Acute Leukemias
Ashwin Kishtagari
Olga Frankfurt
Martin S. Tallman
I. GENERAL FEATURES OF ACUTE LEUKEMIAS
The acute leukemias are a heterogeneous group of disorders characterized by clonal proliferation and abnormal differentiation of neoplastic hematopoietic progenitor cells. Accumulation of immature hematopoietic cells, or blasts, in the bone marrow and peripheral blood ultimately leads to inhibition of normal hematopoiesis. If left untreated, acute leukemias are rapidly fatal.
Over the last 40 years, significant therapeutic advances have been made and many younger patients can now be cured of their disease. The general treatment approach for most patients with acute leukemia includes eradication of the leukemic clone with intensive systemic chemotherapy, followed by some form of consolidation and, in certain cases, maintenance therapy. Despite this strategy, most adults below the age of 55 years and the vast majority of older adults die from their disease.
Numerous questions regarding optimal therapeutic strategies for patients with acute leukemia remain unanswered. Hence, all patients with acute leukemia should be considered candidates for clinical trials and treated in centers where appropriate intensive and comprehensive care can be provided.
A. Epidemiology
The incidence of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is 2.7 and 1.5 per 100,000 of the population, respectively, and is slightly higher in males than in females. Sixty percent of patients with ALL are children, with a peak incidence in the first 5 years of life. The second peak emerges after the age of 60 years. The incidence of AML rises exponentially after the age of 40 years, with the median age of disease presentation at 72 years. In contrast, the median age of patients diagnosed with acute promyelocytic leukemia (APL), a distinct subtype of AML, is 40 years, and the incidence of the disease does not increase with advanced age. While in general the incidence of acute leukemias is slightly higher in the populations of European descent, the incidence of APL may be higher among patients of Hispanic origin.
B. Etiology and risk factors of acute leukemias
Although the association of the acute leukemias with various infectious, genetic, environmental, and socioeconomic factors
has been evaluated extensively, the etiology remains obscure in most cases.
has been evaluated extensively, the etiology remains obscure in most cases.
1. Infection
There is a strong association between Epstein-Barr virus, a DNA virus causing infectious mononucleosis, and Burkitt lymphoma/leukemia.
2. Genetic factors
Genetic factors have been implicated in the pathogenesis of acute leukemia on the basis of epidemiologic studies showing the 25% increased risk of ALL within 1 year in a monozygotic twin of an affected infant. There is also a fourfold increase in the risk of developing leukemia in dizygotic siblings. The risk of developing acute leukemia is significantly higher in patients with Down and Klinefelter syndromes, and conditions with excessive chromosome fragility such as Fanconi anemia, ataxia telangiectasia, and Bloom syndrome.
3. Exposures to chemotherapy and radiation
Exposures to chemotherapy and radiation significantly increase the risk of developing acute leukemias. AML with chromosome 5 and/or 7 abnormality has been reported to occur 2 to 9 years after therapy with alkylating agents. Topoisomerase inhibitors have been linked to the development of AML and ALL with 11q23 aberration, characteristically 1 to 3 years after the exposure. An increased incidence of acute leukemias has been reported after radiation exposure such as atomic bomb explosion, the Chernobyl accident, and therapeutic radiation. Increased incidence of leukemia has also been linked to exposure to gasoline, benzene, tobacco, diesel, motor exhaust, and electromagnetic fields.
C. Clinical and laboratory features
Clinical and laboratory features of acute leukemias and their associated signs and symptoms are shown in Table 19.1.
D. Diagnosis, classification, and prognostic features in acute leukemias
The acute leukemias are generally and broadly divided into AML and ALL on the basis of the morphologic, immunohistochemical, and immunophenotypic characteristics of leukemic blasts, along with the differing cells of origin. Although the peripheral blood smear may be highly suggestive of the diagnosis (if ≥20% blasts), examination of the bone marrow aspirate and core biopsy is essential to confirm the diagnosis and to determine the extent of the disease. Cytogenetic analysis and molecular studies may aid in establishing an accurate diagnosis, estimate prognosis, and guide therapy.
