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Cytogenetic analysis provides some of the strongest prognostic information available, predicting outcome of both remission induction and post-remission therapy.[10] Cytogenetic abnormalities which indicate a good prognosis include t(8;21), inv(16), and t(15;17). Normal cytogenetics portend average-risk AML. Patients with AML that is characterized by deletions of the long arms or monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome 3, t(6;9), t(9;22); or by abnormalities of chromosome 11q23 have particularly poor prognoses with chemotherapy. These cytogenetic subgroups predict clinical outcome in elderly patients with AML as well as in younger patients.[11] The fusion genes formed in t(8;21) and inv(16) can be detected by reverse-transcriptase polymerase chain reaction (RT-PCR), which will indicate the presence of these genetic alterations in some patients in whom standard cytogenetics was technically inadequate. RT-PCR does not appear to identify significant numbers of patients with good risk fusion genes who have normal cytogenetics.[12] Abnormalities of the MLL gene (chromosome 11q23) can also be detected using RT-PCR and may be detected in some cases of leukemia with normal cytogenetics. These molecular diagnostic techniques are not readily available.[1-4,13,14]
Subtypes of AML are acute myeloblastic leukemia (with or without maturation), acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, erythroleukemia, and acute megakaryoblastic leukemia.[15] Morphologic, histochemical, immunologic, and cytogenetic criteria for these distinctions have been standardized.[16,17] Each criterion has subtle prognostic and treatment implications but, for practical purposes, antileukemic therapy is similar for all subtypes. The large lysosomal granules seen in acute promyelocytic leukemia signal the high probability of severe hemorrhagic complications during early induction therapy.[18,19] If the patient demonstrates evidence of disseminated intravascular coagulation, the early institution of low-dose heparin for anticoagulation is commonly used; however, there is some controversy on this point.[20] Aggressive transfusion support with fresh frozen plasma, cryoprecipitate, and platelets is often also necessary. Remission induction of acute promyelocytic leukemia with tretinoin (ATRA), alone or in combination with cytotoxic agents, is an area of clinical evaluation.[21,22] ATRA induction appears to normalize the coagulopathy more quickly than does conventional induction therapy, but it can be associated with the development of hyperleukocytosis and adult respiratory distress syndrome that is steroid-responsive (the so-called "retinoic acid syndrome").[23] Prophylactic heparin is not generally used in patients receiving ATRA induction. The optimal integration of ATRA into the treatment of M3 AML has not been defined (see the Untreated AML section of this summary).
Allogeneic bone marrow transplantation can be considered in patients younger than 60 years of age in first remission if a histocompatible sibling is available as a potential donor. Although data have shown that partially matched donors can also be used in some circumstances, the incidence of severe graft-versus-host disease, delayed engraftment, and graft rejection is significantly increased. Transfusion of blood products from potential donors should be avoided, and histocompatibility testing should be done at the earliest possible time. Although some data suggest that transplantation in patients during their first remission may improve long-term survival, these data need to be confirmed. In some studies, results from chemotherapy alone or high-dose chemotherapy with autologous bone marrow transplantation [24-34] appear to be comparable to those of allogeneic transplantation.[35,36]
As a generalization, most studies demonstrate that the rate of leukemic relapse is decreased following allogeneic bone marrow transplantation in first remission compared with chemotherapy alone. Because of the higher initial mortality with bone marrow transplantation caused by graft-versus-host disease and interstitial pneumonia, however, comparative analyses of the two approaches demonstrate similar overall survivals. An analysis of bone marrow transplant results has also suggested that the same factors that predict for shorter response durations with chemotherapy (i.e., high initial white blood cell count, monocytic morphology, and age) may also result in shorter remission duration following transplantation. Allogeneic bone marrow transplantation has yielded a high rate of complete response in patients for whom initial induction therapy failed,[37] and autologous bone marrow transplantation may produce long-term leukemia-free survival in approximately one third of patients in either first relapse or second complete remission.[38] Results of allogeneic bone marrow transplantation have modestly improved since 1980, largely because of a reduction in transplant-related mortality;[39] further follow-up of these and other studies is needed before firm recommendations can be made.[31,40] It should be noted that transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.[41]
Cytogenetic studies should be performed at the time of diagnosis.[42] As noted above, there is increasing evidence of nonrandom chromosomal rearrangements in some of the subtypes in the French-American-British classification, which have important prognostic significance.[43]
The differentiation of AML from acute lymphocytic leukemia has important therapeutic implications. Histochemical stains, TdT determinations, and cell surface antigen determinations aid in discrimination.
