Myelogenous Leukemia In First Remission Research Articles

Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission

We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n=45) or ASCT arm (n=42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p=0.25). Three-year overall survival (OS) rates were 77 and 68% (p=0.67). Incidence of relapse was 54 and 41% (p=0.22). There was no significant difference in nonrelapse mortality between two arms (p=0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.

Low Socioeconomic Status, Adverse Gene Expression Profiles, and Clinical Outcomes in Hematopoietic Stem Cell Transplant Recipients.

Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis. We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes. Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival. Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT.

Stem Cell Transplant Versus Chemotherapy in Older Adults with Acute Myelogenous Leukemia In First Remission

▪ IntroductionOptimal therapy for older adults with acute myelogenous leukemia (AML) who achieve remission following induction chemotherapy has not been determined. Options include consolidation chemotherapy (CC) or stem cell transplant (SCT) if an appropriate donor is identified. In order to determine whether SCT improved overall survival (OS) or whether associated toxicity was increased, we performed a retrospective study comparing SCT with CC in this older age group. MethodsAll adult patients ages 60 to 75 years with AML in 1st remission (CR1) who underwent a SCT at MSKCC between 2001 and 2013 were reviewed and compared to age-matched patients with AML who achieved CR1 and received CC. A landmark analysis at 3 months following CR1 was used to compare OS for the 2 patient groups. Only SCT patients transplanted by landmark time were included in the analysis. Overall survival was compared using Kaplan-Meier methodology. ResultsSixty-eight patients were identified for the SCT group. Thirty-two patients were identified for the CC group (Table). Stem cell sources included: peripheral blood (n=63), cord blood (n=4) and bone marrow (n=1). Fifty-six patients received a T cell depleted transplant (32 with ClinMACsTM and 24 with IsolexTM ) and 12 received an unmodified product. Conditioning regimens were busulfan/melphalan/ fludarabine (n=54), melphalan/fludarabine (n=4), cyclophosphamide/fludarabine/thiotepa/ TBI (n=4), fludarabine/busulfan (n=3), busulfan/melphalan (n=2) and thiotepa/fludarabine/TBI (n=1). Donors included matched unrelated (n=28), matched related (n=25), mismatched unrelated (n=11) and mismatched cord blood (n=4). For patients in the CC group, induction chemotherapy included cytarabine in combination with either idarubicin (n=21), daunorubicin (n=10), or mitoxantrone plus etoposide (n=1). Forty-four patients received their transplant by the 3 month landmark and 30 patients in the CC group were alive at the landmark and were included in the OS analysis.Patient Characteristics:SCTCCNumber of patients6832Median age at SCT or CC65 (60-75)65 (60-69)Males/Females41/2718/14Median F/U in mos (range)19 (1-83)22 (11-75)Number of deaths within 100 days of SCT or 1st cycle CC6 (9%)2 (6%) [Display omitted] Deaths in the SCT group included 4 patients from infection, 1 from treatment-related toxicity, and 1 from relapsed disease. The estimated OS at 2 years in the landmark groups were 64% in the SCT group and 42% in the CC group (p=0.04). ConclusionsRecognizing the inherent bias when retrospective studies compare SCT and CC, these data support the use of SCT for older patients with AML in CR1 who have an appropriate donor. Despite the older age, there was a statistically significant better OS with low 100 day mortality for those patients who underwent SCT. Disclosures:No relevant conflicts of interest to declare.

Comparison of Reduced-Intensity Hematopoietic Cell Transplantation with Chemotherapy in Patients Age 60-70 Years with Acute Myelogenous Leukemia in First Remission

We compared the outcomes of patients age 60-70 years with acute myelogenous leukemia receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (n = 94) with the outcomes in patients treated with induction and postremission chemotherapy on Cancer and Leukemia Group B protocols (n = 96). All patients included had been in CR1 for at least 4 months. The HCT recipients were slightly younger than the chemotherapy patients (median age, 63 years vs 65 years; P < .001), but there were no significant between-group differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for the HCT recipients (median, 44 days vs 38 days; P = .031). Allogeneic HCT was associated with significantly lower risk of relapse (32% vs 81% at 3 years; P < .001), higher nonrelapse mortality (36% vs 4% at 3 years; P < .001), and longer leukemia-free survival (32%vs15% at 3years; P = .001). Although overall survival was longer for HCT recipients, the difference was not statistically significant (37% vs 25% at 3 years; P = .08). Our findings suggest that reduced-intensity conditioning allogeneic HCT in patients age 60-70 with acute myelogenous leukemia in CR1 reduces relapse and improves leukemia-free survival. Strategies that reduce nonrelapse mortality may yield significant improvements in overall survival.

