Myeloid Leukemia In First Remission Research Articles

Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis

AbstractWe compared the outcomes of unrelated donor (URD, n = 358) with human leukocyte antigen (HLA)–matched sibling donor (MSD, n = 226) transplantations in patients with acute myeloid leukemia (AML) in first complete remission (CR1) having unfavorable cytogenetics at diagnosis. Unfavorable cytogenetic abnormalities were: complex (≥ 3 abnormalities), 32%; and noncomplex involving chromosome 7, 25%; chromosome 5, 9%; 11q or MLL rearrangements, 18%; t(6;9), 5%; and other noncomplex, 10%. URDs were HLA-well-matched (n = 254; 71%) or partially-matched (n = 104; 29%). Three-year leukemia-free survival (LFS) for MSD was 42% (95% confidence interval [CI], 35%-48%) compared with 34% (95% CI, 28%-41%) for HLA-well-matched URD and 29% (95% CI, 20%-39%) for partially-matched URD (P = .08). In multivariate analysis, HLA-well-matched URD and MSD yielded similar LFS (relative risk [RR] = 1.1, 95% CI, 0.86-1.40, P = .44) and overall survival (OS; RR = 1.06, 95% CI, 0.83-1.37, P = .63). LFS and OS were significantly inferior for HLA-partially-matched URD recipients, those with prior myelodysplastic syndrome, and those older than 50 years. All cytogenetic cohorts had similar outcomes. Patients with chronic graft-versus-host disease had a significantly lower risk of relapse (RR = 0.68, 95% CI, 0.47-0.99, P = .05). Hematopoietic cell transplantation (HCT) using HLA-well-matched URD and MSD resulted in similar LFS and OS in AML patients in CR1 with unfavorable cytogenetics. Outcomes of HCT from HLA-partially- matched URD were inferior.

Effect of post-remission chemotherapy preceding allogeneic hematopoietic cell transplant in patients with acute myeloid leukemia in first remission

Patients with acute myeloid leukemia (AML) with intermediate or high risk cytogenetics are often considered for allogeneic hematopoietic stem cell transplant (AHSCT) in first remission. Between attainment of remission and AHSCT, post-remission chemotherapy is frequently administered, though there is no evidence for its effectiveness. This study was performed to determine the impact of post-remission chemotherapy on outcome after AHSCT. A subset analysis was performed to determine whether the influence of post-remission chemotherapy might be different in those with intermediate compared to high risk cytogenetics. There was no significant difference in relapse mortality (RM) (p = 0.70), non-relapse mortality (NRM) (p = 0.12), or survival (OS) (p = 0.15) between post-remission chemotherapy groups. There was no difference in RM, NRM, or OS between cytogenetic groups according to whether they received post-remission chemotherapy. No differential effect between intermediate and high risk cytogenetics was detected (RM, p = 0.80; NRM, p = 0.23; OS, p = 0.26). These data do not show a benefit of post-remission chemotherapy before AHSCT.

Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission

Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients do not have such a donor, however, requiring use of an alternative donor if HCT is undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; ≤9/10, n=29) or MRD (n=135) HCT from 1996–2007. Five-year estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) were 57.9%, 29.7%, and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any endpoint. The adjusted hazard ratios (HR) were 1.43 (0.89–2.30, p=0.14) for overall mortality, 1.17 (0.66–2.08, p=0.60) for relapse, and 1.79 (0.86–3.74, p=0.12) for NRM, respectively, and the adjusted odds ratio (OR) for grades 2–4 acute graft-versus-host disease was 1.50 (0.70–3.24, p=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR=1.16 [0.52–2.61], p=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

Long-Term Outcome of Children with Acute Myeloid Leukemia in First Remission Given Allogeneic HSCT from a Matched Family Donor After a Conditioning Regimen Comprising Busulfan, Cyclophosphamide and Melphalan.