M1, M2, and M3 leukemia show predominantly granulocytic differentiation and differ from one another in the extent and nature of granulocytic maturation; M4 shows both granulocytic and monocytic differentiation; M5 shows predominantly monocytic differentiation; and M6 shows predominantly erythroblastic differentiation. M7 is associated with leukemic megakaryocytes.
Myeloblastic leukemia without maturation (M1)
Of note is that most such cases are associated with abnormalities of
chromosome 16 and may be associated with an improved overall prognosis and
an increased propensity for central nervous system involvement.
abnormal bone marrow with more than 30% blasts and signs and symptoms of the disease, usually accompanied by an abnormal white blood cell count and differential, hematocrit/hemoglobin, and platelet count.
Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1-3]
Treatment is divided into two phases: induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States (see the adult AML in remission section of this summary). Other studies have used more intensive "consolidation" therapy administered for a shorter duration of time after which treatment is discontinued.[4] Consolidation therapy appears to be effective when given either immediately after remission is achieved [4] or when delayed for 9 months.[3]
Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions, as well as for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000 per cubic millimeter rather than 20,000 per cubic millimeter.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, e.g., granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in one randomized trial of AML in patients 55 to 70 years of age (median survival was 10.6 months versus 4.8 months). In this trial, patients were randomized to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow.[9] However, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 and older.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a randomized trial of G-CSF given following induction therapy to patients over age 65, complete response was higher in patients who received G-CSF, due to a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11]
The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and consolidation therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[12,13][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML 55 to 75 years of age showed improved disease-free survival in the group receiving GM-CSF (median disease-free survival for patients who achieved complete remission was 23 months versus 11 months; 2-year disease-free survival was 48% versus 21%), with a trend towards improvement in overall survival (2-year survival was 39% versus 27%, p=0.082) for patients 55 to 64 years of age.[14][Level of evidence: 1iiDi]
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
The two-drug regimen of daunorubicin given in conjunction with cytarabine will result in a complete response rate of approximately 65%. Some physicians opt to add a third drug, thioguanine, to this regimen, although there is little evidence that this three-drug regimen is better therapy. However one study has suggested that the addition of etoposide during induction therapy may improve response duration.[1] Idarubicin appeared to be more effective than daunorubicin, although the doses of idarubicin and daunorubicin may not have been equivalent.[2-5] No significant difference between daunorubicin and mitoxantrone has been reported.[6]
The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of disease-free survival [7,8] or no effect [9,10] compared to conventionally-dosed cytarabine-based induction chemotherapy. Post-hoc analyses of 2 negative trials suggested potential benefit for the intensified therapy in subsets of patients at high risk for treatment failure; [9,10] however, an analysis of a subset of patients with complex cytogenetic abnormalities treated in a randomized multicenter trial in Germany showed improvement in complete remission rate with minimal improvement in event-free survival (CR 56% versus 23%, p=0.04; median event-free survival 1 versus 2 months, p=0.04).[11][Level of evidence: 1iiDi]
AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. A retrospective analysis of patients undergoing allogeneic bone marrow transplantation in this setting showed that the long-term survival for such patients was identical regardless of whether or not patients had received remission induction therapy (disease-free survival was approximately 20%). These data suggest that patients with these subsets of leukemia may be treated primarily with allogeneic bone marrow transplant if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[12][Level of evidence: 3iiiDi]
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[13,14] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[15,16] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.[17,18] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that do not respond to antibiotics.[19] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100 per cubic millimeter for 2 weeks).[20] Norfloxacin and ciprofloxacin have both been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection.[21-23] Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.
