Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies

23

Acute Leukemias

Michael Craig*

Jame Abraham

Brian P. Monahan

*Section of Hematology/Oncology, West Virginia University, Morgantown, West Virginia

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia

Department of Hematology and Medical Oncology, Uniformed Services, University of the Health Sciences, Bethesda, Maryland

Acute leukemia represents a very aggressive, malignant transformation of an early hematologic precursor. The malignant clone is arrested in an immature, blast form; proliferates abnormally; and no longer has the ability to undergo maturation. In contrast, the chronic leukemias are characterized by resistance to apoptosis and by accumulation of nonfunctional cells. Accumulation of the blasts within the bone marrow results in progressive hematopoietic failure, with associated infection, anemia, and thrombocytopenia. It is these complications that often prompt evaluation in newly diagnosed patients.

Acute leukemia continues to present a grave diagnosis because of its rapid clinical course. Patients require aggressive and urgent evaluation and treatment initiation. As a general rule, treatment is expected to improve quality of life and prolong survival. Unfortunately, many patients present at an advanced age and with comorbid conditions, making cytotoxic treatment difficult. Elderly or unwell patients who are given the best supportive care survive only for a few months.

The immature, clonally proliferating cells that form blasts may be derived from myeloid or lymphoid cell lines. Transformation of granulocyte, RBC, or platelet (myeloid) precursors results in acute myelogenous leukemia (AML). Acute lymphoblastic leukemia (ALL) originates from B or T lymphocytes. This general division has implications for different treatment and diagnostic approaches. It is the first step in classifying the leukemic process occurring in the patient.

EPIDEMIOLOGY

  • Estimated new cases in the United States in 2003 were 10,500 for AML and 3,600 for ALL (age-adjusted estimates).
  • AML accounts for 7,800 deaths and ALL accounts for 1,400 deaths annually in the United States (age-adjusted estimates).
  • The risk of developing AML increases with advanced age, the median age being 60 to 69.
  • Seventy-five percent of newly diagnosed patients with AML are older than 60.
  • AML is the most common leukemia in adults (80% of cases).
  • ALL is more common in children; 60% of cases are found in patients younger than 20 years.
  • A small decrease and a plateau in the incidence of new cases has been observed since 1995.

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RISK FACTORS

Most patients will have no identifiable risk for developing leukemia. Table 23.1 lists the conditions that are identified with an increased risk for developing acute leukemia. Most studies have evaluated the relationship between the risk factors and AML. The conditions that are most associated with AML are chronic benzene exposure, exposure to ionizing radiation, and previous chemotherapy. In the case of chronic lymphocytic leukemia (CLL), the herbicide from the Vietnam War era, Agent Orange, has been associated with at least compensable risk.

TABLE 23.1. Risk Factors for Acute Leukemia

AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia.

Exposure: ionizing radiation, benzene, cytotoxic drugs, alkylating agents, cigarette smoking, ethanol use by the mother
Acquired disorders: myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, polycythemia vera, chronic myelogenous leukemia, myeloproliferative disorders, idiopathic myelofibrosis, aplastic anemia, eosinophilic fasciitis, myeloma, primary mediastinal germ cell tumor (residual teratoma elements evolve into myeloid progenitors that evolve into AML years later)
Genetic predisposition: Down syndrome, Fanconi anemia, Diamond-Blackfan anemia, Kostmann syndrome, Klinefelter syndrome, Chromosome 21q disorder, Wiskott-Aldrich syndrome, ataxia-telangiectasia, dyskeratosis congenita, combined immunodeficiency syndrome, von Recklinghausen disease, neurofibromatosis 1, Shwachman syndrome
Familial: nonidentical sibling (1:800), monozygotic twin (1:5), first-degree relative (three times increased risk).
Infection: human T-cell leukemia virus and T-cell ALL

Ionizing Radiation Exposure Explored in Atomic Bomb Survivors

  • Ionizing radiations have a latency period of 5 to 20 years and a peak period of 5 to 9 years in atomic bomb survivors.
  • They exhibit a 20- to 30-fold increased risk of AML and chronic myelogenous leukemia (CML).

Chemotherapy

  • Therapy-related AML may account for 10% to 20% of new cases.
  • It is reported in Hodgkin and non-Hodgkin lymphoma; breast, small cell, germ cell, and ovarian tumors; as well as in patients who have received high-dose therapy.
  • Leukemia associated with alkylating agents may be associated with cytogenetic changes of chromosomes 5, 7, and 13. Often there is a multiyear latent-phase myelodysplastic syndrome preceding the development of AML.
  • Topoisomerase II agents, often with an abnormal chromosome 11q23 in the blasts, can rapidly evolve after initial therapy. Usually, these are preceded by only a brief myelodysplastic state rapidly evolving to AML.
  • Previous high-dose therapy with autologous transplant leads to a cumulative risk of 2.6% by 5 years, especially with total body irradiation (TBI)–containing regimens.

CLINICAL SIGNS AND SYMPTOMS

  1. Ineffective hematopoiesis—results from marrow infiltration by the malignant cells
  • Anemia: pallor, fatigue, and shortness of breath
  • Thrombocytopenia: epistaxis, petechiae, and easy bruising
  • Neutropenia: fever and pyogenic infection.