Abstract 2288Poster Board II-265 Background.More than 80% of children with de novo acute myeloid leukemia (AML) achieve complete remission (CR) after aggressive induction chemotherapy. However, post-remission treatment plays a crucial role in the final outcome of these patients. In this regards, possible post-remission treatments include high dose chemotherapy, as well as autologous or allogeneic hematopoietic stem cell transplantation (HSCT).In the last years, several groups have compared allogeneic HSCT with chemotherapy or autologous HSCT in adults as well and children with AML in first remission. These studies have demonstrated that allogeneic HSCT is superior to the other forms of post-remission therapy in children with AML not carrying favourable cytogenetic characteristics.We herein report the long-term results of a prospective multicenter study aimed at evaluating the safety and efficacy of an original combination of 3 alkylating agents, busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM) as conditioning regimen for patients affected by de novo AML other than the FAB M3 subtype and given allogeneic HSCT from a matched family donor in first haematological CR. Patients and methods.Seventy consecutive patients (40 males and 30 females), affected by de novo AML in first CR, received an allogeneic HSCT from a HLA-matched family donor after a conditioning regimen combining BU (4 mg/Kg/day for 4 days), CY (60 mg/Kg/day for 2 days) and L-PAM (140 mg/m2). BU dosage was adjusted after the pharmacokinetic study performed following the first administration, in order to maintain a concentration to the steady state (Css) comprised between 600 and 900 ng/mL.Transplants were performed in one of the transplant centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP) between 1992 and 2002.Median patient age at HSCT was 7 years (0.5 – 17). Two patients had FAB M0 AML, 25 M1, 17 M2, 12 M4, 21 M5, 1 M6 and 2 M7 AML. Children with M3 AML were excluded from the study. Five patients with CBF anomalies, either isolated or associated with loss of sex chromosome, were considered to have favourable cytogenetics. The median interval between diagnosis and HSCT was 3.9 months (2.9 - 9). All patients were given bone marrow stem cells. GVHD prophylaxis consisted of cyclosporine-A (Cs-A) alone in 89% of patients, the remaining children receiving a combination of Cs-A with short-term methotrexate. Results.Median follow-up for surviving patients is 9 years (range, 6 – 16 years).The conditioning regimen was well tolerated, and no patient died for causes directly attributable to the myeloablative treatment.All patient engrafted, the median time to reach neutrophil and platelet recovery being 13 (7 - 28) and 21 (13 – 115) days, respectively.The cumulative incidence (CI) of grade II-IV acute GVHD was 58% (48 – 71), while that of grade III-IV acute GVHD was 14% (8 – 25). Chronic GVHD incidence was 27% (18 – 39).Ten-years survival probability was 77% (67 - 87), while 10-years disease-free survival (DFS) was 76% (65 - 86). The cumulative incidence of relapse was 17% (10 – 29), while the cumulative incidence of transplant-related mortality was 7% (3 – 17). Results improved over time, DFS being 59% (41 – 78) for patients transplanted before 1997 and 86% (75 – 96) for those transplanted after 1997. No other variables influenced the probability of both survival and DFS. Conclusions.Our study, conducted on a significant number of children affected by AML in first CR and with a very long follow-up demonstrate that allogeneic HSCT from a matched family donor can cure a large proportion of patients. The combination of dose-adjusted BU, CY and L-PAM was safe and well tolerated, with an incidence of TRM of only 7% and no death directly attributable to the conditioning regimen. Furthermore, the combination of 3 alkylating agents showed a good anti-leukemic activity, the probability of leukaemia recurrence being only 17%. Disclosures:No relevant conflicts of interest to declare.

Comparable outcomes of HLA‐matched unrelated and HLA‐identical sibling donor bone marrow transplantation for childhood acute myeloid leukemia in first remission

