Hematopoietic malignancies account for 6%-8% of new cancers diagnosed annually. In the year 2007, an estimated 44,240 new cases of leukemia will be diagnosed, and 21,790 deaths will be attributable to leukemias of all types. The total age-adjusted incidence of leukemia, including both acute and chronic forms, is 9.6 per 100,000 population; the incidence of acute lymphoblastic leukemia (ALL) is 1.5 per 100,000 and of acute myelogenous leukemia (AML) is 2.7 per 100,000 population.
Hematopoietic malignancies account for 6%-8% of new cancers diagnosed annually. In the year 2007, an estimated 44,240 new cases of leukemia will be diagnosed, and 21,790 deaths will be attributable to leukemias of all types. The total age-adjusted incidence of leukemia, including both acute and chronic forms, is 9.6 per 100,000 population; the incidence of acute lymphoblastic leukemia (ALL) is 1.5 per 100,000 and of acute myelogenous leukemia (AML) is 2.7 per 100,000 population.
Gender The incidence of both ALL and AML is slightly higher in males than in females.
Age The age-specific incidence of AML is similar to that of other solid tumors in adults, with an exponential rise after age 40. With regard to ALL, 60% of cases are seen in children, with a peak incidence in the first 5 years of life and a subsequent drop in incidence until age 60, when a second peak emerges.
Race and ethnicity The incidence of acute leukemia is slightly higher in populations of European descent. Also, a report from the University of Southern California indicates that acute promyelocytic leukemia (APL) is more common in Hispanic populations than in other ethnic groups.
There is wide diversity in the behavior of the various subsets of acute leukemias. Thus, it is unlikely that there is one common etiology for these aberrant cellular proliferations. There are, however, some accepted risk factors for leukemogenesis.
Chemical exposure Increased incidence of AML and myelodysplasia (preleukemia) has been reported in persons with prolonged exposure to benzene and petroleum products. The interval between exposure and the onset of leukemia is long (10–30 years). Chromosomal damage is common.
Pesticide exposure also has been linked to some forms of AML. The incidence of AML is beginning to rise in developing countries, as industrialization and pollution increase.
Other environmental exposures Exposure to hair dyes, smoking, and nonionic radiation may also increase the risk of leukemia.
Prior chemotherapy or irradiation Use of alkylating agents, such as cyclophosphamide and melphalan (Alkeran), in the treatment of lymphomas, myelomas, and breast and ovarian cancers has been associated with the development of AML, usually within 3–5 years of exposure and often preceded by a myelodysplastic phase. Cytogenetic abnormalities, particularly monosomy 5, 7, 11, and 17, are common. Concurrent radiation exposure slightly increases the risk of leukemogenesis posed by alkylating agents.
Topoisomerase II inhibitors (etoposide, teniposide [Vumon], doxorubicin and its derivatives, and mitoxantrone [Novantrone]), used to treat ALL, myeloma, testicular cancer, and sarcomas, have also been implicated in leukemogenesis. These agents, in contrast to alkylators, are associated with a short latency per-iod without antecedent myelodysplasia and with cytogenetic abnormalities involving chromosome 11q23 or 21q22 in the malignant clone.
Genetic disorders An increased incidence of AML is seen in patients with Down syndrome, Bloom syndrome, or Fanconi’s anemia, as well as in individuals with ataxia-telangiectasia or Wiskott-Aldrich syndrome. In identical twins younger than age 10, if one child develops leukemia (usually ALL), there is a 20% chance that the other twin will develop leukemia within a year; subsequently, the risk falls off rapidly and joins that of nonidentical siblings, which is three to five times that of the general population.
Effects on hematopoiesis Leukemia manifests symptomatically by its impact on normal hematopoiesis. Thus, easy fatigability, bruising, or bleeding from mucosal surfaces, fever, and persistent infection are all reflections of the anemia, thrombocytopenia, and decrease in functional neutrophils associated with marrow replacement by malignant cells. Bone pain is common in children with ALL (occurring in 40%–50%) but is less common in adults with acute leukemias (5%–10%).
WBC count elevation and pancytopenia Whereas a marked elevation in WBC count is the classic hallmark of leukemia, pancytopenia is more common, particularly in patients of all ages with ALL or in elderly patients with AML, who may have had preexisting marrow dysfunction (myelodysplasia). Only 10% of newly diagnosed patients with either AML or ALL present with leukocyte counts > 100,000/µL. These patients, however, constitute a poor prognostic group and are at increased risk of CNS disease, tumor lysis syndrome, and leukostasis due to impedance of blood flow from intravascular clumping of blasts, which are “stickier” than mature myeloid or lymphoid cells.
Leukostasis may manifest as an alteration in mental status; intermittent or persistent cranial nerve palsies, particularly those involving extraocular muscles; priapism; dyspnea; or pleuritic chest pain, due to small leukemic emboli in the pulmonary vasculature.
Physical findings in AML are usually minimal. Pallor, increased ecchymoses or petechiae, retinal hemorrhage, gingival hypertrophy, and cutaneous involvement are more common with monocytic (M4 or M5) variants of AML than with other variants of AML.
Hepatosplenomegaly and lymphadenopathy Mild hepatosplenomegaly and lymphadenopathy are seen in many cases, particularly in childhood ALL. Massive hepatosplenomegaly occurs infrequently and should raise the suspicion of a leukemia evolving from a prior hematologic disorder, such as chronic myelogenous leukemia (CML) or myelodysplasia. Mediastinal adenopathy is seen in 80% of cases of T-cell ALL, is less common in other ALLs, and is rare in AML.
Visceral involvement is also rare, occurring as an initial manifestation of AML in < 5% of cases, but it may be more frequent during subsequent relapses. These focal collections of blasts, called chloromas or granulocytic sarcomas, can present as soft-tissue masses, infiltrative lesions of the small bowel and mesentery, or obstructing lesions of the hepatobiliary or genitourinary system.
CNS involvement is uncommon at presentation in adult AML (< 1%) and adult ALL (3%–5%). In most instances, CNS involvement is detected by screening lumbar puncture in high-risk patients who are asymptomatic at the time of the puncture. Symptoms, when they do occur, include headache, diplopia, cranial nerve palsies, radicular pain, and/or weakness in a particular nerve root distribution. CNS involvement usually is restricted to leptomeninges; parenchymal mass lesions are uncommon.
Testicular involvement Like the CNS, the testes appear to be a “sanctuary” for isolated relapses in pediatric but not adult ALL. Signs of testicular involvement include painless, asymmetrical enlargement.
Metabolic effects of acute leukemia relate primarily to the rate of cell death.
