Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.     

Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome.

PURPOSE: To improve the effect of allogeneic stem-cell transplantation by sequential use of intensive chemotherapy, reduced-intensity conditioning (RIC), and prophylactic donor lymphocyte transfusions (pDLTs) in high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: In a prospective study of 75 consecutive patients (median age, 52.3 years), high risk was defined by progressive or refractory disease (n = 59), second remission after early relapse (n = 8), or first remission with poor prognosis based on cytogenetics or delayed response to induction therapy (n = 8). Unfavorable karyotypes were found in 49% of informative patients, and 68 patients had medical contraindications against standard conditioning. Fludarabine (30 mg/m2), cytarabine (2 g/m2), and amsacrine (100 mg/m2) for 4 days were used for cytoreduction. After 3 days of rest, RIC consisted of 4 Gy total-body irradiation, antithymocyte globulin, and 80 to 120 mg/kg cyclophosphamide. Thirty-one patients had an HLA-identical sibling donor; 44 patients had an unrelated and/or HLA-mismatched donor. pDLT was given from day +120 in patients who were not receiving immunosuppression and were free of graft-versus-host disease (GvHD). RESULTS: Complete remission was induced in 66 patients (88%). With a median follow-up of 35.1 months (range, 13.6 to 47.6 months), 2-year overall and leukemia-free survival were 42% and 40%, respectively. Outcome of patients with refractory disease or with complex cytogenetic aberrations was identical to that of better prognostic subgroups. Survival was best in patients who received high CD34+ cell numbers, and in patients with limited GvHD. CONCLUSION: Sequential use of intensive chemotherapy, RIC transplantation, and pDLT represents a promising approach to the treatment of high-risk AML and MDS, particularly in patients with most unfavorable prognoses.     

Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome.

PURPOSE: This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS: After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION: Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.     

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.     

Reduced-intensity conditioning therapy with fludarabine,idarubicin, busulfan and cytarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome

We retrospectively analyzed allogenic stem cell transplantation (allo-SCT) outcomes in 82 patients with AML or MDS were conditioned with fludarabine, idarubicin, intravenous-busulfan and cytarabine (FIBA) or busulfan and cyclophosphamide (BuCy). Compared to BuCy regimen, reduced intensity conditioning (RIC) with FIBA was associated with a lower incidence of severe acute GVHD, lower NRM and a similar relapse rate. There was no significant difference in the 3 year overall survival (OS), but this is possibly due to the limited number of patients. The FIBA regimen is promising to replace BuCy regimen because of better security and similar relapse rate.     

Feasibility of the fludarabine busulfan 3 days and ATG 2 days reduced toxicity conditioning in 51 allogeneic hematopoietic stem cell transplantation: A single-center experience

In reduced-toxicity conditioning hematopoietic stem cell transplantation, several studies failed to demonstrate the superiority of one conditioning over another. This study described 51 patients (median age of 58 years) allografted with the new FB3-ATG2 conditioning regimen for myeloid (66%) or lymphoid disease (33%). Comorbidity index ≥3 was noted in 23.5% of patients. Toxicities were close to those observed with RIC. One-year cumulative incidence of acute and chronic GVHD was 18.9% and 39.2%. The 2-year-NRM, DFS and OS were 25%, 57.5% and 66%. The FB3-ATG2 regimen is safe and efficient in both lymphoid and myeloid disorders. However, prospective comparative studies are needed.     

Viewpoint: What is the role of allogeneic haematopoietic cell transplantation in the era of reduced-intensity conditioning--is there still an upper age limit? A focus on myeloid neoplasia.

Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC) allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukaemia effect. We try to answer the following questions in this paper: who should receive RIC HCT? when and how should the transplant be performed? is there an upper age limit and what is the future of RIC HCT?     