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  1. Infiltration of other organs
  • Skin: leukemia cutis in 10%
  • Gum hypertrophy: especially in monocytic leukemia (AML M5)
  • Granulocytic sarcoma: localized tumor composed of blast cells; it imparts poorer prognosis; these sarcomas are occasionally extramedullary leukemia masses associated with 8;21 translocation
  • Liver, spleen, and lymph nodes: common in ALL, occasionally in monocytic leukemia (AML M5)
  • Thymic mass: present in 15% of ALL in adults
  • Testicular infiltration: also a site of relapse for ALL
  • Retinal involvement: may occur in ALL.
  1. Central nervous system (CNS) and meningeal involvement
  • Five percent to 10% of cases at diagnosis, mainly ALL, inv(16) [French–American– British (FAB) M4Eo], and high blast count
  • Analysis and prophylaxis are given in ALL to decrease CNS relapse
  • Symptoms: headache and cranial nerve palsy, but mostly asymptomatic.
  1. Disseminated intravascular coagulation (DIC) and bleeding
  • Very common with promyelocytic leukemia t(15;17); mechanism is related to tissue factor release by granules and fibrinolysis; it worsens with cytotoxic treatment and improves with all-trans retinoic acid (ATRA)
  • Can be present in AML inv(16) or monocytic leukemia or can be related to sepsis.
  1. Leukostasis
  • Occurs with elevated blast count; 25% of patients with ALL present with white blood cell (WBC) count greater than 50,000
  • Symptoms result from capillary plugging by leukemic cells; it is associated with large nondeformable blasts in AML and ALL and is rarely seen in CLL
  • Common signs: dyspnea, headache, confusion, and hypoxia
  • Initial treatment includes leukapheresis, aggressive hydration, and chemotherapy to rapidly lower the circulating blast percentage with drugs (e.g., oral hydroxyurea or intravenous cyclophosphamide)
  • Transfusions should be avoided because these may increase viscosity
  • Leukapheresis is repeated daily in conjunction with chemotherapy until the blast count is less than 50,000.

DIAGNOSTIC EVALUATION

  • History and physical examination are an essential part of diagnosis of acute leukemia.
  • Complete blood count (CBC) and differential, manual examination of peripheral smear, and peripheral blood flow cytometry are considered when circulating blasts are sufficiently abundant to establish a diagnosis without need for bone marrow biopsy.
  • Coagulation tests include prothrombin time (PT), partial thromboplastin time (PTT), D-dimer, and fibrinogen.
  • Electrolytes with calcium, magnesium, phosphorus, and uric acid. Low glucose, potassium, and PO2(partial pressure of oxygen) can occur with delay in analysis of high blast count.
  • Bone marrow biopsy and aspirate (with analysis for morphology), cytogenetics, flow cytometry, and cytochemical stains (Sudan black, myeloperoxidase, acid phosphatase, and specific and nonspecific esterase) are used for diagnosis.
  • Human leukocyte antigen (HLA) testing of patients who are transplant candidates—the test is performed before the patient becomes cytopenic. Specimen requirements are minimal when DNA-based HLA typing is performed.
  • Hepatitis B and C, cytomegalovirus, herpes simplex virus, human T-cell leukemia virus, and human immunodeficiency virus antibody titers are obtained.

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  • Typing and screening of blood products of patients with their consent: Blood product selection should prospectively consider the allogeneic transplant candidacy needs of cytomegalovirus CMV conversion reduction and irradiation to incapacitate donor lymphocytes from contaminating products.
  • Pregnancy test (β-human chorionic gonadotropin).
  • Electrocardiogram (ECG) and analysis of cardiac ejection fraction should be done prior to treatment with anthracyclines.
  • Lumbar puncture—performed when signs and symptoms of ALL or monocytic leukemia are present. Low platelets should be corrected. The procedure may be performed after reduction of peripheral blast count to avoid inoculation of blasts into uninvolved cerebrospinal fluid (CSF). Obtain cell count, opening pressure, protein level, and submit cytocentrifuge specimen for cytology.
  • Central venous access should be obtained using dual-lumen tunnel catheter or triple-lumen line. An implanted port-type catheter is not recommended. Coagulation abnormalities should be corrected if present. It is often possible to initiate induction therapy with normal peripheral veins and await subsidence of coagulopathy to reduce risk of procedural complications.
  • Supplemental testing of fluorescent in situhybridization (FISH) assay for 15;17 translocation is performed when acute promyelocytic leukemia (APL) is suspected, and BCR-ABL test is performed when de novo CML or blast crisis transformation is suspected to be critical. Cytogenetic analysis of blasts will contribute dramatically to subsequent preferred management.