1. AML classification
Currently, the World Health Organization (WHO) classification is used to define AML. The morphology-based French-American-British (FAB) classification, devised in 1976, generally
of historical value, utilizes cytochemical stains and, more recently, immunophenotyping by flow cytometry to differentiate myeloid from lymphoid blasts (Table 19.2). According to the FAB classification, eight subcategories of AML are established on the basis of the type of cell involved and the degree of differentiation (Table 19.3). A more recent WHO classification created
in 1999 and updated in 2008 generated 17 subclassifications of AML, on the basis of the presence of dysplasia, chromosomal translocations, and molecular markers (see Table 19.3).1 Additional changes included the decrease of the diagnostic threshold to 20% blasts (from the original classification of 30%, hence eliminating the refractory anemia with excess blasts in transformation category of myelodysplastic syndrome [MDS]) and the diagnosis of AML regardless of the percentage of marrow blasts in marrows with clonal cytogenetic abnormalities such as t(8;21), t(15;17), and t(16;16) or inv(16), along with evidence of abnormal hematopoiesis.
of historical value, utilizes cytochemical stains and, more recently, immunophenotyping by flow cytometry to differentiate myeloid from lymphoid blasts (Table 19.2). According to the FAB classification, eight subcategories of AML are established on the basis of the type of cell involved and the degree of differentiation (Table 19.3). A more recent WHO classification created
in 1999 and updated in 2008 generated 17 subclassifications of AML, on the basis of the presence of dysplasia, chromosomal translocations, and molecular markers (see Table 19.3).1 Additional changes included the decrease of the diagnostic threshold to 20% blasts (from the original classification of 30%, hence eliminating the refractory anemia with excess blasts in transformation category of myelodysplastic syndrome [MDS]) and the diagnosis of AML regardless of the percentage of marrow blasts in marrows with clonal cytogenetic abnormalities such as t(8;21), t(15;17), and t(16;16) or inv(16), along with evidence of abnormal hematopoiesis.
TABLE 19.1 Clinical and Laboratory Features of Acute Leukemia | ||||||||||||||||||||||||||||||
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TABLE 19.2 Antigens Commonly Demonstrated by Flow Cytometry Techniques | ||||||||||||||||||
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TABLE 19.3 WHO Classification of AML (Simplified) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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2. Prognostic factors in AML
Prognostic factors in AML can be viewed as patient-related (age, performance status [PS]) and leukemic clone-related characteristics. Advanced age is an adverse prognostic factor. Even after accounting for risk factors such as cytogenetics, molecular genetics, presence of antecedent hematologic disorder, and PS, older patients have worse outcome than younger patients: 40% to 60% complete response (CR) rates, and only 5% to 16% 5-year survival.
However, chronologic age alone should not be the only determinant of whether patients receive potentially curative chemotherapy because age is not the most important prognostic factor for either treatment-related mortality (TRM) or resistance to therapy (see Section IV.H.1).
AML-related prognostic characteristics include WBC count at presentation, presence of antecedent hematologic disorder, prior exposure to the cytotoxic therapy, as well as cytogenetic and molecular changes. In fact, cytogenetic and molecular genetic changes in leukemic cells at diagnosis are the most important prognostic characteristic for predicting the rate of remission, relapse, and overall survival (OS). Patients are commonly separated into three risk groups: favorable, intermediate, or adverse (Table 19.4).
On the basis of a retrospective analysis of 1,213 patients with AML treated on Cancer and Leukemia Group B (CALGB) protocols, the 5-year survival for patients with favorable, intermediate, and poor-risk cytogenetics was 55%, 24%, and 5%, respectively.2
a. Favorable-risk AML. Core binding factor (CBF)-AMLs (inv(16), t(8;21) and t(16;16)) have the most favorable outcomes. Normal karyotype (cytogenetically normal [CN]-AML) consists of a molecularly heterogenous group of malignancies. In several, but not all studies, presence of nucleophosmin 1 (NPM1) mutation and absence of internal tandem duplication (ITD) of the FMS-like tyrosine kinase-3 (FLT3) (FLT3- ITD) in CN-AML confers an improved outcome with higher
CR, relapse-free survival (RFS), and event-free survival (EFS) rates, demonstrating rates of CR and OS similar to those of CBF leukemias.
CR, relapse-free survival (RFS), and event-free survival (EFS) rates, demonstrating rates of CR and OS similar to those of CBF leukemias.
