Aaron Cumpston and Michael Craig
Acute leukemia represents a very aggressive, malignant transformation of an early hematologic precursor. The malignant clone is arrested in an immature blast form, proliferates abnormally, and no longer has the ability to undergo maturation. In contrast, the chronic leukemias are characterized by resistance to apoptosis and by accumulation of nonfunctional cells. Accumulation of the blasts within the bone marrow results in progressive hematopoietic failure, with associated infection, anemia, and thrombocytopenia. It is these complications that often prompt evaluation in newly diagnosed patients.
Acute leukemia continues to present a grave diagnosis because of its rapid clinical course. Patients require aggressive and urgent evaluation and treatment initiation. As a general rule, treatment is expected to improve quality of life and prolong survival. Unfortunately, many patients present at an advanced age and with comorbid conditions, making cytotoxic treatment difficult. Elderly or unwell patients who are given the best supportive care survive only for a few months.
The immature, clonally proliferating cells that form blasts may be derived from myeloid or lymphoid cell lines. Transformation of granulocyte, RBC, or platelet (myeloid) precursors results in acute myelogenous leukemia (AML). Acute lymphoblastic leukemia (ALL) originates from B or T lymphocytes. This general division has implications for different treatment and diagnostic approaches. It is the first step in classifying the leukemic process occurring in the patient.
EPIDEMIOLOGY
■Estimated new cases in the United States in 2013 are 14,590 for AML and 6,070 for ALL.
■AML accounts for 10,370 deaths and ALL accounts for 1,430 deaths annually in the United States.
■The risk of developing AML increases with advanced age, the median age being 60 to 69.
■Seventy-five percent of newly diagnosed patients with AML are older than 60.
■ALL is more common in children; 60% to 70% of cases are found in patients younger than 20 years.
RISK FACTORS
Most patients will have no identifiable risk for developing leukemia. Table 23.1 lists the conditions that are identified with an increased risk for developing acute leukemia. Most studies have evaluated the relationship between the risk factors and AML. The conditions that are mostly associated with AML are chronic benzene exposure, exposure to ionizing radiation, and previous chemotherapy.
Ionizing Radiation Exposure Explored in Atomic Bomb Survivors
■Ionizing radiations have a latency period of 5 to 20 years and a peak period of 5 to 9 years in atomic bomb survivors.
■They exhibit a 20- to 30-fold increased risk of AML and chronic myelogenous leukemia (CML).
Chemotherapy
■Therapy-related AML may account for 10% to 20% of new cases.
■Leukemia associated with alkylating agents may be associated with cytogenetic changes of chromosomes 5, 7, and 13. Often there is a multiyear latent-phase myelodysplastic syndrome preceding the development of AML.
■Topoisomerase II agents, often with an abnormal chromosome 11q23 in the blasts, can rapidly evolve after initial therapy. Usually, these are preceded by only a brief myelodysplastic state rapidly evolving to AML.
■Previous high-dose therapy with autologous transplant leads to a cumulative risk of 2.6% by 5 years, especially with total body irradiation (TBI)-containing regimens.
CLINICAL SIGNS AND SYMPTOMS
■Ineffective hematopoiesis: Results from marrow infiltration by the malignant cells
•Anemia: pallor, fatigue, and shortness of breath
•Thrombocytopenia: epistaxis, petechiae, and easy bruising
•Neutropenia: fever and pyogenic infection
■Infiltration of other organs
•Skin: Leukemia cutis in 10%
•Gum hypertrophy: Especially in monocytic leukemia (AML M5)
•Granulocytic sarcoma: Localized tumor composed of blast cells; imparts poorer prognosis; occasionally extramedullary leukemia masses associated with 8;21 translocation
•Liver, spleen, and lymph nodes: Common in ALL, occasionally in monocytic leukemia (AML M5)
•Thymic mass: Present in 15% of ALL in adults
•Testicular infiltration: Also a site of relapse for ALL
•Retinal involvement: May occur in ALL
■Central nervous system (CNS) and meningeal involvement
•5% to 10% of cases at diagnosis, mainly ALL, inv(16) (French–American–British [FAB] M4Eo), and high blast count
•Analysis and prophylaxis are given in ALL to decrease CNS relapse.