Epigenetic priming with decitabine followed by low dose idarubicin and cytarabine in acute myeloid leukemia evolving from myelodysplastic syndromes and higher-risk myelodysplastic syndromes: a prospective multicenter single-arm trial

Patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) or higher-risk MDS have limited treatment options and poor prognosis. Our previous single-center study of decitabine followed by low dose idarubicin and cytarabine (D-IA) in patients with myeloid neoplasms showed promising primary results. We therefore conducted a multicenter study of D-IA regimen in AML evolving from MDS and higher-risk MDS. Patients with AML evolving from MDS or refractory anemia with excess blasts type 2 (RAEB-2) (based on the 2008 WHO classification) were included. The D-IA regimen (decitabine, 20 mg/m² daily, days 1 to 3; idarubicin, 6 mg/m² daily, days 4 to 6; cytarabine 25 mg/m² every 12 hours, days 4 to 8; granulocyte colony stimulating factor [G-CSF], 5 μg/kg, from day 4 until neutrophil count increased to 1.0 × 10⁹/L) was administered as induction chemotherapy. Seventy-one patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS and 27 (38.0%) had RAEB-2. Twenty-eight (63.6%) AML patients achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi): 14 (31.8%) patients had CR and 14 (31.8%) had CRi. Six (22.2%) MDS patients had CR and 15 (55.6%) had marrow complete remission. The median overall survival (OS) was 22.4 months for the entire group, with a median OS of 24.2 months for AML and 20.0 months for MDS subgroup. No early death occurred. In conclusion, the D-IA regimen was effective and well tolerated, representing an alternative option for patients with AML evolving from MDS or MDS subtype RAEB-2.     

Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells.

PURPOSE: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs. PATIENTS AND METHODS: We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate. RESULTS: Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting. CONCLUSION: RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect.     

High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia

Background: The bcl-2 oncoprotein is suggested to be directly involved in the emergence of drug resistance by disrupting or delaying the apoptotic program and promoting tumor survival.Patients and methods: In order to define the clinical relevance of the bcl-2 mRNA expression in acute myeloid leukemia (AML) and its correlation to therapy outcome and prognosis, we analyzed 219 AML bone marrow (BM) samples, including 119 patients with de novo AML at presentation, 37 with AML following myelodysplastic syndrome (MDS), as well as 42 BM samples of AML in relapse and 21 in complete remission (CR) using RT-PCR. For performing quantitative measurements of bcl-2 mRNA, we developed a quantitative RT-PCR.Results: Bcl-2 mRNA was detectable in 133 of 156 (84%) patients at diagnosis and 40 of 42 (95%) at relapse. AML patients with high bcl-2 mRNA expression achieved lower CR rates than those with no or low expression. Concerning the long-term outcome, the overall (OS) and disease-free survival (DFS) was significantly worse in AML patients with high expression levels of bcl-2 mRNA. The three-year OS for all newly diagnosed AML patients was 49% and 10% (P = 0.028), respectively, and 71% and 15% (P = 0.0004) for patients <60 years. Comparable significant differences were observed for the DFS.In AML following MDS and patients >60 years, the bcl-2 expression was not associated with remission rate or survival.Conclusions: The expression of bcl-2 mRNA may serve as a prognostic factor predicting remission outcome and long-term prognosis in AML.     

Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse.

For patients with acute myeloid leukemia (AML) relapsed after allogeneic bone marrow transplantation (BMT), donor leukocyte infusion (DLI) as sole therapy has very limited efficacy. We tested the effects of cytoreductive chemotherapy, followed immediately by G-CSF-primed DLI (chemotherapy followed by DLI, Chemo-DLI), in 16 AML patients who relapsed after allogeneic BMT. In all, 10 of these patients achieved complete remission (CR), four of whom remain alive in CR at a median follow-up of 1488 days after DLI. The 2-year overall survival (OS) for the entire cohort was 31%. The 1-year OS for patients with post-BMT remission of 6 months or longer was 55%, compared with 0% for patients with post-BMT remission of less than 6 months, making post-BMT remission duration the only significant prognostic factor for OS (P=0.015). These findings suggest that Chemo-DLI could induce durable remissions in a proportion of relapsed AML patients with relatively long post-BMT remission duration. All five patients who relapsed after achieving CR with Chemo-DLI relapsed at extramedullary sites in the presence of continuous bone marrow remission, suggesting uneven graft-versus-leukemia effects in different parts of the body. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after Chemo-DLI.     