TABLE 19.4 AML Prognostic Groups Based on Cytogenetic and Molecular Data at Presentation* | ||||||||||||||||||
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b. Intermediate-risk AML. This category includes cases with normal karyotype (CN-AML), trisomy 8, and t(9;11). Presence of c-KIT mutations exert a negative influence of outcome in patients with CBF-AML in retrospective studies; however, the negative influence may be more pronounced in cases with t(8;21) than those with inv(16).
c. Adverse-risk AML. Complex karyotype, defined by the presence of three or more (in some studies five or more) chromosomal abnormalities, occurs in 10% to 12% of patients and is associated with very poor outcome. Monosomal karyotype, a recently proposed cytogenetic category, has a particularly poor survival (5-year OS of 4%). Monosomal karyotype’s poor prognosis may be attributed to its association with p53 mutations. Patients with monosomy of chromosome 5 (-5), and/or 7 (-7), deletions (del) of the long arms of chromosome 5 (del 5q) or 7 (del 7q) and abnormalities of 3q have worse prognosis. CN-AML with ITD of the FLT3 (FLT3-ITD) predict inferior outcomes.
TABLE 19.5 WHO 2008 Classification of ALL | ||||||||||||||||||||||
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3. ALL classification
The diagnosis and classification of ALL is based on cell morphology, immunohistochemistry, as well as immunophenotypic and cytogenetic features. Marrow involvement of more than 25% lymphoblasts is used to differentiate ALL from lymphoblastic lymphoma, in which the preponderance of tumor bulk is in nodal structures.1 Approximately 70% to 75% of adult ALL cases are of precursor B-cell origin; 20% to 25% are of T-cell origin (Tables 19.5 and 19.6).
TABLE 19.6 Immunophenotypes of ALL | ||||||||||||||||||||||||||||||
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4. Prognostic factors in ALL
Although modern intensive chemotherapy regimens have abolished multiple prognostic factors identified in the past, several biologic and clinical features of ALL still predict response to therapy, remission duration, disease-free survival (DFS), and help to determine the intensity of the induction and postremission therapy. Similar to the patients with AML, the outcome of therapy for patients with ALL worsens with increasing age. In multivariate analysis, age over 60 years is associated with a particularly poor prognosis, with shorter remission durations and worse survival.
Presenting WBC counts of greater than 30,000/µL in precursor B-lineage ALL and greater than 100,000/µL in T-cell ALL are adverse prognostic factors predicting shorter duration of remissions. The time required to achieve CR (more than 4 weeks) following induction chemotherapy has been demonstrated to be an adverse prognostic factor in several, but not all, clinical trials.
Similar to AML, cytogenetic abnormalities are one of the most important factors predicting outcome in ALL. Approximately half of the patients with ALL have cytogenetic abnormalities, which usually take the form of translocations rather than deletions, which are seen more commonly in AML. The landmark International ALL trial (UKALLXII/Eastern Cooperative Oncology Group [ECOG] E2993) conducted by the Medical Research Council (MRC; now the National Cancer Research Institute) in United Kingdom and the ECOG in United States identified in a very large number of patients the incidence and clinical associations of more than 20 specific cytogenetic abnormalities.3 t(4;11), t(8;14), complex karyotype (five or more abnormalities), and hypodiploidy (<44 chromosomes) were all associated with poorer EFS and OS compared with patients with other abnormalities. Other adverse cytogenetic abnormalities include t(9;22) (BCR-ABL1), t(1;19), abnormalities in 9p, and rearrangements involving 11q23 (MLL).
BCR-ABL1-like (or Ph-like) ALL is a newly described common subtype of high-risk ALL, which has a gene-expression profile similar to that of BCR-ABL1-positive ALL, including alterations in IKZF1, but lacks the BCR-ABL1 fusion gene. Further mutations in the Ras and JAK/STAT5 pathways are the common mechanism of transformation. This discovery is clinically important owing to the presence of kinase-activating alterations (ABL1, EPOR, JAK2, PDGFRB, EBF1, FLT2, IL7R, SH2B3) that are amenable to treatment with currently available tyrosine kinase inhibitors (TKIs).4
Alternatively, patients with high hyperdiploidy (>50 chromosomes) or a del(9p) were associated with an improved outcome.
5. Acute leukemias of ambiguous lineage
With the expansion of immunophenotyping panels, use of electron microscopy, and gene rearrangement studies for the characterization of acute leukemias, an increasing degree of infidelity of myeloid and lymphoid markers is demonstrated. Cases in which differentiation between AML and ALL is difficult are described by the WHO as “acute leukemia of ambiguous lineage” and comprise those cases that show no evidence of lineage differentiation (i.e., acute undifferentiated leukemia [AUL]) or those with blasts that express markers of more than one lineage (mixed phenotype acute leukemia [MPAL]; see Table 19.3). AUL often expresses human leukocyte antigen (HLA)-DR, CD34, and/or CD38, but by definition lacks lineage-specific markers.
