The Washington Manual of Oncology, 3 Ed.

Acute Leukemias

Armin Ghobadi • Amanda Cashen

  I. PRESENTATION

1.  Subjective. Acute leukemia often presents with symptoms or signs related to pancytopenia or organ infiltration. Severe neutropenia (absolute neutrophil count [ANC] less than 100/μL) predisposes to fever and infection, especially in the sinuses, perirectal area, skin, lungs, and oropharynx. Thrombocytopenia is associated with purpura, petechiae, gingival bleeding, epistaxis, and retinal hemorrhage. Anemia can cause fatigue, shortness of breath, chest pain, or lightheadedness.

       Less common presenting symptoms include lymphadenopathy, splenomegaly, and hepatomegaly, which occur more often with acute lymphoblastic leukemia (ALL) than with acute myeloid leukemia (AML). Five percent to 10% of patients with ALL have involvement of the central nervous system (CNS), causing headache, confusion, and/or focal neurologic deficits. Monocytic subtypes of AML can infiltrate the skin (leukemia cutis) or gingiva, leading to purple, nontender papules or gingival hyperplasia, respectively. Tumors composed of myeloid blasts, known as granulocytic sarcomas or chloromas, can involve almost any organ and may precede bone marrow involvement by AML.

       A syndrome called leukostasis occurs in up to 50% of patients with AML and an absolute blast count (white blood cell [WBC] count × percent circulating blasts) exceeding 100,000/μL. Symptoms include respiratory compromise and CNS manifestations such as headache or confusion. Emergency leukapheresis can be lifesaving. Transfusion of packed red cells may increase blood viscosity and should be minimized until leukapheresis can be performed.

1.  Objective. Approximately half of patients present with an elevated white count, and most have blasts circulating in the peripheral blood. Thrombocytopenia, anemia, and neutropenia are due to suppression of normal hematopoiesis in the bone marrow. Hyperuricemia, hyperphosphatemia, and hypocalcemia may indicate tumor lysis syndrome (TLS). Elevated lactate dehydrogenase (LDH) is found in most patients with ALL and many with monocytic variants of AML. Spurious laboratory values associated with hyperleukocytosis (WBC more than 100,000/μL) and blast cell metabolism can include falsely prolonged coagulation tests, hypoxemia, and hypoglycemia. Disseminated intravascular coagulation (DIC) is common in acute promyelocytic leukemia (APL) and is associated with microangiopathic hemolytic anemia, thrombocytopenia, hypofibrinogenemia, elevated fibrin split products, and prolongation of the prothrombin time.

       The presence of a mediastinal mass on chest radiograph is suggestive of T-cell ALL. Osteopenia or lytic lesions may be seen in up to 50% of patients with ALL.

1. WORKUP AND STAGING. The recommended workup of patients with newly diagnosed acute leukemia is shown in Table 27-1. A thorough history and physical examination is aimed at identifying the duration and severity of symptoms, evidence of extramedullary (including CNS) leukemia, and presence of risk factors like prior exposure to chemotherapeutic agents. Factors that will impact therapeutic decisions include coexisting medical problems, infection with human immunodeficiency virus (HIV) or hepatitis viruses, and presence of full siblings. Comprehensive laboratory testing can uncover organ dysfunction, TLS, DIC, or infection. It is also important to send a peripheral blood specimen for human leukocyte antigen (HLA) typing, as many patients will be future candidates for stem cell transplantation. A multiple-gated acquisition (MUGA) scan or other test of cardiac function is routinely performed before the patient begins anthracycline containing therapy.

TABLE 27-1

Approach to the Newly Diagnosed Patient with Acute Leukemia

History/examination

  Infection: fever; localizing symptoms, especially sinus, mouth, anogenital, skin, and lungs

  Hemorrhage: petechiae, ecchymosis, epistaxis, oral/GI bleeding, visual complaints

  Symptoms of intracranial bleed, including headache and neurologic deficits

  Anemia: exertional dyspnea, CHF, angina, orthostasis, syncope

  CNS leukemia: headache, confusion, neurologic deficits

  Leukostasis: dyspnea, headache, confusion

  Monocytic leukemia: gingival hyperplasia and/or nontender cutaneous nodules

  Other

   Long-standing symptoms suggest preceding myelodysplasia

   Full siblings, allergies, major medical problems

   HIV risk factors, previous hepatitis

   Previous chemotherapy, exposure to benzene

Routine laboratory testing

  Before treatment: blood chemistry, LFT, CBC/manual differential, PT/PTT, FDP, fibrinogen, uric acid, LDH, pregnancy test, HIV, HLA class I/II, urinalysis, type/cross

  During treatment: CBC daily and blood chemistry/LFT twice weekly

Radiographic studies

  Chest radiograph

  MUGA scan

Procedures

  Placement of central venous access

  Lumbar puncture if CNS leukemia is suspected

  Leukapheresis if leukostasis is present

Management of a febrile patient

  Culture blood, urine, suspected sites of infection

  Inspect indwelling line

  Initiate broad-spectrum antibiotics promptly

   Cefepime or ceftazidine or imipenem

   Vancomycin if line infection suspected

   Allergic to β-lactams: ciprofloxacin or levofloxacin and vancomycin

   Clinically septic: add gentamicin

   Oral or possible intra-abdominal infection: add anaerobic coverage

GI, gastrointestinal; CHF, congestive heart failure; CNS, central nervous system; HIV, human immunodeficiency virus; LFT, liver function tests; CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time; FDP, fibrin degradation products; LDH, lactate dehydrogenase; HLA, human leukocyte antigen; MUGA, multiple-gated acquisition.