We retrospectively investigated the outcomes of HLA-matched unrelated BMT (MU-BMT, n = 13) and HLA-identical sibling donor BMT (MS-BMT, n = 17) for childhood AML in CR1 between June 2002 and August 2005. Engraftment of neutrophil and platelet did not differ between the two transplant groups. The cumulative incidence of grade II-IV acute GVHD and any chronic GVHD at three yr was not different between MS-BMT and MU-BMT. Of the 30 patients, four patients experienced relapses (three with MS-BMT, one with MU-BMT) and four patients died of transplant-related complications (two with MS-BMT, two with MU-BMT). A total of 23 patients survived with a median follow-up of 43.2 months. The Kaplan-Meier estimates for EFS rates at three yr were 71% and 77% for MS-BMT and MU-BMT, respectively, and the OS rates were 76% and 77% for MS-BMT and MU-BMT, respectively. The outcome of HLA-matched unrelated BMT is comparable to that of HLA-identical sibling BMT for childhood AML in CR1. HLA-matched unrelated BMT may be recommended for patients who have AML in CR1 without an HLA-matched sibling donor.

Clinical and Serologic Interleukin 2 Receptor α Response to Interleukin-2 in CCG-2961, a Ranomized Phase 3 Trial for Pediatric Acute Myeloid Leukemia.

The Children's Cancer Group conducted a randomized comparison of interleukin-2 (IL-2) to no further therapy (control) in pediatric patients with acute myeloid leukemia in first remission after 3 courses of dose intensive chemotherapy. To assess biologic activity of IL-2, serum samples for soluble IL-2 receptor alpha concentration (sIL-2rα) were collected before induction chemotherapy, and after completing chemotherapy but before (day 0), during (day 4) and after IL-2 (day 18) in those randomized to receive IL-2 and before chemotherapy and at the end of chemotherapy (day 0) and 28 days later in the controls. Of 385 eligible patients, 289 consented to participation in the randomization, and 172 submitted specimens. Patients randomized to IL-2 received IL-2 9 x 106 IU/m²/day by continuous infusion (CI) days 0–3 and 1.6 x 106 IU/m²/day CI days 8–17. At five years disease-free survival (DFS) is 51% + 9% in the IL-2 group and 58% + 8% in the controls (p =0.489), and respective overall survivals are 70% + 8% and 73% + 8% (p= 0.727). At diagnosis, median sIL-2rα concentration was 3342 pg/ml in the IL-2 group (N=34) and 3778 pg/ml in the controls (N=41) (p=0.947). In both groups there was a significant reduction in sIL-2rα concentration between the start and day 0 after chemotherapy. In the IL-2 group median sIL-2rα increased significantly from 1462 pg/ml on day zero to 13659 pg/ml on day 4 (p<0.001) and 8435 pg/ml on day 18 (p<0.001). In the control group day sIL-2rα was 1424 pg/ml on day zero and 1559 pg/ml on day 28. Despite evidence of substantial biologic activity as measured by significant increases in sIL-2rα concentration during IL-2 administration, IL-2 in this dose and schedule had no significant effects on DFS or survival. Furthermore, sIL2αr levels (the pretreatment sIL2rα level, the sIL2rα level obtained after chemotherapy or the level achieved after IL2 treatment) did not correlate with DFS or survival, or treatment-related toxicity.

Hematopoietic cell transplantation–specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences

A new hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was effective in predicting outcomes among patients with hematologic malignancies who underwent HCT at Fred Hutchinson Cancer Research Center (FHCRC). Here, we compared the performance of the HCT-CI to 2 other indices and then tested its capacity to predict outcomes among 2 cohorts of patients diagnosed with a single disease entity, acute myeloid leukemia in first complete remission, who underwent transplantation at either FHCRC or M. D. Anderson Cancer Center (MDACC). FHCRC patients less frequently had unfavorable cytogenetics (15% versus 36%) and HCT-CI scores of 3 or more (21% versus 58%) compared with MDACC patients. We found that the HCT-CI had higher sensitivity and outcome predictability compared with the other indices among both cohorts. HCT-CI scores of 0, 1 to 2, and 3 or more predicted comparable nonrelapse mortality (NRM) among FHCRC and MDACC patients. In multivariate models, HCT-CI scores were associated with the highest hazard ratios (HRS) for NRM and survival among each cohort. The 2-year survival rates among FHCRC and MDACC patients were 71% versus 56%, respectively. After adjustment for risk factors, including HCT-CI scores, no difference in survival was detected (HR: 0.98, P = .94). The HCT-CI is a sensitive and informative tool for comparing trial results at different institutions. Inclusion of comorbidity data in HCT trials provides valuable, independent information.

