Acute Leukemias in Adults

Acute Leukemias in Adults Jonathan E. Kolitz, MD The acute leukemias are clonal hematopoietic neoplasms that cause death by usurping the bone marrow’s ability to produce normal blood elements. The replacement of marrow by primitive progenitor cells (blasts) leads to infection from neutropenia, bleeding from thrombocytopenia and coagulopathies, and anemia. The two major subtypes of acute leukemia are acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). ALL is the predominant acute leukemia of childhood, and the incidence of AML increases with age. AML may be associated with antecedent hematologic disorders, such as the myeloproliferative disorders and the myelodysplastic syndrome (MDS). Such cases of AML, along with those associated with prior exposure to chemotherapy or radiation, are associated with especially poor outcomes.

Diagnosis Once acute leukemia is suspected, diagnostic measures must be rapidly undertaken (Table 1). Readily available in most centers are tools that can categorize the acute leukemia in preparation for specific therapy. In addition to morphology, flow cytometry can rapidly establish a diagnosis of acute leukemia by applying combinations of monoclonal antibody stains directed at antigens known as cluster designation (CD) groups. A panel of 10 or more antigens is generally studied to properly assign lineage. Acute leukemia with minimal expression of lineage-specific antigens may be difficult to categorize. In addition, an occasional leukemia expresses antigens common to more than one lineage (biphenotypic leukemia) or even manifests as two distinct clonal processes. Most often, the combination of morphologic review and the application of the tests outlined in Table 1 satisfactorily establish a diagnosis. Cytogenetics has become an essential tool both for categorizing leukemias and for establishing prognosis and detecting minimal This article was published in: Rakel RE, Bope ET. Conn’s Current Therapy 2008. Section 6. Acute Leukemias in Adults, p. 441-446. © 2008 Elsevier Inc. Dis Mon 2008;54:226-241 0011-5029/2008 $34.00 ⫹ 0 doi:10.1016/j.disamonth.2007.12.004 226

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Table 1. Diagnostic Tests in Acute Leukemia Test Complete blood count and differential DIC screen Chemistry profile, including uric acid, phosphorus, LDH HLA typing

Bone marrow aspirate

Bone marrow biopsy Immunohistochemistry

Flow cytometry FISH Cytogenetics

PCR

Comment Especially in APL, monocytic leukemias

Irrespective of transplantation intent, to identify compatible platelets units if needed Dry tap can occur in extensively infiltrated (packed) marrow or in the presence of fibrosis Permits determination of cellularity, immunophenotyping Chemical stains for lineage, monoclonal antibody stains for specific antigens on paraffin sections from biopsy Stain blasts with monoclonal antibodies directed at lineage-specific antigens Rapidly diagnoses suspected subtypes of acute leukemia, especially APL Analyzes metaphases for numeric and structural changes in banded chromosomes Sensitive technique to measure minimal residual disease. Sensitivity is 1 in 104 to 106 leukemic cells.

Abbreviations: APL, acute promyelocytic leukemia; DIC, disseminated intravascular coagulation; FISH, fluorescence-in-situ-hybridization; HLA, human leukocyte antigen; LDH, lactate dehydrogenase; PCR, polymerase chain reaction.

residual disease (MRD), the remnant of leukemia that is almost invariably subclinically present when a patient is clinically in complete remission (CR). The eradication of MRD is a principal goal of leukemia therapy.

Classification The categorization of acute leukemia has shifted from the original French–American–British (FAB) classification system, which was based on morphology, to the World Health Organization (WHO) classification scheme (Table 2). The WHO system recognizes the original FAB categories but specifies wherever possible subtypes that have distinct clinical and cytogenetic features. It is hoped that as the molecular understanding of acute leukemia evolves, subsets will be shifted from the original FAB to an expanded WHO classification. DM, April 2008

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Table 2. World Health Organization classification of the acute leukemias Acute Myeloid Leukemias ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