Induction chemotherapy followed by allogeneic HCT versus upfront allogeneic HCT for advanced myelodysplastic syndrome: A propensity score matched analysis

To reduce post‐transplant relapse, acute myeloid leukemia (AML) type remission induction chemotherapy has been attempted to reduce disease burden before allogeneic hematopoietic cell transplantation (HCT) in patients with advanced myelodysplastic syndrome (MDS). However, the efficacy of induction chemotherapy before HCT is unclear. We retrospectively analyzed the Japanese registration data of 605 adult patients, who had received allogeneic HCT for advanced MDS between 2001 and 2016, to compare the post‐transplant relapse between patients who received induction chemotherapy followed by allogeneic HCT and those who received upfront HCT. Propensity score matching identified 230 patients from each cohort. There were no significant differences in overall survival and non‐relapse mortality between the two groups. The cumulative incidence of relapse was significantly higher in patients who received induction chemotherapy than those who received upfront HCT. In the subgroup analyses, upfront HCT had a significantly reduced relapse incidence among patients with poor cytogenetics, those with higher international prognostic scoring system at diagnosis, and those who received reduced‐intensity conditioning. Our results suggested that AML type remission induction chemotherapy before HCT did not improve post‐transplant relapse and survival for adult patients with advanced MDS. Upfront HCT is preferable for patients with a poor karyotype.     

HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia.

We conducted a retrospective registry-based analysis to compare the outcome of 361 allogeneic human leukocyte antigen (HLA)-identical peripheral blood stem cell transplants (PBSCT) with reduced intensity conditioning (RIC) to that of 1369 autologous (auto) PBSCT in patients aged 50 years or older with de novo acute myeloid leukemia (AML), performed from 1997 until 2003 and reported to the European Group for Blood and Marrow Transplantation. Median age was 58 and 57 years in the RIC and auto groups, respectively. RIC patients had more advanced disease at the time of transplant. At a median follow-up of 24 months for RIC and 16 months for auto, multivariate analysis showed a lower risk for relapse (RR 0.77, P=0.013) without increased non-relapse mortality (NRM) in RIC patients (RR 1.26, P=0.28). Moreover, leukemia-free survival (RR 1.22, P=0.02) and overall survival (OS) (RR 1.32, P=0.005) were superior in the RIC group. In patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM. Therefore, there was no survival advantage in this subgroup. In patients in 2nd or subsequent CR, LFS and OS were superior in the RIC group. RIC transplants show encouraging results in this older patient population with de novo AML.     

Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience

Background Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. Patients and methods We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. Results Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. Conclusions These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.     

Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting.

PURPOSE: To evaluate the use of reduced-intensity (RI) conditioning with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical family donors in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). PATIENTS AND METHODS: Sixteen patients (median age, 54 years; range, 37 to 66 years) underwent RI-HSCT using a conditioning regimen of fludarabine 25 mg/m2 daily for 5 days and either cyclophosphamide 1 g/m2 daily for 2 days (14 patients) or melphalan 140 mg/m2 for 1 day (two patients). The median number of CD34+ cells and CD3+ cells infused per kilogram of recipient weight was 4.5 x 106 (range, 1.8 to 7.3 x 106 cells) and 2.9 x 108 (range, 0.1 to 9.6 x 108 cells), respectively. RESULTS: There was no transplant-related mortality (TRM) within 100 days of HSCT. Grade 1 to 2 acute graft-versus-host disease (GVHD) occurred in three patients, but neither grade 3 nor grade 4 disease was observed. Chronic GVHD occurred in 10 patients. One patient had cytomegalovirus (CMV) reactivation but did not develop CMV disease. With a median follow-up of 26 months (range, 15 to 45 months), 11 patients are alive (nine in continuous complete remission and one in complete remission after a second transplantation), and five have died (four from disease progression and one from bone-marrow aplasia induced by cyclosporine withdrawal). The 2-year actuarial overall and event-free survival rates were 69% (95% confidence interval [CI], 40% to 86%) and 56% (95% CI, 30% to 68%), respectively. CONCLUSION: This strategy of RI-HSCT resulted in reliable engraftment with low incidence of acute GVHD and TRM. Durable remissions were observed in patients with MDS and AML consistent with a graft-versus-leukemia effect.     