Comparable Outcomes of High-Resolution HLA-Matched Unrelated and HLA-Identical Sibling Donor Stem Cell Transplantation for Childhood Acute Myeloid Leukemia in First Remission.

Purpose: The role of allogeneic stem cell transplantation (SCT) from unrelated donor for childhood acute myeloid leukemia (AML) in first remission remains unclear because of its high transplant-related mortality. In this study, we investigated the role of SCT from high-resolution HLA-matched unrelated donor for childhood acute myeloid leukemia in first remission by comparing the outcomes of SCT from HLA-identical sibling donors and high-resolution HLA-matched unrelated donors. Patients andMethod: Between June 2002 and August 2005, 40 children who have AML in first complete remission received SCT at Saint Mary's hospital in Korea. In SCT from 17 sibling donors (M-SBMT), low-resolution typing (two-digit level) for HLA-A, -B, -C and -DRB1 was performed and all of donor-recipient pairs were 8/8 matches. Unrelated donors and recipients were typed for HLA-A, -B, and -DRB1 by high-resolution molecular typing (four-digit level). Of the 23 unrelated donor-recipients pairs, 14 were 6/6 matches (M-UBMT) and 9 were 5/6 matches (MM-UBMT). Conditioning regimen consisted of busulfan i.v. and cyclophosphamide. All patients received cyclosporin A and short-course methotrexate for GVHD prophylaxis.Results: Of the 40 patients, 27 survived event-free with a median follow-up of 38 months (range, 23–57 months). Median times for neutrophil engraftment were 12 days(range, 11–15 days), 11 days(range, 10–16 days) and 12 days(range, 11–15 days) for M-SBMT, M-UBMT and MM-UBMT, respectively. The number of Grade II-IV acute GVHD was 5 (29%), 7 (50%) and 6 (67%) in the M-SBMT, M-UBMT and MM-UBMT, respectively. One patient in MM-UBMT developed grade III acute GVHD. The number of patients who developed chronic GVHD was 2, 6 and 4 in the M-SBMT, M-UBMT and MM-UBMT,respectively. The number of relapsed patients after SCT was 3, 2 and 1 in the M-SBMT, M-UBMT and MM-UBMT and the number of non-relapse death was 2, 2 and 4, respectively. The Kaplan-Meier estimates for event-free survival at 3 years were 70 ± 11%, 71 ± 12% and 44 ± 17% for M-SBMT, M-UBMT and MM-UBMT, respectively without statistical significance (p=0.38). The Kaplan-Meier estimates for overall survival at 3 years were 76 ± 10%, 71 ± 12% and 44 ± 17% for M-SBMT, M-UBMT and MM-UBMT,respectively (p=0.25).Conclusion: In this study, we showed the outcome of SCT from high-resolpution HLA-matched unrelated donors was comparable with that of SCT from HLA-identical sibling donors in childhood AML in first remission. Therefore, high-resolution HLA-matched unrelated SCT might be recommended in patients without HLA-matched sibling donor in childhood AML in first remission.

Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission

We prospectively compared two strategies of allogeneic PBSCT from HLA-identical siblings in adults with poor-risk AML or myelodysplastic syndrome with >5% marrow blasts in an early disease status (AML or refractory anemia with excess blasts (RAEB type 2) in first remission after chemotherapy or untreated RAEB type 1). Based only on age, all consecutive patients were offered one of two specific transplant protocols. Patients < or =50 years old received conventional high-dose conditioning with cyclophosphamide-TBI and use of CD34+-selected PBSCT (CTCD34+ group), while patients aged >50 years received a reduced-intensity conditioning (RIC) with fludarabine and oral busulphan (FB-RIC). Seventy-five patients entered the study (35 in the CTCD34+ and 39 in the FB-RIC group). The median follow-up was >4 years in both groups. The 4-year non-relapse mortality (NRM) was 19 and 20%, respectively (P=0.8). Relapse and survival were also equivalent in both groups. These results suggest that in this setting, the expected high NRM in elderly patients can be reduced with an RIC regimen.