With recurrent genetic abnormalities AML with t(8;21) (AML-1-ETO) AML with abnormal marrow eosinophils AML with inv(16)(p13q22) or t(16;16)(p13q22) (CBFb-MYH11) [FAB M4Eo] Acute promyelocytic leukemia: AML with t(15;17)(q22q12) (PML-RARa) [FAB M3] AML with MLL (11q23) abnormalities With multilineage dysplasia With or without antecedent myelodysplastic or myeloproliferative disorder Therapy-related Alkylating agent related Topoisomerase II inhibitor related Other types Not otherwise categorized AML, minimally differentiated [FAB M0] AML without maturation [FAB M1] AML with maturation [FAB M2] Acute myelomonocytic leukemia [FAB M4] Acute monoblastic and monocytic leukemias [FAB M5] Acute erythroid leukemia [FAB M6] Acute megakaryoblastic leukemia [FAB M7] Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma

Acute Leukemias of Ambiguous Lineage ● Undifferentiated acute leukemia ● Bilineal acute leukemia ● Biphenotypic acute leukemia Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma ● Precursor B ALL ● Precursor T ALL Note: FAB classifications are given in square brackets following some classifications. Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ETO, ETO (eight twenty-one) gene; FAB, French–American–British classification system; MLL, mixed lineage leukemia.

Prognostic Factors The prognosis of patients with acute leukemia depends on multiple variables. Outcomes of patients with acute leukemia are strongly influenced by the cytogenetic abnormalities present at diagnosis. Important prognostic factors are outlined in Table 3. Listed in Table 3 are several recently identified gene mutations that have been associated with distinct outcomes in the 50% or so of patients with AML who have a normal karyotype, a group regarded as a whole to have an intermediate prognosis. 228

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Table 3. Prognostic factors in acute leukemia Favorable Acute Myeloid Leukemia ● Age ⬍60 years ● t(15;17), t(8;21), inv(16), t(16;16), t(8;21) ● De novo disease ● Nucleophosmin gene mutation* ● CCAAT/enhancer binding protein mutation* Acute Lymphoblastic Leukemia ● Age 2-10 years ● Hyperdiploidy ● Early blast clearance with chemotherapy ● Mature B cell (Burkitt=s leukemia) or T cell phenotype ● WBC ⬍30,000/␮L ● t(12;21) Unfavorable Acute Myeloid Leukemia ● Age ⬎70 years ● Chromosome 7 abnormalities, complex karyotypes, t(6;9); inv(3); t(3;3) ● Multidrug resistance gene expression ● WBC ⬎100,000/␮L ● Fms-like tyrosine kinase (flt3) mutation ● Brain and leukemia cytoplasmic (BAALC) gene mutation* ● ETS-related gene (ERG) mutation* ● Antecedent MDS or myeloproliferative disorder ● Therapy-related AML Acute Lymphoblastic Leukemia ● Age ⬍2 or ⬎10 years ● t(9;22); t(4;11); ⫺7; ?8 ● Pro-B (very early B lineage) phenotype ● Hypodiploidy ● WBC ⬎30,000/␮lL ● Time to CR ⬎4-5 weeks ● MLL gene mutation Abbreviations: AML, acute myeloid leukemia; CR, complete remission; MDS, myelodysplastic syndrome; MLL, mixed lineage leukemia; WBC, white blood cell. *Among the approximately 50% of patients with AML and normal cytogenetics.

Treatment Acute Myeloid Leukemia The therapy of acute leukemia is divided into sequential components. For both AML and ALL, induction therapy involves a period of intensive antileukemic therapy generally given in an inpatient hospital setting. DM, April 2008