       Bone marrow aspiration and biopsy and cytogenetic studies including conventional karyotype analysis and fluorescent in situ hybridization (FISH), multicolor flow cytometry and cytochemistry studies are essential for diagnosis and classification of acute leukemias. Molecular studies using reverse transcriptase polymerase chain reaction (RT-PCR) for FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD mutation), nucleophosmin gene (NPM-1) mutation, c-Kit mutation, and CCAAT/enhancer binding protein alpha gene (CEBPA) mutation have prognostic importance and therapeutic implications on postremission therapy choices in AML. Although recently supplanted by the World Health Organization (WHO) classification, the French–American–British (FAB) classification remains a commonly used system for the description of acute leukemias. The FAB classification relies on morphology, cytochemistry, and flow cytometry to define subtypes of AML (M0 through M7) and ALL (L1 through L3). Application of these criteria requires a thorough examination of the peripheral blood and bone marrow aspirate with enumeration of blasts, which are characterized by a high nucleus/cytoplasm ratio with fine nuclear chromatin and one or more nucleoli. The FAB criteria define AML when greater than 30% blasts are present in the bone marrow aspirate; greater than 20% blasts define AML in the WHO classification. There are a few exceptions. For diagnosis of acute myelomonocytic leukemia, myeloblasts and promonocytes together should comprise at least 20% of bone marrow cellularity. Acute erythroid leukemia is another exception in which >50% erythroid precursors are present in the bone marrow and myeloblasts should account for >20% of nonerythroid cells. Additionally, t(8;21), inv(16), t(16;16), and t(15;17) are diagnostic of AML regardless of blast percentage in bone marrow. The diagnosis of ALL requires demonstration of at least 20% lymphoblasts in bone marrow. Cytochemistry can be helpful in the diagnosis of acute leukemia (for instance, myeloid blasts are positive for myeloperoxidase), but now flow cytometry is the primary method for determining the leukemia subtype. Lymphoid cells are identified by the presence of CD10, CD19, and CD20 (B cell) or CD2, CD3, CD4, CD5, and CD8 (T cell). Myeloid markers include CD13, CD33, and CD117/c-Kit; CD14 and CD64 (monocytic markers); glycophorin A (erythroid); and CD41 (megakaryocytic).

       Subtypes of AML and ALL as defined by the FAB system are of limited prognostic or therapeutic importance. The WHO classification, on the other hand, incorporates cytogenetic and clinical features of known prognostic significance. In the WHO system, AML subtypes are organized into four categories: AML with recurrent genetic abnormalities, AML with multilineage dysplasia (often associated with a preceding myelodysplastic syndrome [MDS]), therapy-related AML, and AML not otherwise categorized (Table 27-2). Therapy-related AML and AML with multilineage dysplasia have a generally poor prognosis, and patients with these subtypes may be candidates for early allogeneic stem cell transplantation. In the WHO classification, ALL is categorized as precursor B-cell ALL or precursor T-cell ALL. Burkitt’s lymphoma/leukemia is grouped with the mature B-cell neoplasms.

       It must be emphasized that cytogenetic studies including conventional karyotype and FISH, and molecular studies for FLT3-ITD, NPM1, c-kit, and CEBPA mutations are crucial for the prognosis and treatment of acute leukemia. Therefore, cytogenetic studies and the above-mentioned molecular studies should be obtained on an initial bone marrow and/or peripheral blood sample. Early recognition of APL (FAB-M3, AML with t[15;17]) is particularly important, as these patients are at risk for DIC, and optimal initial treatment includes all-trans-retinoic acid (ATRA; see Section III.B.). Advantages and pitfalls of diagnostic tools commonly used in the diagnosis of APL are summarized in Table 27-3.

TABLE 27-2

World Health Organization Classification of Acute Myeloid Leukemia

AML with recurrent genetic abnormalities

t(8;21); (AML1/ETO)

inv(16) or t(16;16); (CBFβ/MYH11)

APL (AML with t(15;17) and variants)

11q23 (MLL) abnormalities

AML with multilineage dysplasia

With a preceding MDS or myeloproliferative disorder

Without a preceding MDS or myeloproliferative disorder

Therapy-related AML and MDS

Related to an alkylating agent

Related to a topoisonerase II inhibitor

AML not otherwise categorized

Minimally differentiated

Without maturation

With maturation

Acute myelomonocytic leukemia

Acute monoblastic and monocytic leukemia

Acute erythroid leukemia

Acute megaloblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome.

 III. THERAPY AND PROGNOSIS. In the absence of antileukemic therapy, the median survival of newly diagnosed patients is 2 to 4 months. Chemotherapy induces responses in most patients with acute leukemia, although for many patients remission is short-lived. The goal of induction chemotherapy is complete remission (CR), which is a prerequisite for cure. CR is defined as normalization of blood counts (ANC more than 1,500/μL, platelet more than 100,000/μL), with bone marrow aspirate/biopsy demonstrating fewer than 5% blasts. Postremission therapeutic options include additional chemotherapy or stem cell transplantation. Chemotherapy given during CR can include consolidation (intensity similar to that for induction) and maintenance (reduced intensity administered for 18 to 36 months).

TABLE 27-3

Advantages and Pitfalls of Diagnostic Tools Commonly Used in the Diagnosis of Acute Promyelocytic Leukemia

1.  AML. As stated above, the prognosis for patients with AML is largely determined by the leukemia risk group. Based on cytogenetic profiles, AML is classified into three risk groups. Molecular abnormalities including FLT3-ITD, NPM1, c-Kit, and CEBPA mutations have significant prognostic impacts. National Comprehensive Cancer Network (NCCN) guidelines have included these mutations in risk classification of AML (Table 27-4). Translocation between chromosomes 8 and 21 (AML-ETO, t[8;21]), present in some patients with FAB-M2 AML, and inversion 16, present in most patients with FAB-M4Eo, have a favorable prognosis with chemotherapy alone. Unfavorable cytogenetics, found in 30% to 40% of AML patients, include monosomies or deletions of chromosomes 5 and 7 (–5, –7, 5q–, 7q–) and equal to or greater than three chromosomal abnormalities. Half of patients with AML have intermediate-risk cytogenetics, primarily a normal karyotype. In a large series from the Cancer and Leukemia Group B (CALGB), the 5-year survival rate was 55%, 24%, and 5% for patients with favorable, intermediate, and unfavorable cytogenetics, respectively.

       An active area of investigation is the identification of molecular prognostic factors that can guide therapeutic decisions in patients with normal cytogenetics. One such abnormality is FLT3-ITD mutation, which is present in 20% to 30% of all AML cases and 30% to 40% of normal karyotype AML (NK-AML). FLT3-ITD mutation is associated with a high WBC and a worse prognosis. For instance, among 224 AML patients with normal cytogenetics, 5-year survival was 20% for patients with an FLT3 ITD mutation, versus 42% for those with wild type FLT3. NPM-1 mutations are found in 30% of all AMLs and 50% of NK-AMLs. Isolated NPM-1 mutation in NK-AML is associated with higher CR rates and improved DFS and OS, resulting in outcomes similar to good-risk AMLs. However, patients with both NPM-1 mutations and FLT3-ITD mutations have outcomes more similar to isolated FLT3-ITD mutations. CEBPA mutations can be found in approximately 10% and 15% of all AML patients and patients with NK-AML respectively. NK-AML with CEBPA mutation has a better remission duration and OS similar to core binding factor AML [CBF-AML, another term for AML with t(8:21) and AML with inv(16)]. Double mutation of CEBPA (mutation of both alleles) is less common (5% of NK-AML). A recent study showed that OS benefit of CEBPA mutation is limited to patients with double mutations. This study showed the 8-year OS rates of 54%, 31%, and 34% in double mutation of CEBPA, single mutated CEBPA, and wild type CEBPA respectively.