II. INITIAL SUPPORTIVE MEASURES
Once the diagnosis of acute leukemia has been established, the next 24 to 48 hours are spent preparing the patient for the initiation of cytotoxic chemotherapy. The following issues need to be addressed in almost all individuals facing induction chemotherapy.
A. Hyperleukocytosis, leukostasis, and leukapheresis
Hyperleukocytosis, defined as an absolute blast count of more than 100,000/µL, predisposes to rheologic problems and is associated with increased induction mortality in AML. Leukostasis, manifesting as cerebral and cardiopulmonary dysfunction due to vascular obstruction and/or vessel wall necrosis with hemorrhage, occurs almost exclusively in AML and represents an oncologic emergency. Given the increased risk of early death with hyperleukocytosis, steps to rapidly reduce the blast counts should be undertaken as soon as the diagnosis is made. In the hemodynamically stable patient, leukapheresis is the most rapid way to lower the blast count; however, no impact on long-term outcome has been shown. With very high blast counts (more than 200,000/µL), decreasing the blast count by 50% may have to be the initial goal because mathematic modeling suggests that prolonged leukapheresis after a “3-L exchange” does not significantly decrease the blast count further. Leukapheresis may be repeated daily. Systemic chemotherapy should be initiated immediately after emergent leukapheresis or if leukapheresis cannot be performed. Hydroxyurea 3 to 5 g/m2/day split into three doses daily until WBC are less than 10,000 to 20,000/µL is commonly used. In patients presenting with hyperleukocytosis, an allopurinol dose of 100 mg/m2 every 8 hours (maximum 800 mg/day) is well tolerated for the first 2 days, followed by 300 mg twice a day for 2 to 3 days. Emergent cranial radiation for hyperleukocytosis and cranial nerve palsies (or other severe neurologic deficits) is another treatment modality that may be used.
Blood transfusions in the anemic patient with hyperleukocytosis should be undertaken with great care as an aggressive packed red blood cell transfusion in such patients may precipitate symptoms of hyperviscosity. Unless the patient has symptoms due to anemia, a packed cell volume (hematocrit) of 20% to 25% is a reasonable goal.
B. Hydration and correction of electrolyte imbalance
Dehydration needs to be corrected and adequate urine output maintained to prevent renal failure due to the deposition of cellular breakdown products resulting from the tumor lysis syndrome. In the absence of cardiac disease, normal saline with or without 5% dextrose (D5W) is infused to maintain the urine output at more than 100 mL/hour. The concomitant use of loop diuretics may be necessary in patients with congestive heart failure (CHF).
A variety of electrolyte abnormalities, such as hypocalcemia, hyperphosphatemia, and hyperkalemia, may occur in patients with acute leukemia. Hyperkalemia, defined by a potassium level of greater than 6 mmol/L, caused by massive cellular degradation, may precipitate significant neuromuscular (muscle weakness, cramps, paresthesias) and potentially life-threatening cardiac (asystole, ventricular tachycardia, and ventricular fibrillation) abnormalities. Patients should be treated with oral sodium-potassium exchange resin, such as sodium polystyrene sulfonate 15 to 30 g every 6 hours and/or combined glucose/insulin therapy.
Serum electrolytes, uric acid, phosphorus, calcium, and creatinine should be monitored several times a day, depending on the severity of the clinical condition and degree of metabolic abnormality. Early hemodialysis may be required in patients who develop oliguric renal failure or recalcitrant electrolyte disturbances. An electrocardiogram should be obtained and cardiac rhythm monitored while these abnormalities are corrected.
C. Prevention of uric acid nephropathy
Hyperuricemia is common at presentation and may also occur with the tumor lysis caused by chemotherapy. Allopurinol is the mainstay of prevention of uric acid nephropathy. The usual initial adult dose is 300 mg (150 mg/m2) twice per day for 2 to 3 days, which is then decreased to 300 mg once a day. Allopurinol should be stopped after 10 to 14 days to lessen the risk of rash and hepatic dysfunction. If chemotherapy needs to be initiated urgently, allopurinol at a dose of 100 mg/m2 every 8 hours (maximum 800 mg/day) is well tolerated for 1 to 2 days. With the advent of allopurinol, the role of urine alkalinization has become less clear.