Low Risk of Chronic Graft-versus-Host Disease and Relapse Associated with T Cell–Depleted Peripheral Blood Stem Cell Transplantation for Acute Myelogenous Leukemia in First Remission: Results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303

Graft-versus-host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in complete remission (CR) remains unclear. We performed a phase 2 single-arm multicenter study to evaluate the role of TCD in AML patients in CR1 or CR2 up to age 65 years. The primary objective was to achieve a disease-free survival (DFS) rate of >75% at 6 months posttransplantation. A total of 44 patients with AML in CR1 (n = 37) or CR2 (n = 7) with a median age of 48.5 years (range, 21-59 years) received myeloablative chemotherapy and fractionated total body irradiation (1375 cGy) followed by immunomagnetically selected CD34-enriched, T cell‒depleted allografts from HLA-identical siblings. No pharmacologic GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grade II-IV was 22.7%, and the incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 was 17.4% at 36 months. With a median follow-up of 34 months, DFS for all patients was 82% at 6 months, and DFS for patients in CR1 was 72.8% at 12 months and 58% at 36 months. HCT after myeloablative chemoradiotherapy can be performed in a multicenter setting using a uniform method of TCD, resulting in a low risk of extensive chronic GVHD and relapse for patients with AML in CR1.

Unrelated Donor Transplantation for Acute Myelogenous Leukemia in First Remission

We retrospectively analyzed the outcomes of all acute myelogenous leukemia (AML) patients in first remission (n = 44; median age = 48 years; high-risk cytogenetics = 59%) who received unrelated donor hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen of i.v. busulfan, fludarabine, and antithymocyte globulin (ATG) between January 2002 and November 2009 at our institution. Donor-recipient pairs were matched by high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 typing (10/10 matches, n = 41; 9/10 matches, n = 3). With a median follow-up of 34 months, actuarial 3-year event-free survival (EFS) and overall survival (OS) is 70% and 78%, respectively. The 3-year EFS and OS in patients with and without poor risk cytogenetics is similar (63% versus 82%, P = 0.43 and 78% versus 82%, P = .89, respectively). The 3-year EFS and OS is also similar in patients above age 55 year versus patients age 55 year or younger (80% versus 67%, P = .47 and 80% versus 78%, P = .81, respectively). The 100-day and 3-year cumulative incidence of transplant-related mortality is 5% and 15%, respectively. Six patients have relapsed, and 3 of them are alive and in remission after salvage therapy, with a median follow-up of 23 months. These results indicate that the majority of AML patients eligible for this treatment can achieve long-term disease control.

Impact of Delirium on Distress, Health-Related Quality of Life, and Cognition 6 Months and 1 Year after Hematopoietic Cell Transplant

Delirium commonly occurs during myeloablative hematopoietic cell transplantation (HCT). Little is known about how delirium during the acute phase of HCT affects long-term distress, health-related quality of life (HRQOL), and neurocognitive functioning. This prospective, cohort study examines these outcomes at 6 months and 1 year in 90 patients undergoing HCT. Patients completed a battery assessing distress, HRQOL, and subjective neuropsychological functioning before receiving their first HCT as well as at 6 months and 1 year. Patients with a delirium episode within the 4 weeks after HCT had significantly more distress and fatigue at 6 months (P < .004) and at 1 year (P < .03), compared with patients without delirium. At 1 year, patients with delirium also had worse symptoms of depression and post traumatic stress (P < .03). Patients with delirium had worse physical health on the SF-12 at 6 months (P < .03) and worse mental health on the SF-12 at 1 year (P < .03). At both 6 months and 1 year, patients with delirium after HCT reported worse memory (P < .009) and executive functioning (P < .006). Delirium during the acute phase of HCT is significantly associated with persistent distress, decreased HRQOL, and subjective neurocognitive dysfunction at both 6 months and 1 year.

A tribute to Ernest Beutler

A tribute to Ernest Beutler

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.

Follow-up 26 Years after Treatment for Acute Myelogenous Leukemia

To the Editor: In 1979, we reported the results of treating 19 patients who had acute myelogenous leukemia in first remission with intensive chemotherapy, radiation therapy, and transplantation of ...

Transplantation of IL-2-mobilized autologous peripheral blood progenitor cells for adults with acute myelogenous leukemia in first remission.

In order to improve leukemia-free survival we evaluated the feasibility and efficacy of autologous transplantation of interleukin-2 (IL-2)-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Forty-nine consecutive patients (median age 49, range 21-70) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine/mitoxantrone consolidation chemotherapy with post-recovery IL-2 used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 2.08 x 10(6) CD34+ peripheral blood progenitor cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-one patients received myeloablative chemoradiotherapy followed by the infusion of IL-2-mobilized autologous peripheral blood progenitor cells. The median times to both neutrophil and platelet recovery were 16 days (range, 2-43) and 23 days (8-318+ days), respectively. Twenty-seven patients remain alive with 24 in continued first complete remission. Median remission duration for all eligible patients is 8 months, and actuarial leukemia-free survival is 49+/-15%. The actuarial risk of relapse is 43+/-16%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in three patients and serious organ toxicity in 12. Advanced age was a negative prognostic factor for leukemia-free survival. Results were compared to an age-matched historical control treated with autologous transplantation of chemotherapy-mobilized progenitor cells; no significant difference in favor of IL-2 mobilization could be demonstrated. Our results demonstrate that autologous transplantation of IL-2-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission with minimal toxicity but no clear evidence of benefit in leukemia-free survival.

