Adult Acute Myeloid Leukemia Treatment (Professional) (cont.)
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Recurrent Adult Acute Myeloid Leukemia
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
No standard regimen exists for the treatment of patients with relapsed acute myeloid leukemia (AML), particularly in patients with a first remission duration of less than 1 year.
A number of agents have activity in recurrent AML.[2,3] A combination of mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission. Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results.[3,5,6,7] Mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a complete remission induction rate of 55% in a population including 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients with secondary AML.[Level of evidence: 3iiiDiv] However, in a phase III Eastern Cooperative Oncology Group (ECOG) (E-2995) trial of MEC with or without PSC388, a multidrug resistance modulator, complete response (CR) was only 17% to 25% in a population including relapse at less than 6 months after first complete remission, relapse after allogeneic or autologous bone marrow transplantation (BMT), second or greater relapse, primary induction failures, secondary AML, and high-risk myelodysplastic syndromes.[Level of evidence: 1iiDiv] Thus, treatments with new agents under clinical evaluation remain appropriate in eligible patients with recurrent AML.
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 CRs and 13% of patients 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 (though platelet transfusion independence for at least 1 week was required). Unclear is 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.[11,12] The farnesyltransferase inhibitor tipifarnib (R115777) demonstrated a 32% response rate in a phase I study in patients with relapsed and refractory acute leukemia (two CRs and six partial responses in 24 patients treated) and has entered phase II trials. Clofarabine, a novel purine nucleoside analogue, induced complete remissions in 8 out of 19 patients in first relapse as a single agent  and in 7 out of 29 patients when administered in combination with intermediate-dose cytarabine.[Level of evidence: 3iiiDiv]
A subset of relapsed patients treated aggressively may have extended disease-free survival (DFS); however, cures in patients following a relapse are thought to be more commonly achieved using BMT.[Level of evidence: 3iDii] A retrospective study from the International Bone Marrow Transplant Registry compared adults younger than 50 years with AML in second complete remission who received HLA-matched sibling transplantation versus a variety of postremission approaches. The chemotherapy approaches were heterogeneous; some patients received no postremission therapy. The transplantation regimens were similarly diverse. Leukemia-free survival appeared to be superior for patients receiving BMTs for two groups: patients older than 30 years whose first remission was less than 1 year; and patients younger than 30 years whose first remission was longer than 1 year.[Level of evidence: 3iDii]
Allogeneic BMT from an HLA-matched donor in early first relapse or in second complete remission provides a DFS rate of approximately 30%.[Level of evidence: 3iiiA] Transplantation in early first relapse potentially avoids the toxic effects of reinduction chemotherapy.[3,17,18] Allogeneic BMT can salvage some patients whose disease fails to go into remission with intensive chemotherapy (primary refractory leukemia). Nine of 21 patients with primary refractory AML were alive and disease free at 10 years following allogeneic BMT.[Level of evidence: 3iiiA] Randomized trials testing the efficacy of this approach are not available. Autologous BMT is an option for patients in second complete remission, offering a DFS that may be comparable to autografting in first complete remission.[19,20,21]
Patients who relapse following an allogeneic BMT may undergo an infusion of lymphocytes from the donor (Donor Lymphocyte Infusion or DLI), similar to the therapy patients with relapsing chronic myelogenous leukemia (CML) undergo. (Refer to the Relapsing Chronic Myelogenous Leukemia section of the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.) There are no published studies of any prospective trials examining the role of DLI for patients with AML who relapsed following allogeneic BMT. A retrospective study of European patients found that, out of 399 patients who relapsed after an allogeneic BMT, 171 patients received DLI as part of their salvage therapy. A multivariate analysis of survival showed a significant advantage for the 171 DLI recipients, who achieved a 2-year overall survival from the time of relapse of 21%, compared to 9% for the 228 patients who did not receive DLI (P < .04; RR=0.8; 95% confidence interval, 0.64–0.99).[Level of evidence: 3iiiA] The strength of this finding is limited by the retrospective nature of the study, and the possibility that much of the survival advantage could have been the result of selection bias. Furthermore, the remission rate of 34% reported in this study was considerably less than the 67% to 91% reported for CML. Therefore, even if the survival advantage conferred by DLI is real, the fraction of relapsed AML patients who might benefit from this therapy appears to be quite limited.
Arsenic trioxide, an agent with both differentiation-inducing and apoptosis-inducing properties against acute promyelocytic leukemia (APL) cells, has a high rate of successful remission induction in patients with relapsed 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-RARa transcript after induction or postremission therapy 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.[24,25] Arsenic trioxide is now being incorporated into the postremission treatment strategy of de novo APL patients in clinical trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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