Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis

Background

Bone marrow fibrosis in patients with myelodysplastic syndrome is associated with a poor outcome, but whether the outcome after allogeneic stem cell transplantation is related to the degree of bone marrow fibrosis is unknown.

Design and Methods

Patients with myelodysplastic syndrome and known bone marrow histology (n=721) who underwent hematopoietic stem cell transplantation were classified according to the degree of bone marrow fibrosis into those without fibrosis (n=483), those with mild or moderate fibrosis (n=199) and those with severe fibrosis (n=39) and analyzed regarding engraftment, treatment-related mortality, relapse and survival.

Results

The degree of fibrosis was not associated with disease status or abnormal cytogenetics. The cumulative incidence of engraftment achieved at day +30 in non-fibrotic patients was 93% and was significantly lower in those with mild or moderate fibrosis (89%) and severe fibrosis (75%) (P=0.009). Neutrophil engraftment occurred later in patients with mild or moderate fibrosis and severe fibrosis than in patients without fibrosis (median 17 versus 20 versus 16 days, respectively; P=0.002). The cumulative incidence of relapse at 3 years was significantly higher in patients with severe fibrosis than in those with a lesser degree of fibrosis or no fibrosis (47% versus 28% versus 27%, respectively; P=0.04), resulting in comparable 3-year disease-free survival rates in patients without fibrosis and in those with mild or moderate fibrosis (42% versus 38%, respectively) but a lower disease-free survival rate in those with severe fibrosis (18%; P=0.002). Severe fibrosis remained an independent factor for reduced survival (hazard ratio, 1.9; P=0.006).

Conclusions

Among patients with myelodysplastic syndromes, only severe fibrosis affects survival after hematopoietic stem cell transplantation while patients with mild or moderate fibrosis have an outcome comparable to that of patients without bone marrow fibrosis.     

Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial

Background

Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old.

Design and Methods

We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine.

Results

The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49–1.35) for survival and of 0.67 (95% CI, 0.42–1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22–1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22–1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40–3.42) and that for disease-free survival was 1.02 (99% CI, 0.40–2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65–2.27) for survival and 1.02 (95% CI, 0.56–1.85) for disease-free survival.

Conclusions

Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy. (Eudract number: NCT00002926; http://www.cancer.gov/clinicaltrials/EORTC-06961)     

Response to pretransplant hypomethylating agents influences the outcome of allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndromes

This study describes a retrospective analysis on the transplant outcome of 56 consecutive patients with myelodysplastic syndrome (MDS) according to their response to hypomethylating agents (HMA). While 2‐yr disease‐free survival (DFS) of patients who transformed to acute myeloid leukemia (n = 12) was 25%, that of the remaining patients with MDS according to response to HMA was 73.1%, 68.1%, 50.0%, and 20.8% in G‐COR (group of continuous response, n = 19), G‐NoC (group of no change, n = 15), G‐LOR (group of loss of response, n = 6), and G‐DP (group of disease progression, n = 4), respectively. When dichotomized as G‐COR/G‐NoC versus G‐LOR/G‐DP, significantly different 2‐yr DFS (71.0% vs. 33.3%; P = 0.004) and relapse (14.1% vs. 46.7%; P = 0.016) were demonstrated. On multivariate analysis, G‐LOR/G‐DP [hazard ratio (HR), 3.91; P = 0.008] and poor karyotype at transplantation (HR, 2.69; P = 0.017) were the significant predictors for poor DFS, as G‐LOR/G‐DP was for relapse (HR, 6.28; P = 0.011). DFS was significantly poor in patients with any of the two predictors in all MDS (81.5% vs. 34.9%; P = 0.001) or higher‐risk MDS (HrMDS) at the time of HMA (80.7% vs. 29.2%; P = 0.005). G‐COR showed a trend of better DFS compared with G‐NoC among HrMDS (74.6% vs. 36.5%; P = 0.090). These results implicate the significance of response to HMA on hematopoietic stem cell transplantation (HSCT) outcomes and support the need for future study to verify the suggested strategy of proceeding to transplantation before LOR or DP, especially for HrMDS.     