Transplantation of Autologous Peripheral Blood Progenitor Cells Procured after High-Dose Cytarabine-Based Consolidation Chemotherapy for Adults with Secondary Acute Myelogenous Leukemia in first Remission

Patients with acute myelogenous leukemia secondary to an antecedent hematologic disturbance or cytotoxic chemotherapy are considered to have a very low likelihood of leukemia-free survival regardless of the form of post-remission therapy. The purpose of this study is to evaluate, on the basis of intention to treat, the feasibility and efficacy of high-dose cyt-arabine/anthracycline consolidation chemotherapy followed by autologous transplantation of chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for seventeen adult patients (median age 63, range 27 to 68) with secondary acute myelogenous leukemia in first remission. Ten eligible patients underwent autologous transplantation of peripheral blood progenitor cells procured following high-dose cytarabine/mitoxantrone consolidation chemotherapy used as a method of in vivo purging. A median of 5 collections (range 2 to 13) were reuired to procure a median of 9.27 × 108 total mononuclear cells/kg (range 2.35 to 21.44 × 108 per kg). The median number of CD34-positive progenitor cells was 1.18 × 106 kg (range 0.34 to 30.9 × 106 kg). After preparative conditioning with 11.25 Gy total body radiation and cyclophosphamide (120 mg/kg) and autologous transplantation, the median time to neutrophil and platelet recovery were 18 days (range 12 to 29 days) and 25 days (range 8 to 158+ days), respectively. After a median follow-up for surviving patients of 33.4 months (range 7.5 to 54 months), 9 of 17 patients (53%) remain alive with 7 in continued first remission. The median remission duration is 13 months (3 to 53 months) and actuarial leukemia-free survival at 3 years is 51+25%. Toxicity of autologous peripheral blood progenitor cell transplant included serious liver and pulmonary toxicity in 2 and 1 patient, respectively. Our results demonstrate that a postremission program of high-dose cytarabine-based consolidation chemotherapy followed by autologous transplantation of chemotherapy-mobilized peripheral blood progenitor cells is feasible for patients with secondary acute myelogenous leukemia producing prolonged leukemia-free survival with minimal toxicity.

An Early Phase II Study of Autologous Peripheral Blood Stem Cell Transplantation for Acute Myelogenous Leukemia in First Remission

An Early Phase II Study of Autologous Peripheral Blood Stem Cell Transplantation for Acute Myelogenous Leukemia in First Remission

Intensive sequential post-induction therapy for adults with acute myelogenous leukemia in first remission: Long-term follow-up and results

We designed a post-induction therapy including intensive sequential therapy with non-cross-resistant drugs in an effort to prolong disease-free survival (DFS) for adults with acute myelogenous leukemia. Forty-five patients entered this study and 33 of 35 patients entering complete remission received the post-induction therapy. With a median follow-up for survivors of 3.5 years from complete remission, the actuarial 5-year DFS was 46% ± 19% (95% confidence interval). The five-year DFS for patients over 45 years of age was comparable to that for patients under 45 years of age (50% ± 26% vs 47% ± 28%). Furthermore, the actuarial 5-year DFS for patients who required two courses of induction therapy was comparable to that for patients who required only one course of induction therapy (45% ± 29% vs 50% ± 25%). The toxicity of post-induction therapy was tolerable and no patients died during complete remission.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

Bone marrow transplantation or chemotherapy as post-remission treatment of adult acute myelogenous leukemia

We compared three consolidation regimens in patients with acute myelogenous leukemia in first remission. Thirty-four patients received only intensive consolidation chemotherapy (SIC); 28 patients were scheduled to undergo an autologous bone marrow transplant (auto-BMT) and 44 patients an allogeneic BMT (allo-BMT). Twenty-seven of them were referred in first remission for allo-BMT. Nineteen patients achieved a complete remission after salvage treatment. All other patients obtained a remission after one or two courses of a standard combination of cytosine arabinoside and daunorubicin. Except for the patients who were referred in remission, all patients received intermediate dose cytosine arabinoside and amsacrine as a first consolidation treatment. The median ages of the three groups were 48 (SIC), 39 (auto-BMT) and 33 years (allo-BMT). Two patients relapsed before auto-BMT and 1 before allo-BMT. The median interval from the date of complete remission to the auto- or allo-BMT was 3 months. In total, 80% of the patients of the SIC group relapsed, compared to 50% of the patients belonging to the auto-BMT group and 35% of the 44 patients who were scheduled to receive an allo-BMT. The overall median disease-free survival was 14 months, 30% of the patients being alive and disease-free at 3 years. The disease-free survival rate at three years was 25% for the SIC group, 30% for the allo-BMT group and 40% for the ABMT group (P = 0.45). Our study shows no benefit for bone marrow transplantation over intensive consolidation treatment. However, large randomized trials are required to define the real value of these treatment modalities.