Improved outcome in young adults with de novo acute myeloid leukemia in first remission, undergoing an allogeneic bone marrow transplant

We assessed the outcome of 170 patients with AML in first complete remission, aged 1-47 years (median 29), who had undergone an allogeneic BMT before or after 1990 (n=80 and n=90, respectively); all patients were prepared with cyclophosphamide and TBI; the median follow-up for surviving patients was 13 years. The donor was an HLA-identical sibling in 164 patients. Transplant-related mortality (TRM) was 30% before and 7% after 1990 (P<0.001); relapse-related death (RRD) was 26 and 11% (P=0.002); and actuarial 10-year survival was 42 and 79% (P<0.00001). Patients transplanted after 1990 were older, had a shorter interval diagnosis-BMT, had less FAB-M3 cases, received a higher dose of TBI, a higher marrow cell dose and combined (cyclosporine+methotrexate) GVHD prophylaxis. Patients relapsing after transplant had an actuarial survival of 0 vs 31% if grafted before or after 1990 (P=0.01), and their median follow-up exceeds 10 years. In conclusion, the overall survival of first remission AML undergoing an allogeneic BMT has almost doubled in the past two decades, despite older age and fewer M3 cases. Improvement has come not only from changes in transplant procedures, but also from effective rescue of patients relapsing after transplant.

Comparable Results of HLA Identical Sibling Donor Peripheral Blood Hematopoietic Stem Cell Transplantation after Reduced-Intensity and High-Dose TBI-Based CD34+-Positive Cell Selection Myeloablative Preparative Regimens for High-Risk Myelodysplasia or Acute Myeloid Leukemia in First Remission: Results from a Prospective Study.

We prospectively compared the efficacy of allogeneic PBSCT from an HLA-identical sibling in adults with poor-risk AML or MDS in an early disease status (AML or RAEB type 2 in first CR after chemotherapy or RAEB type 1 with poor prognosis). Poor-risk AML/MDS was defined as the presence at diagnosis of one or more of the following: poor-risk karyoype, normal karyotype with flt-3 duplications or MLL mutations, high level of MRD after consolidation (>0.1%), and, in RAEB type 1, an IPSS3Int-2. Based only on the patients' age, the transplant protocol consisted in conditioning with cyclophosphamide-TBI and use of CD34+-selected PBSCT (CyTBI-CD34+ group, if £ 50 y.o.) or a reduced-intensity conditioning (RIC) with fludarabine and oral busulphan (FluBu-RIC, If > 50 y.o.). Between 1998 and 2005, 74 consecutive patients entered the study (35 in the CyTBI-CD34+ and 39 in the FluBu-RIC group). Both groups differed in some baseline characteristics, mainly younger age in the CyTBI-CD34+ group (median 42 vs. 59 years, p<0.01), a higher transplant comorbidity index in the FluBu-RIC group (median 0 vs. 3 points, respectively, P<0.01), a higher proportion of AML (with respect to RAEB) in CyTBI-CD34+ group (82% vs 54%, respectively, P=0.02), and a higher proportion of poor-risk karyorypes in the FluBu-RIC group (32% vs 72%, respectively, P<0.01). The median follow-up exceeds 4 years in both groups. All patients had sustained donor-engraftment by day +60, except for one lethal graft failure in the CyTBI-CD34+ group. The 4-year probability of OS was and LFS were similar in both groups (52% and 53% in the CyTBI-CD34+ group vs. 53% and 53% in the FluBu-RIC group, respectively, P>0.8 for OS and LFS). In addition, the 4-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 11–38%) and 22% (95% CI 5–39%), respectively (P>0.8), while the incidence of relapse was 22% (95% CI 5–39%) and 25% (95% CI 6–44%), respectively (P>0.8). In univariate analysis, the only variable that decreased OS and LFS by increasing NRM was the patient male/donor female sex combination (n=18 cases). The OS and NRM in these 18 cases were 37% and 40%, respectively, while the 56 cases with other sex combinations had much better outcomes (66% OS and 8% NRM, P=0.004 and P==0.001 for the comparison of OS and NRM, respectively). Trends were seen for improved OS and lower NRM in the CyTBI-CD34+ group in patients less than 40 years of age (P=0.1) and in patients receiving higher doses of CD34+ cells/kg in the FluBu-RIC group (P=0.1). Our single-center results suggest comparable outcomes for RIC alloPBSCT in high-risk adults with poor-risk AML and MDS in an early disease phase.