Outcomes of alemtuzumab-based reduced intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes

This prospective study evaluated the outcomes of 75 successive patients receiving a FBC (fludarabine, busulphan, alemtuzumab) reduced-intensity conditioning (RIC) regimen for myelodysplastic syndromes (MDS) using volunteer unrelated donors(VUD). The prognostic significance of a variety of clinical variables including the recently described haematopoietic cell transplantation co-morbidity index (HCT-CI) was assessed. The median age of the cohort was 52.0 years (range: 19-68 years) with a median follow-up of 1038.5 d. Forty-nine patients (65%) had an International Prognostic Scoring System stage of > or = Intermediate-2, 35 (46%) had intermediate or poor risk cytogenetics, and 23 patients(31%) were human leucocyte antigen-mismatched. The actuarial 3-year overall survival (OS) and disease-free survival (DFS) was 43% [95% confidence interval (CI): 37-49] and 41% (95%CI: 35-47) respectively, and the cumulative incidence of extensive chronic graft-versus-host disease was 22%. On multivariate analysis, presence of either one class II mismatch or a two-antigen mismatch adversely influenced transplant-related mortality, DFS and OS. In addition, disease status at transplantation and the haematopoietic cell transplantation-specific comorbidity index were independent variables for overall survival. In contrast, both advanced age and pre-transplant cytogenetic status did not significantly affect overall outcomes. RIC regimens using VUD was associated with durable long-term survival even in older patients with MDS, and the use of a pre-transplant comorbidity index may help to improve patient selection for transplantation.     

Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation

M. Leithauser, C. Kahl, C. Aepinus, F. Prall, M. Maruschke, H. Riemer, D. Wolff, K. Jost, I. Hilgendorf, M. Freund, C. Junghanss. Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation
Transpl Infect Dis 2010: 12: 251–257. All rights reserved Abstract: Invasive mold infections are a threat to immunosuppressed patients such as patients with graft‐versus‐host disease (GVHD) after allogeneic stem cell transplantation (SCT). Up to 10% of SCT recipients develop invasive aspergillosis (IA). Invasive zygomycosis (IZ) may occur during treatment against IA. Here we report 4 SCT patients with GVHD diagnosed with IZ. All patients had received myeloablative hematopoietic SCT and developed chronic GVHD requiring systemic immunosuppression. Underlying diseases were acute lymphocytic leukemia (2), osteomyelofibrosis, and multiple myeloma. All patients had developed pulmonary infiltration that led to initiation of antifungal therapy. Treatment for IA was voriconazole, caspofungin, or itraconazole. Organs involved with zygomycosis were lung, nasal sinus, skin, and kidney. Treatment with liposomal amphotericin and posaconazole was initiated in all patients, and 2 patients also had surgical debridement as well. Despite intensive treatment, no patient survived. IZ is becoming more common in patients with GVHD on successful treatment for IA. Even non‐specific symptoms are suspicious in this group of patients and need to be evaluated by vigorous diagnostics. Despite effective antifungals and surgical intervention, the prognosis is grim in patients with active GVHD, as immunoreconstitution is mandatory for successful management.     

Donor cell myelodysplastic syndrome after allogeneic stem cell transplantation responding to donor lymphocyte infusion: case report and literature review

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for patients with myelodysplastic syndrome (MDS). Relapses after transplantation however, are not uncommon and are usually due to re-emergence of a recipient derived, neoplastic, stem cell clone. We report a unique case of MDS recurring 5 months after non-myeloablative, sibling, allogeneic SCT. Interestingly, chimerism analysis at relapse showed hematopoiesis to be entirely of donor origin confirming donor cell MDS. Donor lymphocyte infusion (DLI) produced a hematological response lasting several months. Our review of the literature shows donor-derived MDS to be very rare, with only four such cases described previously. In this report, we describe the details of our case and discuss putative mechanisms underlying the genesis of donor cell MDS and the observed response to DLI.     

氟达拉滨联合静脉马利兰的预处理方案治疗髓系恶性血液病的临床研究

目的:评价氟达拉滨(Flu)联合静脉马利兰(Bu)的预处理方案在髓系恶性血液病患者异基因造血干细胞移植(allo-HSCT)中的疗效及静脉Bu的最佳剂量。方法:45例接受allo-HSCT的髓系恶性血液病患者,预处理方案主要采用Bu3.2mg·kg-1.d-1×2～4d,Cy40～50mg/kg×2d,Flu30mg.m-2.d-1×3d,Ara-C2g.m-2.d-1×3d,无关供者移植同时加用兔抗人血清免疫球蛋白(ATG)2.5mg/kg×4d。按静脉Bu用量进一步分为2d组17例,3d组18例,4d组10例。结果:预处理过程无严重不良事件发生,无肝静脉闭塞病(VOD)发生,Ⅱ～Ⅳ度急性移植物抗宿主病(aGVHD)9例(20%),100d移植相关死亡(TRM)1例(2.2%),3年TRM15例(33.3%),3年累计复发3例(6.7%),3年无病生存率(DFS)和3年总体生存率(OS)分别为(60.5±7.5)%和(62.2±7.2)%。与Bu2d组和3d组比较,4d组患者的慢性GVHD的发生率显著增高,TRM有增高趋势;OS显著降低,DFS有降低趋势。结论:Flu联合静脉Bu的预处理方案治疗髓系恶性血液...     

