Acute Myelogenous Leukemia In First Remission Research Articles

Should persons with acute myeloid leukemia have a transplant in first remission?

Despite more than 40 years of extensive study, it remains uncertain which individuals, if any, with acute myelogenous leukemia (AML) in first remission should receive a blood cell or bone marrow transplant versus post-remission chemotherapy (or both). Nevertheless, there is a recent trend toward recommending more transplants in this setting. We consider four myths underlying this recommendation: (1) only individuals achieving second remission benefit from a transplant; (2) there is no effective therapy for relapse other than an allotransplant; (3) we can accurately predict which individuals with AML in first remission need a transplant; and (4) detection of minimal residual disease in first remission will resolve this controversy. We discuss these misconceptions and suggest approaches to resolve this issue.

Clofarabine, Melphalan, and Thiotepa, Followed by Allogeneic Unmodified Bone Marrow or Peripheral Blood Stem Cell Transplant, by Unmodified Double Cord Blood Transplant, or by CD34+ T-Cell Depleted Stem Cell Transplant for the Treatment of Hematologic Malignancies.

Abstract 3144Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed two allograft protocols for patients with hematologic malignancies with a cytoreductive regimen, using CLO in combination with melphalan (Mel) and thiotepa (Thio). Patients on protocol #1 received unmodified bone marrow (BMT), peripheral blood stem cells (PBSCT), or unmodified double unit cord blood (dCBT). Patients on protocol #2 received CD34+ T-cell depleted stem cells (TCD-SCT). Cytoreduction consisted of CLO 20 mg/m2/day × 5, Thio 10 mg/Kg/day × 1 and Mel 70 mg/m2/day × 2. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus (Tacro) and methotrexate (MTX) with unmodified BMT or PBSCT, tacro and mycophenolate mofetil (MMF) with unmodified dCBT, and none with TCD-SCT. Rabbit ATG at 2.5 mg/Kg × 2 or 3 doses was used for the prevention of rejection with the TCD-SCT.To date, 64 pts were treated with this regimen including: unmodified BMT/PBSCT 27 patients, dCBT 15 patients, and TCD-SCT 22 patients. The median age for patients was 10.2 years (range 0.9–58.7) for unmodified SCT and 41.5 (range 0.6–67.2) for TCD-SCT. This was the second SCT for 13 of 27 pts in the BMT-PBSCT group, 2 of 15 pts in the CBT group, and 4 of 22 pts in the TCD group. Patient diagnoses included acute lymphoblastic leukemia (ALL) (N=36), acute myelogenous leukemia (AML) (N=23), and myelodysplastic syndrome (MDS) (N=5). Patients with ALL or AML in first remission (CR1) or CR2 and MDS in CR1 or refractory anemia (RA) were categorized as having good risk disease (GRD), while all other pts were considered to have poor risk disease (PRD), irrespective of all other factors. There were 15 of 27 pts with PRD in the BMT/PBSCT group, 10 of 15 pts in the CBT group, and 9 of 22 pts in the TCD-SCT group.For the unmodified BMT/PBSCT group, donors were HLA-matched related (N=11), mismatched related (N=1), matched unrelated (N=12), or mismatched unrelated (N=3). All CBT recipients received double-unit grafts from 2 mismatched unrelated donors. For the TCD-SCT group, donors were HLA-matched related (N=8), mismatched related (N=1), matched unrelated (N=4), or mismatched unrelated (N=9).Engraftment occurred in 59 of 61 evaluable pts; three pts died before engraftment. One pt recipient of unmodified BMT/PBSCT suffered a late graft failure, and one pt recipient of CBT suffered an early graft failure in the context of sepsis. Grade 2–4 acute GvHD occurred in 8/26 (31%) evaluable pts in the BMT/PBSCT group, 5/13 (38%) evaluable pts in the CBT group, and 4/20 (20%) evaluable pts in the TCD-SCT group.With a median follow-up of 20.5 months for the unmodified SCT groups and 15.4 months for the TCD group, the overall survival (OS) and disease-free survival (DFS) rates were: 53.7% and 41.0% for the BMT/PBSCT group, 51.3% and 41.5% for the CBT group, and 64.1% and 60.7% for the TCD-SCT group.This cytoreductive regimen represents a promising approach for the transplantation of patients with acute leukemias without the use of total body irradiation. This regimen is also sufficiently immunosuppressive to insure consistent engraftment of T-cell depleted transplants. Lastly, it appears to be relatively well tolerated for younger pts requiring a second SCT. Disclosures:Off Label Use: Clofarabine.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Pretransplantation Consolidation Chemotherapy Decreases Leukemia Relapse after Autologous Blood and Bone Marrow Transplants for Acute Myelogenous Leukemia in First Remission