Chemotherapy for patients with acute myeloid leukemia in first remission

Although the majority of patients with acute myeloid leukemia (AML) achieve a complete remission with induction chemotherapy, most will ultimately relapse. Therefore, the optimal postremission therapy for AML remains to be defined, and further improvements in treatment strategies are required. Clinical trials have demonstrated that early intensive consolidation therapy with high-dose cytarabine can produce prolonged responses in up to 40% of patients in remission after standard induction therapy. Equally, however, it has been shown that high-dose cytarabine used in induction therapy can deliver equivalent long-term results. Autologous and allogeneic stem cell transplantation in first remission are also valid alternatives, but the value of low-dose maintenance treatment seems confined to acute promyelocytic leukemia. Further improvement in the treatment of AML is likely to depend on the development of new strategies, such as molecularly targeted or immune therapies.

131I–anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment Trial

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment Trial

Calcitonin A Genotype Is Associated with Risk of Acute Graft-Versus-Host Disease Following Allogeneic Bone Marrow Transplantation for Children with Acute Myeloid Leukemia in First Remission.

Background: Procalcitonin (PCT) is a 13 kD 116-amino acid prohormone. Elevated serum levels of procalcitonin have been noted in patients with bacterial infections such as septicemia, pneumonia and immune-mediated conditions like graft-versus-host disease (GvHD) and organ rejection. In this study, we sought to examine if a single base pair polymorphism (a T to C transition) at position −624 of the calcitonin A gene (CALCA) was associated with risk of acute GvHD.Subjects: 113 children (median age 10 y; range 0.38 – 19.0 y) with de novo acute myeloid leukemia (AML) treated on recent Children's Oncology Group protocols 2891, 2941 or 2961. All of these patients received matched sibling bone marrow transplant (BMT) in first clinical remission. Ablative conditioning consisted of busulfan and cyclophosphamide. All patients received methotrexate until day 100 for GvHD prophylaxis.Methods: All clinical DNA specimens were subjected to whole genome amplification. Genotyping was performed using the 5′-nuclease (TaqMan) assay on the ABI 7700 DNA analyzer (Applied Biosystems).Results: Observed CALCA -624 T>C genotypes in 113 patients were: TT = 52 (46%), TC = 43 (38%) and CC = 18 (16%); T allele = 73 (65%) and C allele = 40 (35%). There were no significant differences in patient characteristics (age, gender, race, study 2891/2941/2961, white blood count at diagnosis, FAB type, or cytogenetics) between the TT vs. combined TC or CC groups. Overall, acute GvHD grade I–IV (Seattle criteria) was observed in 55/113 patients (49%). Nineteen out of 52 (37%) with TT, while 21 out of 43 (49%) with TC, and 15 out of 18 (83%) with CC CALCA genotypes developed acute GvHD. Alternatively, acute GvHD was observed in 37% patients with common TT genotype and in 59% patients with variant TC or CC genotype (p=0.023). The odds ratio for developing acute GvHD (grade I – IV) for children with TC or CC genotypes was 2.5 (CI 1.17, 5.33) compared with those with TT genotype. The difference in observed acute GvHD remained significant when the analyses were limited to more uniform subgroups: 54 patients on single trial, 2961 only (p=0.028) and 42 whites only on 2961 trial (p=0.028). Severe acute GvHD (grade III – IV) was seen in 6/52 (12%) patients with TT vs. 6/61 (10%) in those with TC or CC genotypes; this difference was not statistically significant (p =0.771). There were no significant differences in day +100 transplant related deaths, engraftment, relapse rate or overall survival. Plans: Association between CALCA genotypes and infectious complications will be also analyzed when clinical data abstraction is completed. CALCA −1752 C>G and 3740 A>G genotyping is in progress and clinical correlative analyses will be repeated at genotype and haplotype levels.