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Typically, a central venous catheter is placed to ensure the venous access needed for the chemotherapy and vigorous antibiotic and blood product support required during the period of severe myelosuppression. Induction. The backbone of induction chemotherapy for AML consists of a combination of 3 days of an anthracycline given by short IV bolus with a 7-day continuous IV (CIV) infusion of cytarabine (Ara-C, Cytosar-U) 100-200 mg/m2/day (3- and 7-day regimens). Anthracyclines include daunorubicin (cerubidine) given at doses between 45 and 90 mg/m2, idarubicin (Idamycin) 12 mg/m2, and mitoxantrone (Novantrone) 12 mg/m2, each given daily for 3 days. There are no conclusive data showing that the choice of anthracycline is fundamentally important. Randomized trials have not compared pharmacologically and pharmacodynamically equivalent doses of these agents. An ongoing randomized trial will help clarify if daunorubicin 45 mg/m2 given daily for 3 days differs from twice that dose given in the same manner, both combined with infusional cytarabine, in untreated patients with AML. Increasing the cytarabine infusional dose from 100 mg/m2 to twice that dose has not improved outcomes. Neither has extending the 7-day cytarabine infusion to 10 days. Escalating the dose of cytarabine to 3000 mg/m2 (High-Dose Ara-C, or HiDAC) has not increased the incidence of CR when given during induction. Typical schedules of high-dose cytarabine entail once- or twice-daily administration for 5 or 6 days. A phase III trial suggested that, even in the absence of improvements in CR, high-dose cytarabine given during induction improved relapse-free survival. Similar data exist for the use of etoposide1 (VePesid) during induction, an important third class (epidophyllotoxins) of drugs active against acute leukemia, when given at a dose of 75 mg/m2 IV daily for 7 days. High-dose cytarabine or etoposide has been used by clinicians during induction but is not considered standard of care at this time, particularly in the elderly. Typically, in patients undergoing induction, a bone marrow aspirate and biopsy are done 14 days after starting therapy. Residual leukemia is then treated with a second course of therapy using an abbreviated schedule of the original induction. Therapy may be changed and intensified at that time in select younger patients with minimal evidence of an antileukemic effect, often including high-dose cytarabine. About 60% to 80% of younger patients with previously untreated, de novo AML achieve CR, most with one course of induction therapy. Therapy-related mortality is between 5% and 10%, with deaths occurring 1

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most often as a result of sepsis or hemorrhage, with or without the accompaniment of resistant leukemia. Consolidation. Once CR is attained, it is essential for the younger patient to move on to intensive treatments aimed at eradicating MRD. By the time a morphologic CR is attained, the total body leukemic cell burden may have fallen only 3 logs (from 1012 to 109 cells), so substantial further treatment is needed. Patients with very poor risk karyotypes [complex cytogenetics, chromosome 7 or 3 abnormalities, t(6;9), among others] may be best served by allogeneic transplantation (myeloablative chemotherapy followed by infusion of stem cells from an immunologically matched donor) if a suitable human leukocyte antigen (HLA)matched donor can be identified. For most patients, intensive, repeated cycles of chemotherapy are given, usually with high-dose cytarabine alone or a high-dose cytarabinecontaining combination. Older patients in CR often receive one or two courses of consolidation using the less-intensive combination of 2 days of an anthracycline and 5 days of infusional cytarabine (2 and 5 regimen). Repeated courses of high-dose cytarabine especially benefit patients with the favorable cytogenetics of t(8;21), inv(16), and t(16;16), with a cure fraction of more than 50%. Stem-Cell Transplantation. For the bulk of patients (about 50%) with normal cytogenetics, the choice is between several courses of high-dose cytarabine or a similar variant, or an allogeneic or autologous stem-cell transplant (ASCT). ASCT involves collecting stem cells from a patient in CR, which are then infused back to the patient after myeloablative chemotherapy is given. Prognostic factors are being increasingly described in normal-karyotype AML, but it is premature to make treatment recommendations based on these early data. Several trials have compared intensive chemotherapy with ASCT, and although trends favoring relapse-free survival in patients undergoing ASCT have been seen, only one phase III trial has demonstrated that patients benefited from ASCT given late in their clinical course. The Cancer and Leukemia Group B has shown that ASCT yields results similar to those achieved with four courses of high-dose cytarabine followed by maintenance therapy in patients with normal cytogenetics. It has been suggested that ASCT may be associated with less morbidity than multiple courses of high-dose chemotherapy. The advantage presented by ASCT, that of administering myeloablative doses of chemotherapy, might be negated by failure to eradicate residual leukemia in the infused stem cells. Attempts to improve outcomes have included intensifying the chemotherapy given prior to stem cell collection DM, April 2008