•Symptoms: Headache and cranial nerve palsy, but mostly asymptomatic
■Disseminated intravascular coagulation (DIC) and bleeding
•Very common with acute promyelocytic leukemia (APL); the mechanism is related to tissue factor release by granules and fibrinolysis; generally improves with all-trans retinoic acid (ATRA) of which early initiation is imperative.
•Can be present in AML inv(16) or monocytic leukemia or can be related to sepsis.
■Leukostasis
•Occurs with elevated blast count
•Symptoms result from capillary plugging by leukemic cells.
•Common signs: dyspnea, headache, confusion, and hypoxia
•Initial treatment includes leukapheresis, aggressive hydration, and chemotherapy to rapidly lower the circulating blast percentage with drugs (e.g., oral hydroxyurea or intravenous cyclophosphamide).
•Transfusions should be avoided because these may increase viscosity.
•Leukapheresis is repeated daily in conjunction with chemotherapy until the blast count is <50,000.
DIAGNOSTIC EVALUATION
■History and physical examination are an essential part of diagnosis of acute leukemia.
■Complete blood count (CBC), differential and manual examination of peripheral smear, and peripheral blood flow cytometry are considered when circulating blasts are sufficiently abundant to establish a diagnosis.
■Coagulation tests include prothrombin time (PT), partial thromboplastin time (PTT), D-dimer, and fibrinogen.
■Electrolytes with calcium, magnesium, phosphorus, and uric acid. Low glucose, potassium, and PO2 (partial pressure of oxygen) can occur with delay in analysis of high blast count.
■Bone marrow biopsy and aspirate (with analysis for morphology), cytogenetics, flow cytometry, and cytochemical stains (Sudan black, myeloperoxidase, acid phosphatase, and specific and nonspecific esterase) are used for diagnosis.
■Human leukocyte antigen (HLA) testing of patients who are transplant candidates—the test is performed before the patient becomes cytopenic. Specimen requirements are minimal when DNA-based HLA typing is performed.
■Hepatitis B and C, cytomegalovirus, herpes simplex virus, human T-cell leukemia virus, and human immunodeficiency virus antibody titers are obtained.
■Pregnancy test (β-human chorionic gonadotropin), if applicable
■Electrocardiogram (ECG) and analysis of cardiac ejection fraction should be done prior to treatment with anthracyclines.
■Lumbar puncture: Performed when signs and symptoms of neurologic involvement are present. Low platelets should be corrected. The procedure may be performed after reduction of peripheral blast count to avoid inoculation of blasts into uninvolved cerebrospinal fluid (CSF). Obtain cell count, opening pressure, and protein level, and submit cytocentrifuge specimen for cytology.
■Central venous access should be obtained. An implanted port-type catheter is not recommended. Coagulation abnormalities should be corrected if present. It is often possible to initiate induction therapy with normal peripheral veins and await subsidence of coagulopathy to reduce risk of procedural complications.
■Supplemental testing of fluorescent in situ hybridization (FISH) assay for 15;17 translocation is performed when APL is suspected; and a BCR-ABL test is performed when CML in blast phase or ALL is suspected.
■Cytogenetic and gene mutation analysis of blasts will contribute dramatically to subsequent preferred management and prognosis.
INITIAL MANAGEMENT
The initial management of acute leukemia involves the following:
■Hydration with IV fluids (2 to 3 L/m2 per day).
■Tumor lysis prophylaxis should be started.
■Blood product support suggestions for prophylactic transfusions are hemoglobin level <8 and platelet level <10,000. Platelet trigger threshold can be higher in the context of fever or bleeding (<20,000 suggested), cryoprecipitate can be used if fibrinogen level is <150, and fresh frozen plasma (FFP) can be used to correct significantly elevated levels of PT and PTT. Platelet trigger should be increased in APL patients to <50,000. The minimum “safe” platelet level required to prevent spontaneous hemorrhage is not known. Additional platelet optimization strategies include avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and clopidogrel-like agents.