Hyperuricemia with possible interstitial or ureteral obstruction is seen predominantly in AML with moderate leukocytosis; this condition may be exacerbated by a rapid response to chemotherapy and the “tumor lysis syndrome” (hyperuricemia with renal insufficiency, acidosis, hyperphosphatemia, and hypocalcemia), which may occur within the first 24–48 hours after initiating chemotherapy. To prevent this complication, all patients should receive allopurinol and urine alkalinization before marrow-ablative chemotherapy is initiated. In patients with high tumor burden, renal insufficiency, or acidosis prior to initiation of chemotherapy, rasburicase may offer a more rapid treatment for hyperuricemia. (For a more detailed discussion of hyperuricemia and tumor lysis syndrome, see chapter 45.)
Coagulopathies can also complicate the hemostatic defects associated with thrombocytopenia. Disseminated intravascular coagulation (DIC) is most often seen in APL (French-American-British Cooperative group [FAB] subtype M3) due to release of procoagulants from the abnormal primary granules, which activate the coagulation cascade, leading to decreased factors II, V, VIII, and X, and fibrinogen, as well as rapid platelet consumption. Lysozyme released from monoblasts in M4 and M5 subtypes of AML can also trigger the clotting cascade. Finally, DIC can occur following asparaginase (Elspar) chemotherapy for ALL.
Abnormalities on the CBC raise the possibility of leukemia. The diagnosis is substantiated pathologically by a bone marrow examination.
All patients should have cytochemistry, immunophenotyping by fluorescent-activated cell sorter (FACS) using monoclonal antibodies directed at leukemia-specific antigens and cytogenetic analysis of the marrow or peripheral blood blasts at diagnosis. Other tests used to evaluate metabolic abnormalities (electrolytes, creatinine, and liver function tests) and coagulopathies are also needed at diagnosis. A lumbar puncture should be performed at diagnosis in all pediatric patients with ALL and in all patients with neurologic symptoms regardless of age and pathology.
Acute leukemias comprise a group of clonal disorders of maturation at an early phase of hematopoietic differentiation. Morphology and cytochemical stains designed to detect intracellular myeloperoxidase or esterases have been the traditional methods used to classify acute leukemias into either myeloid or lymphoid derivations.
Precursor B-cell acute lymphoblastic leukemia (cytogenetic subgroups)
Precursor T-cell acute lymphoblastic leukemia
Burkitt-cell leukemia [t(8;14) or t(8;22)]
Coupling these traditional methods with cytogenetic analysis and highly specific monoclonal antibodies directed against cell-surface antigens has led to the detection of new prognostic factors and has provided an approach to detect minimal residual disease.
In 1997, a panel of hematopathologists met to update the FAB classification of hematologic malignancies, which was based on morphology and cytochemistry alone. They proposed a new classification, incorporating immunophenotyping, cytogenetics, and clinical disease features, which has been adopted by the World Health Organization (WHO; Tables 1 and 2).
The new WHO classification retains the morphologic subgroups of the FAB system in the subgroup of “AML not otherwise categorized” but has created new categories that recognize the importance of certain cytogenetic translocations as predictors of response to therapy. In this category are AML with t(8;21)(q22;q22), AML with abnormal eosinophils and inv(16)(p13;q22) or t(16;16)(p13;q11), AML with 11q23 mixed-lineage leukemia abnormalities, and APL with t(15;17)(q22;q11-12) variants (Table 1).
The WHO classification also attempts to deal with the evidence that, in many older patients, marrow dysfunction antedates the onset of acute leukemia. These myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoietic production and disrupted maturation of one or more cell lines. These abnormalities are often accompanied by loss of chromosomal material, particularly loss of chromosomes –5 or –5q, –7 or –7q, and –3 or –20. As the bone marrow becomes more dysfunctional, increasing numbers of blasts are seen in the marrow.
In the FAB classification, the demarcation line between myelodysplasia and AML was 30% marrow blasts. However, patients with 20%–29% blasts (previously classified as refractory anemia with excess blasts in transition [RAEB-t]) have a biologic behavior and poor survival similar to those of patients with AML. WHO recommended lowering the threshold for the diagnosis of AML to 20% marrow blasts and deleting the FAB category of RAEB-t. In addition, patients with 5%–20% blasts who have t(15;17), t(18;21), or inv(16) are considered to have AML rather than MDS and should receive AML treatment.
The WHO system further subdivides the AML patients with dysplastic maturation into those with or without antecedent cytopenias (usually 3 months prior to diagnosis had been the arbitrary cutoff point) and those with a history of prior exposure to chemotherapy agents (alkylating agents, epipodophyllotoxins, or others). In 2003, the International Working Group for the Diagnosis and Standardization of Response Criteria accepted the WHO classification as the standard for AML diagnosis.
The genetic profile of malignant cells has been found to vary widely from normal, with many genes being either overexpressed or suppressed. DNA microarray techniques allow the simultaneous analysis of thousands of genes that are being studied in AML and ALL for their predictive ability to define cohorts of patients with similar outcomes; this process may in turn allow the selection of candidate genes that can be used as therapeutic targets in the future.
Lymphoblastic leukemias can arise from either B-cell or T-cell progenitors that arrest at an early stage of maturation and then proliferate. Marrow involvement of > 25% lymphoblasts is used as the demarcation line between lymphoblastic lymphoma, in which the preponderance of tumor bulk is in nodal structures, and ALL. Approximately 75% of adult ALLs are B cell in derivation and 25% are T cell.
Precursor B-cell ALL Most B-cell leukemias are early or “pre-B” cell, expressing CD19 and CD10 (the common acute leukemia antigen [cALLa]) but lacking surface or cytoplasmic immunoglobulin; this group of early B-cell leukemias has a more favorable prognosis than that of B-cell leukemias in which the cells have a more mature phenotype. Chromosomal rearrangements juxtaposing an oncogene with a promoter region are often seen in this disease category. A small fraction (2%) of patients with precursor B-cell ALL lack CD10 expression. Patients with CD10 disease have a high incidence of MLL gene expression (83%) and a very poor disease-free survival (12%) at 2 years. The new WHO classification identifies these cytogenetic subgroups (Table 2).
Mature B-cell ALL The more mature B-cell ALL, or Burkitt-cell leukemia, is associated with translocations of the c-myc gene on chromosome 8 and the immunoglobulin heavy-chain gene on chromosome 14q32 in 80% of cases or with the light-chain genes of chromosome 2p11 or 22q11 in the other 20%. Burkitt-cell leukemia has increased in frequency recently, as it is one of the lymphoproliferative disorders that occur in individuals infected with the human immunodeficiency virus (HIV); leukemia may appear early in the course of the HIV infection, before the onset of opportunistic infections or severe T-cell deficiency (see chapter 27).