INITIAL MANAGEMENT

The initial management of acute leukemia involves the following:

  • Hydration with i.v. fluids, 1,500 to 2,000 mL per day.
  • Tumor lysis prophylaxis should be started.
  • Blood product support suggestions for prophylactic transfusions are hemoglobin level less than 8 and platelet level less than 10,000. Platelet trigger threshold can be higher in the context of fever or bleeding (less than 20,000 suggested), cryoprecipitate can be used if fibrinogen level is less than 100, and fresh frozen plasma (FFP) can be used for significantly elevated levels of PT and PTT. The minimum “safe” platelet level required to prevent spontaneous hemorrhage is not known. Additional platelet optimization strategies include avoidance of cyclooxygenase-2 (COX-2)–selective nonsteroidal antiinflammatory drug (NSAID), aspirin, and clopidogrel-like agents.
  • WBC filter (if CMV-negative blood inventory is not available) should be used and blood products should be irradiated in those patients who are future allogeneic transplant candidates.
  • Fever and neutropenia require blood and urine cultures, followed by treatment with appropriate antibiotics (see Chapter 36), and imaging.
  • Therapeutic anticoagulation should be given with extreme caution in patients during periods of extreme thrombocytopenia. Adjustment of prophylactic platelet transfusion thresholds or anticoagulants is required.
  • Suppression of menses
  • Medroxyprogesterone (Provera) 10 mg daily or twice daily.

Tumor Lysis Syndrome

  • Tumor lysis syndrome can be spontaneous or can be induced by chemotherapy.
  • Risk factors include elevated uric acid, high WBC count, elevated lactate dehydrogenase (LDH), high tumor burden, and those factors that are already present spontaneously in tumor lysis at presentation.
  • Laboratory tests indicate elevated creatinine, low calcium, high phosphorus, acidosis, and coagulopathy.

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  • The patients should be initiated on allopurinol 300 mg twice daily for 3 days, followed by once daily until risk is resolved.
  • For hydration, alkalinizing fluids (0.5N saline with 50 mEq sodium bicarbonate 2,000 mL per day) should be considered.
  • Rasburicase (Elitek) 0.15 mg per kg i.v. daily should be used for up to 5 days if the patient is in tumor lysis at presentation or has rising creatinine level or hyperuricemia during induction.
  • Hemodialysis may be required in refractory cases or urgently in the setting of life-threatening hyperkalemia, or volume overload if oliguric (see Chapter 38).

CLASSIFICATION OF ACUTE MYELOGENOUS LEUKEMIA

There are two current systems to classify AML. One system has been suggested by the World Health Organization (WHO) and incorporates recurrent cytogenetic abnormalities and prognostic groups (see Table 23.2). Marrow blasts should make up 20% of the nucleated cells within the aspirate unless t(8;21) or inv(16) is present. The French-American-British (FAB) classification is also used and classifies AML into eight subtypes. The blasts may be characterized as myeloid lineage by the presence of Auer rods; a positive myeloperoxidase, Sudan black, or nonspecific esterase stain; and the immunophenotype shown by flow cytometry. Cell surface markers associated with myeloid cell lines include CD13, CD33, CD34, c-kit, and HLA-DR. Monocytic markers include CD64, CD11b, and CD14. CD41 (platelet glycophorin) is associated with megakaryocytic

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leukemia, and glycophorin A is present on erythroblasts. HLA-DR–negative blast phenotype is uniquely seen in APL and serves as a rapidly available test in confirming the suspicion of this subtype requiring a specific induction therapy.

TABLE 23.2. The World Health Organization (WHO) and French–American–British (FAB) Classification of Myeloid Leukemia

AML, acute myelogenous leukemia; MDS, myelodysplasia.

AML with recurrent genetic abnormalities

·   AML with t(8;21) (usually FAB M2)

·   AML with abnormal bone marrow eosinophils and inv(16) or t(16;16) (usually FAB M4Eo)

·   Acute promyelocytic leukemia with t(15;17) (FAB M3)

·   AML with 11q23 abnormalities

AML with multilineage dysplasia

·   Following MDS or myeloproliferative disorder

·   Without prior MDS but with dysplasia in 50% cells in two cell lines

AML and MDS, therapy related

·   Alkylating agent or radiation related

·   Topoisomerase II related

·   Others

AML not otherwise categorized

·   AML minimally differentiated (FAB M0)

·   AML without maturation (FAB M1)

·   AML with maturation (FAB M2)

·   Acute myelomonocytic leukemia (FAB M4)

·   Acute monocytic leukemia (FAB M5)

·   Acute erythroid leukemia (FAB M6)

·   Acute megakaryocytic leukemia (FAB M7)

·   Acute basophilic leukemia

·   Acute panmyelosis with myelofibrosis

·   Myeloid sarcoma

CLASSIFICATION OF ACUTE LYMPHOBLASTIC LEUKEMIA

The WHO classification of ALL divides the disease into precursor B-cell, precursor T-cell, and Burkitt-cell leukemia. Immunophenotyping of B-lineage ALL reveals lymphoid markers (CD19, CD20, CD10, TdT, and immunoglobulin). T-cell markers include TdT, CD2, CD3, CD4, CD5, and CD7. Burkitt-cell leukemia is characterized by a translocation between chromosome 8 (the c-myc gene) and chromosome 14 (immunoglobulin heavy chain), or chromosome 2 or 22 (light chain) regions.