■Blood products should be irradiated and a WBC filter (if CMV-negative blood inventory is not available) should be used in those patients who are future allogeneic transplant candidates.
■Fever and neutropenia require blood and urine cultures, followed by treatment with appropriate antibiotics (see Chapter 36), and imaging.
■Therapeutic anticoagulation should be given with extreme caution in patients during periods of extreme thrombocytopenia. Adjustment of prophylactic platelet transfusion thresholds or anticoagulants is required.
■Suppression of menses: Medroxyprogesterone (Provera) 10 mg daily or twice daily.
Tumor Lysis Syndrome
■Tumor lysis syndrome can be spontaneous or can be induced by chemotherapy.
■Risk factors include elevated uric acid, high WBC count, elevated lactate dehydrogenase (LDH), and high tumor burden.
■Laboratory tests indicate elevated potassium, phosphorus, and uric acid; with a resulting decrease in calcium.
■The patients should be initiated on allopurinol 300 mg twice daily for 3 days, followed by once daily until risk is resolved.
■For hydration, alkalinizing fluids (0.5 NS with 50 mEq sodium bicarbonate) could be considered to increase solubility of uric acid, minimizing intratubular precipitation. Caution should be taken since alkanizing the urine also promotes calcium–phosphate complex deposition, and considering the availability of uricolytic agents (rasburicase), alkalinization is typically not utilized.
■Rasburicase (Elitek) should be used if the patient has hyperuricemia and an elevated creatinine on presentation or has hyperuricemia uncontrolled with allopurinol. Prophylactic rasburicase is not necessary with proper uric acid monitoring, due to quick onset of action of rasburicase.
■Hemodialysis may be required in refractory cases or urgently in the setting of life-threatening hyperkalemia, or volume overload if oliguric (see Chapter 38).
CLASSIFICATION
Acute Myelogenous Leukemia
There are two current systems to classify AML. The most commonly used criterion is from the World Health Organization (WHO) and incorporates recurrent cytogenetic abnormalities and prognostic groups (Table 23.2). Marrow blasts should make up 20% of the nucleated cells within the aspirate unless t(8;21) or inv(16) is present. The FAB classification is also used and classifies AML into eight subtypes. The blasts may be characterized as myeloid lineage by the presence of Auer rods; a positive myeloperoxidase, Sudan black, or nonspecific esterase stain; and the immunophenotype shown by flow cytometry. Cell surface markers associated with myeloid cell lines include CD13, CD33, CD34, c-kit, and HLA-DR. Monocytic markers include CD64, CD11b, and CD14. CD41 (platelet glycophorin) is associated with megakaryocytic leukemia, and glycophorin A is present on erythroblasts. HLA-DR–negative blast phenotype is commonly seen in APL and serves as a rapidly available test in confirming the suspicion of this subtype requiring a specific induction therapy.
Acute Lymphoblastic Leukemia
The WHO classification of ALL divides the disease into precursor B-cell, precursor T-cell, and Burkitt-cell leukemia. Immunophenotyping of B-lineage ALL reveals lymphoid markers (CD19, CD20, CD10, TdT, and immunoglobulin). T-cell markers include TdT, CD2, CD3, CD4, CD5, and CD7. Burkitt-cell leukemia is characterized by a translocation between chromosome 8 (the c-myc gene) and chromosome 14 (immunoglobulin heavy chain), or chromosome 2 or 22 (light chain) regions.
PROGNOSTIC GROUPS
Acute Myelogenous Leukemia
Those patients who are older (>60 years) and those with an elevated blast count at diagnosis (>20,000) have a worse prognosis. Chemotherapy-related AML and prior history of myelodysplasia (MDS) impart a lower chance of obtaining complete remission (CR) and long-term survival. Table 23.3 illustrates the prognostic groups according to cytogenetics.