T-cell ALL is frequently associated with translocations of T-cell receptor genes on chromosome 14q11 or 7q34 with other gene partners. T-cell ALL had been associated with a poor prognosis when treated with conventional ALL regimens but now is associated with a better prognosis if treated with aggressive antimetabolite therapy. Precursor T-cell ALL has a poorer outcome.
Infection with human T-cell leukemia virus-1 (HTLV-1) should be looked for in patients with T-cell ALL presenting with hypercalcemia and lytic bone lesions. HTLV-1 infection is endemic in southern Japan, the southern Pacific basin, the Caribbean basin, and sub-Saharan Africa. High infection rates are also seen in parts of Iran, India, and Hawaii. Recent immigrants from endemic areas retain a risk of infection similar to that of their point of origin. However, fewer than 0.1% of persons carrying HTLV-1 will develop T-cell leukemia.
A subset of patients with leukemia exhibit features of both myeloid and lymphoid differentiation. These patients were originally classified as having mixed- lineage leukemia. Patients with a leukemic clone that expresses two or more ALL antigens and one myeloid antigen comprise 20% of adult ALL cases. Although expression of myeloid antigen is considered to be a poor-risk feature in children, it does not constitute a distinct poor-risk feature in adults.
Immunophenotyping has also helped define a group of patients with undifferentiated myeloid leukemia (M0) who previously were likely to be treated as if they had ALL. These leukemias have a primitive morphology and lack myeloperoxidase. On immunophenotyping, they express at least one early myeloid antigen, usually CD13 or CD33, and no T- or B-cell markers. Based on immunophenotyping, undifferentiated leukemias are treated in the same manner as myeloid malignancies.
Cytogenetic abnormalities have a significant impact on the prognosis of patients with ALL. Approximately half of patients with ALL have cytogenetic abnormalities; they usually take the form of translocations of genetic information, rather than deletions of genetic material, which are seen more commonly in AML.
Philadelphia chromosome The most ominous cytogenetic abnormality in ALL is the translocation of the abl gene from chromosome 9 to the breakpoint cluster region on chromosome 22, forming a new gene product (BCR-ABL) with tyrosine kinase activity. This translocation, referred to as the Philadelphia chromosome (Ph), is found in 95% of cases of CML and in 20%–30% of newly diagnosed adults with ALL.
The fusion protein produced by the Bcr-Abl translocation in Ph+ ALL (p190) differs from the product seen in CML (p210); the p190 product is a smaller protein than the p210 product and has higher tyrosine kinase activity. Use of polymerase chain reaction (PCR) techniques that target only the p210 product will significantly underestimate the incidence of Ph+ ALL. In a recent update of the German ALL trials, 37% of patients were Ph+, with 77% showing the p190 product vs 23% showing the p210 product.
Although patients with Ph+ ALL may attain a morphologic remission with conventional chemotherapy (82%), almost all such patients will have persistent molecular evidence of disease. Patients who do achieve a molecular remission have a longer duration of remission than those who continue to express p190 or p210 activity (30 vs 12 months).
Recently, the GIMEMA group published outcomes data of a large trial of adult patients with ALL in which both cytogenetic data and molecular probes for specific gene products were combined to define prognostic groups. The molecular abnormalities that were evaluated were t(9;22) BCR-ABL, t(4;11)/ MLL-AFA, t(1;19) E2A/PBX1, 9p/p15-p16 deletions, and 6q deletions. Categories based primarily on classic karyotypes were normal, hyperdiploid, and miscellaneous structural abnormalities of uncertain significance.
The use of molecular probes was particularly informative in patients with failed karyotypic analysis or normal cytogenetics. The use of the BCR-ABL probe increased the number of cases with a t(9;22) abnormality from 64 to 104 (26% of patients in the trial); more than 50% of add(9p)/p15-p16 abnormalities were detected only by molecular testing. Patients with t(9;22), t(4;11), and t(1;19) had disease-free intervals of 0.4–0.6 years, whereas those with del(6q), hyperdiploid, or pseudodiploid karyotypes had intermediate disease-free survival of 1.3–1.6 years; those with a normal karyotype or del(9p)/p15-p16 had better outcomes (2.9 and 4 years, respectively).
Other translocations Translocations involving the mixed-lineage leukemia gene at chromosome 11q23 are partnered with several other chromosomes, including 4q21, 9q22, and 19q13. Translocations involving chromosome 11q23 are frequently seen in secondary leukemias, particularly those arising after chemotherapy with etoposide or teniposide. Although most of these translocations are associated with AML, ALL has also arisen in this setting. All the 11q23 translocations, as well as the more common (1;19) translocation, are associated with poorer outcomes when compared with similar immunophenotypes coupled with normal cytogenetics.
Treatment for patients with ALL and AML can be subdivided into two or three phases. Induction chemotherapy is the initial treatment designed to clear the marrow of overt leukemia. This phase usually involves multiple drugs that cause pancytopenia for 2–3 weeks.
The purpose of consolidation therapy is to further reduce the residual leukemic burden in patients who are in morphologic remission. Molecular markers of residual disease can often be detected after induction chemotherapy, which indicates the need for further treatment. The intensity of consolidation therapy varies, depending on the risk of relapse (based primarily on cytogenetic risk groups) and patient age.
Maintenance chemotherapy using low-dose oral chemotherapy for 18–24 months has been shown to prolong relapse-free survival in pediatric patients with ALL and in adults with APL. Its value is less clear in adults with ALL; maintenance is rarely used in AML.
TREATMENT OF ALL
Although 70%–80% of pediatric patients with ALL can anticipate a prolonged remission or cure of disease with combination chemotherapy, the overall long-term disease-free survival for adults with ALL is 35%–50%. Poorer outcomes in adults are attributed to a higher incidence of unfavorable cytogenetic abnormalities [t(9;22), t(8;14), or t(4;11)t(1;19)] or coexpression of myeloid antigens, as well as to higher WBC counts at diagnosis.
Adults also have poorer tolerance for some of the chemotherapeutic agents used in treatment, such as asparaginase, as well as higher rates of infection and comorbid disease, all of which result in increased end-organ toxicity and frequent treatment delays.
Recent reports have emphasized a difference in outcomes for adolescents and young adults dependent upon treatment using pediatric or adult ALL protocols. In a comparison of 177 adolescents (15 to 20 years old) treated on the French pediatric trial vs adult regimens, the complete remission (CR) rate was 98% vs 81% and the 5-year event-free survival rate was 67% vs 41%. The pediatric regimen had significantly higher doses of asparaginase and prednisone and had much higher thresholds for dose reductions and interruption of therapy.