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(in vivo purging) as well as ex vivo purging of stem cell collections with high doses of cytotoxic agents or monoclonal antibodies (or both). The use of peripheral stem cells reduces the time to hematopoietic engraftment. Whether overall treatment outcomes will improve with the increased use of peripheral blood rather than marrow as a source of stem cells remains to be seen. Allogeneic transplants are limited to the 30% to 35% or so of eligible patients who have a donor. Although the risk of infusing leukemic cells is eliminated in allogeneic transplants, greater risks exist related to the immunologic effect of infused donor T cells against host tissues (graftversus-host disease, GVHD). The other important consequence is the development of a direct antileukemic effect called graft-versus-leukemia (GVL). In younger patients, especially those younger than 30 years, GVHD tends to be manageable, and outcomes in AML patients receiving transplants in first CR can be excellent. The risk of GVHD and associated complications greatly increases with age. The high-dose chemotherapy, given with or without total body irradiation, can cause unacceptable toxicities in older patients. An attempt to counter this problem has been the ongoing exploration of reduced-intensity transplants, in which low doses of immunosuppressive agents such as fludarabine1 (Fludara), antithymocyte globulin1 (Atgam, others), alemtuzumab1 (CamPath), melphalan1 (Alkeran), or busulfan1 (Myleran PO or Busulfex IV) are used to suppress host defenses sufficiently to permit engraftment of donor stem cells. This can lead to a curative GVL effect in some patients. The relative safety of the preparative regimen can be negated, however, by the development of severe GVHD. Methodologies to enhance the GVL effect while limiting the sequelae of GVHD are being actively studied. Select patients older than 60 years, and even older than 70 years, have been treated using this approach. Maintenance. Unlike in ALL, there is no evidence that lower doses of chemotherapy given for prolonged periods after induction and consolidation (maintenance therapy) improve survival, although time to relapse may be favorably affected. Overall, about 30% of patients with AML younger than 60 years with other than favorable cytogenetics are cured. Older Patients. Older patients present a special challenge. Patients older than 60 years, and especially older than 70 years, are more likely to harbor resistant forms of AML associated with poor-risk cytogenetic features and multidrug-resistance phenotypes. Comorbid conditions limit toler1

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ance for severely myelotoxic therapies. Nonetheless, a good performance status predicts a more favorable outcome, even in older patients. The patient’s physiologic state must be factored in with other established predictors of outcome in deciding whether or with what to treat older patients with AML. Several randomized trials suggest that treatment of older patients who have AML can lead to better outcomes with respect to survival than purely supportive or palliative approaches. Ideally, investigational therapies should be evaluated in this high-risk patient population. Select older patients can benefit from intensive therapies used in younger patients, such as the 7- and 3-day regimens described earlier. Depending on performance status and other prognostic factors, the probability of a patient older than 60 years entering CR using conventional induction treatment is 30% to 50%, with therapy-related mortality of 20% to 40%. Only about 10% are long survivors. For many patients, investigational agents, attenuated doses of conventional induction regimens, or alternative therapies that have been most often used in high-risk MDS may be considered. A non-anthracyclinecontaining combination of the topoisomerase I inhibitor topotecan1 (Hycamptin, 1.5 mg/m2/day by CIV) and cytarabine 2 g/m2, each given daily for 5 days, has moderate activity in older patients with AML, as does the non-cytarabine-containing combination of mitoxantrone (Novantrone) 10 mg/m2 and etoposide1 (Toposar) 100 mg/m2 each given daily IV for 5 days. Fludarabine1 25 to 30 mg/m2 IV daily for 4 days has been combined with high-dose cytarabine and filgrastim (Neupogen) in the non-anthracycline-containing FLAG (fludarabine, cytarabine, granulocyte colonystimulating factor [G-CSF]) regimen. Hypomethylating agents that induce the expression of silenced genes, such as 5-azacytidine1 (Vidaza, 75 mg/m2 SC daily for 7 days every 4 weeks) or2 decitabine1 (Dacogen), using various doses and schedules, may have activity in select older patients with AML, as may low doses of cytarabine (10 mg/m2 SC bid for 14-21 days every 28 days). Low-dose cytarabine has also been recently combined with arsenic trioxide3 (Trisenox) in an investigational regimen for elderly patients with AML. Clofarabine (Clolar) is a newly developed nucleoside analogue that might have activity in older patients with AML. The optimal dose and schedule remain under study. 1

Not FDA approved for this indication. Approved for MDS, not acute leukemia. 3 Orphan drug in the United States. 2