Rasburicase, a recombinant urate oxidase, is a safe and effective alternative to allopurinol. Although the recommended dose of rasburicase is 0.15 to 0.2 mg/kg/day for 5 days, at our institution an excellent control of hyperuricemia was achieved with a lower dose of 3 mg/day.
D. Correction of coagulopathy
Hemostatic defects secondary to thrombocytopenia may be potentiated by the presence of consumption coagulopathy (disseminated intravascular coagulation [DIC]). Life-threatening bleeding complications are particularly common in patients with APL because of the presence of DIC and primary and secondary fibrinolysis, and proteolysis (see Section V). Lysozyme released from monoblasts in M4 and M5 subtypes of AML may trigger a clotting cascade leading to consumption coagulopathy. In ALL, therapy with L-asparaginase (L-Asp) may lead to DIC. Additionally, sepsis may contribute to coagulopathy in newly diagnosed patients with acute leukemias. Frequent monitoring of coagulation parameters and adequate replacement with cryoprecipitate or fresh frozen plasma products in appropriate patients is critical.
E. Blood product support
Most patients with acute leukemia present with evidence of bone marrow failure. Symptomatic anemia, hemoglobin less than 8 g/dL, thrombocytopenia less than 10,000/µL, as well as signs of bleeding, must be treated. The threshold below which platelet transfusion is needed may be higher (e.g., 20,000/µL) if conditions known to increase the risk of bleeding such as severe mucositis, fever, anemia, and coagulopathy are present. Blood products should be leukoreduced to decrease the risk of febrile nonhemolytic transfusion reaction; alloimmunization to HLAs, which may lead to subsequent refractoriness to platelet transfusion; and transmission of cytomegalovirus (CMV). Additionally, blood products should be gamma irradiated to reduce the risk of transfusion-related graftversus-host disease (GVHD). Patients who are potential candidates for stem cell transplant (SCT) should be screened for CMV and receive CMV-negative blood until CMV status is determined.
F. HLA typing
Patients who are candidates for SCT should be HLA typed prior to the initiation of therapy because chemotherapy-induced severe myelosuppression will not leave enough lymphocytes for HLA typing.
G. Fever or infection
Patients frequently have a fever or an infection at initial diagnosis. The cardinal rule is that all patients with acute leukemia and fever are presumed to have an infection until proved otherwise. Given the additional myelosuppressive and immunosuppressive effects of chemotherapy, severe infections should be treated aggressively before initiating chemotherapy. However, the antibiotic treatment frequently needs to be administered concurrently with induction chemotherapy. Patients with acute leukemia need a careful physical examination daily. There should be close attention toward potential sites of infection, including the fundi, sinuses, oral cavity, intertriginous areas, perineum (attempts are made to avoid
internal rectal examination during neutropenia), and catheter sites. A dental consultation at the time of diagnosis is often useful.
internal rectal examination during neutropenia), and catheter sites. A dental consultation at the time of diagnosis is often useful.
H. Vascular access
Because of the need for several sites of venous access for at least 1 month, a multiple-lumen implantable catheter (e.g., Hickman catheter or peripherally inserted central catheter line) must be placed as soon as possible (except in patients suspected to have APL). An implantable port is not recommended for patients with leukemia because there is higher risk of infection and hematoma at the access site. Because of the coagulopathy in patients with APL, the placement of a long indwelling catheter is avoided altogether if at all possible and certainly until the coagulopathy has been completely corrected and the patient is in a CR. A risk of life-threatening bleeding in patients with APL is present even when most or all of the routine coagulation studies are normal.
I. Suppression of menses
A serum human chorionic gonadotropin (β-hCG) assay (pregnancy test) should be done in all premenopausal women prior to initiation of chemotherapy. It may be desirable to prevent menses during chemotherapy to avoid the severe menorrhagia due to the thrombocytopenia. Medroxyprogesterone (Provera) 10 mg twice per day may be started 5 to 7 days before the expected starting time of the next menstrual period. It may be increased to 10 mg three times per day or higher if breakthrough bleeding occurs. Medroxyprogesterone acetate IM (Depo-Provera) is contraindicated in the thrombocytopenic and neutropenic patient.