The initial goal of therapy is to rapidly reduce the leukemic burden to a level undetectable by conventional methods of light microscopy and flow cytometry, a state that is deemed a CR. Two standard induction regimens have been used in adults with ALL?the Hoelzer regimen, developed by the Berlin-Frankfurt-Munster (BFM) multicenter group, and the Larson regimen, developed by the Cancer and Leukemia Group B (CALGB). Along with the standard induction schemas, two newer regimens, the Hyper-CVAD regimen from M. D. Anderson and the Linker regimen (2002 version), which have a similar induction drug dosing as the older regimens but include much higher doses of antimetabolites (cytarabine and methotrexate) and etoposide for dose-dense consolidations, are outlined in Table 3 along with the standard induction schemas. Overall, complete remissions are obtained in 80%–94% for adults younger than age 60 treated with any of these regimens.
The addition of an anthracycline to the standard pediatric leukemia induction regimen of vincristine, prednisone, and asparaginase increased the CR rate in adults from 50%–60% to 70%–85% in several series. In a recent CALGB study, the use of cytokines, ie, granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]), during induction in patients older than 60 years of age reduced treatment-related mortality from 31% to 5% when compared with placebo-treated controls.
The US Food and Drug Administration (FDA) recently approved pegaspargase (Oncaspar) as a component of a multiagent chemotherapy regimen for the first-line treatment of patients with ALL. The drug had originally been approved only for ALL patients who were allergic to native forms of asparaginase.
T-cell ALL There is evidence that patients with T-cell ALL may benefit from early treatment with cytarabine (Ara-C) and cyclophosphamide. Pharmacologic studies show high levels of Ara-C triphosphate accumulation in T lymphoblasts and synergy between cyclophosphamide and Ara-C in cell lines of T-cell malignancies. T lymphocytes also have a lower expression of polyglutamate synthetase than pre-B blasts. Randomized trials in children with T-cell ALL showed that the use of high-dose methotrexate (up to 5 g/m2) improved outcome.
Mature B-cell ALL Patients with the more mature B-cell ALL (Burkitt-cell leukemia) experienced an improvement in survival when high doses of cyclophosphamide, methotrexate, and Ara-C were incorporated early in the treatment course. The probability of leukemia-free survival improved from 35% with standard ALL induction to 60%–70% with these newer regimens.
The BFM, CALGB, Linker (2002), and Hyper-CVAD consolidation regimens for ALL are outlined in Table 3. As yet, no randomized trials have compared these regimens. However, in sequential studies from Memorial Sloan-Kettering Cancer Center and the BFM group, as well as the Linker study, use of multiple cycles of non–cross-resistant drugs for 3 to 8 cycles after remission followed by maintenance with methotrexate and mercaptopurine (Purinethol) resulted in overall long-term disease-free survival rates of 38%–52%.
Long-term outcome data of 288 patients treated with Hyper-CVAD showed an 81% CR rate after 1 cycle and a 92% rate after 1 cycle each of A&B (see Table 3); a 5% overall death rate during induction was noted, although treatment-related mortality reached 15% in patients older than age 60 despite the use of G-CSF. At a median follow-up of 63 months, the 5-year disease-free survival was 38%, similar to that reported in the BFM and CALGB trials. In this series, adverse prognostic factors for disease-free survival were age ≥ 45 years, poor performance status, WBC > 50,000/µL, Ph+ cytogenetics, more than 1 cycle to achieve a CR, or > 5% residual blasts at day 14. Patients with none or one of these factors had a 52% 5-year disease-free survival rate, vs 37% for patients with 2 or 3 factors and only 10% for patients with ≥ 4 risk factors.
In the 2002 Linker trial, which intensifies the consolidation with alternating cycles of higher dose Ara-C (HDAC) and etoposide alternating with cycles of high-dose methotrexate, the 5-year relapse-free survival rate was 52% overall and 60% for patients with standard-risk features. Prognostic features that were associated with a poor outcome in this study included pre-B ALL with > 100,000/µL WBC count at diagnosis, cytogenetic abnormalities involving chromosome 11q23 or t(9;22), and time to remission > 30 days. Without either allogeneic or autologous transplantation, all high-risk patients relapsed within a short (1–9 month) time.
The French LALA-94 trial of 922 patients was designed to look at postremission therapy that was stratified by risk of relapse. The standard-risk patients who achieved CR with 1 cycle of induction therapy were randomized to receive either conventional cyclophosphamide, Ara-C, and mercaptopurine or early intensification with intermediate-dose Ara-C (1 g/m2 × 8 doses) and mitoxantrone.
In this group, there was no difference in 5-year disease-free survival (33% conventional vs 37% early intensification, with an overall survival at 5 years of 44%). High-risk patients included those with defined cytogenetic risks (excluding Ph+), WBC > 30,000/µL, and CNS disease at diagnosis or who required more than 35 days to achieve CR. Patients with a sibling donor received allogeneic transplant in CR, with the remainder randomized to receive either the early intensification chemotherapy or autologous transplant. The 5-year disease-free survival was 45% for those receiving allogeneic transplant and 23% for those without a donor.
There was no significant difference in overall survival with chemotherapy vs autologous transplant, but there was a different pattern of relapse, with fewer late relapses in the autologous patients (disease-free survival 25% vs 13% for chemotherapy only). The patients with Ph+ disease were randomized to receive allogeneic transplant with either a sibling or unrelated donor or autologous transplant. Although allogeneic transplant resulted in a significantly better 3-year disease-free survival (34%) than autologous transplant (15%); these outcomes indicate the need for improved consolidation strategies.
Prognostic factors for relapse In all the large European and American trials, there are several common factors associated with poor outcome. The most consistent factor is the presence of t(9;22), t(4;11), or (1;19) cytogenetic abnormalities. Increasing age and higher leukocyte counts at presentation are also poor-risk features. A recent international trial involving more than 1,500 patients confirmed prior observations that in Ph-negative patients, age (> 35 years), WBC count > 30,000/µL for precursor B-cell ALL and > 100,000/µL for T-cell ALL and lineage itself are prognostic factors of overall and disease-free survival. Younger patients with low WBC counts had a 55% 5-year disease-free survival rate vs 34% for patients with either the age or WBC parameters listed above and 5% for patients with poor-risk features. In addition, the rapidity of response has been an important prognostic factor for outcome, with the time point for expectation of clearance of marrow blasts shortening from 28 days in the BFM trial to 14–17 days with the Linker regimen and day 8 in both with the most recent French (LALA 94) trial and the pediatric ALL trials.
