturation, differentiation, and apoptosis without producing marrow hypoplasia.

1. Induction. Simultaneous administration of ATRA and anthracycline-based chemotherapy results in 95% CR rates. Development of primary resistance has been reported in a few anecdotal cases only and essentially does noThexist in true APL. Several randomized clinical trials demonstrated not only that addition of ATRA to chemotherapy leads to the improved EFS and OS compared to chemotherapy alone, but that a simultaneous administration of ATRA and chemotherapy is superior to a sequential one in terms of CR rates (87% versus 70%), 4-year relapse rate (RR; 20% versus 36%), and 4-year OS (71% versus 52%). The choice of an-thracycline is still debated; in the ATRA era, idarubicin is more frequently used as a monotherapy, while DNR is mainly used in combination with other drugs (typically cytarabine).

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The role of cytarabine in the induction regimens for APL remains controversial, as comparable CR rates have been reported using ATRA/DNR/cytarabine and ATRA/idarubicin regimens. In a randomized trial reported by the European APL group, patients treated with ATRA/DNR had higher rates of CR, but demonstrated increased rates of relapse compared to those of patients treated with ATRA/DNR/cytarabine. Another randomized trial demonstrated similar rates of CR, RR, and OS between ATRA/idarubicin and ATRA/DNR/cytarabine arms; additionally, a small increase in mortality in remission was noted in the group receiving cytarabine.

ATO-based therapy may be considered in patients for whom an anthracycline-based regimen is contraindicated. After the demonstration of impressive outcomes in the treatment of patients with relapsed APL pioneered in China and replicated in the Western populations, at least four clinical trials addressed the role of ATO in the front-line setting. The CR rates in these studies were 86% to 95%; however, arsenic was combined with ATRA and/or chemotherapy and/or GO in some patients, particularly those presenting with leukocytosis.

2. Consolidation. High rates of molecular remissions (approximately 95%) after at least two cycles of postinduction anthracycline-based chemotherapy have led to the adoption of this strategy as the standard for consolidation. The benefit of ATRA addition to consolidation chemotherapy has not been demonstrated in randomized trials. However, historical comparison of consecutive trials carried independently by GIMEMA and PETHEMA groups showed statistically significant improvement in outcome with the addition of ATRA to chemotherapy.

The role of cytarabine in consolidation has remained controversial, as several retrospective analysis conducted in the pre-ATRA era failed to show the difference in outcome with its addition. In ATRA-containing regimens, the role of cytarabine remains unresolved. However, there is a definitive role for intermediate-dose cytarabine or HDAC in patients who present with high-risk disease (high risk for relapse) with a WBC greater than 10,000/uL. As already mentioned, a recent randomized study by the European APL group reported an increased risk of relapse with the omission of cytarabine from the induction and consolidation. However, such results might have been attributed to the type and dose of anthracycline and the lack of ATRA given in consolidation. The joint analysis of European APL and PETHEMA groups demonstrated a significantly reduced cumulative incidence of relapse in younger patients (younger than 65 years) with lower risk APL (WBC less than 10 × 109/L) treated with anthracycline monotherapy in the PETHEMA LPA99 trial compared to that of patients treated with a regimen including cytarabine in the European APL 2000 trial. However, a trend in favor of cytarabine administration was observed in high-risk patients (WBC greater than 10 × 109/L). Similarly, results of a recently published Italian study suggested an advantage of adding cytarabine to the ATRA-based therapy in high-risk patients.

Based on the available data, it has been our practice to add at least one cycle of cytarabine therapy for patients younger than 60 years who present with elevated WBC (greater than 10 × 109/L) and provide an anthracycline–ATRA combination for patients with low- and intermediate-risk disease.

Recently, the use of ATO administered in combination with ATRA and chemotherapy has been supported by the results of the large randomized North American Intergroup study. In this study, two cycles of ATO, 25 days each (5 days per week for 5 weeks) administered on achievement of CR and before the standard post-remission therapy with two courses of DNR and ATRA, resulted in significantly better EFS and OS compared to that of patients receiving chemo-ATRA consolidation alone. However, the outcomes of the control arm (chemo-ATRA alone) was significantly worse than those reported by other groups using ATRA and anthracycline-based chemotherapy. Consequently, some consider the use of ATO in front-line consolidation restricted to clinical trials. In addition, more patients are being treated with ATO in induction and consolidation with minimal chemotherapy.

3. The role of HSCT. Because of the high cure rates with ATRA and chemotherapy combinations, there is no role for a routine use of HSCT for patients with APL in molecular remission after consolidation chemotherapy. Given the poor prognosis of those very few patients who have evidence of MRD after completion of consolidation therapy, allo-HSCT should be considered. Due to the rapid progression from positive MRD to overt hematologic relapse, additional therapy (such as ATO) should be administered to reduce the tumor burden and hopefully achieve a molecular remission prior to transplantation. If an HLA-matched donor is not available or a patient's PS precludes the allo-HSCT, therapy with ATO, GO, or both might be considered. For patients who achieve a molecular remission, subsequent auto-HSCT may be considered as part of consolidation therapy. Although such approaches lead to good clinical results, it is also possible that similar rates of long-term remission could be obtained with multiple courses of ATO and/or GO.

4. Maintenance. In the pre-ATRA era, several studies showed a definitive benefit of maintenance chemotherapy. Because the ATRA became standard therapy, a combination of ATRA and low-dose chemotherapy was superior to ATRA alone, chemotherapy alone, and observation in terms of RR and DFS. However, the results of two recent studies showed no advantage of maintenance therapy in patients who achieved a molecular remission after the third cycle of consolidation. The optimal schedule, dose, duration of maintenance therapy, as well as a targeted patient population, are still under investigation. Therapeutic recommendations for APL outside of clinical trials are given in Table 18.13.

D. APL differentiation syndrome (DS)

APL DS (formerly retinoic acid syndrome [RAS]) is a complication of ATRA therapy that manifests by unexplained fever, weight gain, respiratory distress, pericardial and pleural effusion, periodic hypotension, and acute renal failure. Typically, RAS occurs between the second day and the third week of ATRA therapy, with the incidence between 5% and 27% and a mortality rate (for those who develop RAS) between 5% and 29%. Although a rising WBC count may be a risk factor for RAS, it may occur with a WBC count below 5000/(µL. If the WBC count is greater than 5000 to 10,000/(µL on presentation, ATRA and chemotherapy should be given concurrently. If the WBC count rises to more than 10,000/(µL during ATRA monotherapy, induction chemotherapy should be added. Regardless of the WBC count or the risk of neutropenic sepsis, at the first sign of RAS, dexamethasone (10 mg IV twice per day) should be initiated. If the symptoms are mild, ATRA may be continued concomitantly with steroids under careful observation. However, if the symptoms are severe or do not respond to steroid therapy, ATRA should be temporarily discontinued. Several uncontrolled trials reported a very low mortality rate with the prophylactic corticosteroid therapy in patients with leukocytosis; however, no prospective randomized studies were conducted to address this issue.