J. Birth control and fertility
Given the potential teratogenic effects of cytotoxic chemotherapy, appropriate measures for preventing conception must be addressed with women of reproductive age undergoing chemotherapy. Although there are no clear data linking chemotherapy in the male partner to teratogenic effects in the fetus, it is prudent to suggest that appropriate birth control measures be undertaken in this situation as well.
Late effects of chemotherapy, such as infertility, need to be considered in younger patients. Sperm cryopreservation should be offered to men of reproductive age prior to initiation of chemotherapy.
Gonadal function in women seems to be less affected by cytotoxic chemotherapy. Cryopreservation of fertilized eggs is currently available, while cryopreservation of unfertilized eggs may be conducted on the investigational basis.
K. Psychosocial support
Patients with acute leukemia are usually previously healthy individuals who have suddenly had to accept the possibility of their own imminent mortality. Intensive psychological and spiritual support by the health care team, family, and religious leaders is critical for maintaining the patient’s sense of well-being.
III. THERAPEUTIC PRINCIPLES AND APPROACH TO THE THERAPY OF ACUTE LEUKEMIA
A. Therapeutic aim
The goals of chemotherapy are to eradicate the leukemic clone and reestablish normal hematopoiesis in the bone marrow. Long-term survival is seen only in patients in whom a CR is attained. Although leukemia therapy is toxic and infection is the major cause of death during therapy, the median survival time of untreated (or unresponsive) acute leukemia is 2 to 3 months, and most untreated patients die of bone marrow failure and its complications. The doses of chemotherapy are never reduced because of cytopenia, because lowered doses still produce the unwanted side effects (further marrow suppression) without having as great a potential for eradicating the leukemic clone and ultimately improving marrow function.
B. Forms of chemotherapy and response criteria
1. Induction chemotherapy
Induction chemotherapy is initial intensive chemotherapy given in an attempt to eradicate the leukemic clone and to induce a CR. The term complete response depicts patients who achieve recovery of normal peripheral blood counts with recovery of bone marrow cellularity, including the presence of less than 5% blast cells, in the absence of extramedullary disease. The aim of induction chemotherapy is to reduce the leukemia cell population by several logs from the clinically evident total-body tumor burden of 1012 leukemia cells (about 1 kg), commonly seen at diagnosis, to below the cytologically detectable level of 109 cells. It is important to note that because achievement of initial CR represents only a 3- to 6-log leukemia cell reduction, a substantial leukemia cell burden persists, and patients usually relapse within months if further therapy is not administered. Induction therapy is typically initiated as soon as diagnostic workup has been completed, as there is retrospective data suggesting that treatment outcome might be adversely impacted when treatment is delayed by more than 5 days from the diagnosis.
2. Postremission chemotherapy
Postremission chemotherapy is administered subsequently to achievement of a CR in a further attempt to eradicate the residual, but often undetectable, leukemic clone. In a younger patient population, considering the relatively high rate of CR after the induction, future advances are likely to occur through improved postremission therapy. Patients older than 60 years tend to achieve suboptimal CR rates and should be enrolled in investigational protocols aimed at improving induction and consolidation therapy.
a. Consolidation therapy involves repeated courses of the same drugs at similar or higher doses as those used to induce the remission, which are given soon after the remission has been achieved. Consolidation often requires further hospitalization.
b. Maintenance therapy pertains primarily to ALL and includes low doses of drugs designed to be administered on an outpatient basis for up to 2 years. In AML, this strategy applies only to APL.
3. The definition of response
The definition of response is based on the peripheral blood counts and the status of the recovered bone marrow. If the marrow is hypoplastic, it is imperative to repeat the bone marrow biopsy to document remission on recovery.
a. CR is the return of the complete blood count to a “normal” absolute neutrophil count (ANC) of more than 1,500/µL and to a platelet count of more than 100,000/µL in conjunction with a normal bone marrow (i.e., normal cellularity, less than 5% blasts or promyelocytes and promonocytes, an absence of obvious leukemic cells, and absence of extramedullary disease). Presence of minimal residual disease (MRD) as determined by flow cytometry or PCR analysis is a predictor of the relapse. Relapse rates range from 0% in patients with a reduction to less than 10-4 leukemic cells detected at the completion of the induction (compared with leukemia cell burden at diagnosis) to 14% in those with 10-3 to 10-4 cells to 89% in patients with 1% residual disease.
b. Partial response is the persistence of morphologically identifiable residual leukemia (5% to 15% leukemic cells in the bone marrow).
