Current Clinical Trials

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.)

Adult acute myeloid leukemia (AML) in remission is defined as a normal peripheral blood cell count (absolute neutrophil count >1,000/mm³ and platelet count >100,000/mm³) [1] and normocellular marrow with less than 5% blasts in the marrow and no signs or symptoms of the disease. In addition, no signs or symptoms are evident of central nervous system leukemia or other extramedullary infiltration. Because the vast majority of AML patients meeting these criteria for remission have residual leukemia, modifications to the definition of complete remission have been suggested, including cytogenetic remission, in which a previously abnormal karyotype reverts to normal, and molecular remission, in which interphase fluorescence in situ hybridization (FISH) or multiparameter flow cytometry are used to detect minimal residual disease. Immunophenotyping and interphase FISH have greater prognostic significance than the conventional criteria for remission.[2,3]

Although individual patients have been reported to have long disease-free survival (DFS) or cure with a single cycle of chemotherapy,[4] 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 (ECOG), all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration.[5] Current approaches to postremission therapy include short-term, relatively intensive chemotherapy with cytarabine-based regimens similar to standard induction clinical trials (postremission chemotherapy), postremission chemotherapy with more dose-intensive cytarabine-based treatment, high-dose chemotherapy or chemoradiation therapy 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), no convincing evidence is available with AML that maintenance therapy provides prolonged DFS beyond shorter-term, more dose-intensive approaches, and few current treatment clinical trials include maintenance therapy.

Nontransplant postremission therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and have yielded reported long-term DFS rates from 20% to 50%.[6-9] A large randomized trial that compared three different cytarabine-containing postremission therapy regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine.[6] Intensification of cytarabine dose or duration of postremission chemotherapy with conventionally dosed cytarabine did not improve disease-free or OS in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial.[10,11] The duration of postremission therapy has ranged from one cycle [7,9] to four or more cycles.[6,8] The optimal doses, schedules, and duration of postremission 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 [12] and/or pulmonary toxic effects [13] 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 g/m²/dose when compared with 2 g/m²/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), but no improvement in OS when compared to chemotherapy-based postremission regimens. 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. The DFS rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.[14-16] 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. 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 DFS rates less than 35%.[17] Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that postremission chemotherapy does not lead to an improvement in DFS or OS for patients in first remission undergoing allogeneic bone marrow transplant from an HLA-identical sibling.[18][Level of evidence: 3iiiA]

Autologous bone marrow transplantation yielded DFS rates between 35% and 50% in patients with AML in first remission. Autologous bone marrow transplantation has also cured a smaller proportion of patients in second remission.[19-25] 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 postremission chemotherapy, and the role of ex vivo treatment of the graft with chemotherapy, such as 4-hydroperoxycyclophosphamide (4-HC) [23] or mafosphamide,[24] or monoclonal antibodies, such as anti-CD33.[25] Purged marrows have demonstrated delayed hematopoietic recovery; however, most studies that use unpurged marrow grafts have included several cycles of postremission 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 postremission therapy, followed by unpurged autologous bone marrow transplantation following preparative therapy of total-body radiation therapy, etoposide, and cyclophosphamide. In an intent-to-treat analysis, actuarial DFS was approximately 50%, which is comparable to other reports of high-dose postremission therapy or purged autologous transplantation.[26][Level of evidence: 3iiDii]

A randomized trial by ECOG and the Southwest Oncology Group (SWOG) compared autologous bone marrow transplantation using 4-HC-purged bone marrow with high-dose cytarabine postremission therapy.[27] No difference in DFS was found between patients treated with high-dose cytarabine, autologous bone marrow transplantation, or allogeneic bone marrow transplantation; however, OS was superior for patients treated with cytarabine compared with those who received bone marrow transplantation.[27][Level of evidence: 1iiA]

A randomized trial has compared the use of autologous bone marrow transplantation in first complete remission to postremission chemotherapy, with the latter group eligible for autologous bone marrow transplantation in second complete remission. The two arms of the study had equivalent survival.[28] Two randomized trials in pediatric AML have shown no advantage of autologous transplantation following busulfan/cyclophosphamide preparative therapy and 4HC-purged graft when compared with postremission chemotherapy including high-dose cytarabine.[29,30] An additional randomized Groupe Ouest Est d'etude des Leucemies et Autres Maladies du Sang (GOELAMS) trial of autologous bone marrow transplantation versus intensive postremission chemotherapy in adult AML, using unpurged bone marrow, also showed no advantage to receiving autologous bone marrow transplantation in first remission.[31] 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%.[32][Level of evidence: 3iiiDii]

An analysis of the SWOG/ECOG (S-9034/E-3489) randomized trial of postremission 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.[33] 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.[34][Level of evidence: 3iiiDiv] Whenever possible, patients should be entered on clinical trials of postremission 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;[35] however, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using postremission chemotherapy.[36] 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 postremission therapy, 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 postremission 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 DFS of 8% to 30% for patients with treatment-related leukemia or myelodysplasia).[37] 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 DFS rate of 35%; detailed prognostic factors for these patients were not provided.[21] 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.

Allogeneic stem cell transplantation can be performed using stem cells obtained from a bone marrow harvest or a peripheral blood progenitor cell harvest. In a randomized trial of 175 patients undergoing allogeneic stem cell transplantation, with either bone marrow or peripheral blood stem cells, for a variety of hematologic malignancies using methotrexate and cyclosporine to prevent graft-versus-host disease, the use of peripheral blood progenitor cells led to earlier engraftment (median neutrophil engraftment = 16 vs. 21 days, median platelet engraftment = 13 vs. 19 days).[38] The use of peripheral blood progenitor cells was associated with a trend toward increased graft-versus-host disease but comparable transplant-related death. The relapse rate at 2 years appeared lower in patients receiving peripheral blood progenitor cells (hazard ratio [HR] = 0.49; 95% confidence interval [CI], 0.24–1.00); however, OS was not significantly increased (HR for death within 2 years = 0.62; 95% confidence interval, 0.38–1.02).[38]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with adult acute myeloid leukemia in remission. 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.

References

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