Graft clonogenicity and intensity of pre-treatment: factors affecting outcome of autologous peripheral hematopoietic cell transplantation in patients with acute myeloid leukemia in first remission

A total of 22 patients with acute myeloid leukemia (AML) in first complete remission receiving autologous blood stem cell transplantation (ABSCT) were investigated in order to determine factors affecting outcome. All but two patients had a normal karyotype and received the same high-dose chemotherapy followed by G-CSF-mobilized peripheral blood stem cells after the second (n=5) or third (n=17) course of induction and post-remission chemotherapy, respectively. With a median follow-up of 30 months, the median disease-free survival is 24.1 months. Univariate analysis showed that three chemotherapy cycles before ABSCT were associated with a significant better disease-free survival (P=0.0018) and overall survival (P=0.0033), whereas the presence of an FLT3-mutation (n=6) showed no impact. The number of megakaryocytic progenitors (CFU-MK) infused tended to correlate with primary platelet engraftment (P=0.07) and were predictive for neutrophil (P=0.011) and platelet counts (P=0.009) 180 days after transplantation. Patients receiving a higher amount of CFU-MK had a better event-free survival (P=0.02). Our data suggest that the content of CFU-MK within the graft predicts the quality of hematological recovery and long-term disease control. Additionally, a minimum of three chemotherapy cycles before ABSCT seems to be associated with an improved outcome.

Post-remission therapy of acute myeloid leukemia in first remission

Post-remission therapy of acute myeloid leukemia in first remission

A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine

AbstractThe value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/m2 × 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 × 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m2 daily × 5, idarubicin × 2, etoposide × 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P = .66), survival following randomization (61% vs 62%; P = .91), or the cumulative incidence of relapse (43% vs 51%; P = .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit.

Utility of Prophylactic Autologous Stem Cell Collection for Patients with Acute Myeloid Leukemia in First Remission.

High-dose therapy and autologous stem cell transplant (SCT) is an option for patients with AML most commonly performed in first complete remission (CR1) or CR2. Stem cell (SC) collection in CR1 typically follows consolidation. SC collection in CR2 is limited by the need to achieve a second remission prior to harvest, and the use of additional induction therapy that may result in marrow toxicity and SC depletion. In addition, a SC product collected in CR2 might be more likely to have leukemia cell contamination that could contribute to subsequent relapse. Prophylactic collection of SC from patients in CR1 who are not imminently going on to SCT may therefore be reasonable and theoretically could improve outcome of SCT in CR2. However, many patients never relapse, and for those who do, alternative options, and the need to achieve a 2nd CR, further limit the chance that these cells will be used. The morbidity and cost of SC collection, and the need for prolonged storage, call into question the practice of routine prophylactic SC harvest. To determine the utility of SC collection in CR1, we identified 67 patients with AML who had autologous SCs collected between 1995 and 2002. Charts were reviewed to assess whether the collection was prophylactic or for immediate use and we reviewed the timing and outcomes of transplant. 61/67 patients had SCs collected in CR1, 5 in CR2, 1 in CR3. 22 had collection for imminent therapeutic use and 45 for potential future use. Among the 22 patients whose cells were collected for planned SCT, cells were collected in CR1 in 17 cases and CR2 in 5 cases. 11 (50%) remain in CR a median of 58 mo (range 4–103) after SCT, and 11 died a median of 11 mo (4 – 28) after SCT. Causes of death were relapse (n=8), transplant related mortality (TRM) (n=1), TRM after allogeneic SCT (n=1), and unrelated causes (n=1). Of 17 patients transplanted in CR1, 8 (47%) remain in CR. Of the patients whose cells were both collected and used in CR2, 3/5 remain in remission 8, 53, and 103 mo after SCT and 2 died of relapse 10 and 24 mo after SCT. 5/45 patients whose stem cells were collected prophylactically in CR1 used these cells for SCT in CR2 a median of 16 months (15 – 28) after collection. 2/5 of these patients remain in CR 21 mo and 51 mo and 3 had died of relapsed disease 9–12 mo after SCT. Stem cells remain unused in 40 of these patients and 21 (53%) remain in CR a median of 39 mo (7–98 ) after collection. 15/21 remain in CR without further therapy. 3 patients are currently alive receiving therapy for relapse and therefore may use cells in the future. 6 patients are in CR after allogeneic SCT in CR1 (2), CR2 (3) or untreated relapse (1). 16/40 will never use stored cells. 12 died of disease a median of 10 mo (4–22) after prophylactic SC collection and 4 died from complications of allogeneic SCT in CR1 (3) or CR2 (1). In summary, of the 45 patients with SCs harvested prophylactically in AML CR1, 5/21 (23%) who required further therapy went on to use these cells with 2/5 long-term survivors. Another 24 have done well with initial therapy but remain at risk for relapse and may use SCs in the future. In our experience, prophylactic autologous SC harvest and storage from patients with AML in CR1 remains a reasonable option. Additionally, SCT for AML in CR has resulted in frequent long-term remission at our institution.