IV. THERAPY FOR ADULT AML (OTHER THAN APL)
The day that induction chemotherapy is started is arbitrarily called day 1. Bone marrow aspiration and biopsy are typically repeated on day 14. If the bone marrow is severely hypoplastic with fewer than 5% residual blasts or if the bone marrow is aplastic, no further chemotherapy is given, and the patient is supported until bone marrow recovery occurs (usually 1 to 3 weeks more). A bone marrow examination is repeated 2 weeks later (about days 26 to 28). Once a CR has been documented, the potential benefit of further consolidation therapy should be determined on an individual basis.
A. Induction therapy
Factors that influence the choice of the initial chemotherapeutic agents include the patient’s age, cardiac function, and PS. Historically, an age of 60 years has been considered a cutoff point to recommending induction chemotherapy due to the higher prevalence of unfavorable cytogenetics, antecedent myelodysplasia, expression of multidrug-resistant protein, as well as frequency and severity of comorbid conditions affecting the ability to tolerate intensive chemotherapy. However, age alone should not be used as the sole determinant of whether given older adults should receive intensive induction chemotherapy or alternative less intensity strategy. The
initial drug doses outlined below are based on the presence of normal hepatic and renal function and do not require modification for depressed (or elevated) peripheral blood counts.
initial drug doses outlined below are based on the presence of normal hepatic and renal function and do not require modification for depressed (or elevated) peripheral blood counts.
1. “3 + 7”
During the last 40 years, a series of clinical trials have identified an induction regimen of 3 days of anthracycline (daunorubicin [DNR] 60 to 90 mg/m2/day, idarubicin 10 to 12 mg/m2/day, or mitoxantrone, an anthracenedione, 12 mg/m2/day) and 7 days of cytarabine (Ara-C) 100 to 200 mg/m2, which is considered standard (Table 19.7). With such regimens, the anticipated rate of CR in younger patients (younger than 55 to 60 years) is 60% to 80%. No other intervention has been convincingly demonstrated to be better. Several randomized trials have compared DNR at 45 to 60 mg/m2 with idarubicin, mitoxantrone, aclarubicin, and amsacrine; with respect to OS, none of the agents appeared to be superior to DNR at the equivalent doses. In younger patients, idarubicin, which attains a higher intracellular drug concentration, was shown to induce higher remission rates, longer response duration, and improved OS. However, in older adults, a randomized trial showed no benefit of one anthracycline/anthracenedione over the other. In a randomized clinical trial, a higher dose of DNR (90 mg/m2/day) resulted in a higher rate of CR (70.6 vs. 57.3, p < 0.001) and improved OS (23.7 vs. 15.7 months, p = 0.003) as compared with a lower (than standard) dose (45 mg/m2/day).5,6 Doses that exceed 45 mg/m2/day for induction are now considered standard. Those with an unfavorable cytogenetic profile, FLT3-ITD and mixed lineage leukemia partial tandem duplication (MLL PTD) mutations did not benefit from the higher doses of DNR in an initial ECOG analysis.5
2. Cytarabine dose intensification
The merit of cytarabine dose intensification has been explored in several clinical trials. The results indicate that the rate of CR
was not affected by the administration of high-dose cytarabine (HiDAC) compared with the standard dose.
was not affected by the administration of high-dose cytarabine (HiDAC) compared with the standard dose.
Induction therapy with HiDAC plus DNR is associated with greater toxicity than standard dose Ara-C plus DNR, but without improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HiDAC increases the toxicity but not survival or DFS. Hence, the use of HiDAC induction outside the clinical trial is not recommended.
TABLE 19.7 Commonly Administered Induction Regimens in AML | ||||||||||||||||||
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3. Other regimens
Many permutations to the standard “7 + 3” regimen have been studied over the years in an attempt to improve the CR rate of induction therapy and prolong survival. The addition of other agents such as 6-thioguanine and etoposide (3 + 7 + 3) to the “7 + 3” regimen have improved the CR rate and response duration in some studies, but these regimens produce increased toxicity without improvement in OS.