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The anti-CD33 monoclonal antibody– calicheamycin construct gemtuzumab ozogamycin (Mylotarg) can induce CR in a small fraction (about 20%) of older patients with untreated AML. The approved dose and schedule when used as a single agent is 9 mg/m2 IV on days 1 and 15. Various combinations of this antibody with chemotherapy are being investigated. The orally available farnesyl transferase inhibitor tipifarnib (Zarnestra)1 has proven disappointing when used as a single agent. Investigational Therapy. Relapsed and refractory disease and AML in the elderly demand the use of investigational therapies. High-dose cytarabine can occasionally induce response in a patient resistant to a conventional anthracycline– cytarabine regimen. For almost all suitable patients, a CR achieved after an initial induction failure or a second CR must be rapidly consolidated with a transplant-based strategy. Investigational approaches have involved novel agents with inhibitory properties directed against proliferative, differentiation, immunomodulatory, angiogenic, and drug-resistance pathways. Efforts to improve outcomes by inhibiting P-glycoprotein, a transmembrane drug efflux pump that confers multidrug resistance, have had limited success. A partial list of novel agents, most of which are being studied in AML but some of which may be active in ALL, is presented in Table 4. Ongoing efforts are assessing the use of these agents alone and in combination with chemotherapy. Filgrastim1 (and sargramostin, Leukine) are myeloid growth factors that have been studied in AML to hasten myeloid recovery as well as to stimulate proliferation of leukemic cells in order to increase their susceptibility to cell cycle-active cytotoxic agents such as cytarabine. Benefits have been, at best, marginal, with some indication that periods of neutropenia and hospital stays are reduced but without clear evidence that survival is increased. Studies looking at cell cycle activation effects have been conflicting but mostly negative.

Acute Promyelocytic Leukemia Acute promyelocytic leukemia (APL) represents a paradigm for a malignancy that is yielding to targeted strategies that are not principally dependent on cytotoxic agents. Representing only about 5% to 10% of adult AML, 70% to 80% of patients with newly diagnosed disease can now expect to be cured. All-trans-retinoic acid (ATRA, tretinoin, Vesanoid) induces terminal 1

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Table 4. Investigational therapies of acute leukemia Drug

Mechanism of Action

Bevacizumab (Avastin)* SU5416 (Semaxanib)† SU11248 (Sugen)† Tipifarnib (Zarnestra)† Lonafarnib (SCH66336)† Valproic acid (Depakote)* SAHA* PKC412† MLN518† CEP701† Decitabine* Imatinib (Gleevec)* Dasatinib (BMS-354825)‡ Oblimersen (Genasense)† Interleukin-2 (Proleukin)* PR-1† Hum-195-Bismuth 213† Alemtuzumab (CamPath)* VNP40101M (Cloretazine)† Troxacitabine (Troxatyl)† Zosuquidar† Cyclosporin A (Sandimmune)*

VEGF inhibitor VEGF-R, c-kit, and flt-3 inhibitor VEGF-R, c-kit, and flt-3 inhibitor Farnesyl transferase inhibitor Farnesyl transferase inhibitor Histone deacetylase inhibitor Histone deacetylase inhibitor flt-3 inhibitor flt-3 inhibitor flt-3 inhibitor DNA methyltransferase inhibitor bcr-abl inhibitor: Ph? ALL, AML bcr-abl, src inhibitor, Ph? ALL, AML bcl-2 mRNA inhibitor (antisense therapy) T and NK cell stimulant Vaccine for AML Radiolabeled monoclonal antibody for AML Monoclonal antibody for ALL Alkylating agent Purine nucleoside analogue Inhibitor of multidrug resistance Inhibitor of multidrug resistance

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; NK, natural killer cells; Ph, Philadelphia chromosome; SAHA, suberoylanilide hydroxamic acid; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor. Definitions: bcr-abl, gene product of the Ph (Philadelphia) chromosome translocation t(9;22); c-kit, transmembrane tyrosine kinase (CD117); DNA methyltransferase, inhibition promotes gene transcription; farnesyl transferase, enzyme in ras pathway; flt-3, fms-like transmembrane tyrosine kinase; histone deacetylase, inhibition promotes histone disassembly and gene transcription; multidrug resistance, major mediator of resistance to anthracyclines, vinca alkaloids, and epidophyllotoxins is a transmembrane drug efflux pump, p-glycoprotein, or mdr-1. *Not FDA approved for this indication. †Investigational drug in the United States. ‡Approved for ALL in 2006. http://www.fda.gov/cder/foi/label/2006/022072lbl.pdf