E. Relapsed APL

Two studies conducted in the pre-ATO era suggested a benefit for preemptive therapy at the development of the molecular relapse compared with treatment initiated at the time of frank hematologic relapse. Although the benefit of early intervention with the ATO-based therapy remains to be proven, the high risk of hemorrhagic death and development of APL MDS associated with overt disease argues strongly in favor of an early intervention. Hence, molecular monitoring of MDS every 3 months for 3 years is recommended (see Table 18.13).

1. Arsenic trioxide (ATO). Approximately 10% to 20% of patients treated with a combination of ATRA and chemotherapy eventually relapse. Although second remissions with standard therapy are common, particularly if the last exposure to ATRA occurred more than 6 to 12 months prior to relapse, they are not durable. Several clinical trials show that ATO has remarkable activity in this patient population, leading to its FDA approval in this setting. Preclinical mechanisms of action of ATO include apoptosis and APL cell differentiation. Chinese investigators demonstrated CR rates of at least 85% and 2-year DFS of 40% in patients with relapsed APL. A U.S. multicenter study of ATO for induction and consolidation therapy for relapsed APL confirmed the high CR and long-term survival rates, and most importantly, 85% rate of molecular remission after the completion of the consolidation therapy. Combination of ATO with other active agents (ATRA, chemotherapy, GO) for relapsed APL (induction and consolidation phases) are actively being studied.

ATO either alone or in combination with ATRA results in remission rates in excess of 90% in previously untreated patients. Incorporation of ATO into the consolidation regimen if first CR has been evaluated by the North American C9710 Intergroup APL trial. The most significant toxicities associated with ATO therapy include ventricular arrhythmia caused by the prolongation of QT interval, hyperleukocytosis, and APL differentiation syndrome.

2. Gemtuzumab ozogomycin (GO). A high rate of CD33 expression on the promyelocytes and in vitro activity of GO in ATRA- and ATO-resistant leukemia cell lines provided a rationale for the GO therapy in patients with APL. In patients with evidence of molecular relapse, single-agent GO reinstated the molecular remission in 14 of 16 patients, while 2 patients suffered from the disease progression. Combination of GO and ATRA in previously untreated patients resulted in an 88% CR rate. The optimal role of GO for the therapy of APL are currently explored in clinical trials.

GO was voluntarily removed from the market and is not readily available in routine clinical practice.

3. HSCT in relapsed APL. Despite the high initial CR rates in relapsed disease, many patients relapse following ATO-based treatment. Results of retrospective studies have demonstrated that HSCT may be an effective option at this point or on achievement of second CR following ATO therapy. Auto-HSCT is associated with lower transplant-related mortality and is a reasonable option for patients in molecular remission and prolonged (greater than 1 year) first CR. Allo-HSCT is associated with a higher rate of transplant-related mortality but offers greater antileukemic activity due to the GVL effect. It could be recommended for patients who fail to achieve a complete molecular remission or those with short CR duration. Table 18.14 gives recommendations for treatment of relapsed APL.

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VIII. THERAPY FOR ADULT ALL

Over the last 35 years, significant advances have been made in the management of adult ALL. Current therapeutic strategies incorporate a more intensive induction and postremission regimens and take into account biologic and clinical features of the disease. Despite an excellent initial response to therapy (CR 80% to 90%), the overall long-term DFS is 35% to 50% in adult patients with ALL. Most chemotherapeutic regimens for ALL have been developed as complete programs without testing the contributions of the individual components, and they had not been compared to one another in a rigorous prospective randomized fashion. All patients undergoing therapy for ALL should be enrolled in clinical trials.

The goals of intensified therapy are to eliminate leukemia cells, as determined by light microscopy and flow cytometry, prior to the emergence of drug-resistant clones, to restore normal hematopoiesis, and to provide adequate chemoprophylaxis for the sanctuary sites such as the CNS. A typical ALL regimen consists of induction, consolidation/intensification, and maintenance; CNS prophylaxis is usually administered during induction and consolidation.

Recent data from phase II trials demonstrate that young adults who were treated on adult protocols fared significantly worse than the same age group treated on pediatric protocols. This superior outcome has been attributed to the more intensive treatment on pediatric protocols, which include high-dose steroids and L-Asp as well as better adherence to the therapy by patients, parents, and doctors. Currently, clinical trials evaluating the pediatric-type therapy in adult patients up to the age of 40 years are ongoing.

A. Induction

The addition of an anthracycline to the standard pediatric ALL induction regimen of vincristine, prednisone, and L-Asp increased CR rates in adults from 50% to 60% to 70% to 90% and median duration of the disease remission to approximately 18 months. In some studies, dexamethasone has been substituted for prednisolone due to its higher in vitro activity and better CNS penetration. However, findings of a small, randomized study showed that an augmented dose of prednisolone produced results comparable to those achieved with dexamethasone in the context of intensive chemotherapy. Although L-Asp proved to be of value in the preanthracycline era, and in pediatric trials produced better survival when administered during induction and/or postinduction phases, its role in anthracycline-based adult programs is evolving. Given the significant toxicity of L-Asp, many investigators do not recommend its use in older patients; however, incorporation of L-Asp in intensive regimens for young adults is actively investigated. The newer pegylated form of L-Asp (peg-asp) has a prolonged half-life and has been FDA-approved for pediatric ALL. The CALGB 9511 trial substituted peg-asp for native asparaginase and demonstrated CR rate of 76%, median OS of 22 months, and DFS at 7.5 years of 21%.

Attempts to further improve the outcome of patients with ALL led to the incorporation of agents such as cytarabine, cyclophosphamide, etoposide, mitoxantrone, and MTX in induction and postinduction therapy. It is unclear whether intensification with additional agents or using multiple phases of induction therapy improved CR rates in the unselected patients; however, it may benefit certain subgroups. The use of growth factors during induction may alleviate complications of prolonged bone marrow suppression and avoid delays in delivering dose-intensive chemotherapy. In a double-blind, randomized trial conducted by CALGB, administration of G-CSF shortened the duration of neutropenia from 29 days in the placebo group to 16 days in G-CSF group. The CR rates were higher with G-CSF (90% versus 81%), whereas induction mortality was higher in the placebo group (11% versus 4%).