TABLE 27-4

AML Risk Status by NCCN

Risk status	Cytogenetics	Molecular abnormalities
Better-risk	inv(16) or t(16;16) t(8;21) t(15;17)	Normal cytogenetics with NPM1 mutation in the absence of FLT3-ITD or isolated biallelic CEBPA mutation
Intermediate-risk	Normal cytogenetics +8 alone t(9;11)	t(8;21, inv(16), and t(16;16) with c-KIT mutation
Poor-risk	Complex cytogenetics (>3 clonal chromosomal abnormalities −5, 5q−, −7, 7q− 11q23—non t(9;11) inv(3), t(3;3) t(6;9) t(9;22)	Normal cytogenetics with FLT3-ITD mutation

       C-Kit mutation is another molecular abnormality with significant prognostic impact in AML with t(8;21) and AML with inv(16). The main mutation clusters are in exon 17 and exon 8. C-kit mutations are seen in approximately 20% to 30% of patients with CBF-AML. In good-risk CBF-AML, c-kit mutation increases the risk of relapse and decreases OS, especially in patients with t(8;21). According to current NCCN guidelines, CBF-AML with c-kit mutation is considered intermediate-risk AML.

       For more than 20 years, standard remission induction chemotherapy for AML has included treatment with cytarabine (cytosine arabinoside, ara-C) and an anthracycline. The most common regimen combines 7 days of continuous infusion cytarabine (100 to 200 mg/m²/day) with 3 days of daunorubicin or idarubicin (7 + 3; Table 27-5). A bone marrow examination is repeated 14 to 21 days after starting treatment, and patients with bone marrow cellularity 20% or greater and more than 5% blasts are considered to have residual disease. Patients with persistent disease may achieve a remission after a second, usually abbreviated, course of cytarabine and anthracycline (5 + 2). Sixty percent to 70% of patients achieve a CR after standard induction chemotherapy, with neutrophil (ANC more than 500/μL) and platelet (more than 20,000/μL) recovery occurring an average of 21 to 25 days after the start of therapy. Failure to achieve CR with induction chemotherapy can result from resistant leukemia or early death. Therapy-related mortality increases with age, poor performance status, and underlying organ dysfunction and can be as high as 30% to 40% in elderly patients. Resistant leukemia is associated with a preceding hematologic disorder and adverse cytogenetics, both of which are found more commonly in elderly patients.

TABLE 27-5

Acute Myelogenous Leukemia Chemotherapeutic Regimens

7 and 3 chemotherapeutic regimen for newly diagnosed AML^a

Ara-C, 100 mg/m²/day, as a continuous infusion for 7 days

Idarubicin 12 mg/m²/day or Daunorubicin, 45–90 mg/m²/day × 3 on days 1, 2, 3 of ara-C

Administration of additional chemotherapy: Perform bone marrow on day 14 of chemotherapy; if cellularity is >20% and blasts are >5%, administer second cycle of chemotherapy (5 and 2): same doses as above with 5 days of ara-C and 2 days of daunorubicin

High-dose ara-C consolidation regimen^b

Cytosine arabinoside: 3.0 g/m² in 500-mL D5W infused i.v. over 3-h period every 12 h twice daily, days 1, 3, 5 (total, six doses)

Before each dose, patients must be evaluated for cerebellar dysfunction; if present, stop drug and do not resume; one way to monitor cerebellar function is to have patients sign name on sheet of paper before each dose; for significant change in signature, physician should evaluate patient before any further therapy is given

To avoid chemical keratitis, administer dexamethasone eye drops, 0.1% 2 drops OU q6h starting 1 h before first dose and continued until 48 h after last dose

APL regimens^c

ATRA+ATO regimen:

Remission induction: Daily ATO (0.15 mg/kg) IV, plus oral ATRA (45 mg/m²) until morphologic CR or for a maximum of 60 days

Consolidation therapy: ATO(0.15 mg/kg) IV, 5 days per week, 4 weeks on 4 weeks off, for a total of 4 courses, and ATRA (45 mg/m²) daily 2 weeks on and 2 weeks off for a total of 7 courses

ATRA+Chemotherapy:

Remission induction: IV idarubicin (12 mg/m²/day) on days 2, 4, 6, and 8 plus daily oral ATRA (45 mg/m²) until morphologic CR or for a maximum of 60 days

Consolidation therapy: 3 consolidation courses consisting of idarubicin 5 mg/m²/day on days 1–4 (first cycle), mitoxantrone 10 mg/m²/day on days 1–5 (second cycle), and idarubicin 12 mg/m² on day 1 (third cycle). Additionally, ATRA 45 mg/m²/day is given simultaneously with chemotherapy from day 1 to day 15 during each consolidation cycle

Maintenance therapy: 2-year maintenance therapy with oral 6-mercaptopurine 50 mg/m²/day, intramuscular methotrexate 15 mg/m²/week alternating with ATRA 45 mg/m²/day given for 15 days every 3 months

AML, acute myelogenous leukemia; ara-C, cytosine arabinoside.

^aFrom Bloomfield CD, James GW, Gottlieb A, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981;58:1203–1212, and Bob L, Gert JO, Wim van P, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–1248, with permission.

^bFrom Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896, with permission.

^cFrom Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–121, with permission.

       Patients will invariably relapse if they do not receive additional therapy after achieving CR. In contrast, postremission treatment can result in a cure rate of up to 40%. Commonly used consolidation strategies include high-dose cytarabine (HDAC) or allogeneic stem cell transplantation. HDAC (Table 27-4) can overcome resistance to conventional doses of the drug, producing CR in approximately 40% of patients with resistant leukemia. On this basis, trials of HDAC consolidation for AML in first CR (CR1) were carried out. The value of HDAC consolidation was demonstrated in a CALGB trial, which randomized 596 patients in CR1 to consolidation with four cycles of conventional-dose (100 mg/m²/day × 5 days), intermediate-dose (400 mg/m²/day × 5 days), or high-dose (3.0 g/m², total of six doses over 5 days) cytarabine. Among patients less than or equal to 60 years old, 4-year progression-free survival was 44% for HDAC consolidation versus 24% for conventional-dose cytarabine. Patients older than 60 did poorly regardless of the type of consolidation they received, with fewer than 20% achieving durable remission. The subgroup analysis of this trial underlines the critical role of cytogenetics for predicting the outcome of consolidation therapy for AML. The estimated likelihood of cure among patients with favorable cytogenetics (t[8;21] and inv16) who received HDAC was 84% versus less than 25% for patients with unfavorable cytogenetics.