Molecular techniques, such as PCR amplification of leukemia-specific sequences of RNA or DNA, have been used in research settings to reveal residual leukemia cells. These sensitive techniques can detect the persistence of cells with the leukemic phenotype at a sensitivity of 1 cell in 104 normal cells in patients who are deemed to be in CR by conventional techniques. In two pediatric studies, detection of leukemia-specific gene rearrangements ( ≥ 1 cell in 104 normal cells) 5–6 months after initiation of treatment was associated with a high relapse rate.
A confirmatory study in adults with standard-risk ALL using a combination of aberrant immunophenotyping and PCR amplification of T-cell receptor or immunoglobulin gene rearrangements was recently reported. Patients who had no detectable residual disease by day 11 from the start of induction therapy had a 3-year disease-free survival rate of 92% compared with 65% for those with no residual disease by week 16. Patients who had detectable minimal residual disease beyond that point had a 3-year disease-free survival of only 12%.
High-risk patients Although the BFM regimen is now standard therapy for good-prognosis patients, high-risk patients are being selected for dose-intensive therapies, including HDAC and methotrexate or etoposide, high-dose methotrexate, and asparaginase.
For patients with Ph+ ALL, several centers have begun combining imatinib (Gleevec) with induction and consolidation chemotherapy. In series from both Japan and the United States, the addition of imatinib during induction has resulted in a CR rate of 95%–100% after 1 cycle of induction, and patients have achieved molecular remission documented by PCR in 50%–60% of patients within 2 months.
Transplantation Recent series have reported a disease-free survival rate of 55%–68% for “high-risk” patients with ALL undergoing transplantation during first CR. When treated with conventional-dose chemotherapy prior to the discovery of imatinib, patients with Ph+ ALL had a disease-free survival rate of < 10% regardless of other risk factors and a median time to relapse of 12 months. These patients should be referred for allogeneic or matched-unrelated donor (MUD) transplantation expeditiously upon attaining a CR. Several centers are incorporating imatinib along with conventional consolidation chemotherapy in patients with Ph+ ALL to try to reduce the leukemic burden further before transplantation, primarily in patients awaiting an unrelated donor transplant. Trials using imatinib post allogeneic transplantation to reduce relapse rates are also in progress. (Strategies for the most effective use of the various transplant options are discussed in chapter 36.)
CNS relapse occurs at a much higher frequency in patients with ALL compared with those with AML. The rate of CNS relapse was 20% in the first year in a pediatric ALL trial in which the CNS therapy was attenuated to a subtherapeutic level.
Patients with ALL require preemptive therapy for occult CNS disease with either (1) intrathecal methotrexate and/or Ara-C combined with cranial irradiation or (2) high-dose systemic Ara-C or methotrexate combined with intrathecal therapy.
Maintenance therapy with daily mercaptopurine and weekly methotrexate for 18–24 months beyond consolidation remains the standard of care for children with ALL. In adults, the benefit of maintenance therapy is less certain. In low-risk adults, who may have an outcome more similar to that in the pediatric population, maintenance therapy would appear to be justified (see Table 3 for maintenance regimens). In individuals who have mature B-cell ALL, it is unlikely that maintenance therapy has any effect. In other high-risk adult populations, more than half of patients relapse while on maintenance therapy, indicating the need for other strategies to eradicate minimal residual disease.
Treatment of relapsed adult ALL is a major challenge. Since most protocols for initial treatment incorporate 6 to 11 agents with different cytotoxic mechanisms, a selection process for drug resistance has occurred. The overall remission rate for relapse therapy is 30%–40%, with a median duration of remission of 6 months.
Salvage strategies include reinduction with the initial regimen in patients with late relapse or high-dose antimetabolites (Ara-C or methotrexate [see hyper-CVAD regimen, Table 3]) in those who relapse early. Recent experimental approaches include monoclonal antibodies directed against leukemia-specific antigens conjugated to either radionuclides or toxins, tyrosine kinase inhibitors, allogeneic or autologous transplantation, or new agents. In clinical trials, Ara-C has produced a CR in 53% of T-cell ALL induction failures on first relapse and in 27% in second relapse in children; responses of 25% have been reported in adults.
Clofarabine (Clolar) has been approved for treatment of relapsed refractory ALL in children. Of 25 patients, 5 achieved a CR, including children who had relapsed following allogeneic transplantation. The maximum tolerated dose was 52 mg/m2 infused over 1 hour daily for 5 days. Significant toxic effects include capillary leak syndrome, hepatotoxicity, and skin rash.
In individuals with Ph+ ALL or CML in lymphoid blast crisis, imatinib can induce remissions in up to 30% of patients. These remissions are short-lived, but imatinib may control the leukemia long enough for a donor to be identified, thus providing an option for an allogeneic transplant in second remission, which carries a better outcome than a transplant performed with active disease. In patients with relapsed Ph+ ALL, the addition of interferon-alfa-2a (Roferon-A) to imatinib has shown durable remissions (> 18 months) in five of six patients who were not candidates for transplantation.
Dasatinib (Sprycel), recently approved by the FDA for imatinib-resistant Ph+ leukemias, can provide short-term salvage therapy for patients whose disease progresses while receiving combinations of imatinib and chemotherapy.
Nelarabine (Arranon) has also recently been approved for the treatment of T-cell lymphoblastic disease. In a recommended dose of 1,500 mg/m2 on days 1, 3, and 5, this agent has produced response rates of 30%–50% in heavily pretreated patients.
TREATMENT OF AML
Although the chemotherapeutic agents used in the initial therapy for AML have not changed much in the past 30 years, our knowledge of the biology of leukemia has increased. The identification of prognostic factors can provide more realistic expectations of response to standard treatment and can define the population for whom investigational therapy is appropriate early in the course of disease.
Prognostic factors Cytogenetic abnormalities and mutation of the fetal liver tyrosine kinase (FLT3) gene are the major predictors of remission and risk of relapse for patients with AML. Patients with translocation of genetic materials involving core binding regions [t(15;17), t(8;21) inv(16), or t(16;16)] have a good prognosis, with remission rates of 88% and 5-year disease-free survival rates of 55%–90%, whereas patients with loss of genetic material from chromosome 5 or 7 (–5 or –5q, –7 or –7q) and complex karyotypic abnormalities (defined as more than three abnormalities) have lower rates of CR (30%–40%) and disease-free survival (5%) at 5 years. Patients with either normal or intermediate cytogenetic abnormalities have a CR rate of 67% and a 5-year disease-free survival rate of 25%, based on data from a large CALGB trial.