B. Consolidation (intensification) therapy

This typically includes three to eight cycles of non–cross-resistant drugs administered after the remission induction. As mentioned previously, no randomized studies have compared the plethora of existing regimens (Linker trial, French LALA-94 trial, CALGB 8811 study, the MRC UKALL XA, GIMEMA ALL 0288 trial, the PETHEMA ALL-89 randomized trial, hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone [CVAD], or R-hyper-CVAD).

C. Maintenance

The benefit of maintenance therapy in adult patients with ALL is unclear. In patients with low-risk disease, who enjoy outcomes similar to pediatric patients, maintenance therapy appears to be justified. Considering that more than half of the high-risk patients relapse while undergoing maintenance therapy, alternative strategies of eradicating MRD are urgently needed. The utility of maintenance therapy has been questioned for patients with T-cell ALL, and it is not given for patients with mature B-cell ALL or those with Philadelphia (Ph1) chromosome–positive disease.

The traditional maintenance regimen is given for approximately 2 years and includes daily doses of 6-mercaptopurine, weekly doses of MTX, and monthly doses of vincristine and prednisone. Dose intensification or extension of maintenance beyond 3 years does not appear to be of benefit, whereas its omission has been associated with shorter DFS.

D. Recommendations for the therapeutic regimens for pre-B–and T-cell lineage ALL

Although T-cell ALL previously had a poor prognosis with standard induction and maintenance chemotherapy, with the advent of more intensive chemotherapy regimens, response rates and long-term DFS are comparable with those for precursor B-cell ALL. A response rate of 100% and a projected long-term DFS of 59% was demonstrated by the regimen devised by Linker and colleagues1 in 2002 for T-cell ALL. The CALGB 8811 protocol produced a 100% CR rate with a 63% 3-year RFS for a similar group of patients. Precursor B-cell and T-cell ALL are treated with similar regimens in most contemporary protocols.

1. Berlin-Frankfurt-Muenster(BFM)-like regimens (MRC/ECOG). TheMRC/ECOG ALL treatment regimen should be considered for patients regardless of age who are thought to be able to withstand the rigors of an intensive program.

a. Induction (consisting of two phases):

bull Phase I, weeks 1 to 4.

bull Vincristine* 1.4 mg/m2 (maximum 2 mg) IV push on days 1, 8, 15, and 22, and

bull Prednisone 60 mg/m2 by mouth on days 1 to 28 (followed by rapid taper over 7 days), and

bull DNR** 60 mg/m2 IV push on days 1, 8, 15 and 22, and

bull L-Asp 10,000 U IV (or intramuscularly) once daily on days 17 to 28.

bull Phase II, weeks 5 to 8, should be postponed until the total WBC exceeds 3 × 103/(µL.)

bull Cyclophosphamide 650 mg/m2 IV on days 1, 15 and 29, and

bull Cytarabine 75 mg/m2 IV on days 1 to 4, 8 to 11, 15 to 18, and 22 to 25, and

bull 6-Mercaptopurine 60 mg/m2 by mouth once daily on days 1 to 28.

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b. CNS treatment and prophylaxis. If CNS leukemia is present at diagnosis, MTX IT or via an Ommaya reservoir is given weekly until blasts are cleared form the CNS fluid. Additionally, 24 Gy cranial irradiation and 12 Gy to the spinal cord are administered concurrently with phase II induction. If CNS leukemia is not present at diagnosis, MTX 12.5 mg IT on day 15 in phase I and MTX 12.5 mg IT on days 1, 8, 15, and 22 in phase II are given.

___________

* The vincristine dose should be modified to 50% for paresthesia proximal to the distal interphalangeal joints and stopped entirely for major muscle weakness, cranial nerve palsy, or severe ileus.

** DNR and vincristine doses should be modifi ed on a weekly basis according to the serum bilirubin.

c. Intensification therapy begins 4 weeks after induction phase II and should be postponed until the WBC is greater than 3 × 103/µL.

bull MTX 3 g/m2 IV on days 1, 8, and 22

bull Leucovorin rescue starting at 24 hours 10 mg/m2 by mouth or IV every 6 hours × 12 or until the serum MTX concentration is less than 5 × 10−8 M, and

bull L-Asp 10,000 U on days 2, 9, and 23.

d. Consolidation therapy (for patients not proceeding to allo-HSCT). Given after intensification when the WBC is higher than 3000/(µL and the platelet count is higher than 100,000/(µL.)

bullCycle I consolidation

bull Cytarabine 75 mg/m2 IV on days 1 to 5, and

bull Vincristine 2 mg IV on days 1, 8, 15, and 22, and

bull Dexamethasone 10 mg/m2 by mouth on days 1 to 28, and

bull Etoposide 100 mg/m2 IV on days 1 to 5.

bullCycle II consolidation (begins 4 weeks from day 1 of first cycle or when WBC exceeds 3000/(µL)

bull Cytarabine 75 mg/m2 IV on days 1 to 5, and

bull Etoposide 100 mg/m2 IV on days 1 to 5.

bullCycle III consolidation (begins 4 weeks from day 1 of second cycle or when WBC exceeds 3000/ (µL)

bull DNR 25 mg/m2 IV on days 1, 8, 15, and 22, and

bull Cyclophosphamide 650 mg/m2 IV on day 29, and

bull Cytarabine 75 mg/m2 IV on days 31 to 34 and 38 to 41, and

bull 6-Thioguanine 60 mg/m2 by mouth on days 29–42.

bullCycle IV consolidation (begins 8 weeks from day 1 of third cycle or when WBC exceeds 3000/(µL).

bull Cytarabine 75 mg/m2 IV on days 1 to 5, and

bull Etoposide 100 mg/m2 IV on days 1 to 5.

e. Maintenance for adult ALL by MTX- and 6-mercaptopurine-based therapy. Pulses of vincristine and prednisone are given as “reinforcement” because they have relatively little toxicity. Maintenance therapy should be continued for 2.5 years from start of intensification.

bull 6-Mercaptopurine 75 mg/m2/day by mouth, and

bull Vincristine 2 mg IV every 3 months, and

bull Prednisone 60 mg/m2 by mouth for 5 days every 3 months with vincristine, and

bull MTX 20 mg/m2 by mouth or IV once per week for 2.5 years.