Special consideration must be given to induction therapy for acute promyelocytic leukemia (PML). It is now well-recognized that oral administration of tretinoin (all-transretinoic acid (ATRA); 45 milligrams per square meter per day) can induce remission in 70% to 90% of patients with M3 AML (ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RAR-alpha gene rearrangement).[24-30] ATRA induces terminal differentiation of the leukemic cells, followed by restoration of non-clonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in the majority of patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. Administration of ATRA can lead to hyperleukocytosis, as well as a syndrome of respiratory distress now known as the "retinoic acid syndrome." Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[31] The optimal management of ATRA-induced hyperleukocytosis has not been established; neither has the optimal post-remission management of patients who receive ATRA induction. However, two large cooperative group trials have demonstrated a statistically significant relapse-free and overall survival advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.[32,33] A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared to ATRA induction followed by chemotherapy given in remission (relative risk of relapse at 2 years, 0.41, P=.04).[34][Level of evidence: 1iiDi] This trial also showed a disease-free survival benefit to maintenance therapy, which consisted of either 6-mercaptopurine plus methotrexate (relative risk of relapse, 0.41), intermittent ATRA (relative risk of relapse, 0.62), or a combination of all three drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in overall survival (relative risk of relapse, 0.36, P=.0057). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by 3 cycles of consolidation and maintenance therapy. The 2 treatment protocols differed only in the addition of non-anthracycline drugs during consolidation cycles in the Italian study; doses of anthracyclines were identical between the 2 trials. Essentially identical relapse-free survival suggests that the non-anthracycline drugs (cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to the outcome of patients with acute promyelocytic leukemia induced with ATRA plus anthracycline.[35][Level of evidence: 3iiiDi]
Presence of the unique fusion transcript PML-RAR-alpha (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early.[36] In addition, a retrospective review of randomized trials from the Southwest Oncology Group has suggested that the dose-intensity of daunorubicin administered in induction and consolidation chemotherapy may significantly impact on remission rate, disease-free survival, and overall survival in patients with M3 AML.[37] Although most patients currently receive ATRA in their induction therapy, for patients who do not, careful management of coagulopathy is required. Coagulopathy is occasionally a problem in patients undergoing induction with ATRA plus chemotherapy. This coagulopathy can lead to catastrophic intracranial bleeding, but can be well-controlled with low-dose heparin infusion, or with aggressive replacement of platelets and clotting factors.[38]
Treatment options for remission induction therapy:
1. One of the following equivalent combination chemotherapy regimens:
Although individual patients have been reported to have long disease-free survival or cure with a single cycle of chemotherapy,[1] postremission therapy is always indicated in therapy that is planned with curative intent. In a small randomized study conducted by the Eastern Cooperative Oncology Group, all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration.[2] Current approaches to postremission therapy include short-term, relatively intensive chemotherapy with cytarabine-based regimens similar to "standard" induction clinical trials (consolidation chemotherapy), consolidation chemotherapy with more dose-intensive cytarabine-based treatment, high-dose chemotherapy or chemoradiotherapy with autologous bone marrow rescue, and high-dose marrow-ablative therapy with allogeneic bone marrow rescue. While older studies have included longer-term therapy at lower doses ("maintenance"), there is no convincing evidence in AML that maintenance therapy provides prolonged disease-free survival beyond shorter-term, more dose-intensive approaches, and few current treatment clinical trials include maintenance therapy.
Nontransplant consolidation therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and have yielded reported disease-free survival rates from 20% to 50%.[3-6] A large randomized trial that compared three different cytarabine-containing consolidation regimens showed a clear benefit in survival to patients younger than 60 years of age who received high-dose cytarabine.[3] Intensification of cytarabine dose or duration of consolidation chemotherapy with conventionally- dosed cytarabine did not improve disease-free or overall survival in patients 60 years of age or older.[7,8] The duration of consolidation therapy has ranged from one cycle [4,6] to four or more cycles.[3,5] The optimal doses, schedules, and duration of consolidation chemotherapy have not been determined. Therefore, to address these issues, patients with AML should be included in clinical trials at institutions that treat large numbers of such patients.
Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurologic [9] and/or pulmonary toxic effects [10] and should be administered by physicians experienced in these regimens at centers that are equipped to deal with potential complications. In a retrospective analysis of 256 patients who received high dose bolus cytarabine at a single institution, the most powerful predictor of cytarabine neurotoxicity was renal insufficiency. The incidence of neurotoxicity was significantly greater in patients treated with twice daily doses of 3 grams per square meter per dose when compared with 2 grams per square meter per dose.