Addition of gemtuzumab ozogamicin (GO) to conventional chemotherapy did not improve CR rates or DFS. As a consequence, the U.S. Food and Drug Administration (FDA)-accelerated approval from 2000 was withdrawn. However, a recent meta-analysis found that the addition of GO significantly reduced the risk of relapse and improved 5-year OS when added to induction chemotherapy, particularly in those with favorable (5-year OS of 55.2% vs. 76.3%, p = 0.0005) and intermediate-risk (5-year OS of 34.1% vs. 39.4%, p = 0.007) disease.7
The use of an anthracycline or an anthracenedione is contraindicated in patients with severe underlying cardiac disease, particularly if the patient has had a recent myocardial infarction or has an ejection fraction of less than 50%. The choice of therapy in this situation is HiDAC, although the optimum dose and schedule of HiDAC therapy are not known (i.e., number of doses, dosage, infusion rate; see Table 19.7).
B. Residual disease
Patients who have residual disease at day 28 should be considered primary treatment failures and have alternative therapy initiated. If a significant response has been demonstrated at the marrow examination on days 10 to 14 (greater than 50% to 60% reduction in leukemic infiltration) but residual leukemia persists, a second course of similar chemotherapy is given (or an alternative regimen such as HiDAC). Patients with significant involvement with leukemia on days 10 to 14 (less than 40% to 50% leukemic reduction) should receive an alternative chemotherapy regimen. There is no dose modification for the second course based on blood cell counts. The doses of drugs may be decreased for the second cycle if the total dose of anthracycline would be cardiotoxic or if hepatic dysfunction attributed to the chemotherapy develops.
TABLE 19.8 HiDAC Consolidation Regimens | ||||
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C. Postremission therapy
Despite attaining a CR, the majority of patients with AML relapse, necessitating further therapy aimed at eradication of the residual yet undetected leukemic clone. There are three general treatment strategies for postremission therapy: consolidation chemotherapy, autologous (auto-), or allogeneic (allo-) hematopoietic stem cell transplant (HSCT). Although the optimum postremission strategy remains to be defined, almost all younger adults with AML benefit from further therapy. The type of postremission therapy should be determined on the basis of prognostic factors, particularly age, cytogenetic, and molecular genetic findings at diagnosis. Patients with AML in first CR should be considered candidates for investigational protocols examining postremission therapy options. For patients who cannot be enrolled in protocol studies, the approach to postinduction therapy is shown in Table 19.8. Consolidation should be initiated when the peripheral blood counts have returned to normal (ANC more than 1,500/µL and platelet count more than 100,000/µL), marrow cellularity is normal, infections have resolved, and mucositis has cleared.
Current data suggest that HiDAC offers a distinct advantage over SDAC consolidation in patients younger than 55 to 60 years of age. A landmark study conducted by CALGB demonstrated that four cycles of HiDAC (3 g/m2 every 12 hours on days 1, 3, and 5) are superior to four courses of intermediate cytarabine (400 mg/m2 continuous intravenously [IV] on days 1 to 5) or SDAC (100 mg/m2 continuous IV on days 1 to 5). More than 40% to 50% of patients will be in a continuous CR 5 years after consolidation with HiDAC. The beneficial effect of cytarabine dose intensification, however, was restricted to patients with CBF-AML and, to a lesser extent, to patients with CN-AML, whereas outcome of patients with other cytogenetic abnormalities was not affected by the cytarabine dose.8
The addition of other agents such as DNR or amsacrine to HiDAC consolidation therapy has failed to show improvements in long-term outcomes.
1. Favorable-risk AML
Postremission therapy with three to four cycles of HiDAC or other intensive cytotoxic regimen is considered standard for younger adults with c-KIT– CBF-AML, NPM1+/FLT3-ITD -, and double-mutated CEBPA (see Table 19.8). A retrospective study conducted by CALGB demonstrated that three or more cycles of HiDAC (cumulative dose: 54 to 72 g/m2) are superior to a single cycle (18 g/m2); however, in a joint collaboration between the M.D. Anderson Cancer Center, SWOG, and ECOG, reporting a large number of patients with CBF-AML, the outcome even among patients treated with HiDAC or any postremission therapy was not as favorable as previously reported in earlier series with many fewer patients. Neither auto- nor allo-HSCT showed an advantage over consolidation therapy in first remission.
However, several subsets of CBF-AML, such as t(8;21) with high WBC, CBF-AML with c-KIT mutation, or persistence of MRD, do poorly with the conventional therapy and may benefit from the allo-HSCT.
2. Intermediate-risk AML
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