       HDAC can produce significant neurotoxicity, primarily cerebellar dysfunction and, less commonly, somnolence or confusion. Cerebellar function should be assessed before each dose, and the drug should be stopped if there is evidence of neurotoxicity. A sensitive way to assess cerebellar function is to ask the patient to sign his or her name on a signature record before each dose. Another unique toxicity of HDAC is keratitis, which can be prevented by administration of dexamethasone eye drops, 0.1%, two drops to each eye every 6 hours, from the time treatment is started until 48 hours after HDAC ends. Other potential toxicities of HDAC include an erythematous rash, often worse on the palms and soles, and hepatic dysfunction.

       Several trials have examined the role of consolidation with allogeneic transplantation for patients younger than 55 to 60 years with AML in CR1. In these studies, transplantation was associated with improved leukemia-free survival compared with chemotherapy. However, the studies did not consistently show improvement in OS, probably because transplantation is associated with higher treatment-related mortality and because some patients who relapse after consolidation chemotherapy can be salvaged with transplantation. These trials also found that cytogenetic risk group was the major determinant of survival, regardless of whether consolidation was with chemotherapy or transplantation.

       The available data from clinical trials allow therapeutic recommendations to be made for some groups. Because 60% to 70% of patients with AML and favorable risk achieve 3-year survival with intensive consolidation that includes HDAC, chemotherapy is the treatment of choice for this group. On the other hand, patients with poor risk have a very low disease-free survival with conventional chemotherapy. For these patients, allogeneic transplant in CR1 is the treatment of choice, if a matched sibling or matched unrelated donor (MUD) can be identified. Optimal treatment for patients with intermediate risk is not clear. Consolidative chemotherapy and allogeneic stem cell transplantation are both accepted postremission strategies for intermediate-risk patients.

       When patients with AML relapse after conventional chemotherapy, they generally do so within 3 years. The risk of relapse more than 5 years after diagnosis is 5% or less. For patients with relapsed AML and for those who do not achieve CR despite optimal induction chemotherapy, the only treatment option with curative potential is stem cell transplantation. For patients with an HLA-matched donor, allogeneic transplant is the treatment of choice among those younger than 60. Recent results with reduced intensity regimens suggest that, in the absence of major medical problems, older patients can safely undergo allogeneic transplant. However, relapse is common, and only 20% to 30% of those transplanted in second CR (CR2) are cured. Disease status at transplant (CR2 vs. relapse) and the presence or absence of graft-versus-host disease are the most important prognostic factors.

       Because outcomes are poor when patients are transplanted with active AML, an attempt is often made to achieve CR before transplant. Salvage chemotherapeutic regimens for relapsed or refractory disease include HDAC ± an anthracycline, etoposide with mitoxantrone, or fludarabine containing regimens. Participation in a clinical trial is strongly recommended.

       Gemtuzumab ozogamicin (Mylotarg), a recombinant, humanized anti-CD33 antibody conjugated to the cytotoxic agent calicheamycin, was approved by FDA in the year 2000 for the treatment of relapsed AML in patients 60 years or older. CD33 is present on leukemic blasts in more than 80% of patients with AML and is also expressed by committed hematopoietic progenitors. When the antibody binds to CD33, calicheamycin is internalized, leading to cell death. Gemtuzumab ozogamicin was removed from the market in 2010 in view of safety concerns raised by a randomized trial.

17.  APL. APL is a distinct clinical and pathologic subtype of AML, characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17. The breakpoint on chromosome 17 disrupts a gene that encodes a nuclear receptor for retinoic acid (RAR-α), and its translocation, most commonly to chromosome 15, results in a fusion protein, PML-RAR-α. Detection of PML-RAR-α is associated with a good prognosis. Indeed, patients with APL who achieve CR have better long-term survival than do other patients with AML. Given its unique response to specific therapy, rapid and accurate diagnosis is crucial. It is now commonly accepted that molecular evidence of the PML/RAR-α rearrangement is the hallmark of this disease, as it may be found in the absence of t(15,17).

       As soon as the diagnosis of APL is entertained, it is critical to identify and manage APL-associated coagulopathy. Five percent to 10% of patients with APL die of hemorrhagic complications during induction chemotherapy, and approximately half these deaths occur within the first week of diagnosis. Consequently, monitoring DIC with twice-daily serum fibrinogen levels and aggressive replacement with cryoprecipitate (5 to 10 units for fibrinogen less than 100 mg/dL) is common clinical practice during the first weeks of treatment of APL. Patients may also require liberal transfusion of fresh frozen plasma. If coagulopathy or bleeding is present, the platelet count should be maintained greater than 30 to 50,000/μL.

       APL is categorized to three risk groups based on white blood count and platelet count: (1) low risk with WBC ≤10,000/μL and platelet count >40,000/μL, (2) intermediate risk with WBC ≤10,000/μL and platelet count <40,000/ μL, and (3) high risk with WBC >10,000/μL. Outcomes of intermediate-risk and low-risk APL are similar when arsenic trioxide (ATO) is used in consolidation treatment; as a result, APL is mainly categorized to high risk with WBC >10,000/μL, and low/intermediate risk with WBC ≤10,000/μL. Treatment of APL has three phases: induction, consolidation, and maintenance. The goal of induction treatment is morphologic CR. Molecular CR (absence of PML/RAR-α in bone marrow by RT-PCR) is the goal of consolidation.

       A distinguishing feature of APL is its sensitivity to ATRA. The advantage of including ATRA in the front-line therapy for APL has now been clearly established in several randomized trials, with CR rates ranging from 72% to 95%, and a 3- to 4-year disease-free survival of 62% to 75%. These studies also found that disease-free survival is improved when ATRA is given concurrently with anthracycline-based chemotherapy. ATRA with an anthracycline, often combined with cytarabine, remains the standard of care for patients with high-risk APL.

       In some studies, cytarabine was omitted inconsequently from induction and/or consolidation regimens. Given the lack of randomized trials, long-term results of these trials are needed to clarify the role cytarabine plays in the management of APL. A recent randomized phase III trial (APL0406) compared ATRA plus arsenic trioxide (ATO) with ATRA plus idarubicin in low/intermediate-risk APL. The investigational arm received ATRA plus ATO daily until morphologic CR followed by consolidation with ATO 5 days a week for 4 weeks every 8 weeks for 4 courses and ATRA daily for 2 weeks every 4 weeks for 7 courses. The control arm received ATRA plus idarubicin induction followed by consolidation with ATRA plus idarubicin followed by maintenance treatment with ATRA and low-dose chemotherapy. The CR rate was 100% in the ATRA plus ATO arm and 95% in the ATRA plus idarubicin arm. Two-year event-free survival rates were 97% in the ATRA plus ATO arm and 86% in the ATRA plus idarubicin arm, confirming noninferiority and maybe superiority of ATRA plus ATO for induction and consolidation in low-/intermediate-risk APL. On the basis of these results, ATRA plus ATO and ATRA plus idarubicin are both acceptable induction regimens for low-/intermediate-risk patients, but ATRA plus ATO is often preferred for its efficacy and tolerability.