2. CALGB 881 consists of a five-drug combination devised to achieve more rapid cytoreduction during the induction phase. For B-cell–lineage ALL, it produced an 82% CR rate with 41% DFS at 36 months. Patients in remission receive multiagent consolidation treatment, CNS prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. CALGB 8811 should be considered for patients, regardless of age, who are thought to be able to withstand the rigors of an intensive program.

a. Induction for patients 60 years or younger

bull Cyclophosphamide 1200 mg/m2 IV on day 1, and

bull DNR 45 mg/m2 IV on days 1, 2, and 3, and

bull Vincristine 2 mg IV on days 1, 8, 15, and 22, and

bull Prednisone 60 mg/m2/day by mouth on days 1 to 21, and

bull L-Asp 6000 IU/m2 SC on days 5, 8, 11, 15, 18, and 22.

b. Induction for patients older than 60 years

bull Cyclophosphamide 800 mg/m2 on day 1, and

bull DNR 30 mg/m2 on days 1, 2, and 3, and

bull Prednisone 60 mg/m2/day on days 1 to 7.

c. Early intensification (two cycles)

bull IT MTX 15 mg on day 1, and

bull Cyclophosphamide 1000 mg/m2 IV on day 1, and

bull 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 14, and

bull Cytarabine 75 mg/m2/day SC on days 1 to 4 and 8 to 11, and

bull Vincristine 2 mg IV on days 15 and 22, and

bull L-Asp 6000 U/m2 SC on days 15, 18, 22, and 25.

d. CNS prophylaxis and interim maintenance

bull Cranial irradiation 2400 cGy on days 1 to 12, and

bull IT MTX 15 mg on days 1, 8, 15, 22, and 29, and

bull 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 70, and

bull MTX 20 mg/m2 by mouth on days 36, 43, 50, 57, and 64.

e. Late intensification

bull Doxorubicin 30 mg/m2 IV on days 1, 8, and 15, and

bull Vincristine 2 mg IV on days 1, 8, and 15, and

bull Dexamethasone 10 mg/m2/day by mouth on days 1 to 14, and

bull Cyclophosphamide 1000 mg/m2 IV on day 29, and

bull 6-Thioguanine 60 mg/m2/day by mouth on days 29 to 42, and

bull Cytarabine 75 mg/m2/day SC on days 29 to 32 and 36 to 39.

f. Prolonged maintenance (monthly until 24 months from diagnosis)

bull Vincristine 2 mg IV on day 1, and

bull Prednisone 60 mg/m2/day by mouth on days 1 to 5, and

bull MTX 20 mg/m2 by mouth on days 1, 8, 15, and 22, and

bull 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 28.

3. Other vincristine, prednisolone, and daunorubicin (VPD)-based regimens.

A number of variations on the basic VPD program have been described. VPD should be used for patients who are thought not to be able to tolerate a more intensive chemotherapy program. Some options are shown in parentheses.

a. Induction

bull Vincristine 2 mg IV on days 1, 8, 15, (22), and

bull Prednisone 40 or 60 mg/m2 by mouth on days 1 to 28 or days 1 to 35, followed by rapid taper over 7 days, and

bull DNR 45 mg/m2 IV on days 1 to 3, and

bull L-Asp 500 IU/kg (18,500 IU/m2) IV on days 22 to 32.

b. CNS prophylaxis is given as six doses of IT MTX and whole-brain irradiation starting on approximately day 36.

c. Maintenance. Maintenance is usually started once the marrow suppression and the oral toxicity of the CNS prophylaxis have cleared. Maintenance may be given in a pulse or a continuous manner. Although allopurinol is usually not needed after remission is achieved, the dose of 6-mercaptopurine should be decreased by 75% when given concomitantly with allopurinol.

d. Pulse maintenance is an 8-week cycle consisting of three courses of MTX and 6-mercaptopurine given every 2 weeks, followed by a 2-week pulse of vincristine and prednisone.

bull MTX 7.5 mg/m2 by mouth on days 1 to 5 during weeks 1, 3, and 5, and

bull 6-Mercaptopurine 200 mg/m2 by mouth on days 1 to 5 during weeks 1, 3, and 5, and

bull Vincristine 2 mg IV on day 1 during weeks 7 and 8, and

bull Prednisone 40 mg/m2 by mouth on days 1 to 7 during weeks 7 and 8.

Oral MTX should be taken in a single daily dose because splitting the daily dose significantly increases the mucositis. Approximately three doses of IT MTX are needed once maintenance has started. The schedule should be coordinated so that the IT MTX is given on day 1 of the 5 scheduled days of oral MTX. On those days when IT MTX is given, the oral MTX is not given. Pulse maintenance is given for 3 years.

Dose adjustments for hematologic toxicity from the MTX and 6-mercaptopurine should be made based on blood cell counts obtained before the start of each course.

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e. Intensification with cytarabine and DNR given as “7 + 3” and “5 + 2” does not improve remission duration or OS compared with pulse maintenance in randomized, prospective trials.

4. Hyper-CVAD

a. Odd cycles (1, 3, 5, and 7)

bull Cyclophosphamide 300 mg/m2 IV every 12 hours on days 1 to 3, and

bull Mesna 600 mg/m2/day by continuous infusion on days 1 to 3, and

bull Vincristine 2 mg IV on days 4 and 11, and

bull Doxorubicin 50 mg/m2 IV on day 4, and

bull Dexamethasone 40 mg/day on days 1 to 4 and days 11 to 14.

bullIT therapy: MTX 12 mg day 2 each course, and

bull Cytarabine 100 mg day 7 each course (if CNS leukemia is present, increase therapy to twice weekly until the CSF cell count normalizes).

b. Even cycles (2, 4, 6, and 8).

bull MTX 1 g/m2 IV over 24 hours on day 1, and

bull Leucovorin 50 mg IV to start 12 hours after MTX, then 15 mg IV every 6 hours until serum MTµLess than 1 × 10−8 M, and

bull Cytarabine 3 g/m2 IV infusion over 1 hour every 12 hours × four doses on days 2 and 3 (reduce cytarabine dose to 1 g/m2 for patients older than 60 years old), and

bullIT therapy: MTX 12 mg day 2 each cycle, and

bull Cytarabine 100 mg day 7 each cycle (if CNS leukemia is present, increase therapy to twice weekly until the CSF cell count normalizes).

c. Maintenance therapy for 2 years

bull 6-Mercaptopurine 50 mg by mouth twice a day, and

bull MTX 20 mg/m2/week by mouth.