Acute Lymphoblastic Leukemia
As in AML, patients with ALL have a worse prognosis when presenting with advanced age or elevated WBC count. Burkitt-cell (mature B-cell) leukemia or lymphoma has an improved prognosis with intensive chemotherapy and CNS treatment; it usually has a translocation involving chromosome 8q24. Table 23.4 lists the prognostic groups according to cytogenetic analysis. The presence of t(9;22) (Philadelphia chromosome) is the most common abnormality in adults. It is present in 20% to 30% of patients with ALL and in up to 50% of patients in the B-cell lineage. Long-term survival is dismal in this group if treated by chemotherapy alone, and patients are recommended to undergo allogeneic transplantation if they are a suitable candidate in first CR.
TREATMENT
Acute Myelogenous Leukemia (Non–t(15;17) Acute Promyelocytic Leukemia)
The goal of induction chemotherapy is to obtain CR, which has been shown to correlate with improved survival. CR is the elimination of the malignant clone (marrow blasts <5%) and recovery of hematopoiesis (absolute neutrophil count [ANC] >1,000 and platelet count >100,000). Patients typically have a leukemia cell burden of approximately 10 × 1012 that is reduced to approximately 10 × 109 by induction. This residual disease is essentially undetectable but will lead to relapse in weeks to months if more therapy is not administered. Additional intensive “consolidation” cycles of chemotherapy are given to further reduce the residual burden in the hope that host immune mechanisms can suppress the residual leukemia population, thereby leading to sustained CR. The general approach to induction chemotherapy for adults is shown in Table 23.5. Patients should be considered for clinical trials if available.
In general:
■Addition of high-dose cytarabine (HDAC) or etoposide has been evaluated in published regimens for induction that may benefit some patients younger than 60. These additions have not been demonstrated to be conclusively superior to 3 days of anthracycline and 7 days of cytarabine alone.
■Bone marrow aspiration should be repeated at approximately day 14. If significant residual blasts are present, induction chemotherapy should be repeated (consider “5 + 2” in Table 23.6). If significant disease is present (<50% reduction in disease volume), induction should be repeated or a change in the regimen to age-appropriate HDAC should be considered.
■Older (>60) patients may benefit from treatment. HDAC requires dose reduction due to CNS toxicity.
■Older patients or patients not fit for intensive induction chemotherapy (i.e., 7 + 3) may be candidates for therapy with azacitidine or decitabine. These hypomethylating agents have lower CR rates (approximately 20% to 30%) but are better tolerated than intensive therapies.
Supportive Care
■Infection is a major cause of morbidity and mortality. Prophylactic antibacterials (quinolones), antifungals (fluconazole or posaconazole), and antivirals (acyclovir) are typically given during these periods of prolonged neutropenia. Broad-spectrum antimicrobials are used for neutropenic fever (see Chapter 35).
■Growth factors such as granulocyte colony-stimulating factor (G-CSF) are associated with shortened length of neutropenia and are of demonstrated value in patients older than 55 years. Growth factors are not routinely recommended in younger patients but can be safely added if necessary. Initiation of G-CSF is delayed until after day 14, when bone marrow shows a satisfactory induction pattern. Growth factors may have the most benefit in those patients with infectious complications.
■Steroid eye drops are required during HDAC infusions to reduce risk of exfoliative keratitis.
Acute Myelogenous Leukemia Consolidation, Non–t(15;17)
The consolidation options for those patients who enter CR are shown in Table 23.6. HDAC especially may benefit those patients with good-risk disease [t(8;21) or inv(16)]. These good-risk patients should not receive transplantation in CR1. Consolidation usually consists of four cycles (the minimum effective dose and number of cycles are not clear). Older patients do not seem to benefit from more than one to two consolidation cycles. Patients with preceding MDS or poor-risk cytogenetics should receive an allogeneic transplantation, if possible. Patients with standard-risk cytogenetics should be considered for an allogeneic transplant, especially if they have a matched sibling donor. Gene mutations may assist in the proper identification of standard-risk patients who would benefit from allogeneic transplant in CR1 (see the Allogeneic Transplant section).