       Maintenance is the final phase in APL treatment. Several studies have shown that the addition of maintenance therapy with ATRA and/or chemotherapy after intensive postremission consolidation is associated with improved disease-free and overall survival. However, many questions remain unanswered. There is controversy regarding the benefit of maintenance therapy in APL patients who receive ATO as a part of consolidation and are in molecular CR after consolidation. Additionally, the optimal maintenance regimen is still unknown. In one study, the combination of ATRA (45 mg/m²/day, 15 days every 3 months) with 6-mercaptopurine (90 mg/m²/day, orally) and methotrexate (15 mg/m²/week, orally) was associated with the lowest relapse rates, especially for APL patients with a high WBC. An approach for the treatment of patients with newly diagnosed APL is summarized in the algorithm in Figure 27-1.

       Initial response evaluation to induction treatment should be done by bone marrow aspiration and biopsy upon count recovery (approximately 5 weeks after the start day of induction). Owing to differentiation effects of ATRA, early response evaluation (day 14 bone marrow biopsy) will be misleading. The goal of induction treatment is morphologic CR. Cytogenetic studies are usually normal at this time. PCR for PML/RAR-α is usually positive at this time and is not considered induction failure. Molecular CR (PCR negativity) is the goal of consolidation treatment; therefore, evaluation for molecular CR should be done after at least 2 cycles of consolidation. Patients who have not achieved a molecular remission at the completion of consolidation should receive salvage therapy (discussed in the subsequent text). RT-PCR should be used to monitor for disease relapse, and the emergence of a detectable PML-RARα transcript is reason to consider salvage therapy.

       The two most important factors affecting CR rates and survival in patients with APL are age and the WBC at diagnosis. Age younger than 30 and WBC less than 5,000 to 10,000/μL are favorable prognostic factors. In contrast, several other biologic features such as the type of PML-RARα isoform, additional karyotypic abnormalities, and expression of the reciprocal RARα-PML transcript do not appear to influence outcome. Recent data suggest that the expression of CD56 antigen on promyelocytes is associated with an increased risk of relapse.

       Although ATRA is usually well tolerated, some patients develop a unique complication called retinoic acid syndrome (RAS). RAS occurs usually early after initiation of ATRA (7 to 12 days) and is diagnosed on clinical grounds. It is characterized by unexplained fever (80%), weight gain (50%), respiratory distress (90%), lung infiltrates (80%), pleural (50%) or pericardial effusion (20%), hypotension (10%), and renal failure (40%). RAS is the most serious toxicity of ATRA and is often, but not always, associated with the development of hyperleukocytosis. Its incidence varies from 6% to 25%, and mortality is variable (7% to 27%). The best approach to predict, prevent, or treat this syndrome has not been established. Early institution of corticosteroids (dexamethasone, 10 mg i.v. twice daily) simultaneous with cytoreduction (induction chemotherapy or hydroxyurea) is associated with rapid resolution of the syndrome in most patients. Discontinuation of ATRA is common practice after onset of RAS. RAS has not been observed when ATRA was given as maintenance therapy.

Figure 27-1. Proposed algorithm for patients with newly diagnosed APL (acute promyelocytic leukemia), ATRA, all-trans-retinoic acid.

       Approximately 10% to 25% of patients treated with ATRA-based therapy ultimately relapse. The duration of first CR and the achievement of a second PCR-negative remission after reinduction have been shown to be prognostic determinants. The first choice for salvage therapy is usually ATO. In a U.S. trial, 85% of patients treated with relapsed APL treated with ATO achieved a CR, 91% of whom had a molecular remission. However, most patients will relapse without additional therapy, which may include additional course of ATO, chemotherapy, and/or autologous or allogeneic stem cell transplantation. Toxicities of ATO include QT prolongation, which rarely may lead to torsades de pointes, and APL differentiation syndrome, which is similar to RAS.

       Patients with APL who undergo autologous stem cell transplantation while in second remission have a 30% 7-year leukemia-free survival. However, after stratification according to PCR status of the grafted marrow, it appears that patients transplanted with PML-RARα–negative marrow cells are more likely to have prolonged clinical and molecular remissions. In contrast, relapse after autologous transplant is inevitable in patients with persistently positive PCR after reinduction and consolidation therapy. Allogeneic stem cell transplantation may be the preferable treatment modality in this setting.

1.  ALL. For ALL, clinically meaningful subtypes are defined by immunophenotype (B-progenitor, B cell, and T cell) as determined by flow cytometry. As for AML, cytogenetics is of critical prognostic and therapeutic value. Translocation between chromosomes 12 and 21 (TEL-AML, t[12;21]), found in 25% of pediatric ALL but rarely in adult ALL, is associated with a good prognosis. Cytogenetics associated with a poor prognosis include abnormalities of 11q23 (mixed lineage leukemia [MLL]) and presence of the Ph chromosome (BCR-ABL, t[9;22]).

       Accurate subtyping of ALL is essential for appropriate treatment. Approximately 70% to 75% of patients have B-precursor, 20% to 25% have T-cell, and approximately 5% have mature B-cell ALL. Mature B-cell ALLexpresses surface-membrane immunoglobulin and is characterized by the t(8;14), which results in fusion of the myc oncogene with part of the immunoglobulin heavy-chain gene. Variant translocations involve mycand light-chain genes (t[2;8], t[8;22]). Mature B-cell ALL is the leukemic equivalent of Burkitt’s lymphoma and is arbitrarily defined by the presence of more than 20% blasts in the bone marrow. B-cell ALL/Burkitt is a rapidly proliferating neoplasm, and treatment is often complicated by TLS. Treatment for mature B-cell ALL differs from that for other types of ALL in that intensive chemotherapy is given over a relatively short period (2 to 8 months) without maintenance chemotherapy. Important components of this therapy include high total doses of cyclophosphamide and/or ifosfamide given in fractions over several days along with HDAC and high-dose methotrexate. Addition of the anti-CD20 monoclonal antibody rituximab to the chemotherapeutic regimen appears to improve CR rate and disease-free survival. Intrathecal chemotherapy is included in the therapy of mature B-cell ALL, because without adequate prophylaxis, CNS relapse is common. With an aggressive combination of chemotherapy and intrathecal therapy, 50% to 70% of patients achieve long-term disease-free survival.