Allogeneic bone marrow transplantation results in the lowest incidence of leukemic relapse, even when compared with bone marrow transplantation from an identical twin (syngeneic bone marrow transplantation). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic bone marrow transplantation as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis. Disease-free survival rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.[11-13] The use of allogeneic bone marrow transplantation as primary postremission therapy is limited by the need for a human leukocyte antigen (HLA)-matched sibling donor and the increased mortality from allogeneic bone marrow transplantation of patients who are older than 50 years of age. The mortality from allogeneic bone marrow transplantation that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series. The use of matched, unrelated donors for allogeneic bone marrow transplantation is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with disease-free survival rates less than 35%.[14] Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that consolidation chemotherapy does not lead to an improvement in disease-free or overall survival for patients in first remission undergoing allogeneic bone marrow transplant from an HLA-identical sibling.[15][Level of evidence: 3iiiA]
Autologous bone marrow transplantation yielded disease-free survival rates between 35% and 50% in patients with AML in first remission. Autologous bone marrow transplantation has also cured a lesser proportion of patients in second remission.[16-22] Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%. Ongoing controversies include the optimum timing of autologous stem cell transplantation, whether it should be preceded by consolidation chemotherapy, and the role of ex vivo treatment of the graft with chemotherapy, such as 4-hydroperoxycyclophosphamide (4-HC) [20] or mafosphamide [21], or monoclonal antibodies, such as anti-CD33.[22] Purged marrows have demonstrated delayed hematopoietic recovery; however, most studies that use unpurged marrow grafts have included several cycles of consolidation chemotherapy and may have included patients who were already cured of their leukemia.
In a prospective trial of patients with AML in first remission, City of Hope investigators treated patients with one course of high-dose cytarabine consolidation, followed by unpurged autologous bone marrow transplantation following preparative therapy of total body irradiation, etoposide, and cyclophosphamide. In an intent-to-treat analysis, actuarial disease-free survival was approximately 50%, which is comparable to other reports of high-dose consolidation therapy or purged autologous transplantation.[23][Level of evidence: 3iiDi]
A randomized trial by the Eastern Cooperative Oncology Group and the Southwest Oncology Group compared autologous bone marrow transplantation using 4-HC-purged bone marrow with high-dose cytarabine consolidation therapy.[24] No difference in disease-free survival was found between patients treated with high-dose cytarabine, autologous bone marrow transplantation, or allogeneic bone marrow transplantation; however, overall survival was superior for patients treated with cytarabine compared to those who received bone marrow transplantation.[24][Level of evidence: 1iiA]
A randomized trial has compared the use of autologous bone marrow transplantation in first complete remission to consolidation chemotherapy, with the latter group eligible for autologous bone marrow transplantation in second complete remission. The two arms of the study had equivalent survival.[25] Two randomized trials in pediatric AML have shown no advantage of autologous transplantation following busulfan/cyclophosphamide preparative therapy and 4HC-purged graft when compared to consolidation chemotherapy including high-dose cytarabine.[26,27] An additional randomized trial of autologous bone marrow transplantation versus intensive consolidation chemotherapy in adult AML, using unpurged bone marrow, also showed no advantage to receiving autologous bone marrow transplantation in first remission.[28] It is possible that certain subsets of AML may specifically benefit from autologous bone marrow transplantation in first remission. In a retrospective analysis of 999 patients with de novo AML treated with allogeneic or autologous bone marrow transplantation in first remission in whom cytogenetic analysis at diagnosis was available, patients with poor-risk cytogenetics (abnormalities of chromosomes 5, 7, 11q, or hypodiploidy) had less favorable outcomes following allogeneic bone marrow transplantation than patients with normal karyotypes or other cytogenetic abnormalities. Leukemia-free survival for the patients in the poor-risk groups was approximately 20%.[29][Level of evidence: 3iiiDi]
An analysis of the ECOG/SWOG randomized trial of post-remission therapy according to cytogenetic subgroups suggested that in patients with unfavorable cytogenetics, allogeneic bone marrow transplantation was associated with an improved relative risk of death; whereas in the favorable cytogenetics group, autologous transplantation was superior. These data were based on analysis of small subsets of patients, and were not statistically significant.[30] While secondary myelodysplastic syndromes have been reported following autologous bone marrow transplantation, the development of new clonal cytogenetic abnormalities following autologous bone marrow transplantation does not necessarily portend the development of secondary myelodysplastic syndromes or AML.[31][Level of evidence: 3iiiD] Whenever possible, patients should be entered on clinical trials of post-remission management.
Because bone marrow transplantation can cure about 30% of patients who experience relapse following chemotherapy, some investigators suggested that allogeneic bone marrow transplantation can be reserved for early first relapse or second complete remission without compromising the number of patients who are ultimately cured.[32] However, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using consolidation chemotherapy.[33] Good-risk factors include t(8;21), inv(16) associated with M4 AML with eosinophilia, and t(15;17) associated with M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6;9), t(9;22), and a history of myelodysplasia or antecedent hematologic disorder. Patients in the good-risk group have a reasonable chance of cure with intensive consolidation, and it may be reasonable to defer transplantation in that group until early first relapse. The poor-risk group is unlikely to be cured with consolidation chemotherapy, and allogeneic bone marrow transplantation in first complete remission is a reasonable option for patients with an HLA-identical sibling donor. However, even with allogeneic stem cell transplantation, the outcome for patients with high-risk AML is poor (5-year disease-free survival of 8% to 30% for patients with treatment-related leukemia or myelodysplasia).[34] The efficacy of autologous stem cell transplantation in the poor-risk group has not been reported to date but is the subject of active clinical trials. Patients with normal cytogenetics are in an intermediate-risk group, and postremission management should be individualized or, ideally, managed according to a clinical trial.