PROGNOSTIC GROUPS IN ACUTE MYELOGENOUS LEUKEMIA

Those patients who are older (older than 60) and those with an elevated blast count at diagnosis (>20,000) have a worse prognosis. Chemotherapy-related AML and prior history of myelodysplasia (MDS) imparts a lower chance of obtaining complete remission (CR) and long-term survival. A history of trisomy 21 may impart a good prognosis. Table 23.3 illustrates the prognostic groups according to cytogenetics.

TABLE 23.3. Cytogenetic Risk Groups in Treated Adult Acute Myelogenous Leukemia (AML) Cases

From Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1312–1320, with permission.

Favorable risk (5-yr survival with therapy as high as 40%)

·   t(15;17)

·   inv(16), del(16q), t(16;16)

·   t(8;21) with or without complex karyotype and del(9q)

Standard risk (5-yr survival with therapy approximately 20%)

·   no cytogenetic abnormality identified (i.e., normal)

·   all other cytogenetic abnormalities not associated with a specific prognosis

Poor risk (5-yr survival with therapy <10%)

·   –5, –7

·   inv(3) or t(3;3)

·   t(9;22)

·   11q23 (MLL) abnormalities

·   three or more abnormalities

·   t(6;9)

PROGNOSTIC GROUPS IN ACUTE LYMPHOBLASTIC LEUKEMIA

As in AML, patients with ALL have a worse prognosis when presenting with advanced age or elevated WBC count. B-cell phenotypes have a worse prognosis than T-cell phenotypes. Burkitt-cell (mature B-cell) leukemia or lymphoma has an improved prognosis with intensive chemotherapy and CNS treatment; it usually has a translocation involving chromosome 8q24. Table 23.4 lists the prognostic groups according to cytogenetic analysis. The presence of

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t(9;22) (Philadelphia chromosome) is the most common abnormality in adults. It is present in 20% to 30% of patients with ALL and in up to 50% of patients in the B-cell lineage. Long-term survival is dismal in this group if treated by chemotherapy alone. (These adults are not treated with maintenance chemotherapy and are recommended to undergo allogeneic transplantation if they are a suitable candidate in first CR.)

TABLE 23.4. Prognostic Groups in Adult Acute Lymphoblastic Leukemia (ALL)

Poor risk:

·   t(9;22)

·   t(4;11)

·   Hypodiploid

·   t(1;19)

Good risk:

·   8q24 translocations

·   t(12;21)

·   t(10;14)

·   t(7;10)

TREATMENT INDUCTION IN ACUTE MYELOGENOUS LEUKEMIA [NON–t(15;17) ACUTE PROMYELOCYTIC LEUKEMIA]

The goal of induction chemotherapy is to obtain CR, which has been shown to correlate with improved survival. CR is the elimination of the malignant clone (marrow blasts <5%) and recovery of hematopoiesis [absolute neutrophil count (ANC) >1,000 to 1,500 and platelet count >100,000]. Patients typically have a leukemia cell burden of approximately 10 × 1015 that is reduced to approximately 10 × 1012 by induction. Additional intensive “consolidation” cycles of chemotherapy are given to further reduce this residual burden in the hope that host immune mechanisms can suppress the residual leukemia population, thereby leading to sustained CR. The general approach to induction chemotherapy for adults is shown in Table 23.5. Patients should be considered for clinical trials if available.

TABLE 23.5. Standard Induction for Acute Myelogenous Leukemia (AML)

“7 + 3,” 7 d of cytarabine and 3 d of anthracycline:

Cytarabine 100–200 mg/m2 daily as continuous infusion × 7 d with Idarubicin 12 mg/m2 daily bolus for 3 d

Or

Daunorubicin 45–60 mg/m2 daily bolus for 3 d

Or

Mitoxantrone 12 mg/m2 daily bolus for 3 d

In general:

  • Idarubicin may be the preferred anthracycline agent in AML.
  • Addition of high-dose cytarabine (HDAC) or etoposide has been evaluated in published regimens for induction that may benefit some patients younger than 60. These additions have not been demonstrated to be conclusively superior to 3 days of anthracycline and 7 days of cytarabine alone. Multiple regimens are available; Table 23.6 shows a choice evaluated in a randomized trial.

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  • Bone marrow aspiration should be repeated at approximately 14 days. If residual blasts are present (>5%), induction chemotherapy should be repeated (consider ‘5 + 2’ in Table 23.7). If significant disease is present (<40% to 50% reduction in disease volume), induction should be repeated or a change in the regimen to age-appropriate HDAC should be considered.
  • Elderly (older than 65) patients may benefit from treatment. HDAC should be avoided because of excess CNS toxicity and commonly observed poor survival prospects regardless of therapy selection.

TABLE 23.6. Southwest Oncology Group (SWOG) Regimen for HDAC Induction

Cytarabine 2 g/m2 over 1 h q12h on d 1–6 (12 doses) and daunorubicin 45 mg/m2/day bolus on d 7–9 (three doses)

TABLE 23.7. Consolidation of Acute Myelogenous Leukemia

Age <60

·   Cytarabine 3 mg/m2 infused over 2 h, q12h on d 1, 3, and 5 (six doses).

·   Creatinine 1.5–1.9 mg/dL: Decrease cytarabine 1.5 g/m2 per dose.