5. R-Hyper-CVAD (CD20+ ALL)

bull Rituximab 375 mg/m2 IV over 2 to 6 hours on days 1 and 11 of odd cycles and days 2 and 8 of even cycles; total of eight doses over the first four cycles.

E. Mature (Burkitt) B-cell ALL

Mature B-cell ALL is rare, constituting 2% to 4% of cases of adult ALL and is associated with human immunodeficiency virus (HIV) syndrome. The leukemic cells are characterized by FAB-L3 morphology, expression of monoclonal surface immunoglobulins, and specific nonrandom chromosomal translocations: t(8;14)(q24;q32), t(2;8)(q12;q24), t(8;22)(q24;q11). Characteristic clinical features include frequent CNS involvement, lymphadenopathy, splenomegaly, and high serum LDH level. In the past, the results of the treatment of B-cell ALL in both children and adults had been poor, with a CR rate of about 35% and long-term leukemia-free survival (LFS) of less than 10%. The current pediatric studies designed specifically for B-cell ALL, utilizing shorter-duration, dose-intensive systemic chemotherapy and early CNS prophylaxis/treatment, have substantially improved the CR rate to about 90% and the DFS to 50% to 87%.

With use of these therapeutic strategies in children as a template, clinical trials with young adults have demonstrated long-term survival rates of 70% to 80%. The German BFM group reported the improvement of CR rate from 44% to 74%, the probability of DFS from 0% to 71%, and the OS from 0% to 51% when the intensive treatment was compared with standard ALL regimens.

The hyper-CVAD regimen induced aCR rate of 90% and a cure rate of 70% in patients younger than 60 years of age, and a CR rate of 67% with a cure rate of only 15% in older patients.

Addition of anti-CD20 antibody rituximab to the hyper-CVAD regimen induced CR in 86% of patients, with 3-year OS, EFS, and DFS of 89%, 80%, and 88%, respectively. Nine elderly patients achieved a CR with 3-year OS rate of 89% (1 patient died from infection in CR).

Hyper-CVAD therapy in combination with a highly active antiretroviral therapy (HAART) regimen in HIV-positive patients resulted in a CR rate of 92%, with more than 50% of patients alive at 2 years after the diagnosis. The outcome appeared to be improved in patients taking HAART medications early in the course of the therapy.

For all adult patients with mature B-cell ALL, we recommend HIV testing, CNS prophylaxis, and hyper-CVAD therapy.

F. Minimal residual disease (MRD) in ALL

The aim of induction therapy in ALL is to reduce the leukemia cell population from 1012 cells to below the cytologically detectable level of 109 cells. At this point, a substantial leukemia cell burden (i.e., MRD) persists and patients relapse within months without subsequent therapy. Various techniques such as flow cytometry and PCR, using either fusion transcript resulting from the chromosomal abnormalities or patient-specific junctional regions of rearranged Ig and TCR genes, can be used to detect approximately one to five blasts/100,000 nucleated cells.

There is a significant correlation between the presence of MRD and early disease recurrence, particularly with greater than 10−2 residual blasts per 2 × 105 mononuclear bone marrow cells immediately after the disease remission or greater than 10−3 at a later time.

Although adults have higher MRD levels at the completion of induction, and the risk of recurrence is higher with low levels of MRD compared with children, continuous MRD assessment at several points also was predictive in adults. The German Multicenter Study for Adult Acute Lymphoblastic Leukemia prospectively monitored 196 patients with standard-risk ALL at up to nine time points during the first year of therapy with quantitative PCR analysis. Based on the persistence of MRD over time, three risk groups were identified with a 3-year risk of recurrence ranging from 0% (low-risk group) to 94% (high-risk group).

G. CNS disease

Although uncommon at diagnosis (less than 10%), without CNS directed therapy, 50% to 75% of patients will develop CNS disease. Prophylaxis is therefore an essential part of ALL therapy, as it has clearly been shown to reduce the incidence of CNS disease.

1. Principles of diagnosis, prophylaxis, and management of CNS disease

bull Obtain the diagnostic lumbar puncture (LP) once the leukemic blasts are cleared from the peripheral blood (to preclude the CNS contamination in the event of traumatic LP). The first dose of IT chemotherapy could be given at the same time.

bull Presence of lymphoblasts in the CSF (5 lymphocytes/(µL and blasts on the differential or any lymphoblasts in the CSF) usually signify CNS disease.

bull Patients presenting with clinical symptoms consistent with CNS involvement, such as headache, altered sensorium, and cranial nerve (particularly cranial nerve VI) palsy warrant an immediate CNS imaging and LP because neurologic dysfunction is most amenable to therapy within the first 24 hours. Infectious meningitis also must be excluded in the immunocompromised host.

bull Consider Ommaya placement for patients with diagnosed CNS involvement.

bull Isolated CNS relapse usually heralds bone marrow relapse if systemic therapy is not changed. Therefore, isolated CNS relapse is usually treated with systemic reinduction chemotherapy and IT chemotherapy, followed by cranial irradiation.

Depending on the protocol, CNS prophylaxis includes IT chemotherapy with MTX, Ara-C, and steroids; high-dose systemic chemotherapy with MTX, Ara-C, L-Asp, craniospinal irradiation (XRT); or a combination of the above. None of the combinations have been definitively proven to be superior to the others. The role of XRT has become controversial because of the significant neurologic complications such as seizures, intellectual and cognitive impairment, dementia, and development of secondary CNS malignancy. In addition, most chemotherapy regimens now administer either or both HDAC and high-dose MTX.

In adults, features that correlate with high-risk of development of CNS disease include mature B-cell ALL, serum LDH higher than 600 u/L, and proliferative index of less than 14% (% S-phase + G2M-phase).