Allogeneic Stem Cell Transplantation in Patients With FLT3-ITD Mutated AML: Transplantation in CR1 Is the Decisive Factor for Good Outcome

BackgroundPatients with internal tandem duplication in fms-related tyrosine kinase receptor gene 3 (FLT3-ITD)-mutated acute myeloid leukemia (AML) have a dismal prognosis and the only curative option seems to be allogeneic stem cell transplantation (alloSCT). However, its timing is still matter of debate.Patients and MethodsWe retrospectively analyzed 73 consecutive AML patients with FLT3-ITD (median age 53, range 20-68 years) allografted with consistent policy to try to refer them all for upfront alloSCT in first complete remission (CR1).ResultsWith a median follow-up of 44 (range, 5-135) months the 5-year overall survival (OS)/disease-free survival (DFS) probabilities were 49%/47%. The cumulative incidence of relapse and nonrelapse mortality (NRM) were 37% and 14%, respectively. The estimated 5-year OS for patients who received transplantation in CR1 was 62% versus 0% for patients who received transplantation beyond CR1. Multivariable analysis identified stem cell transplantation beyond CR1 as the key factor for poor OS (hazard ratio [HR], 5.41; P < .0001), DFS (HR, 4.41; P = .0002), and high relapse incidence (HR, 8.08; P < .0001). Acute graft versus host disease Grade ≥3 predicted higher NRM (HR, 3.80; P = .059) as well as inferior OS (HR, 2.04; P = .0079). No association of patient age, nucleophosmin status, donor type, conditioning, and other variables on the survival was detected.ConclusionAlloSCT should be regarded with urgency as soon as CR1 is achieved in this subset of AML patients.     

急性髓系白血病自体造血干细胞移植后的维持化疗

 目的　评价急性髓系白血病（AML）自体造血干细胞移植（AHSCT）后维持治疗的疗效。方法　AHSCT治疗AML患者12例,除1例在移植后第20天复发、1例出现再生障碍性贫血外,余10例均在移植后接受标准方案化疗（M3用维甲酸）。结果　12例患者AHSCT后平均生存时间1933（25～4936）d;其中8例患者生存至今,已持续完全缓解91（18～162）个月;5年无病生存率为57.9 ％。结论　应用AHSCT结合移植后维持化疗,可以减少AML复发,延长无病生存期。     

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia

IntroductionNo standard salvage chemotherapy regimen is available for relapsed or refractory (RR) acute myeloid leukemia (AML). Preclinical data have suggested synergy in vitro between cytarabine and imatinib mesylate (IM) on AML cell growth inhibition. After demonstrating the safety and feasibility in a phase I study, we conducted a phase II clinical study of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) regimen combined with IM for patients with RR-AML.Patients and MethodsWe performed a single-institution 2-stage phase II study. The primary endpoint was the remission rate measured using the standard AML response criteria. The secondary endpoints included overall survival (OS) and progression-free survival (PFS).ResultsFrom August 2009 to April 2011, 38 patients were treated at the Moffitt Cancer Center. Their median age was 62 years (range, 26-79 years). Of the 38 patients, 7 (18%) had refractory AML, 19 (50%) had early relapse, and 12 (32%) had late relapse. At the original diagnosis, only 2 patients had favorable risk factors, 18 had intermediate risk, and 16 had poor risk; for 2 patients, the karyotype was missing. The overall response rate for all 38 evaluable patients was 37%. The median OS was 11.1 months (95% CI, 4.8-13.4 months), the median PFS was 4.9 months (95% CI, 1.6-11.7 months). Among the responders, 8 of 14 patients subsequently underwent allogeneic hematopoietic cell transplantation.ConclusionCLAG plus IM was well tolerated, with encouraging signs of activity in patients with poor-risk AML.     

Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia.

PURPOSE: To improve outcome for older patients with poor-prognosis myeloid malignancies by using allogeneic hematopoietic stem-cell transplantation (alloHSCT) from unrelated and sibling donors after reduced-intensity conditioning (RIC). PATIENTS AND METHODS: Nineteen older patients (median age, 64 years; range, 60 to 70 years) with active myeloid malignancies were treated with an RIC regimen that was based on fludarabine, melphalan, and carmustine followed by alloHSCT from matched unrelated (n = 12) or sibling donors (n = 7). Before transplantation, patients had a median of 50% bone marrow blasts (range, 0% to 70%). Graft-versus-host-disease (GvHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil or methotrexate. Eleven of 12 patients with an unrelated donor also received anti-T-lymphocyte globulin (ATG). RESULTS: Engraftment was successful for all 19 patients. Seventeen assessable patients achieved complete response (CR). Four patients experienced relapse; three achieved CR again after donor lymphocyte infusion (n = 1) or a second alloHSCT (n = 2). Six patients died as a result of relapse (n = 2), GvHD-associated complications (n = 2), or fungal infections (n = 2), resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days (range, 595 to 1,028 days), 13 of 19 patients are alive, resulting in a 1-year survival rate of 68% (95% confidence interval, 48% to 89%). CONCLUSION: In older patients with untreated poor-prognosis leukemia, this RIC regimen combined with alloHSCT sufficiently reduces the leukemic burden, resulting in a high CR rate. When ATG is added, matched unrelated donor transplantation can be performed safely in older patients. For these patients, early transplantation after diagnosis offers a fair chance of cure.     

Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older.

PURPOSE: To evaluate outcomes of ablative allogeneic hematopoietic cell transplantation (HCT) in older patients with hematologic malignancies. PATIENTS AND METHODS: We treated 52 patients from 1979 to 2002 with a median age of 62.8 years (range, 60.1 to 67.8 years) using ablative preparative regimens followed by allogeneic HCT from sibling donors. Diagnoses included myelodysplastic syndrome (MDS; n = 35), chronic myeloid leukemia (CML; n = 8), acute myeloid leukemia (AML; n = 6), and other (n = 3). Conditioning regimens included cyclophosphamide (CY) and busulfan (BU) (67%), total-body irradiation and CY (21%), BU-fludarabine (10%), and CY (2%). RESULTS: Eighteen (35%) of 52 patients are alive at a median of 4.6 years (range, 0.8 to 9.1 years) after transplantation. Median overall survival (OS) and progression-free survival were 300 and 218 days, respectively. Three-year OS and relapse rates are estimated to be 34% and 24%, respectively. Nonrelapse mortality (NRM) rates at 100 days and 3 years are estimated to be 27% and 43%, respectively. Grade 3 to 4 acute graft-versus-host disease (GVHD) occurred in 20% of patients, and chronic extensive GVHD was described in 53% of patients. Fourteen (40%) of 35 patients with MDS are alive at a median of 2.8 years (range, 0.8 to 8.2 years). Four of six patients with CML in chronic or accelerated phase are alive at a median of 6.9 years (range, 4.1 to 9.1 years) after transplantation. None of the patients with AML, CML in blast crisis, or other diagnoses have survived. Patients who underwent transplantation after 1993 had improved survival. CONCLUSION: These data suggest that allogeneic HCT is feasible in selected patients > or = 60 years of age, although novel methods to reduce NRM while maintaining efficacy are needed.