Acute Promyelocytic Leukemia, t(15;17)
The t(15;17) brings together the retinoic acid receptor-α and the promyelocytic leukemia genes, allowing for transduction of a novel protein (PML/RARα). The protein plays a role in blocking differentiation of the promyelocyte, thereby allowing abnormal accumulation within the marrow space. Because the characteristic translocation occurs in this subgroup of AML, therapy incorporates ATRA, which acts as a differentiating agent. Table 23.7 shows a treatment summary in APL.
■Therapy with ATRA should be started immediately upon suspicion of APL; therapy can be tailored pending genetic confirmation.
■Time to attain remission may be more than 30 days and a bone marrow biopsy is not performed on day 14.
■PCR should be followed for PML-RAR: Reinduction therapy should be considered if PCR is still positive postconsolidation; also, levels should be followed during the maintenance phase. A return of the transcript to positive heralds relapse.
■ATRA syndrome (retinoic acid syndrome) consists of capillary leak and cytokine release resulting in fever, leukocytosis, respiratory compromise (dyspnea and infiltrates), weight gain, effusions (pleural and pericardial), renal failure, and hypotension. This syndrome occurs in 25% of patients during induction, with peak occurrences at 1 and 3 weeks into therapy, and is associated with a rapidly rising neutrophil count. Treat with dexamethasone 10 mg IV BID × 3 days, and then taper over 2 weeks. Discontinuation of ATRA can be considered in severe cases. ATRA may still be safely employed in consolidation or maintenance-phase therapy because the ATRA syndrome is limited to the induction-period neutrophilia.
■A similar differentiation syndrome, not involving ATRA, is seen with the use of arsenic trioxide.
■Prognosis with APL is very good, with 90% of patients attaining a CR and >70% long-term disease-free survival.
■Patients are typically classified as high-risk (WBC ≥10,000), intermediate-risk (WBC <10,000 and platelets ≤40), or low-risk (WBC <10,000 and platelets >40) disease at diagnosis.
■ATRA + arsenic trioxide is an alternative option for untreated patients unable to tolerate anthracyclines. Preliminary data show excellent outcomes with ATRA + arsenic when compared to standard anthracycline-containing regimens.
Relapsed Disease
■Arsenic trioxide 0.15 mg/kg/day until second CR
•Median of 57 days to remission.
•Baseline electrolytes (Ca, K, Mg), creatinine, and ECG (for prolonged QT interval).
•Monitoring: At least weekly electrolytes and ECG. Keep K > 4.0 mEq/L and Mg > 2.0 mg/dL and reassess if QTc interval >500.
•Patients commonly develop APL differentiation syndrome similar to ATRA.
•Eighty-five percent of patients achieve CR.
•Arsenic trioxide may be given as consolidation at a dose of 0.15 mg/kg/day, 5 days per week (Monday through Friday) for 25 doses.
■Patients achieving CR (PCR negative) should receive consolidation with an autologous transplant, if eligible. Patients with persistent positive PCR results should be considered for an allogeneic transplant.
Relapsed or Refractory Acute Myelogenous Leukemia
Relapse of AML after initial CR is very common (60% to 80% of all cases). Relapse occurring within 6 months of induction or a patient never attaining remission with induction (refractory disease) complicates many induction attempts. The prognosis for long-term survival in this subset of patients is very poor with chemotherapy alone, and all patients who are able to tolerate the treatment should be evaluated for allogeneic transplantation. Some treatment approaches are described below.
■Reinduction with “7 + 3” or HDAC.
•Reinduction may be an option for those patients who relapse more than 6 to 12 months after induction.
•Subsequent remissions are usually of shorter duration (<50% of the duration of the preceding remission).
■Etoposide, mitoxantrone, ± cytarabine (EM or MEC).
■FLAG: fludarabine, cytarabine, and G-CSF (can be combined with idarubicin or mitoxantrone).
■Clofarabine +/– cytarabine or cyclophosphamide.
■FLT3 inhibitors may have activity (sorafenib, midostaurin, and quizartinib), but are currently investigational.