Internal duplication of FLT3 can be found in one-third of patients with normal cytogenetics or in patients with t(15;17) (APL) but is uncommon in either poor-risk karyotypes or non-APL translocations. This abnormality does not appear to have an impact on remission, but it is a predictor for relapse (74% relapse rate in FLT3 patients with a normal karyotype vs 46% for patients without FLT3).
Mutations of nucleophosmin protein (NPM1), which shuttle nucleic acids and proteins from the nucleus to the cytoplasm as well as binding p53, are a newly reported common abnormality, most prevalent (47%) in patients with a normal karyotype. Although there is frequent overlap with FLT3 mutations, patients with an isolated NMP1 mutation and a normal karyotype have a 60% disease-free survival versus 40% for those with either wild-type or mutations of both FLT3 and NMP1 and 20% for those with an isolated FLT3 mutation.
Poor-risk cytogenetics, antecedent MDS, and a high incidence of multidrug resistance (MDR-1) protein are found more commonly in patients older than age 60, which accounts for the lower CR rates (30%–55%) seen in older individuals compared with their younger counterparts (remission rates, 60%–80%). Many older patients with preexisting MDS may clear marrow blasts with antileukemic treatment but may still have impaired hematopoiesis and persistent cytopenias, since they may have no normal residual stem cells to repopulate the marrow.
For the majority of patients with AML, induction chemotherapy is initiated before cytogenetic information is available; the notable exception is with APL-FAB-M3, which has a distinctive morphology and clinical presentation. The gene product of the t(15;17) translocation can be rapidly confirmed by PCR when the clinical diagnosis is suspected. Since the therapy for APL differs significantly from that for the other AML subtypes, it is important to make this distinction.
Ara-C and an anthracycline such as daunorubicin or idarubicin (Idamycin) have been the standard drugs used for AML induction chemotherapy for 30 years (Table 4). Depending on the prognostic groups, remission rates of 60%–80% are seen in younger (< age 60) patients and of 35%–55% in patients older than age 60. Other agents such as mitoxantrone and etoposide also have antileukemic activity, but no significant increase in remission rates or relapse-free survival have been seen when mitoxantrone was substituted for an anthracycline or etoposide was added to infusional Ara-C and daunorubicin. Mitoxantrone and etoposide were compared with Ara-C and daunorubicin as induction for patients older than age 55 in SWOG (Southwest Oncology Group) trials; CR rates were 44% for Ara-C and daunorubicin and 33% for mitoxantrone and etoposide, and median survival was 8 and 6 months, respectively.
Gemtuzumab ozogamicin (Mylotarg), an anti-CD33 antibody conjugated to the drug calicheamicin, was originally approved for the treatment of relapsed AML in older patients. Currently, there are two clinical trials in Great Britain and the United States evaluating the addition of gemtuzumab ozogamicin to standard Ara-C and daunorubicin or fludarabine, idarubicin, Ara-C, and G-CSF. Preliminary reports from the British trial showed a CR rate of 86%.
Gemtuzumab ozogamicin has also been used as a single agent for induction in patients > 61 years who were considered too frail for conventional therapy with Ara-C and daunorubicin. A CR rate of 33% was achieved in 18 patients aged 61 to 75 years; no benefit was seen in 22 patients older than age 75 due to high early mortality (7 of 22 patients).
Another strategy to improve remission rates has been to use higher doses of Ara-C during induction. Both the Australian Leukemia Study Group (ALSG) and the SWOG compared standard Ara-C and daunorubicin (and etoposide in the ALSG trial) with high-dose Ara-C in patients < 50 years (Table 4). The CR rates were 71% and 74% for standard vs high-dose therapy in the ALSG study and 55% vs 58% in the SWOG trial. In both studies, there was a significantly higher disease-free survival for the high-dose arm at 5 years and (48% vs 25% for ALSG and 33% vs 22% for SWOG) but no difference in overall survival due to increased early toxicity.
Subgroups of patients may benefit from high-dose Ara-C. In the SWOG trial, patients with CD34+ blasts had a low CR rate of 36% with standard Ara-C but an equivalent rate to those with CD34– blasts (58%) when treated with high-dose Ara-C. There was a strong correlation between CD34 positivity and MDR-1 expression is this cohort, leading to the inference that high-dose Ara-C might help overcome drug resistance.
However, a recent 1,700-patient German trial showed no difference in disease-free survival when two cycles of high-dose Ara-C and mitoxantrone (HAM) were compared with one cycle of standard Ara-C-containing regimen followed by HAM. The overall disease-free survival was 40% for both arms in patients younger than age 60 and 29% for those older than age 60; 80% of young patients received both cycles, while only one-third of patients over 60 received cycle 2 irrespective of dose intensity of the initial cycle.
Therapy-related AML has a particularly poor prognosis. At best, only 50% of patients will achieve a remission, usually of brief duration (median, 5 months), despite the use of aggressive drug combinations. Allogeneic or unrelated-donor transplants appear to offer the only curative option in these patients, achieving a 3-year disease-free survival rate of 25% in two studies of allogeneic transplantation.
GM-CSF An Eastern Cooperative Oncology Group (ECOG) study showed that granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]), used following completion of induction chemotherapy in older patients (55–70 years old), shortened the duration of neutropenia by 6 days and, thus, decreased treatment-related mortality, leading to both an improved CR rate and longer survival. The FDA approved GM-CSF for use in this setting. However, other trials using different cytokines in younger patients have not shown a survival benefit.
Once remission of AML is attained, consolidation chemotherapy is required to achieve a durable remission or cure. Standard consolidation regimens are listed in Table 4.
Increased dose intensity In a CALGB study, 596 patients in CR were assigned to receive four courses of postremission Ara-C in one of three dosages: 100 mg/m2 as a continuous infusion for 5 days, 400 mg/m2 as a continuous infusion for 5 days, or 3 g/m2 as a 3-hour infusion every 12 hours on days 1, 3, and 5. For patients ≤ 60 years old, the percentage of patients in CR at 4 years was significantly higher in the HDAC group (44%) than in either the 400-mg/m2 or 100-mg/m2 group (29% and 24%, respectively). For patients > 60 years old, consolidation dose intensity had no impact on disease-free survival, with all groups plateauing at a rate of 16% by 2 years.
Other approaches to consolidation include 1 to 3 cycles of consolidation followed by autologous or allogeneic bone marrow transplantation. Both of these approaches also tend to be limited to patients < 60 years old and have produced long-term disease-free survival rates of 45%–60% in several studies. (See chapter 36 for a more detailed discussion of transplantation approaches.) Long-term disease-free survival is strongly influenced by cytogenetic abnormalities present at diagnosis, and transplant options should be considered for patients with high-risk features while in first remission due to poor outcomes with conventional chemotherapy.