       Treatment of B-progenitor and T-cell ALL in adults was adapted from regimens developed for high-risk childhood ALL. Therapy is comprised of four components: induction, consolidation, and maintenance, as well as CNS prophylaxis. For induction, combinations of vincristine, prednisone or dexamethasone, L-asparaginase, and an anthracycline result in CR rates of 75% to 90%. Inclusion of cyclophosphamide and cytarabine appears to increase CR rate and remission duration, particularly among patients with T-cell ALL. Standard consolidation therapy includes treatment with several cycles of chemotherapy that include agents used during induction, along with antimetabolites such as 6-mercaptopurine and methotrexate. Several trials have examined the role of intensive consolidation including HDAC and high-dose methotrexate. Patients with Ph+ ALL benefit from the incorporation of a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib, into the treatment regimen.

       Whereas CNS relapse is very uncommon in AML, in the absence of CNS prophylaxis, the risk of CNS relapse in ALL exceeds 10%; therefore, consolidation therapy has usually included intrathecal chemotherapy and cranial radiation. However, cranial radiation may be associated with long-term neurologic sequelae including impaired cognition. Recent studies indicate that the combination of intrathecal prophylaxis and CNS-penetrating chemotherapy is associated with a risk of CNS relapse similar to that achieved with intrathecal prophylaxis and cranial radiotherapy.

       For patients with B-progenitor and T-cell ALL, induction and consolidation usually occupy the first 6 months after diagnosis. Patients then go on to receive maintenance chemotherapy. The most commonly used regimen includes daily oral 6-mercaptopurine, weekly oral methotrexate, a single intravenous dose of vincristine monthly, and 5 days of prednisone/month. Maintenance therapy is continued until 24 to 36 months after diagnosis. With this approach, the likelihood of 5-year disease-free survival is approximately 25% to 50%.

       In addition to the importance of cytogenetics in determining the outcome of ALL, presenting white count and age have independent prognostic significance in multivariate models. Another important factor is the rate of clearance of blast cells; patients who achieve CR rapidly are more likely to achieve durable remission. On the basis of data from CALGB, adult B-progenitor and T-cell ALL can be divided into three prognostic groups. Good-risk patients are characterized by all of the following: absence of adverse cytogenetics; age less than 35; presenting WBC less than 30,000/μL; and remission achieved within 4 weeks of diagnosis. These patients have a 50% to 75% likelihood of 3-year disease-free survival with chemotherapy, so that transplant is reserved for relapse. Poor-risk patients are characterized by any of the following: adverse cytogenetics (particularly t[9;22]); for B progenitor, presenting WBC greater than 100,000/μL; more than 4 weeks to achieve CR; and age older than 60. For these patients, 3-year disease-free survival is 0% to 20% with conventional chemotherapy, so that allogeneic transplant is the treatment of choice for patients younger than 60 with histocompatible donors. Older patients may be candidates for allogeneic transplant if they are in good health. Although no randomized trial has been done to evaluate the effect of TKI maintenance after stem cell transplantation for Ph+ ALL, several small studies suggest maintenance TKI results in a better DFS and OS in Ph+ ALL. The remaining intermediate-risk patients represent approximately one-third of all cases of ALL and primarily include patients younger than 60 with B-progenitor ALL. For these patients, chemotherapy is the treatment of choice, because transplantation has not been proven to improve survival.

       Most adult patients with ALL will experience disease relapse. Reinduction is most successful if the patient has been in CR for more than 1 year before relapse. Salvage chemotherapeutic regimens can include HDAC, etoposide, or alkylating agents. The araguanosine analog nelarabine is active in relapsed T-cell ALL. As for patients with relapsed AML, allogeneic stem cell transplantation is the only potentially curative therapy for patients with relapsed ALL, and eligible patients who achieve a second remission should proceed as quickly as possible to transplantation.

       Over the last several years, there have been significant advances in immunotherapy for ALL. The majority of ALLs are pre-B ALL with more than 90%, 80%, and 50% expressing CD19, CD22, and CD20 respectively. Immunotherapy for ALL can be classified to four categories: (1) naked antibody, (2) Bispecific T cell engagers (BiTE), (3) chimeric antigen receptor (CAR)–based T cell therapy, and (4) immunotoxins. Several studies have shown that adding rituximab to induction and consolidation of CD20+ pre-B ALL improve DFS and OS. Rituximab is currently being evaluated in a randomized trial for patients with Philadelphia chromosome negative CD20+ ALL. The investigational agent blinatumomab, a CD19 BiTE (Bispecific T cell Engagers), is one of the most promising new treatments for ALL. It has demonstrated activity in elimination of minimal residual disease and high rate of CRs in patients with relapsed ALL. CD19 CAR (Chimeric Antigen Receptor)–based immunotherapy is another emerging treatment for ALL. Several early phase studies have shown promising results. Several studies using CD19 immunotoxin are in early phase of development.

1.  CNS involvement with acute leukemia. Patients with acute leukemia who develop neurologic symptoms or signs should be evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) of the head and, in the absence of a mass lesion, proceed to lumbar puncture. Cerebrospinal fluid (CSF) should be sent for glucose, protein, routine cultures, Gram’s stain, cryptococcal antigen, cell count with differential, and cytology. In the absence of contamination with peripheral blood, patients with blasts in the CSF should receive intrathecal chemotherapy, preferably through an Ommaya reservoir. Cranial radiotherapy can also be considered. Intrathecal therapy may include methotrexate, 12 to 15 mg, or cytarabine, 50 to 100 mg. Drugs must be preservative-free and sterile. Cytology and cell count with cytospin differential should be repeated with each intrathecal treatment until blasts have cleared. Intrathecal therapy is given twice weekly until blasts have cleared and then monthly for 6 to 12 months.

       The sudden onset of unexplained cranial nerve palsy in a patient with acute leukemia is usually due to CNS leukemia, regardless of whether the CSF shows blasts. Such patients should be treated as described above. Because isolated CNS relapse of leukemia is generally followed soon thereafter by systemic relapse, salvage chemotherapy followed by allogeneic transplant should be considered if patients relapse with CNS involvement.