Age >60

·   “5 + 2:” Cytarabine 100 mg/m2 daily as continuous infusion for 5 d and anthracycline agent (idarubicin 12 mg/m2, daunorubicin 45–60 mg/m2, or mitoxantrone 12 mg/m2) bolus daily for 2 d.

Or

·   If age of patient is 60–70, good performance status and renal function: Intermediate dose cytarabine 1 g/m2 q12h on d 1, 3, 5.

SUPPORTIVE CARE

  • Infection is a major cause of morbidity and mortality. Prophylactic antibiotics and antifungals are often used during prolonged neutropenia with uncertain benefit. Broad-spectrum antimicrobials are used for neutropenic fever (see Chapter 36).
  • Growth factors such as granulocyte colony stimulating factor (G-CSF) are associated with shortened length of neutropenia and are of demonstrated value in patients older than 65 years. Initiation of G-CSF, when employed, is delayed until after day 14, when bone marrow shows a satisfactory induction pattern. Growth factors may benefit most those with fever or infection.
  • Dexamethasone eye drops are required during HDAC infusions to reduce risk of exfoliative keratitis.

TREATMENT—ACUTE MYELOGENOUS LEUKEMIA CONSOLIDATION, NON–t(15;17)

The consolidation options for those patients who enter CR are shown in Table 23.7. HDAC especially may benefit those patients with good-risk disease [t(8;21) or inv(16)]. Consolidation usually consists of two to four cycles (the minimum effective number is not known). Patients with preceding MDS or very poor risk cytogenetics may proceed to allogeneic transplantation.

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TREATMENT—ACUTE PROMYELOCYTIC LEUKEMIA, t(15;17)

The t(15;17) brings together the retinoic acid receptor-α and the promyelocytic leukemia genes, allowing for transduction of a novel protein (PML-RAR). The protein plays a role in blocking differentiation of the promyelocyte, thereby allowing abnormal accumulation within the marrow space. Because characteristic translocation occurs in this subgroup of AML, therapy incorporates ATRA, which acts as a differentiating agent. Table 23.8 shows a treatment summary in APL.

TABLE 23.8. Treatment of Acute Promyelocytic Leukemia

ATRA, all-trans retinoic acid; 6-MP, 6-mercaptopurine; MTX, methotrexate.

Induction

·   ATRA 45 mg/m2/d PO divided into two doses, daily until CR and

·   Anthracycline: Idarubicin 12 mg/m2 every alternate days for four doses (d 2, 4, 6, 8) or daunorubicin 50–60 mg/m2 daily for 3 d.

Consolidation

·   Alternating anthracycline/anthracenedione: Idarubicin 5 mg/m2 daily for 5 d (first consolidation), then mitoxantrone 10 mg/m2 daily for 6 d (second consolidation), followed by idarubicin 12 mg/m2times one dose (third consolidation)

Or

·   2 cycles of daunorubicin 50–60 mg/m2 daily for 3 d

Maintenance (2 yr)

·   ATRA 45 mg/m2 daily for 15 d q3mo

·   6-MP 100 mg/m2 daily

·   MTX 10 mg/m2 weekly

Management notes:

  • Time to attain remission may be more than 30 days and a bone marrow biopsy is not performed on day 14.
  • PCR should be followed for PML-RAR: high-dose cytarabine should be considered if positive postconsolidation is present; also, levels should be followed during the maintenance phase. A return of the transcript to positive heralds relapse.
  • APL syndrome (retinoic acid syndrome) consists of capillary leak and cytokine release resulting in fever, respiratory compromise (dyspnea and infiltrates), weight gain, renal dysfunction, effusions (pleural and pericardial), and hypotension. This syndrome occurs in 20% of patients during induction, often around day 7, and is associated with a rapidly rising neutrophil count. Treat with dexamethasone 10 mg i.v. b.i.d. Discontinuation of ATRA or use of leukocyte apheresis should be considered in severe cases. ATRA may be safely employed in maintenance phase therapy because the ATRA syndrome is limited to the induction-period neutrophilia.
  • A similar syndrome, not involving ATRA, is seen with the use of arsenic trioxide.

Prognosis with APL is very good, with 90% of patients attaining a CR and 70% long-term disease-free survival. Those patients with WBC counts greater than 10,000 and platelets less than 40,000 at diagnosis may have increased risk of relapse.

Relapsed Disease:

  1. Arsenic trioxide 0.15 mg/kg/day until second CR
  • Average of 35 days to remission
  • Daily electrolytes, ECG (prolonged QT interval) determinations, neuropathy assessment
  • Twenty-five percent of patients may develop APL syndrome similar to ATRA

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  • Eighty-five percent of patients have achieved CR
  • Arsenic trioxide may be followed by further cycles at a dose of 0.15 mg/kg/day for 25 doses.
  1. Autologous transplant with PCR-negative harvest or allogeneic transplant should be considered.

TREATMENT OF RELAPSED OR REFRACTORY ACUTE MYELOGENOUS LEUKEMIA

Relapse of AML after initial CR is very common (60% to 80% of all cases). Relapse occurring within 6 months of induction or a patient never attaining remission with induction (refractory disease) complicates many induction attempts. The prognosis for long-term survival in this subset of patients is very poor with chemotherapy alone, and all patients who are able to tolerate the treatment should be evaluated for allogeneic transplantation. Other options are described in the following.