Routine CNS prophylaxis is recommended only for adult patients with AML at high risk of CNS recurrence, ie, patients with a WBC count > 50,000/µL at presentation or those with myelomonocytic or monocytic AML (FAB M4 or M5). Patients receiving HDAC (≥ 7.2 g/m2) for induction or consolidation therapy achieve therapeutic drug levels in the CSF, obviating the need for intrathecal therapy. Patients given conventional Ara-C doses may be treated with intrathecal methotrexate (12 mg IT) or Ara-C (30 mg IT). Both agents can be combined with hydrocortisone (30 mg IT) for patients with active CNS disease.
TREATMENT OF REFRACTORY OR RELAPSED AML
Patients who do not respond to initial therapy or who relapse within 6 months of attaining a CR, as well as those with antecedent myelodysplasia or therapy-related AML, are considered to have relatively resistant disease.
Efforts to overcome drug resistance have focused on (1) HDAC-containing regimens, (2) new agents, (3) targeted therapy using leukemia-specific monoclonal antibodies conjugated with radionuclides or toxins, and (4) nonchemotherapeutic agents to block the drug efflux pump associated with MDR-1 gene expression.
HDAC High doses of Ara-C (2–3 g/m2 for 8-12 doses) paired with mitoxantrone, etoposide, methotrexate, or fludarabine have produced short-lived CRs in 40%–60% of relapsed patients with AML (see Table 5 for dosage regimens). Response rates were higher in patients who had received standard-dose Ara-C for induction and who had subsequently relapsed than in those in whom induction therapy had failed. The median duration of remission was 4–6 months.
Combinations of mitoxantrone and etoposide have been reported to produce a 40%–50% CR rate in patients who had relapsed or for whom standard dose Ara-C and anthracycline had failed, again with a median duration of remission of 4–6 months. Combinations of intermediate-dose Ara-C (1 g/m2/d for 6 days) with mitoxantrone and etoposide produced CR rates of 79% in relapsed patients and 46% in those who did not respond to induction therapy or had AML evolving from MDS, with a median CR duration of 8 months.
New agents Topotecan (Hycamtin) in combination with Ara-C has been reported to produce a CR in 35%–70% of patients with high-grade myelodysplasia.
Nucleoside analogs, such as cladribine (2-CdA) and fludarabine, showed activity in pediatric AML. A British trial reported a 61% CR rate for a combination of fludarabine, Ara-C, G-CSF, and idarubicin, with a median CR duration of 7 months. The combination of gemcitabine (Gemzar; 600 mg/m2/hr, with infusion durations escalating from 6–12 hours) and mitoxantrone (12 mg/m2/d × 3 days) beginning on day 1 was used to treat 26 patients with relapsed or refractory AML and 8 patients with MDS or CML blast crisis. Five CRs and six partial remissions (PRs) were seen in the patients with AML and four CRs and one PR were seen in the MDS/CML group. The maximum tolerated duration of gemcitabine infusion was 12 hours, with stomatitis and esophagitis being the nonhematologic toxicities in 50% of patients. Another nucleoside analog, clofarabine, showed a 16% remission rate in a phase I-II trial in patients with relapsed AML.
Another class of chemotherapeutic agents that are being evaluated are farnesyl transferase inhibitors, which target signal transduction pathways. One of these agents, tipifarnib (Zarnestra), showed a 29% response rate as a single agent in patients with relapsed or refractory AML. Currently, SWOG is evaluating two different doses and schedules of this drug in patients at least 70 years old with newly diagnosed AML. Temozolomide (Temodar), an oral alkylating agent currently approved for the treatment of astrocytoma, has been shown to have activity against myeloid malignancy, with a 20% clearance of marrow blasts in 18 patients with high-risk myeloid malignancy following a 7-day course of medication. Prolonged marrow aplasia was the dose-limiting toxicity.
Another approach being studied in older patients is the use of hypomethylating agents, such as decitabine or azacitidine, either alone or in combination with histone deacetylase inhibitors, such as valproic acid, for the initial treatment of older patients with AML. Response rates of 15%–25% have been reported.
Targeted therapy Gemtuzumab ozogamicin has been approved by the FDA for the treatment of relapsed AML in older patients (Table 5). Aggregate data from three trials involving 277 patients, with a median age of 61, showed a 26% complete response rate, with a median remission duration of 6.4 months.
Treatment-related toxicity was low; the only infusional side effects were fever/chills and slow platelet plus granulocyte recovery (≥ 5 weeks). No cardiac or cerebellar toxicities were reported. Liver function abnormalities were reported in 25%–30% of patients. The median CR duration for responding patients was 9 months.
Multidrug resistance modification Cyclosporine is a potent inhibitor of p-glycoprotein–mediated drug efflux. A SWOG trial compared HDAC, 3 g/m2/d × 5 d, followed by daunorubicin, 45 mg/m2/d as a continuous infusion on days 6-8, either alone (arm 1) or together with cyclosporine, 16 mg/m2/d as a continuous infusion on days 6–8 (arm 2) in 226 patients with relapsed or refractory AML. Although the CR rates were similar for arms 1 and 2 (33% vs 40%), the relapse-free survival rates favored patients treated with the MDR modifier (9% for arm 1 vs 34% for arm 2 at 2 years; P = .03). The overall survival rate was also superior (12% for arm 1 vs 22% for arm 2 at 2 years; P = .04). Survival and induction response improved with increasing concentrations of daunorubicin intracellularly in cyclosporine-treated patients, suggesting that cyclosporine enhanced anthracycline cytotoxicity. Trials substituting the cyclosporine analog valspodar (PSC-833, Amdray) have not demonstrated a significant improvement in CR rate or survival.
Transplantation Although none of the previous options currently offers more than a 10%–15% chance of long-term disease-free survival, they do provide temporary cytoreduction sufficient to permit further high-dose treatment strategies, such as bone marrow transplantation using sibling, unrelated donor or purged autologous marrow. Allogeneic bone marrow transplantation achieves a 30%–40% disease-free survival rate at 5 years in patients transplanted during first relapse or second remission. Autologous bone marrow transplantation also has curative potential for patients beyond first CR, with most large series reporting disease-free survival rates of 30%–35% in selected patients (usually those with good-risk cytogenetics or initial CR duration longer than 1 year).
Reduced-intensity conditioning regimens are being explored as treatment options in older patients and in those with comorbidity that would otherwise preclude full-dose allogeneic transplantation. Preliminary results from several centers have shown 1- and 2-year disease-free survival rates of 50% for patients aged 55 to 70 years receiving reduced-intensity allogeneic transplantation for consolidation of first remission.
New methods of marrow purging and post-transplant immune stimulation also are being explored to decrease relapse-related mortality.