 IV. COMPLICATIONS AND SUPPORTIVE CARE

8.  Transfusions. Essentially all adults with acute leukemia will require support with multiple platelet and red cell transfusions. In the absence of bleeding, platelet transfusions can safely be withheld until the platelet count is less than or equal to 10,000/μL. Patients who are bleeding or need a surgical procedure should have their platelet count maintained at greater than 50,000/μL (greater than 100,000/μL for CNS bleeding). Menstruation should be suppressed to reduce uterine blood loss. The threshold for routine transfusion of red blood cells may vary from patient to patient. The policy at Washington University is to transfuse blood to maintain hemoglobin at greater than 8.0 g/dL. However, younger patients may tolerate lower levels, whereas older patients and those who are critically ill may require a higher threshold value for red cell transfusion. Hypofibrinogenemia, usually the result of DIC or treatment with L-asparaginase, should be treated with cryoprecipitate when the fibrinogen decreases to less than 100 mg/dL. All blood products must be irradiated (2,850 cGy), in order to prevent transfusion-related graft-versus-host disease.

       Poor response to platelet transfusions may occur when leukocyte contamination of blood products results in alloimmunization. Platelet refractoriness can be reduced by transfusing leukoreduced products and minimizing the number of transfusions a patient receives. Patients with poor increments to platelet transfusions may respond to HLA-matched products. Family members are a potential source of HLA-matched products, although the use of products from related donors may increase the risk of rejecting a subsequent sibling-donor allogeneic stem cell transplant.

       An effort should be made to prevent transfusion-related infection with cytomegalovirus (CMV) in any patient who is a potential candidate for allogeneic transplant, as reactivation of CMV after allogeneic transplant can result in life-threatening or fatal disease. To this end, CMV-seronegative patients should receive products that have been collected from seronegative donors. If such products are not available, then the risk of CMV transmission may be reduced by leukoreduction of platelet products. Patients who are CMV seropositive may receive blood products from seropositive or seronegative donors.

1.  Infection. Infection is a major cause of death in patients with acute leukemia. These patients are at high risk for infection primarily due to prolonged periods of neutropenia. In addition, indwelling catheters and compromised mucosal barriers (mucositis or enteritis from chemotherapy) provide portals of entry for infectious agents. Because most infections arise from the patient’s own microbial flora, rigorous isolation procedures are not necessary. However, good hand washing is always important, and patients should wear a mask when in crowds. Food-borne infection is very uncommon, and it is reasonable to prohibit only consumption of uncooked meat.

       Antimicrobial prophylaxis during periods of neutropenia and/or immunosuppression can reduce the incidence of some viral, fungal, and bacterial infections. Acyclovir (400 PO t.i.d. or 125 mg/m² i.v. b.i.d.) is recommended for patients with a history of cold sores or herpes simplex seropositivity. Patients with ALL are treated with a long course of steroids and are therefore at risk for Pneumocystis pneumonia. They should receive Pneumocystisprophylaxis with either trimethoprim/sulfamethoxazole 1 double strength (DS) b.i.d. 2 days/week, dapsone 100 mg daily, or aerosolized pentamidine, 300 mg monthly. During periods of neutropenia or prolonged steroid use, nystatin (15 mL, swish and swallow 5 times a day) or clotrimazole troche (5 times daily) can reduce oral candidiasis. The use of other antibiotics for infection prophylaxis is controversial. Oral fluoroquinolones reduce the risk of infection with gram-negative organisms, but they are associated with an increased risk of gram-positive bacteremia and fluoroquinolone-resistant Pseudomonas aeruginosa. Because prophylaxis with systemic antifungals has not been shown to reduce the risk of treatment-related mortality, their routine use during induction chemotherapy is not recommended.

       Fever greater than 38.3°C in a neutropenic patient (ANC less than 500/μL) requires prompt evaluation and treatment, as bacterial infections can become rapidly life-threatening. Blood and urine should be cultured, and empiric broad-spectrum antibiotics (cefepime or ceftazidime, 1 g i.v.) should be administered. Vancomycin should be added for the following indications: severe mucositis, evidence of a catheter-related infection, fever equal to or greater than 40°C, hypotension, or known colonization with resistant streptococci or staphylococci. Patients with allergy to β-lactams may receive aztreonam or a fluoroquinolone with vancomycin. Febrile patients with hypotension or respiratory distress should receive at least one dose of an aminoglycoside antibiotic (gentamicin 5 mg/kg i.v.). When fevers and neutropenia persist for more than 3 days and no source of infection has been identified, empiric antifungal coverage can be added (caspofungin 70 mg i.v. loading dose × 1 then 50 mg i.v. qd or fluconazole 400 mg i.v. qd). Febrile patients with newly diagnosed or relapsed acute leukemia should receive empiric broad-spectrum antibiotics whether or not they are neutropenic.

       Once antibiotics are begun, they are continued until neutrophil recovery (ANC greater than 500/μL), even if fever resolves. Otherwise, the choice and duration of antimicrobial therapy is dictated by the source of infection. Bacteremia is treated with a 10- to 14-day course of antibiotics. Indwelling catheters should be removed for fungemia, persistent bacteremia, or Staphylococcus aureus or Pseudomonas bacteremia. Patients with a history of Aspergillus or Mucor sp. infection should receive prolonged antifungal therapy, especially if profound neutropenia is likely during subsequent courses of chemotherapy.

       Typhlitis (neutropenic enterocolitis) is a syndrome of right-sided colonic inflammation in neutropenic patients. It presents with fever, abdominal pain, and tenderness that can mimic appendicitis. The etiology is unclear. Treatment is with broad-spectrum antibiotics, including anaerobic coverage, and nasogastric suction. Surgical intervention is reserved for patients with bowel perforation or suspected bowel necrosis.