differentiation and apoptosis in APL cells. It can induce CR in most patients with APL given alone at a dose of 45 mg/m2 PO daily in two divided doses for 30 to 45 days, but it cannot eradicate the disease by itself. The combination of anthracycline-based chemotherapy and ATRA induces CR and polymerase chain reaction (PCR, a highly sensitive assay for MRD, see Table 1) negativity in 70% to 80% of patients. A non-anthracycline-containing combination using arsenic trioxide (Trisenox, 0.15 mg/kg IV over 2 hours daily until CR and then repeated for 4 to 6 cycles) with or without ATRA induces similar outcomes, DM, April 2008

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although long-term follow-up is shorter than with chemotherapy-containing regimens. APL is sensitive to anthracyclines, so consolidation courses consisting, for example, of two courses of daunorubicin 50 mg/m2 IV daily for 3 days, usually given in combination with ATRA, induces a high cure fraction. The results of a phase III North American Intergroup trial in which untreated patients were randomized to receive or not receive two courses of arsenic trioxide in addition to anthracycline-based chemotherapy have shown results favoring the arsenic arm. Patients with APL who present with high WBC counts (⬎10,000/␮L) have adverse outcomes, and attempts have been made to improve their prognosis using strategies that include gemtuzumab ozogamicin (Mylotarg) (APL strongly expresses CD33) or treatment with high-dose cytarabine. Maintenance therapy with ATRA for a year, with or without the oral chemotherapy agents methotrexate (Rheumatrex, others) 20 mg/m2 orally once per week and 6-mercaptopurine (Purinethol) 60 mg/m2 orally daily, has been used to prevent relapse in APL. It may be that patients who are molecularly negative by PCR after completing induction and consolidation do not need maintenance. This question is posed in a planned phase III trial. ATRA needs to be given intermittently because it can induce its own metabolism. Patients treated with ATRA or arsenic trioxide can develop a differentiation syndrome marked by fever, dyspnea, weight gain, pulmonary infiltrates, pleural effusions, and even death. This can result, in part, from interactions between maturing leukemic promyelocytes and the pulmonary vascular endothelium as well as cytokine release. Most patients respond to interruptions in drug therapy and brief courses of dexamethasone 10 mg IV twice daily. APL generally manifests with a low WBC count and evidence of coagulopathy, including severe hypofibrinogenemia. ATRA helps to reverse the coagulopathy, but it is critical to maintain the fibrinogen greater than 100 mg/dL and the platelet count higher than the traditional 10,000 to 20,000/␮L. Nonrandomized clinical experience suggests that keeping the platelet count higher than 50,000/␮L in APL is important until laboratory evidence of disseminated intravascular coagulation (DIC) reverses. There are no convincing data to support the use of low-dose heparin or antifibrinolytic agents in APL. Relapsed APL is generally approached with an attempt at reinduction using regimens similar to those that were initially effective. ASCT has 236

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been an active salvage therapy in APL in second CR, although an allogeneic transplant could be considered in suitable high-risk patients.