■In cases of isolated CNS relapse, it should be considered that systemic relapse almost always follows soon and that a systemic therapy is also required.
Acute Lymphoblastic Leukemia
General scheme: induction, consolidation, maintenance, and CNS treatment.
Several strategies exist for the treatment of adult ALL. Table 23.8 illustrates the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen employed in many North American centers. The Larson regimen reported by Cancer and Leukemia Group B (CALGB) Study 9111, shown in Table 23.9, is also commonly employed. Other options based on the Hoelzer and Linker regimen are also available. Burkitt-cell leukemia (mature-B ALL, L3) can be treated with hyper-CVAD without maintenance therapy but requires aggressive CNS treatment to prevent relapse. Adolescent and young adult patients (age ≤40) with ALL should be treated with pediatric regimens.
Supportive Care
The regimens described previously incorporate growth factors to reduce neutropenia and allow more scheduled chemotherapy to proceed. All patients will require blood product support at some point during the treatment. Those patients treated with hyper-CVAD receive prophylactic antimicrobials (i.e., levofloxacin 500 mg daily, fluconazole 200 mg daily, and valacyclovir 500 mg daily).
Central Nervous System Disease
■CNS is a sanctuary site.
■CNS disease is diagnosed by the presence of neurologic deficits at diagnosis or by five or more blasts per microliter of CSF.
■Therapy for CNS disease is intrathecal (IT), methotrexate (MTX), or cytarabine (Ara-C), often alternating. These will be given twice weekly until disease clears, then weekly for 4 weeks, and then resume the prophylaxis schedule. Radiation (fractionated to 2,400 to 3,000 cGy) can also be considered, being aware of potential late-term cognitive toxicities.
■Prophylaxis decreases CNS relapse from 30% to <5%. The prophylactic chemotherapy schedule is dependent on the relapse risk.
■In the hyper-CVAD regimen, patients with high-risk disease (i.e., LDH level >2.3 times upper limit of normal or elevated proliferative index) should receive eight prophylactic IT treatments, and those with low-risk disease (no factors) receive six prophylactic IT treatments. Patients with mature B-cell disease or a history of documented CNS involvement will require 16 IT therapies. No prophylactic cranial irradiation is given.
Relapsed Acute Lymphoblastic Leukemia
Marrow is the most common site of relapse, but relapse can occur in testes, eye, and CNS. Patients with late relapse (more than 6 months to 1 year from induction) may respond to reinduction with the original regimen. Early relapse or refractory disease will require changing the treatment plan and evaluation for allogeneic transplantation. Several chemotherapy options are available, including
■HDAC with idarubicin, mitoxantrone, or fludarabine
■Methotrexate, vincristine, asparaginase (not PEG), steroids (MOAD)
■Imatinib, dasatinib, or nilotinib (if Ph positive)
■Hyper-CVAD, if not given initially
■Vinorelbine with mitoxantrone, fludarabine, steroids, or rituximab
■Nelarabine
■Clofarabine +/– cytarabine or cyclophosphamide
■Liposomal vincristine
■Investigational monoclonal antibody agents (blinatumomab, epratuzumab, inotuzumab, ozogamicin, etc.)
Use of Targeted Therapies in Acute Lymphoblastic Leukemia
1.Rituximab (Rituxan)
•Anti-CD20 chimeric murine–human monoclonal antibody
•Given in addition to the previously noted regimens in front-line treatment, if CD20+
2.Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib
•Tyrosine kinase inhibitors targeting the Philadelphia chromosome [t(9;22)].
•Imatinib should be considered in addition to previously noted regimens in front-line treatment, if Ph positive.
•Role in maintenance therapy is unknown at this time, but could be considered.
•May be used as treatment or palliation in patients unable to tolerate aggressive chemotherapy.
•Choice of tyrosine kinase inhibitor agent should be selected based on BCR/ABL mutation analysis.
TRANSPLANTATION
Autologous Transplant
■Autologous transplant appears to have minimal benefit in acute leukemia in CR1.
■Autologous transplant could be considered for patients achieving CR2, without availability of an allogeneic donor.