  1. Gemtuzumab ozogamicin (Mylotarg)
  • Gemtuzumab ozogamicin is an anti-CD33 monoclonal antibody conjugated with calicheamicin.
  • The dosage is 9 mg per m2as 2-hour infusion on days 1 and 15.
  • It is approved for use in adults older than 60 years in first relapse.
  • Thirty percent of patients achieved CR (13% without complete platelet recovery).
  • Side effects include nausea, thrombocytopenia, and increase in liver enzyme levels.
  • WBC count should be reduced to less than 30,000 before treatment.
  • Gemtuzumab ozogamicin is not for patients who may undergo allogeneic transplantation due to increased risk of venoocclusive disease (VOD).
  • Overall treatment-related morbidity can be considered similar to that of conventional chemotherapy induction.
  1. Reinduction with “7 + 3” or high-dose cytarabine
  • Reinduction may be an option for those patients who relapse more than 12 months after induction.
  • Remission rates are approximately 50%, although usually of shorter duration (<50% of the duration of the preceding remission).
  1. FLAG: Fludarabine, Cytarabine, and G-CSF (can be combined with idarubicin or mitoxantrone)
  • CR is obtained in 55% of patients.
  1. Liposomal daunorubicin and cytarabine combination is used at high dose.
  • CR is 29% and overall response rate is 40%.
  1. Etoposide, mitoxantrone, ± cytarabine (EM or MEC)
  2. In cases of isolated CNS relapse, it should be considered that systemic relapse almost always follows soon and that a systemic therapy is also required.

TREATMENT OF ACUTE LYMPHOCYTIC LEUKEMIA

General scheme: induction, consolidation, maintenance, and CNS treatment.

Several strategies exist for the treatment of adult ALL. Table 23.9 illustrates the Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen employed in many North American centers. The Larson regimen reported by Cancer and Leukemia Group B (CALGB) Study 9111, shown in Table 23.10, is also commonly employed. Other options based on the Hoelzer and Linker regimen are available. Burkitt-cell leukemia (mature-B ALL, L3) is not included because of high resistance to typical induction chemotherapy. It can be treated with hyper-CVAD without maintenance therapy but requires aggressive CNS treatment to prevent relapse.

TABLE 23.9. The Hyper-CVAD and MTX/HIDAC Regimen

G-CSF, granulocyte colony stimulating factor; CNS, central nervous system; POMP, 6- mercaptopurine–methotrexate–vincristine–prednisone; HIDAC, high-dose cytosine arabinoside; MTX/HIDAC, methotrexate/high-dose cytosine arabinoside.
a Dosing interval based on risk stratification (see text).
b Maintenance therapy was not given in Burkitt-cell leukemia/lymphoma.

Cycle 1, 3, 5, 7

·   Cyclophosphamide 300 mg/m2 i.v. over 2 h q12h d 1–3 (six doses)

·   Mesna 600 mg/m2/d i.v. as continuous infusion d 1–3, complete 12 h post cyclophosphamide

·   Vincristine 2 mg i.v. d 4, 11

·   Doxorubicin 50 mg/m2 i.v. d 4

·   Dexamethasone 40 mg PO daily d 1–4 and 11–14

·   G-CSF 10 µg/kg/d s.c. starting d 5

Cycle 2, 4, 6, 8

·   Methotrexate 200 mg/m2 i.v. over 2 h on d 1, followed by

·   Methotrexate 800 mg/m2 over 22 h on d 1

·   Leucovorin 50 mg i.v. starting 12 h after methotrexate completed, followed by leucovorin 15 mg i.v. every 6 h × eight doses, dose adjusted on the basis of methotrexate levels as well. Meticulous monitoring of methotrexate levels is required to ensure appropriate leucovorin scheduling. Rapidly changing renal function during or shortly after the methotrexate infusion should prompt consideration for urgent measures to mitigate toxicity (higher leucovorin doses, infusion of investigational carboxypeptidase-G to cleave plasma methotrexate to inactive fragments).

·   Cytarabine 3 g/m2 i.v. over 2 h every 12 h on d 2 and 3 (four doses)

·   Methylprednisolone 50 mg i.v. twice daily d 1–3

·   G-CSF 10 µg/kg/d s.c. starting d 4

CNS Prophylaxisa

·   Methotrexate 12 mg intrathecal (IT) d 2 of the course

·   Cytarabine 100 mg IT d 8 of the course

Maintenance therapyb (POMP)

·   6-Mercaptopurine 50 mg PO three times daily

·   Methotrexate 20 mg/m2 PO, weekly

·   Vincristine 2 mg i.v. monthly

·   Prednisone 200 mg/d for 5 d each month

Dosage adjustments

·   Vincristine reduced to 1 mg if bilirubin >2 mg/dL

·   Doxorubicin decreased to 25% for bilirubin 2–3 mg/dL, decreased to 50% if bilirubin 3–4 mg/dL, and decreased 75% if bilirubin >4 mg/dL

·   Methotrexate reduced to 25% if creatinine 1.5–2 mg/dL, reduce to 50% if creatinine >2 mg/dL

·   HIDAC decreased to 1 g/m2 if patient >60 yr, creatinine >2 mg/dL, or MTX level >20 µmol/L

·   May need to decrease MTX/HIDAC doses for toxicity

TABLE 23.10. The Larson Regimen

CNS, central nervous system.
Dosage reductions for age >60 yr: cyclophosphamide 800 mg/m2 d 1, daunorubicin 30 mg/m2 i.v. d 1–3, and prednisone 60 mg/m2/d PO d 1–7.