2. The commonly used regimens for CNS prophylaxis include the following:

bull MTX 12 mg/m2 (maximum 15 mg), diluted in preservative-free saline, given IT once a week for 6 weeks. Some investigators also give 10 mg of hydrocortisone succinate IT to prevent lumbar arachnoiditis. The IT MTX is then given in an “in-and-out” manner. One to two mL of the MTX solution is injected into the spinal canal. Then, 0.5 to 1 mL of spinal fluid is withdrawn back into the syringe. This in-and-out process is repeated until all of the MTX has been given. This method is used to ensure that the MTX is actually given into the subarachnoid space. Leucovorin 5 to 10 mg may be given orally every 6 hours for four to eight doses to ameliorate the mucositis, although this usually is not needed unless the patient is receiving concurrent systemic MTX. Complications of MTX include chemical arachnoiditis and leukoencephalopathy.

bull In the M.D. Anderson hyper-CVAD regimen, IT MTX 12 mg on day 2 and cytarabine 100 mg was administered on day 8 of each of eight cycles to high-risk patients and of each of four cycles in low-risk patients.

bull Cranial irradiation with IT MTX is usually initiated within 2 weeks of attaining a CR when classic maintenance is given. Cranial irradiation is usually given to the cranial vault (anteriorly to the posterior pole of the eye and posteriorly to C2) in 0.2-Gy fractions for a total of 18 to 24 Gy. The spine is not irradiated because marrow toxicity significantly limits the ability to give further chemotherapy. Common acute complications of radiation include stomatitis, parotitis, alopecia, marrow suppression, and headaches.

3. Therapy for overt CNS leukemia is similar to the CNS prophylaxis.

bull Cranial irradiation is usually given to a total of 30 Gy in 1.5- to 2-Gy fractions.

bull IT chemotherapy is given in the manner described for CNS prophylaxis and is repeated every 3 to 4 days, with appropriate laboratory studies being done with each lumbar puncture. When blast cells are no longer seen on the cytospin preparation, two more doses of IT drug are given, usually followed by a monthly “maintenance” IT injection.

bull Some investigators advocate either a simultaneous or alternating administration of IT Ara-C and MTX.

bull The use of systemic therapy with HDAC 1 to 3 g/m2 IV infusion over 2 hours every 12 hours is also effective for the treatment of CNS leukemia. A practical approach is to initiate IT chemotherapy until HDAC is started. Further IT therapy can then be given based on the results of subsequent CSF analysis after the HDAC is completed.

bull A slow-release formulation of Ara-C (DepoCyt) that maintains cytotoxic concentrations for approximately 14 days has been demonstrated to be effective for the treatment of lymphomatous meningitis and solid tumors and is under evaluation in acute leukemia.

H. ALL in older adults

The therapeutic advances and improved outcomes in children and young adults with ALL did not occur in older patients with ALL. Likely reasons include fundamental biologic difference in the spectrum of ALL in this patient population, presence of coexisting medical conditions, and decreased ability to tolerate intensive chemotherapy. Additionally, older patients have been frequently excluded from clinical trials. The correlation of age and outcome has been well documented in patients with ALL treated on the five sequential CALGB studies. The CR rates of patients younger than 30 years, between 30 to 59 years, and older than 59 years were 90%, 81%, and 57%, respectively. Based on the data provided by Hoelzer and Pagano et al. for patients older than 60 years treated with intensive chemotherapy from 1990 to 2004, the weighted mean CR rate was 56%; 23% suffered from early mortality and 30% had primary refractory disease.

In a randomized clinical trial evaluating the use of growth factors during chemotherapy for ALL, older patients enjoyed the greatest benefit. Thus, it is recommended to administer growth factors during ALL treatment in older adults.

Full doses of VPD-based induction protocols are used in elderly patients with ALL. Some investigators decrease the dose of vincristine by 50%. The MRC/ECOG and CALGB 8811 regimens should be considered for patients who are thought to be able to tolerate more intensive therapy.

Underlying cardiac disease may preclude the use of an anthracycline for induction therapy. An active program is MTX, vincristine, peg-asp, and dexamethasone (MOAD), developed by the ECOG, which is given in sequential 10-day courses (minimum three, maximum five) until remission is achieved. Once a CR has been attained, two additional courses of MOAD are given.

1. Induction

bull MTX 100 mg/m2 IV on day 1 (increase by 50% on courses 2 and 3 and by 25% each additional course until mild toxicity is achieved), and

bull Vincristine 2 mg IV on day 2, and

bull L-Asp 500 IU/kg (18,500 IU/m2) IV infusion on day 2, and

bull Dexamethasone 6 mg/m2/day by mouth on days 1 to 10.

2. Consolidation therapy is repeated every 10 days for six courses.

bull MTX (final dose from induction) IV on day 1, and

bull L-Asp 500 IU/kg (18,500 IU/m2) IV infusion on day 2.

3. Cytoreduction begins on day 30 of the last consolidation cycle of MTX and L-Asp. Cytoreduction is given monthly for 12 months.

bull Vincristine 2 mg IV on day 1, 30 minutes before MTX, and

bull MTX 100 mg/kg (3.7 g/m2) IV infusion over 6 hours on day 1, and

bull Leucovorin 5 mg/kg (185 mg/m2) divided into 12 doses starting 2 hours after the MTX infusion over days 1 to 3, and

bull Dexamethasone 6 mg/m2/day by mouth on days 2 to 6.

4. Maintenance begins on day 30 of the last course of cytoreduction. It is repeated monthly until relapse.

bull Vincristine 2 mg IV on day 1, and

bull Dexamethasone 6 mg/m2/day by mouth on days 1 to 5, and

bull MTX 15 mg/m2 by mouth weekly, and

bull 6-Mercaptopurine 100 mg/m2 by mouth daily.

I. Therapy for Ph1 + ALL

1. Background. In the era before tyrosine kinase inhibitors (TKIs), despite only slightly lower rates of CR in Ph1+ ALL patients (60% to 80%) compared to those with Ph1-disease, the long-term DFS was dismal (less than 10%), with allo-HSCT being the only modality offering a meaningful DFS. The MRCUKALLXII/ ECOG2993 international prospective ALL trial compared the outcomes of patients with Ph+ ALL treated with matched-sibling allo-HSCT, matched unrelated allo-HSCT, auto-HSCT, and consolidation/maintenance chemotherapy. The 5-year RR was lower in the allo-HSCT group (29%) than with the auto-HSCT/ chemotherapy group (81%), while the 5-year survival rates were 43% and 19%, respectively. The TRM, not surprisingly, was higher in the patients undergoing allo-HSCT: 43% for matched unrelated allo-HSCT, 37% for matched-sibling HSCT, 14% for auto-HSCT, and 8% for chemotherapy.

However, introduction of TKIs into clinical practice improved the options and outcomes of patients with Ph+ ALL.