Controversy exists over whether pretransplantation consolidation chemotherapy affects the outcome of subsequent autotransplantation for acute myelogenous leukemia (AML). The current study was undertaken to determine the association between previous consolidation and outcome of autotransplantation for AML in first remission. Posttransplantation outcomes of 146 patients receiving no consolidation were compared with those of 244 patients receiving standard-dose (<1 gm/m 2) and 249 patients receiving high-dose (1-3 gm/m 2) cytarabine, using proportional hazards regression to adjust for differences in prognostic variables. One-year transplantation-related mortality was similar among the cohorts. Five-year relapse rates were 49% (95% confidence interval CI} = 39%-58%) with no consolidation, 35% (95% CI = 29%-42%) with standard-dose cytarabine, and 40% (95% CI = 33%-48%) with high-dose cytarabine ( P = .07). Five-year leukemia-free survival rates were 39% (95% CI = 30%-47%) with no consolidation, 53% (95% CI = 46%-60%) with standard-dose cytarabine, and 48% (95% CI = 40%-56%) with high-dose cytarabine ( P = .03). Similarly, 5-year overall survival was better in those patients receiving consolidation: 42% (95% CI = 34%-51%) with no consolidation, 59% (95% CI = 52%-65%) with standard-dose cytarabine, and 54% (95% CI = 46%-61%) with high-dose cytarabine ( P = .01). Although most patients received 1 or 2 cycles of consolidation, the number of courses had no detectable effect on transplantation outcome. In multivariate analysis, risks of relapse and treatment failure were lower in the patients receiving consolidation, especially among those patients receiving blood cell grafts. Outcomes with standard-dose and high-dose cytarabine were similar. Based on our findings, we recommend that patients with AML in first remission receive consolidation before undergoing autotransplantation.

Cytogenetic Classification Systems and Overall Survival Following Bone Marrow Transplant (BMT) for Acute Myelogenous Leukemia (AML).

Risk-adapted therapy for AML in first complete remission generally calls for allogeneic BMT for patients with poor risk cytogenetics. However, poor risk cytogenetics is defined differently in commonly-applied classification schemes. We hypothesized that differences in cytogenetic classification might result in differences in survival after BMT. From September 1991 to December 2003, we treated 47 patients with AML in first complete remission with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 42 years (range 18 to 60). At the time of diagnosis, 35 patients had either a normal karyotype or at least one clonal abnormality. Cytogenetic analysis was unavailable for the other 12 patients. The 47 patients were then classified according to the SWOG/ECOG (Blood 96:4075, 2000), MRC (Blood 92:2322, 1998), or CALGB (Blood 100:4325, 2002) cytogenetic classification systems and analyzed for overall survival. With a median follow-up of 4.9 years, 3 year overall survival for various cytogenetic risk groups are displayed in the table:SWOG/ECOGCALGBMRCIntermediate risk69%63%74%Poor risk43%42%18%Unknown risk45%52%45%Concordance indices were 0.58 for CALGB, 0.60 for SWOG, and 0.66 for MRC, demonstrating a slight superiority of the MRC system. Consistent with reports of large, prospective randomized trials of BMT for AML in first remission, patients with poor risk cytogenetics have worse overall survival compared to patients with intermediate risk cytogenetics. Overall survival appears to be different for patients classified as poor risk by MRC criteria. Larger, prospective studies are needed to confirm this observation, but our results suggest that standardized, international cytogenetic risk criteria are needed to develop risk-adapted strategies for the treatment of AML.

Impact of Allogeneic Stem Cell Transplantation (ASCT) on Outcome of Biphenotypic Acute Leukemia (BAL):.

Biphenotypic acute leukemia is a rare disease accounting for approximately 10% of acute leukemias using the new scoring system. No standard therapeutic approach exists for this entity. In addition, the prognosis for these patients (pts) is poor and thought to be worse than for acute myelogenous leukemia (AML). ASCT may provide improved disease free survival for patients with high risk AML, but its role in BAL is unknown. We undertook a retrospective study of pts with BAL to determine if outcome was similar following ASCT to pts with AML in first remission. Between 7/93 and 2/04, nine patients with BAL who underwent ASCT were identified. Criteria for the diagnosis of BAL was based on the scoring system adapted from the European Group of Immunological Classification of Leukemia. Pts with Philadelphia positive acute lymphoblastic leukemia (ALL) were excluded. Cytogenetics at presentation included 1 pt with deletion7 and trisomy 8, 1 with 11q23, 2 with complex karytoype, 4 with normal cytogenetics ,1 unknown. Six pts were treated with an AML induction of Idarubicin/Cytarabine, two with an ALL regimen Daunorubicin/Vincristine/Prednisone and one with an Idarubicin- AML based first induction, and then a combination of an ALL/AML reinduction at first relapse. Eight pts were in first complete remission (CR) and one pt in second CR at ASCT. Median age at ASCT was 34 years (range 11–60). Median time from diagnosis to ASCT was 3.4 mos (range 1.5–5.2). Seven pts received sibling donor (SIB) and two received unrelated donor (URD) stem cells. Two pts received marrow and seven received peripheral stem cells. The conditioning regimen consisted of 1320cGy total body irradiation (TBI)+VP16 60mg/kg in 6 pts, 1320cGy TBI+Cyclophosphamide 120mg/kg in 1 pt, Fludarabine125mg/m2+Melphalan 140mg/m2 in 2 pts. Seven received a Cyclosporin- based graft versus host disease prophylaxis regimen (GVHD) and two a Tacrolimus- based regimen. Six pts developed grade III GVHD. Two patients died of pulmonary toxicity, one of GVHD, one from infection and one from disease relapse. One year overall survival (OS) is 39%( 95% CI 13–73). The relapse rate at one year was 20%. In conclusion, despite unfavorable cytogenetics in many patients, relapse rates are low following ASCT for BAL and comparable to pts undergoing ASCT for AML. Future approaches include methods to reduce transplant related mortality which was the major cause of reduced survival in this series.

Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors.

To review published controlled clinical trials examining the benefit of escalated chemotherapy in patients with hematologic and solid malignancies. Studies were obtained by searching Medline and CancerLit and by review of bibliographies of published trials. We reviewed studies that examined dose-intense (DI) chemotherapy alone, in combination with hematopoietic colony-stimulating factors (CSFs), or high-dose therapy (HDT) with autologous bone marrow support (ABMT). DI therapy without CSF or ABMT has not been shown to improve overall outcome in any tumor except consolidative therapy of acute myelogenous leukemia (AML). In solid tumors, many published studies suggest that less than standard-intensity chemotherapy is suboptimal, but few studies that examined higher compared with standard-dose therapy have shown a significant difference in outcome. No studies have convincingly demonstrated improved overall survival (OS) with DI therapy with CSF support. The use of HDT with ABMT has been shown to improve survival in multiple myeloma (MM), as well as relapsed intermediate- and high-grade non-Hodgkin's lymphoma (NHL). High-dose chemotherapy with ABMT is promising in patients with metastatic breast cancer (MBC), but it should not yet be considered a standard approach for these patients. DI chemotherapy is an acceptable and standard therapeutic maneuver for patients with AML in first remission, MM, and relapsed aggressive NHL. In solid tumors, the use of DI chemotherapy either alone or with cytokine support has not been shown to improve outcome and should not be considered standard therapy. Current randomized trials should provide definitive answers about the role of DI therapy in solid tumors.

Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment.

Results of postremission chemotherapy for adults with acute myelogenous leukemia (AML) were assessed in two sequential prospective studies involving similar induction therapy and two courses of intensive consolidation treatment. Fifty-six patients achieving remission on the acute leukemia protocol (ALP3) study received high-dose cytarabine and daunorubicin as course one and standard-dose cytarabine and daunorubicin as course two. Results are compared with forty-six patients achieving remission on the ALP2 study who received azacitidine and doxorubicin as consolidation course one and standard-dose cytarabine, daunorubicin, and thioguanine as course two. The ALP3 regimen resulted in a significantly improved 5-year disease-free survival of 32% +/- 19% versus 20% +/- 11% for the ALP2 study (P = .03). Survival from remission was also improved, 40% +/- 14% versus 24% +/- 12% (P less than .01). Favorable prognostic factors for disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults less than or equal to 45 years of age was 58% +/- 19% with the ALP3 postremission chemotherapy regimen, comparable to most studies of BMT for AML in first remission. Actuarial 5-year survival for ALP3 patients greater than 60 years of age was 18% +/- 20% with no improvement compared with ALP2.

Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia.

Ninety-seven children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) received HLA-identical bone marrow transplants from sibling donors, after preparation with 1320 cGy of hyperfractionated total-body irradiation and high-dose cyclophosphamide. Kaplan-Meier product-limit estimates (means +/- SE) of disease-free survival at five years among patients with ALL in second remission, third remission, and fourth remission or relapse were 64 +/- 9, 42 +/- 14, and 23 +/- 11 percent, respectively, with probabilities of relapse of 13 +/- 7, 25 +/- 13, and 64 +/- 16 percent. Among patients with AML in first remission, second remission, and third remission or relapse, five-year disease-free survival estimates were 66 +/- 10, 75 +/- 15, and 33 +/- 19 percent, with respective relapse probabilities of 0, 13 +/- 12, and 67 +/- 19 percent. The most frequent cause of death in patients in early remission (ALL in second or third remission or AML in first or second remission) was bacterial sepsis, fungal sepsis, or both, most often in the presence of acute or chronic graft-versus-host disease. Among patients with ALL who received transplants while in second remission, the duration of the initial remission had no effect on the probability of relapse after transplantation. The only pretransplantation factor that significantly affected outcome was the disease status at the time of transplantation; patients in early remission had better disease-free survival. We conclude that transplantation after preparation with hyperfractionated total-body irradiation and cyclophosphamide is an effective mode of therapy in children with refractory forms of acute leukemia.