Course I: Induction (4 wk).

·   Cyclophosphamide 1,200 mg/m2 i.v. d 1a

·   Daunorubicin 45 mg/m2 i.v. d 1–3a

·   Vincristine 2 mg i.v. d 1, 8, 15, 22

·   Prednisone 60 mg/m2/d PO d 1–21a

·   L-Asparaginase (Escherichia coli) 6,000 IU/m2 s.c./i.m. d 5, 8, 11, 15, 18, 22

·   G-CSF 5 µg/kg/d subcutaneously (s.c.) starting d 4

 

Course IIA (4 wk; repeat once for Course IIB)

·   Methotrexate 15 mg intrathecal (IT) d 1

·   Cyclophosphamide 1,000 mg/m2 i.v. d 1

·   6-Mercaptopurine 60 mg/m2/d PO d 1–14

·   Cytarabine 75 mg/m2/d s.c. d 1–4 and 8–11

·   Vincristine 2 mg i.v. d 15 and 22 (two doses)

·   L-Asparaginase (E. coli) 6,000 IU/m2 s.c./i.m. d 15, 18, 22, 25 (four doses)

·   G-CSF 5 µg/kg/d s.c. starting d 4.

 

Course III: CNS prophylaxis and interim maintenance (12 wk)

·   IT Methotrexate 15 mg d 1, 8, 15, 22, 29

·   Cranial irradiation 2,400 cGy (fractionated) d 1–12

·   6-Mercaptopurine 60 mg/m2/d PO d 1–70

·   Methotrexate 20 mg/m2 PO d 36, 43, 50, 57, 64

 

Course IV: Late intensification (8 wk)

·   Doxorubicin 30 mg/m2 i.v. d 1, 8, 15

·   Vincristine 2 mg i.v. d 1, 8, 15

·   Dexamethasone 10 mg/m2/d PO d 1–14

·   Cyclophosphamide 1,000 mg/m2 i.v. d 29

·   6-Thioguanine 60 mg/m2/d PO d 29–42

·   Cytarabine 75 mg/m2/d s.c. d 29–32 and 36–39

 

Course V: Prolonged maintenance (until 24 mo from diagnosis)

·   Vincristine 2 mg i.v. d 1 of every 4 wk

·   Prednisone 60 mg/m2/d PO d 1–5 of every 4 wk

·   6-Mercaptopurine 60 mg/m2/d PO d 1–28

·   Methotrexate 20 mg/m2 PO d 1, 8, 15, 22

 

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SUPPORTIVE CARE

The regimens described previously incorporate growth factors to reduce neutropenia and allow more scheduled chemotherapy to proceed. All patients will require blood product support at some point during the treatment. Those patients treated with hyper-CVAD receive prophylactic antimicrobials (i.e., levofloxacin 500 mg daily, fluconazole 200 mg daily, and valacyclovir 500 mg daily). Prophylactic trimethoprim–sulfamethoxazole and valacyclovir 500 mg were given three times per week during the first 6 months of maintenance.

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THERAPY FOR CENTRAL NERVOUS SYSTEM DISEASE

  • CNS is a sanctuary site.
  • CNS disease is diagnosed by the presence of neurologic deficits at diagnosis orby 5 or more blasts per microliter of CSF.
  • Therapy for CNS disease is radiation (fractionated to 2,400 to 3,000 cGy) and intrathecal (IT) methotrexate (MTX) or cytarabine (Ara-C).
  • Prophylaxis decreases CNS relapse from 30% to less than 5%. The prophylactic radiation and chemotherapy schedule intensity are dependent on the relapse risk.
  • Radiation and IT MTX are equivalent to systemic high-dose chemotherapy and IT chemotherapy. There are potential late-term cognitive toxicities in treated subjects.
  • In the hyper-CVAD regimen, patients with high-risk disease (i.e., LDH level >600, mature B-cell disease, or elevated proliferative index) receive 16 IT treatments, those with lowrisk disease (no factors) receive 4 IT treatments, and those with unknown disease receive 8 IT doses.

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TREATMENT OF RELAPSED ACUTE LYMPHOBLASTIC LEUKEMIA

Marrow is the most common site of relapse but relapse can occur in testes, eye, and CNS. Patients with late relapse (more than 1 year from induction) may respond to reinduction with the original regimen. Early relapse or refractory disease will require transplantation or changing treatment plan. Several options are available, including:

  • high-dose cytarabine with idarubicin, mitoxantrone, or fludarabine
  • dose escalation of imatinib [Philadelphia-positive (Ph-positive)]
  • hyper-CVAD, if not given initially.