Acute Lymphoblastic Leukemia Approximately 30% to 40% of adults with ALL are cured. CR rates are high, approaching 90% in patients younger than 60 years, but relapse rates are substantially higher than in childhood ALL. One important reason for this disparity is that the Ph chromosome is far more common in adults than in children (30% to 40% versus 5%). Also, the favorable t(12;21) is overrepresented in childhood ALL. Furthermore, children with ALL have been treated more intensively than adults, using higher doses of cytotoxic agents with shorter treatment-free intervals and more aggressive use of prophylactic therapy aimed at preventing central nervous system (CNS) relapse. The backbone of induction therapy for ALL consists of weekly doses of vincristine 2 mg IV weekly for 4 weeks combined with prednisone 60 mg/m2 PO daily for 21 days or dexamethasone 6 mg/m2 orally daily for 14 to 21 days. Response rates have increased as additional drugs have been added to the induction framework, so that a typical induction regimen for adult ALL often includes cyclophosphamide (600-1200 mg/m2 IV once on day 1 or 300 mg/m2 IV bid for 3 days in a regimen called HyperCVAD), daunorubicin (45-80 mg/m2 IV daily on days 1 to 3 and L-asparaginase, Elspar, 6000 U/m2) SC or IM biweekly for 6 doses. PEG-asparaginase (Oncaspar) 2500 IU/m2 IM or IV given twice during induction 2 weeks apart has also been used. A two-drug induction regimen using a high-dose anthracycline (eg, mitoxantrone 60-80 mg/m2 IV3 given once) with high-dose cytarabine has been studied, which is then followed in patients achieving CR by more traditional anti-ALL regimens. Childhood regimens have intensified further the use of L-asparaginase. Achieving CR by 4 to 5 weeks after starting induction is prognostically important. For the majority of patients in CR, repeated cycles of multiple agents with both antileukemia effects and the capacity for crossing the blood-brain barrier are given. This is because the CNS is a major sanctuary site in ALL. Efforts are directed early in therapy to identify or eradicate occult disease in the CSF. High doses of methotrexate (1000 to 3500 mg/m2 IV) are given, followed by rescue with folinic acid (leucovorin) 25 to 50 mg PO every 6 hours until serum methotrexate levels drop to less than 05 M. High-dose cytarabine (3000 mg/m2 IV daily for 2-3 days) is also an active anti-ALL agent that, along with methotrexate, penetrates well into the CSF. Repeated courses using these DM, April 2008

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agents, with or without cyclophosphamide, L-asparaginase, and 6-mercaptopurine, are given over a period of about 6 months, after which about 18 months of lower-dose maintenance therapy is given, usually using monthly courses of vincristine (2 mg IV day 1), and oral pulses of prednisone (60 mg/m2) or dexamethasone (6 mg/m2) on days 1 to 5, daily doses of oral 6-mercaptopurine (60 mg/m2), and weekly doses of oral methotrexate (20 mg/m2). Variants of these regimens are described in the references. The incidence of CNS disease has been reduced to 5% to 10% using prophylactic therapies as discussed earlier, along with repeated intrathecal instillations of methotrexate (6 mg/m2/dose) and cytarabine (30 mg/m2/ dose), alone or in combination, via the lumbar route or intraventricularly using an Omaya reservoir. Commonly, 6 to 12 prophylactic treatments are given during induction and consolidation. Prophylactic cranial irradiation (up to 2400 cGy) has also been used. Because radiotherapy can induce cognitive defects, especially when combined with high-dose antimetabolite-based treatments, attempts are being made to clarify whether or not systemic and intrathecal treatments can suffice to prevent CNS disease, without cranial radiotherapy. In the setting of established CNS disease, most practitioners favor using whole-brain radiotherapy in addition to vigorous intrathecal treatments. Drug resistance in the significant minority of patients with Ph⫹ ALL is being countered using targeted therapies that inhibit the specific product of the fusion gene that occurs in that disease (bcr-abl). Imatinib1 (Gleevec) 600 to 800 mg orally daily induces transient remissions in a significant minority of patients with Ph⫹ ALL. Other inhibitors include nilotinib (Tasigna),1 a more potent bcr-abl inhibitor, and dasatinib (Sprycel) which inhibits additional oncogenic pathways besides bcr-abl. Ongoing trials are clarifying the efficacy of cytotoxic therapies in combination with imatinib.1 It is still critical to identify donors for allogeneic transplantation in patients with Ph⫹ ALL entering into CR. ASCT is also being studied in Ph⫹ ALL in conjunction with imatinib and chemotherapy. T-lineage ALL has been believed to have an inferior outcome to B-lineage ALL, but current intensive adult regimens have yielded outcomes in T-cell disease that are at least as good as those seen in the other ALL subtypes. Mature B lineage ALL (Burkitt’s leukemia or L3 ALL) is a highly proliferative form of acute leukemia, which demands distinct treatment 1