131I-Anti-CD45 Antibody Plus Busulfan/Cyclophosphamide in Matched Related Transplants for Acute Myeloid Leukemia in First Remission.

Patients with AML in first remission undergoing conventional matched related hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality following transplant. In an attempt to improve outcome by decreasing relapse, we conducted a Phase I/II study in which targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody is combined with busulfan (BU) and cyclophosphamide (CY). Patients (median age 41) received a trace (~5mCi) 131I-labeled dose of 0.5 mg/kg anti-CD45 (BC8) murine monoclonal antibody followed by serial quantitative gamma camera imaging and a bone marrow biopsy for estimation of radiation absorbed doses to target organs (marrow and spleen) and non-target organs (liver, lung, and kidney). Fifty-two of 59 patients (88%) had a higher estimated radiation absorbed dose to marrow and spleen than to any normal organ. Forty-six of these were treated with 102 to 298 mCi 131I delivering an estimated 5.3 to 19 (mean 11.3) Gy to bone marrow, 17 to 72 (mean 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. Patients then received targeted BU (AUC 600–900 ng/ml), CY (120 mg/kg), and infusion of HLA-matched related marrow (n = 40) or peripheral blood stem cells (n = 6). The non-relapse mortality (NRM) was 17%, as eight patients died of transplant-related causes (sepsis-2, idiopathic pneumonia syndrome-1, viral pneumonia-3, and fungal pneumonia-2). Nine patients (20%) relapsed 3 to 38 months post-transplant, and 28 patients (61%) are surviving disease-free 7 to 124 months (median 49 months) post-transplant. For 26 patients (62%) with intermediate risk cytogenetics, 18 (69%) are surviving disease-free, with only 3 (12%) relapsing. Fifteen patients (33%) were considered high risk based on unfavorable cytogenetics or secondary AML; 7 of these 15 (46%) are surviving disease-free and 5 (33%) have relapsed. Because of the known impact of features such as age and cytogenetic risk group on post-HCT outcome, we compared our data to data from the International Bone Marrow Transplant Registry (IBMTR) on first remission AML patient conditioned with BU/CY alone prior to HCT. Over a 10-year period, 980 IBMTR patients (median age 28) were transplanted using a median BU dose of 16 mg/kg (range 8–21 mg/kg) and a median CY dose of 120 (range 62–232). Of the 509 IBMTR patients with known cytogenetics at diagnosis, 466 (92%) had intermediate-risk cytogenetics. Using a Cox regression model for overall mortality and adjusting for age and cytogenetics risk differences, the hazard for mortality among 131I-BC8 Ab/BU/CY patients is 0.65 times that of registry patients receiving BU/CY only (95% CI 0.35 to 1.08, p = 0.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is both feasible and well tolerated, and has the potential to improve survival for patients undergoing HCT for AML in first remission.