■It may be performed in older patients (age >60).
Allogeneic Transplant
■Allogeneic transplant has the added benefit of “graft versus leukemia” effect.
■In the setting of unrelated donor searches, the prolonged time needed to identify a donor needs to be considered at the time of diagnosis. Referral to a transplant center is preferred as early as possible in the treatment plan.
■It is considered for all patients with relapsed or refractory disease, as it is the option that may yield long-term survival.
■It is performed in the first CR or early in the course for those patients with poor-risk cytogenetics or transformation from MDS.
■Patients with good-risk AML [t(8;21), inv(16), or t(15;17)] should not be transplanted in CR1.
■Patients with intermediate-risk cytogenetics may be offered allogeneic transplant, especially if they have a sibling donor.
■Gene mutations may be able to help stratify intermediate-risk patients as poorer or more favorable outcome, assisting in the decision of the usefulness of transplantation in CR1. NPM1 and CEBPA mutations (without FLT3/ITD mutations) may have a good prognosis and may not benefit from transplant in CR1. FLT3 mutations are a negative predictor of outcome.
■When transplanted in CR1, overall survival is 50% to 60%; it decreases to 25% to 40% when performed for patients in CR2, and is <10% for patients with refractory disease.
■Nonmyeloablative transplantation is reasonable for those patients unable to proceed with ablative treatment secondary to age or comorbidities.
■BMT CTN 0901 currently ongoing evaluating the role of reduced-intensity conditioning compared to myeloablative preparative regimens for allogeneic transplant in patients with AML.
PROGNOSIS AND SURVIVAL
Adults with acute leukemia remain at high risk for disease-related and treatment-related complications. In AML, the prognostic characteristics of the disease are associated with survival. Good-risk AML is associated with 80% to 90% CR rate, and long-term disease-free survival is 60% to 70% in younger patients treated with HDAC. Poor-risk features are associated with only a 50% to 60% chance of obtaining a CR, and a high risk of relapse is observed in those patients who enter CR. Additionally, gene mutations have been identified as correlating with prognosis in AML, especially in the intermediate-risk group where there are no cytogenetics that can guide therapy. In these patients, FLT3 mutations confer a poor prognosis. In patients who are FLT3 negative, NPM1 and CEBPA seem to be a good prognostic subgroup.
CR and long-term outcome have improved for adult patients with ALL who were receiving intensive courses of chemotherapy. With the Larson regimen, 85% obtained CR (39% older than 60 years). The hyper-CVAD course yielded a CR of 91% (79% for patients older than 60 years). Median duration of CR was 30 months with Larson regimen and was 33 months with hyper-CVAD. Five-year survival was approximately 40%.
REVIEW QUESTIONS
1.A 51-year-old man is newly diagnosed with AML with cytogenetics revealing a translocation (8;21). He has no other significant comorbidities and has a good performance status. What would be the most appropriate course of therapy for this patient?
A.Induction chemotherapy followed by four cycles of low-dose cytarabine therapy
B.Induction chemotherapy followed by four cycles of HDAC therapy
C.Induction chemotherapy followed by autologous hematopoietic cell transplant
D.Induction chemotherapy followed by allogeneic hematopoietic cell transplant
2.A 32-year-old female presents with bruising, fatigue, and persistent fevers for 2 weeks. Her WBC is 2,700, hemoglobin is 6.4, and platelets count is 16. Her fibrinogen is <70 and PT is elevated at 22 (INR 2.2). What should be the next step in the management of this patient?
A.Hydration and allopurinol
B.Urgent bone marrow biopsy and aspiration
C.Treatment with idarubicin or daunorubicin
D.Initiation of ATRA
3.A 59-year-old man is diagnosed with precurser B-cell ALL. He is found to be CD19 positive and CD20 negative. Cytogenetic analysis reveals a translocation 9;22 resulting in a BCR-ABL fusion gene. What targeted therapy should be added to his chemotherapeutic plan?
A.Rituximab
B.Imatinib
C.Alemtuzumab
D.Ofatumumab
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