Imatinib mesylate (Gleevec), a potent selective inhibitor of the bcr-abl tyrosine kinase, has been shown in phase I and II clinical trials to have substantial (20% to 58% CR), albeit nonsustained (42 to 123 days) activity in patients with relapsed and refractory Ph+ ALL. Administration of imatinib to 20 patients relapsed after the allo-HSCT induced a CR in 55%. Imatinib monotherapy in previously untreated patients resulted in a CR rate of approximately 95%, without the associated toxicity of chemotherapy. Incorporation of imatinib in the front-line hyper-CVAD chemotherapy is associated with hematologic CR rates consistently higher than 90% and molecular responses higher than 50%. Concurrent administration of imatinib and chemotherapy results in greater antileukemic efficacy than sequential administration.

Dasatinib (BMS-354825), a second-generation oral kinase inhibitor that targets bcr-abl and SRC kinases, demonstrated significant activity in imatinib-resistant Ph+ ALL. In a recent study, 70% (7 out of 10) of patients with Ph+ ALL and chronic myelogenous leukemia with lymphoid blast crisis achieved a major hematologic response with dasatinib. Early studies of dasatinib and chemotherapy in patients with untreated Ph+ ALL revealed rapid hematologic clearance of bone marrow blasts and residual disease with manageable toxicity profile.

Nilotinib (AMN107) is a new, orally active, aminopyrimidine-derivative TKI that appears to have some activity in imatinib-resistant Ph+ ALL. One in ten patients with relapsed Ph+ ALL (hematologic relapse) had a partial hematologic response, and one of three patients with molecularly relapsed Ph+ ALL had a complete molecular remission.

Despite high remission rates and favorable DFS, the long-term outcome of TKIs with or without chemotherapy remains to be defined. It has been our practice to proceed with an allo-HSCT for patients achieving adequate responses.

2. Recommendations for Ph+ALL

bull Hyper-CVAD chemotherapy with 600 mg of imatinib, administered daily for 14 days with each cycle; or with induction cycle and then continuously thereafter; if tolerated, dose may be increased to 800 mg for indefinite maintenance therapy if allo-HSCT is not possible.

bull Hyper-CVAD chemotherapy with 100 mg of dasatinib, administered for 14 days with each cycle, followed by maintenance 100 mg of dasatinib with vincristine and prednisone for 2 years if allo-HSCT is not an option.

bull For eligible patients, allo-HSCT still remains a therapeutic goal.

bull The role of TKIs posttransplant remains to be defined.

bull TKIs combined with low intensity therapy (vincristine, steroids) is of benefit for older and frail patients who are not candidates for more aggressive therapy and who are at higher risk of induction mortality and death in CR. For example, in GIMEMA LAL201B protocol, 800 mg of imatinib was given with 40 mg/m2/day of prednisone for 45 days.

J. Salvage therapy for ALL

Although a second remission can usually be achieved in 10% to 50% of adults with ALL, it tends to be short-lived (6 to 7 months). If a second remission can be attained, suitable patients with relapsed ALL should be evaluated for the allo-HSCT. Salvage therapies typically mirror variation of drug combinations used in the front-line protocols, including combinations of vincristine, steroids, and anthracyclines; combinations of MTX and L-Asp; and HDAC-containing regimens. Novel agents are incorporated in to the salvage regimens continuously. None of the programs used for relapse is distinctly superior to the others, and any perceived differences are likely attributable to the usual biases of study selection.

bull Vincristine, doxorubicin, and dexamethasone chemotherapy results in CR rates of 39%, median CR duration of 7 months, and median survival of 6 months; 2-year DFS was 20% and OS was 8%.

bull “7 + 3” (cytarabine and DNR) as used for the induction of AML is active in ALL. Vincristine and prednisone may be added.

bull Etoposide and cytarabine are given every 3 weeks for up to three courses until marrow hypoplasia and remission are achieved. They are then repeated monthly until relapse.

bull Etoposide 60 mg/m2 IV every 12 hours on days 1 to 5, and

bull Cytarabine 100 mg/m2 IV bolus every 12 hours on days 1 to 5.

bull HDAC-based regimens have been reported to induce CR rates in 17% to 70% of patients. HDAC as a single agent has modest activity in ALL, with a CR rate of about 34% and a median remission duration of 3.6 months. The addition of idarubicin or mitoxantrone increases the response rate to 60%, but the median response time remains 3.4 months.

bull Cytarabine and fludarabine comprise an active noncardiotoxic combination. The median response duration is 5.5 months. Neurotoxicity is low. A second course can be given in 3 weeks if needed.

bull Induction

 bull Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 6, and

 bull Fludarabine 30 mg/m2/day IV over 30 minutes 4 hours before cytarabine on days 2 to 6.

bull Consolidation is given monthly for two to three courses.

  bull Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 4, and

  bull Fludarabine 30 mg/m2/day IV over 30 minutes 4 hours before cytarabine on days 1 to 4.

bull Maintenance

  bull 6-Mercaptopurine 50 mg by mouth twice a day, and

  bull MTX 20 mg/m2/week by mouth.

bull FLAG-IDA induced a 39% CR rate in patients with relapsed/ refractory ALL. The responders received the second cycle followed by allo-HSCT and achieved a DFS of 6 months (3 to 38 months) and OS of 9 months (7 to 38 months).

  bull Fludarabine 30 mg/m2/day IV over 30 minutes on days 1 to 5, and

  bull Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and

  bull Idarubicin 10 mg/m2/day on days 1 to 3, and

  bull G-CSF 5 μg/kg SC 24 hours after the completion of chemotherapy and until neutrophil regeneration.

bull Hyper-CVAD (see Section VIII.H.4) therapy achieves CR rates similar to a combination of HDAC, mitoxantrone, and GM-CSF (44% versus 30%); however, the survival is improved.

bull MOAD (see Section VII.H)

bull L-Asp has been administered in combination with MTX, anthracyclines, vinca alkaloids, and prednisone with RRs ranging from 33% to 79% and median DFS from 3 to 6 months. Sequential MTX and L-Asp resulted in significant stomatitis (dose-limiting toxicity); 23% of treated patients had allergic reactions to L-Asp.

bullInduction

  bull MTX 50 to 80 mg/m2 IV on day 1, and

  bull L-Asp 20,000 IU/m2 IV 3 hours after MTX on day 1, followed by

  bull MTX 120 mg/m2 IV on day 8, and

  bull L-Asp 20,000 IU/m2 IV on day 9.

  bull Repeat day 8 and 9 doses for MTX and L-Asp every 7 to 14 days until remission is attained.

bullMaintenance is repeated every 2 weeks.

  bull MTX 10 to 40 mg/m2 IV on day 1, and

  bull L-Asp 10,000 IU/m2 IV on day 1.