1.  Growth factors. The use of myeloid growth factors in acute leukemia remains controversial despite multiple randomized trials. Treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF) after induction chemotherapy shortens the duration of ANC less than 500/μL by 3 to 6 days. The duration of hospitalization and antibiotic use are also shortened by treatment with growth factors. Although the effectiveness of chemotherapy is not compromised by the use of these agents, most evidence indicates that growth factors do not improve the likelihood of CR or long-term survival. Often, growth factors are reserved for older patients or for those with life-threatening infection.
2.  Intravenous access. All patients with acute leukemia should have a central venous catheter placed. Temporary catheters, such as the Hohn catheter, are usually chosen because fever, coagulopathy, or poor increments with platelet transfusion represent relative contraindications to placement of a more permanent, tunneled catheter.
3.  Tumor lysis syndrome. TLS (see Chapter 35) is a complication of rapid tumor breakdown after chemotherapy. Clinically, it is marked by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute oliguric renal failure. Risk factors for TLS include B-cell ALL, WBC greater than 50,000/μL, LDH greater than 1,000 IU/L, renal dysfunction, and elevation of the uric acid or phosphorus before treatment. All patients with newly diagnosed acute leukemia should be vigorously hydrated to maintain urine output at more than 2.5 L/day, and volume status should be closely monitored. If the patient’s renal function is normal, allopurinol, 600 mg, is given the day before chemotherapy, followed by 300 mg daily until the WBC is less than 1,000/μL. If the pretreatment uric acid is more than 9 mg/dL, rasburicase can be used in place of allopurinol to reduce the uric acid level rapidly. Patients at high risk for TLS should have electrolytes, calcium, magnesium, and phosphorus monitored two to three times daily for the first 2 to 3 days of induction chemotherapy.
4. FOLLOW-UP. Patients who are in a CR after induction and consolidation therapy require close follow-up. The highest risk of relapse of acute leukemia is within the first 3 years of completion of treatment. During that time, patients should be evaluated with history, physical examination, and complete blood count (CBC) every 2 to 3 months. Bone marrow biopsy should be repeated routinely every 3 to 6 months, or if the blood counts fall or blasts are observed in the peripheral blood. Because patients may have disease relapse at extramedullary sites, suspicious skin or soft tissue lesions should be biopsied to rule out granulocytic sarcoma, and new neurologic deficits should be evaluated by brain imaging and lumbar puncture to rule out CNS leukemia. Molecular monitoring of APL (i.e., RT-PCR for PML-RARα) should be performed every 2 to 3 months for 3 years’ postconsolidation for patients at high risk of relapse, particularly those with a presenting WBC of more than 10,000/αL. Relapse of acute leukemia is very uncommon after approximately 5 years, and follow-up can become less frequent after that.

 VI. EPIDEMIOLOGY AND RISK FACTORS. Approximately 13,000 new cases of acute leukemia are diagnosed in the United States each year. The annual incidence of AML is approximately 3.5 per 100,000 and of ALL is approximately 1.5 per 100,000 persons. Although acute leukemia represents only 5% of all new cancer cases, acute leukemia is the most common cause of cancer death for persons younger than 35 years. ALL has a bimodal age distribution. Most cases occur in childhood, with a peak incidence at approximately age 5 years, and there is a second increase in incidence after 60 years of age. The incidence of AML increases steeply beyond 50 years, and the median age is approximately 65 years.

     Fewer than 5% of cases of acute leukemia can be attributed to prior exposure to a leukemogenic agent. Ionizing radiation and benzene are clearly associated with an increased risk of acute AML, with an average latency of approximately 5 years. Two classes of chemotherapeutic agents are associated with an increased risk of acute leukemia (secondary leukemia). Alkylating agents can cause AML approximately 4 to 8 years after exposure. AML that arises in this setting is often associated with a preceding MDS and adverse cytogenetics, particularly abnormalities of chromosomes 5 and 7. Topoisomerase II inhibitors such as etoposide or anthracyclines are associated with AML or mixed lineage leukemia (MLL) with a short (1- to 2-year) latency without a preceding hematologic disorder. The most common cytogenetic abnormalities associated with topoisomerase II inhibitors involve the MLL gene at 11q23. Given the poor prognosis of treatment-related leukemia, allogeneic transplantation in first complete remission (CR) should be considered if a donor is available.

     Rare families with a genetic predisposition to acute leukemia have been described, but in the vast majority of cases, there is no clear hereditary risk. However, acute leukemia does occur more frequently in family members than would be expected by chance. Full siblings have an approximately twofold increase in risk, and the concordance rate of infantile leukemias in identical twins has been reported to be as high as 25%. The only infectious agent associated with acute leukemia is human T-lymphocyte leukemia virus (HTLV)-1, which causes T-cell adult leukemia/lymphoma. Congenital disorders that have an increased risk of acute leukemia include Down syndrome, disorders associated with increased chromosomal fragility (Bloom’s syndrome and Fanconi’s anemia), and those associated with immunodeficiency (X-linked agammaglobulinemia and ataxia telangiectasia).

 VII. FUTURE DIRECTIONS

1.  Monitoring of minimal residual disease. After remission induction, most patients with acute leukemia receive several additional courses of aggressive chemotherapy with the goal of eliminating subclinical leukemia. A sensitive and specific technique for detection of minimal residual disease (MRD) could provide important prognostic information, allowing for rational treatment decisions. As discussed earlier, detection of MRD has already an important role in the therapy of APL: detection of the PML-RARα fusion transcript after consolidation therapy identifies patients at high risk for clinical relapse. Monitoring MRD in other AML subtypes is difficult because molecular rearrangements amenable to PCR have been found in a relatively small proportion of patients. Mutlicolor flow cytometry can be used to detect abnormal leukemic immunophenotypes. Monitoring MRD in ALL is facilitated by the presence of clonotypic T cell–receptor gene or immunoglobulin heavy-chain gene rearrangement. Also, BCR-ABL can be followed in patients with Ph+ ALL. However, the role of MRD monitoring and the necessity of obtaining an MRD negative status remain to be defined for AML and ALL.
2.  Identification of molecular prognostic factors. Although cytogenetics have proved to be extremely valuable for the risk stratification of patients with acute leukemia, there remain a significant proportion of patients who fall into the “intermediate” or indeterminant group. Molecular markers in addition to FLT3-ITD, NPM1, and CEBPA mutations are being sought to distinguish which intermediate-risk patients would benefit from more aggressive therapy such as stem cell transplantation. Mutations in IDH1/IDH2 and DNMT3A can be found in approximately 15% and 30% of NK-AML respectively. The prognostic importance of these mutations requires further studies. Gene expression profiling using microarray technology and whole genome/exome sequencing may better classify patients into risk groups, as well as identify new therapeutic targets.
3.  New therapies. Given the high rate of relapsed and resistant disease among adults with acute leukemias, the need for new, effective therapies is significant. Newer drugs for the treatment of relapsed acute leukemia include clofarabine, a purine nucleoside with activity in both AML and ALL and the araguanosine analog nelarabine, which is active in relapsed T-cell ALL. Imatinib and other inhibitors of the BCR-ABL tyrosine kinase have activity in Ph+ ALL and are being investigated as part of upfront therapy or for treatment of relapsed disease. Promising agents for the treatment of AML include the hypomethylating agents azacitidine and decitabine, histone deacetylase inhibitors, farnesyl transferase inhibitors, FLT3 inhibitors, and the immunomodulatory drug lenalidomide. Many of these new agents are being investigated for the treatment of elderly AML patients, for whom current therapies are particularly toxic and generally ineffective. BiTE- and CAR-based immunotherapy may change the ALL treatment paradigm profoundly.

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