The rapid engraftment kinetics of peripheral blood progenitor cells demonstrated in trials of high-dose therapy for epithelial neoplasms has led to interest in the alternative use of autologous and allogeneic peripheral blood progenitor cells as rescue for myeloablative therapy for the treatment of AML. One pilot trial of the use of autologous transplantation with unpurged peripheral blood progenitor cells in first remission had a 3-year disease-free survival of 35%; detailed prognostic factors for these patients were not provided.[35] This result appears inferior to the best results of chemotherapy or autologous bone marrow transplantation and suggests that the use of peripheral blood progenitor cells be limited to clinical trials. Similarly, peripheral blood allogeneic stem cell transplantation is under evaluation. There is some evidence that this modality may carry a high risk of chronic graft-versus-host disease, and thus should also be restricted to clinical trials.[36]
There are a number of agents with activity in recurrent AML.[2-8] A study with mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission.[9] Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results.[8,10-12]
The immunotoxin gemtuzumab ozogamicin has been reported to have a 30% response rate in patients with relapsed AML expressing CD33. This included 16% of patients who achieved complete responses and 13% who achieved a CRp, a new response criteria defined for this trial. CRp refers to clearance of leukemic blasts from the marrow, with adequate myeloid and erythroid recovery but with incomplete platelet recovery (although platelet transfusion independence for at least 1 week was required). It is not clear whether the inadequate platelet recovery is due to megakaryocyte toxic effects of gemtuzumab or to subclinical residual leukemia. The long-term outcomes of patients who achieve CRp following gemtuzumab are not yet known. Gemtuzumab induces profound bone marrow aplasia similar to leukemia induction chemotherapy and also has substantial hepatic toxic effects, including hepatic venoocclusive disease.[13,14] The farnesyltransferase inhibitor R115777 demonstrated a 32% response rate in a phase I study in patients with relapsed and refractory acute leukemia (2 complete responses and 6 partial responses in 24 patients treated) and has entered phase II trials.[15]
A subset of relapsed patients treated aggressively may have extended disease-free survival; however, cures in patients following a relapse are thought to be more commonly achieved using bone marrow transplantation.[12] A retrospective study from the International Bone Marrow Transplant Registry compared adults younger than 50 years of age with AML in second complete remission who received HLA-matched sibling transplantation versus a variety of consolidation approaches.[16] The chemotherapy approaches were heterogeneous; some patients received no consolidation therapy. The transplantation regimens were similarly diverse. Leukemia-free survival appeared to be superior for patients receiving bone marrow transplants for two groups: patients older than 30 years of age whose first remission was less than one year; and patients younger than 30 years of age whose first remission was longer than one year.
Allogeneic bone marrow transplantation in early first relapse or in second complete remission provides a disease-free survival rate of approximately 30%.[17] Therefore, some investigators advocate allogeneic bone marrow transplantation in early first relapse to avoid the toxic effect of re-induction chemotherapy.[17-19] Allogeneic bone marrow transplantation can salvage some patients whose disease fails to go into remission with intensive chemotherapy.[12] Autologous bone marrow transplantation is a reasonable option for patients in second complete remission, offering a disease-free survival that may be comparable to autografting in first complete remission.[20-22]
Arsenic trioxide, an agent with both differentiation- and apoptosis-inducing properties against acute promyelocytic leukemia cells, has a high rate of successful remission induction in patients with relapsed acute promyelocytic leukemia (APL). Clinical complete remissions have been reported in 85% of patients induced with arsenic trioxide, with a median time to clinical complete remission of 59 days. Eighty-six percent of evaluable patients tested negative for the presence of PML-RAR-alpha transcript after induction or consolidation with arsenic trioxide. Actuarial 18-month relapse-free survival was 56%. Induction with arsenic trioxide may be complicated by APL differentiation syndrome (identical to ATRA syndrome), prolongation of QT interval, and neuropathy.[23,24]
Studies exploring the utility of autologous bone marrow transplantation in early first relapse are in progress.[25] Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.[26]
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