USE OF MONOCLONAL ANTIBODIES IN ACUTE LYMPHOBLASTIC LEUKEMIA

  1. Rituximab (Rituxan)
  • Anti-CD20 chimeric murine–human monoclonal antibody
  • May have a role in addition to the previously noted regimens in front-line therapeutic combinations
  • Palliation in those patients who are not able to tolerate intensive regimens.
  1. Alemtuzumab (Campath-1H)
  • Anti-CD52 chimeric monoclonal antibody employed in relapsed CLL
  • Limited experience in relapsed and refractory disease, but may have a role in palliation
  • Side effects include fever, rigor, nausea with infusion, and prolonged lymphopenia.
  1. Gemtuzumab ozogamicin (Mylotarg)
  • Anti-CD33 monoclonal antibody conjugated with calicheamicin (dose listed in preceding text)
  • 30% of ALL patients may express CD33 (55% Ph-positive cases).

TRANSPLANTATION

Autologous Transplant

  • Autologous transplant is a further consolidation for patients with poor-risk disease who have no donors for allogeneic transplant.
  • It may be performed after intensive consolidation chemotherapy.
  • It may be performed in older patients (as old as 60 to 70).
  • It may increase disease-free survival.

Allogeneic Transplant

  • Allogeneic transplant has the added benefit of “graft versus leukemia” effect.
  • Its increased short-term toxicity may limit the ability to proceed with the transplantation.
  • In the setting of unrelated donor searches, the prolonged time needed to identify a donor needs to be considered at the time of diagnosis.
  • It is considered for all patients with relapsed or refractory disease, as it is the option that may yield long-term survival.
  • It is performed in the first CR or early in the course for those patients with poor risk cytogenetics, t(9;21), or MDS, especially with a matched-related donor.
  • It may be associated with increased failure-free survival.
  • When transplanted in first CR, overall survival is 60%; it decreases to less than 35% when performed for patients with relapsed disease, and is lower than 10% for patients with refractory disease.
  • Nonmyeloablative transplantation is being explored for those patients unable to proceed with ablative treatment secondary to age or illness.

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PROGNOSIS AND SURVIVAL

Adults with acute leukemia remain at high risk for disease-related and treatment-related complications. In AML, the prognostic characteristics of the disease are associated with survival. High-risk AML is associated with 80% to 90% CR rate, and long-term disease-free survival is 60% to 70% in younger patients treated with HDAC. Poor-risk features are associated with only a 50% to 60% chance of obtaining a CR, and a high risk of relapse is observed in those patients who enter CR.

CR and long-term outcome have improved for adult patients with ALL who were receiving intensive courses of chemotherapy. With the Larson regimen, 85% obtained CR (39% older than 60 years). The hyper-CVAD course yielded a CR of 91% (79% for patients older than 60 years). Median duration of CR was 30 months with Larson regimen and was 33 months with hyper-CVAD. Five-year survival was approximately 40%.

SUGGESTED READINGS

Beutler E, Lichtman M, Coller B, et al., eds. Williams hematology, 6th ed. New York: McGraw-Hill, 2001.

Bloomfield C, Lawrence D, Byrd J, et al. Frequency of prolonged remission duration after high-dose cytarabine in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998;58:4173–4179.

Byrd J, Mrozek K, Dodge R, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325–4336.

Cortes J, Estey E, O'Brien S, et al. High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia. Cancer 2001;92:7–14.

Estey E. Therapeutic options for acute myelogenous leukemia. Cancer 2001;92:1059–1073.

Ferrando A, Look AT. Clinical implications of recurring chromosomal and associated molecular abnormalities in acute lymphoblastic leukemia. Semin Hematol 2000;37:381–395.

Garcia-Manero G, Kantarjian HM. The hyper-CVAD regimen in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am2000;14:1381–1396.

Garcia-Manero G, Thomas D. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am2001;15:163–205.

Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1312–1320.

Hoelzer D, Gokbuget N, et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002;99:4379–4385.

Hoffman R, Benz E, Shattil S, et al., eds. Hematology, 3rd ed. New York: Churchill Livingstone, 2000.

Jaffe E, Harris N, Stein H, et al., eds. World health organization classification tumors: pathology and genetics of tumours of haemotopoietic and lymphoid tissues. Lyon: IARC Press, 2001.

Larson RA. Recent clinical trials in acute lymphoblastic leukemia by the Cancer and Leukemia Group B. Hematol Oncol Clin North Am2000;14:1367–1379.

Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB Study 9111. Blood 1998;92:1556–1564.

Leone G, Voso MT, Sica S, et al. Therapy related leukemias: susceptibility, prevention, and treatment. Leuk Lymphoma 2001;41:255–276.

Maris M, Niederwieser D, Sandmaier B, et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003;102:2021–2030.

Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105–109.

Sievers EL, Larson RA, Stadmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001;19:3244–3254.

Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern cooperative Oncology Group Study. Blood 2000;96:4075–4083.

P.323

 

Soignet SL, Frankel SR, Douer D, et al. United States multicenter trial of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–3860.

Tallman M, Nabhan C, Feusner J, et al. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002;99:759–767.

Weick J, Kopecky K, Appelbaum F, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1996;88:2841–2851.