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that concentrates on the use of antimetabolites (high-dose methotrexate and high-dose cytarabine as described earlier for consolidation therapy of ALL) early in therapy along with an anthracycline, vincristine, cyclophosphamide, and corticosteroids. The risk of CNS disease is especially high in Burkitt’s leukemia, and vigorous prophylactic CNS therapy is needed. Unlike typical ALL regimens, short-term (3 months or less) cyclic therapy without maintenance therapy is curative. Somewhat more prolonged regimens using similar drugs and most recently including the anti-CD20 monoclonal antibody rituximab (375 mg/m2 given every 3 weeks) have also been studied. Older patients might better tolerate such less dose-intense regimens. More than 80% of younger adults and perhaps 40% to 50% of older adults are cured. For both typical B lineage ALL and Burkitt’s leukemia, judicious use of filgrastim (5 ␮g/kg/day SC) given daily after chemotherapy cycles will hasten myeloid recovery and reduce infectious risk. Future directions in treating ALL include improving prognostic factor analysis, studying the more intensive childhood regimens in younger adults (younger than 30 years), continuing to refine CNS prophylactic measures, and evaluating new agents. Alemtuzumab1 is being studied in the MRD setting in patients with ALL. Clofarabine is active in relapsed ALL and will be studied in earlier patients. Except for very poor risk patients, the role of early allogenic transplant in ALL remains undefined. Nelarabine (Arranon) is a newly approved purine nucleoside analogue. At a dose of 1500 mg/m2 IV on days 1, 3, and 5 every 21 days, it is active in relapsed and refractory T-ALL. It is hoped that outcomes in both forms of acute leukemia will improve with the intelligent use of new agents in the context of carefully designed and conducted clinical trials.

Current Diagnosis ● ● ● ●

Leukocytosis and increased blasts or leukopenia (aleukemic leukemia). Anemia and/or thrombocytopenia. Adenopathy, organomegaly, bone pain more common in ALL. Central nervous system and/or testicular involvement more common in ALL. ● High LDH, tumor lysis syndrome more common in l3 all (Burkitt’s leukemia). ● Coagulopathy typical in APL. ● Bone marrow aspirate and biopsy must include routine Wright–Giemsa stain, complete immunophenotype using flow cytometry and immuno1

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histochemistry, and cytogenetics for appropriate diagnostic categorization and for prognostic purposes. Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; LDH, lactate dehydrogenase; APL, acute promyelocytic leukemia.

Current Therapy ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

AML in patients younger than 60 years and favorable cytogenetics. Anthracycline/cytarabine induction. High-dose cytarabine consolidation ⬁ 3-4 cycles. AML under age 60, unfavorable cytogenetics, including normal. Anthracycline/cytarabine induction followed by either high-dose cytarabine consolidation or stem cell transplantation. Acute promyelocytic leukemia. Anthracycline with or without cytarabine plus all-trans-retinoic acid induction. Anthracycline consolidation ⬁ 2 cycles generally with all-transretinoic acid. Maintenance therapy with all-trans-retinoic acid, with or without po 6-mercaptopurine and methotrexate (role being determined). High-dose cytarabine, mylotarg, and arsenic trioxide in untreated patients being studied. AML in patients older than 60 years. Options as in patients younger than 60 years in select patients. Investigational therapies. ALL. Five-drug induction regimen (see text). Consolidation therapy with high-dose cytarabine and methotrexate, l-asparaginase, 6-mercaptopurine, cyclophosphamide. Maintenance therapy with vincristine, steroids, po 6-mercaptopurine, and methotrexate for 18 months. CNS prophylaxis with systemic and intrathecal therapies. Cranial radiotherapy is an option but is potentially toxic. L3 ALL (Burkitt’s leukemia). Short-course intensive high-dose cytarabine, methotrexate therapy plus anthracycline, vincristine, cyclophosphamide; intensive systemic and intrathecal CNS prophylactic therapy. No maintenance. Rituximab (Rituxan) may be effective.

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BIBLIOGRAPHY Kolitz JE. Acute myeloid leukemia and the myelodysplastic syndromes. In:Chang AE, Ganz PA, Hayes DF, et al., editors. Oncology: An Evidence-Based Approach. New York, NY: Springer, 2006. p. 1151-72. Odenike OM, Michaelis LC, Stock W. Acute lymphoblastic leukemia. In: Chang AE, Ganz PA, Hayes DF, et al., editors. Oncology: An Evidence-Based Approach. New York, NY: Springer, 2006. p. 1173-201. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166-78. Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 2005;105:3019-25. Tallman MS, Gilliland DG, Rowe JM. Drug therapy of acute myeloid leukemia. Blood 2005;106:1154-63.

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