K. Novel and investigational strategies for the therapy of ALL

It is unlikely that altering the sequence of currently available chemotherapeutic agents or increasing their intensity will produce a qualitative improvement in the outcome of adult patients with ALL. A number of experimental approaches are currently being evaluated in clinical trials (Table 18.15). Among those, nelarabine is a soluble prodrug of 9-β-D-arabinofuranosylguanine that has activity in recurrent T-lineage lymphoid malignancies and was approved by the FDA for this indication in 2005. Response rates of 33% and 41% have been achieved in a group of 121 children and 39 adults with T-cell leukemia/lymphoma. The median OS was 20 weeks in adult patients. Neurotoxicity is a major side effect of nelarabine and is both dose- and schedule-dependent; it can be minimized by every other day administration rather than daily. Clofarabine, another nucleoside analogue, has received FDA approval for pediatric patients with ALL who have failed at least two prior induction regimens. Studies of this drug alone or in combination (with cyclophosphamide, for example) are ongoing.

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L. Hematopoietic stem cell transplantation in ALL

1. Auto-HSCT for patients in first remission appears to offer no advantage over chemotherapy, based on the data for the small prospective trials reported to date and prospective randomized MRCUKALLXII/ECOG2993 ALL data, due to high rates of relapse.

2. Allo-HSCT. The optimal patient selection and timing of allo-HSCT remains unresolved. Patients receiving matched-sibling HSCT in first CR reach a survival rate of 50% (20% to 81%). Although allo-HSCT for high-risk patients in first CR has been widely accepted, recent data from the MRCUKALLXII/ ECOG2993 International ALL Trial suggest that that advantage may have been overestimated, particularly owing to a high rate of mortality, but the benefit of HSCT may extend to standard-risk patients. This is in contrast to prior studies that have not demonstrated an advantage to allo-HSCT compared to standard chemotherapy for patients with ALL without high-risk features in first CR. However, many of these trials have lacked sufficient numbers of patients, have used varied patient selection criteria, or did not allow for direct, prospective comparisons.

According to the data collected by the international Bone Marrow Transplant Registry, 9-year DFS was not different for patients treated with chemotherapy and allo-HSCT (32% versus 34%). High TRM in the HSCT group was the main reason for poor outcome, whereas the recurrence rate was twice as high in the chemotherapy group (66% versus 30%)

The benefit of allo-HSCT in high-risk patients with ALL was shown by a large French multicenter trial (LALA87), which compared the allo-HSCT with chemotherapy or auto-HSCT in first CR. Although 5-year OS for all risk groups combined was not significantly different (48% versus 35%, p = 0.08), for patients with high-risk disease, both 5-year OS (44% versus 22%) and DFS (39% versus 14%) were significantly better with allo-HSCT. Similarly, the 10-year OS for the high-risk group was 44% with allo-HSCT and only 11% in the chemotherapy/auto-HSCT arm; in the standard-risk population, the corresponding numbers were 49% and 39% (p= 0.6), respectively.

Prospective data generated from the MRCUKALLXII/ECOG2993 International ALL Trial, which included 1929 patients aged 15 to 59 years, allowed patients with HLA-matched siblings to undergo allo-HSCT; the rest were randomized to receive auto-HSCT or chemotherapy. The results can be summarized as follows: (1) for all patients, CR rate was 90% and 5-year OS was 43%; (2) for Ph1-negative patients treated with matched-sibling allo-HSCT, the 5-year OS was 53% and 45% for the combined cohort of auto-HSCT and consolidation chemotherapy; (3) the 5-year survival for the standard-risk group (defined as Ph1-negative, age under 36 years, time to CR less than 4 weeks, and WBC less than 30,000/(µL for B-cell lineage and less than 100,000/(µL for T-cell lineage) was superior for those who had a donor compared with those who had not (62% versus 52%; p = 0.02); (4) the 5-year survival rate for high-risk patients was not significantly different whether patients had a donor or not (41% versus 35%, p = 0.2; transplant-related toxicity abrogated the effect of a reduction in the recurrence rate); (5) postremission chemotherapy produced superior EFS and OS compared with auto-HSCT (p = 0.02 and p = 0.03, respectively).

Despite the high risk of early toxicity, matched-sibling allo-HSCT should be considered for most patients with ALL in first CR, with standard-risk disease.

As less than 30% of suitable patients with ALL have an HLA-matched sibling donor (MSD), extensive work has been aimed at improving the outcome of the transplantations from alternative donor sources, including partially matched related donors, MUDs, and UBC blood. A recently published trial compared the outcomes of auto-HSCT and MUD HSCT in 260 patients with ALL in first and second CR. Although TRM was higher and risk ofrecurrence was lower in MUD HSCT recipients, the 5-year LFS and OS rates were similar (37% versus 39% and 38% versus 39%, respectively). A similar trend toward comparable outcomes from MUDs and MSDs was observed in other studies. A recently published retrospective analysis of 623 patients with ALL undergoing HSCT from autologous (n = 209), MSDs (n = 245), unrelated (n = 100), and UCB (n = 69) sources demonstrated 5-year OS, LFS, and RRs of 29%, 26%, and 43%, respectively. Two-year TRM was 28%. Mismatched unrelated donor transplants yielded higher TRM (relative risk, 2.2; p 0.01) and lower OS (relative risk, 1.5; p = 0.05) than MSD and UCB HSCT. Autograft-ing yielded significantly more relapse (68%; p 0.01) and poor LFS (14%; p = 0.01). HSCT in first CR yielded much better outcomes than later HSCT. With related donors, MUD, and UCB sources, 5-year LFS was 40%, 42%, and 49%, respectively, while relapse was 31%, 17%, and 27%, respectively. The authors concluded that allo-HSCT, not auto-HSCT, results in durable LFS. Additionally, UCB HSCT led to the outcome similar to that of MSDs or MUDs.

In recent years, the outcomes of allo-HSCT with RIC have been published in small patient series. Low TRM and OS up to 30% at 3 years suggests that RIC HSCT is a viable modality for selected patients who are not candidates for HSCT with standard conditioning.

Based on the available data, we advocate the use of HSCT from MSD and alternative sources for physically fit Ph1+ patients in CR1 as well as patients with relapsed disease in second remission. For Ph1+ patients without a suitable donor, we would continue intensive consolidation chemotherapy accompanied by TKIs followed by maintenance chemotherapy with TKIs.

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