TREATMENT OF APL
APL represents a uniquely homogeneous subset of AML defined by its cytogenetic abnormality, t(15;17), which results in fusion of the retinoic acid receptor (RAR) α-gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. This abnormality yields the PML/RAR-α fusion protein, detectable by PCR techniques, which is useful for both diagnosis and evaluation of minimal residual disease (MRD). Most (80%) patients with APL have characteristic hypergranular blasts; laboratory evidence of DIC is present in 70%–90% of patients at diagnosis or shortly after. Although low-dose heparin (5–15 U/kg/h) and factor replacement are used as supportive adjuncts during chemotherapy, hemorrhagic events contribute 10%–15% excess mortality during induction chemotherapy for APL compared with other AML subtypes.
Because of the unique biology and specific clinical features of APL, induction and consolidation regimens for APL differ from strategies used for other FAB types.
Involvement of the RAR-α gene in the pathogenesis of APL suggested the use of retinoids as therapy. A study from Shanghai showed CR rates of 85% with all-trans-retinoic acid (ATRA, tretinoin, Vesanoid). ATRA offered the advantages of a shorter neutropenic period (2 weeks) and slightly faster resolution of DIC (4 vs 7 days), as compared with standard chemotherapy with Ara-C and daunorubicin. Normalization of marrow morphology and cytogenetics requires 30–60 days of ATRA.
APL syndrome Approximately 25% of patients with APL develop “differentiation syndrome” (formerly known as ATRA syndrome). Symptoms of this syndrome are fever, respiratory distress with pulmonary infiltrates or pleural effusions, and cardiovascular collapse. Temporary pseudotumor cerebri is a fairly common (10%) side effect of ATRA. Although these symptoms most often correlate with leukocytosis (WBC count > 10,000/µL), many patients develop symptoms with WBC counts between 5,000 and 10,000/µL. The syndrome is seen in patients treated with ATRA as well as in those treated with arsenic trioxide (Trisenox).
Treatment of this syndrome involves prompt use of high-dose steroids, initiation of either hydroxyurea or conventional Ara-C/daunorubicin chemotherapy to control leukocytosis, and temporary discontinuation of ATRA or arsenic trioxide.
Standard-dose Ara-C and daunorubicin produced CR rates of 70%–80% within disease-free survival rates of 40%–50%. WBC and platelet counts at presentation correlate with the risk of relapse. Patients with a WBC < 10,000/µL and a platelet count > 40,000/mL have a disease-free survival of 97%; those with a WBC < 10,000/µL and a platelet count < 40,000/mL have a disease-free survival of 86%; those with a WBC > 10,000/µL have a disease-free survival of 78%.
Three large studies have shown that ATRA in combination with anthracycline-based chemotherapy results in an improved long-term disease-free survival. The French APL 93 trial compared sequential ATRA followed by chemotherapy with concomitant ATRA plus chemotherapy (see Table 6, first regimen). Patients achieving CR received 2 cycles of consolidation therapy and then were randomized to receive 1) intermittent ATRA (2 weeks every 3 months for 2 years), 2) low-dose oral chemotherapy (mercaptopurine and methotrexate for 2 years), 3) both, or 4) observation. The CR rate in both induction arms was 92%. However, relapse rates were 6% for the ATRA plus chemotherapy arm vs 16% for ATRA followed by chemotherapy (P = .04).
A total of 289 patients were randomized to receive maintenance treatment. Relapse rates at 2 years were 30% for patients who received no maintenance treatment, 18% for patients receiving ATRA maintenance therapy alone, 14% for patients receiving chemotherapy without ATRA, and 7% for patients receiving chemotherapy plus ATRA. Overall survival was significantly better in patients receiving maintenance chemotherapy with or without ATRA for 2 years.
The Italian AIDA study used only ATRA and idarubicin for induction. The CR rate was 95%, with only 5% mortality during induction, suggesting that Ara-C is not required to achieve remission (Table 6). However preliminary reports from the French APL 2000 study, which compared daunorubicin (60 mg/m2 for 3 days) and ATRA alone with a regimen that also used infusional Ara-C during induction and consolidation, showed a reduction in the relapse rate (3.8% vs 11.9%) for the arm with Ara-C and a disease-free survival rate of 94% vs 83%.
Small single-institution series have reported favorable remission and disease-free survival rates in patients induced with arsenic trioxide alone (86% complete response) or combined with ATRA (95% for low- and intermediate-risk patients). High-risk patients had poorer response rates (75% complete response) despite the addition of gemtuzumab ozogamicin (9 mg/m2) on day 1 of induction therapy.
New agents Arsenic trioxide is now the standard reinduction therapy for patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. As a single agent, arsenic trioxide has produced a CR in 34 of 40 patients (85%) with relapsed APL, with 86% of patients achieving molecular remission. Relapsed patients who achieved a molecular remission with arsenic trioxide alone had a median relapse-free survival of 18 months; those who received arsenic trioxide followed by autologous transplantation have had relapse-free survivals in excess of 70% at 2 years. Allogeneic transplantation should be reserved for those who do not achieve a molecular remission.
Although liver toxicity was reported with the use of arsenic trioxide in the original Chinese studies, the most significant toxicities in the US multicenter trial were the “APL syndrome,” ventricular arrhythmia in patients with prolongation of the AT/QTc interval on ECG, and peripheral neuropathy. It is important to monitor potassium, magnesium, and calcium levels closely, almost daily, during arsenic trioxide therapy; maintaining these levels near the upper range of normal is important in preventing arrhythmia.
The most recent US Intergroup APL trial incorporated arsenic trioxide in consolidation therapy for APL in first CR. Patients were randomized to receive either 2 cycles of daunorubicin plus ATRA or 2 cycles of arsenic trioxide followed by 2 cycles of daunorubicin plus ATRA for consolidation. Patients were then randomized to receive maintenance with either ATRA alone or in combination with mercaptopurine and methotrexate. The data from the trial are currently being analyzed.
Gemtuzumab ozogamacin is also an effective agent for patients with relapsed APL. In a small series, 91% of patients with a molecular relapse of APL achieved a molecular remission following two doses of gemtuzumab ozogamicin (6 mg/m2).
Monitoring response to therapy Reverse-transcriptase (RT) PCR for the PML/RAR-α fusion protein can be used to follow response to therapy. The marker clears slowly, with many patients still testing positive following induction therapy. However, patients with persistence of PML/RAR-α at the end of consolidation therapy are at high risk of relapse, as are those with reemergence of the marker following a period without detectable protein. Salvage chemotherapy should be considered for patients with persistent or recurrent confirmed molecular relapse.
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