Feasibility of peripheral blood progenitor cell harvest and transplantation in patients with poor-risk myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of clonal haematological disorders with a highly unfavourable prognosis. Allogeneic bone marrow transplantation offers the sole possibility for cure and prolonged survival, but is only available for a minority of patients. Therefore, we investigated the feasibility of PBPC collection and transplantation in 11 patients with high-risk myelodysplasia who were not eligible for allogeneic bone marrow transplantation. In six patients, PBPC were harvested after mobilization with G-CSF alone. Five patients were harvested during the recovery phase of intensive chemotherapy combined with G-CSF. This resulted in seven patients in an adequate CD34 progenitor yield >1 × 10⁶/kg. Six patients obtained a CFU-GM content of the PBPC harvest >10 ×10⁴/kg. Five patients were subsequently transplanted following a standard BuCy4 regimen. The median to ANC (absolute neutrophil count) ≥0.5 and 1.0 × 10⁹/l was respectively 14 d (range 10–18) and 16 d (range 11–25). Platelets were self-supporting ≥20 × 10⁹/l after a median of 41 d (range 8–144). One patient had a persistent lack of platelet engraftment unresponsive to infusion of back-up bone marrow.
These data demonstrate that in selected patients with high-risk MDS, adequate PBPC collection appears feasible, enabling the harvest of sufficient cell numbers required for rapid and stable engraftment after reinfusion. Improvement in mobilization efficiency may enable the collection of higher CD34⁺ progenitor cell numbers required for more rapid platelet engraftment. PBPC transplantation may be an alternative treatment option for patients who lack an allogeneic marrow donor. Follow-up is, however, still too limited to draw any conclusion regarding the long-term cure rate.     

同胞全相合异基因造血干细胞移植治疗95例骨髓增生异常综合征患者的临床分析

 目的 探讨同胞全相合异基因造血干细胞移植(allo-HSCT)治疗骨髓增生异常综合征(MDS)的疗效与时机。方法 回顾分析2003年1月—2012年12月采用同胞全相合allo-HSCT治疗MDS及MDS转急性髓性白血病(AML)95例。采用改良马利兰+环磷酰胺或氟达拉滨的预处理方案,行骨髓和/或外周血干细胞移植。结果 95例患者中93例白细胞植活,Ⅱ~Ⅳ度急性移植物抗宿主病(aGVHD)累计发生率为12.9%±3.5%;慢性移植物抗宿主病(cGVHD) 3年累计发生率为80.3%±4.9%。3年累计复发率(RR)为25.9%±4.7%,非复发死亡率(NRM)为16.1%±4.0%。3年预期总生存(OS)率及无病生存 (DFS) 率分别为69.9%±5.0%和58.0%±5.4%。多因素分析显示,发生Ⅱ~Ⅳ度aGVHD和不发生cGVHD是OS的独立危险因素;国际预后积分系统(IPSS)分组是DFS的独立预后因素。将难治性贫血伴原始细胞增多转化型(RAEB-t)及MDS转AML患者(31例)分为移植前未化疗、化疗未缓解、化疗缓解3组,3年OS率分别为33.9%、32.7%、100.0%,化疗缓解组OS率明显高于另外两组(P<0.05),DFS率、RR率差异无统计学意义。结论 同胞全相合allo-HSCT是治疗MDS的有效手段,IPSS可预测移植后疗效,对于移植前疾病进展的患者,争取缓解后行allo-HSCT可能提高疗效,但尚需进一步临床对照研究。
        

Postallogeneic monitoring with molecular markers detected by pretransplant next‐generation or Sanger sequencing predicts clinical relapse in patients with myelodysplastic/myeloproliferative neoplasms

Relapse is the major cause of treatment failure after allogeneic stem‐cell transplantation (AHSCT) for patients with myelodysplastic syndrome/myeloproliferative syndrome neoplasms (MDS/MPN). We evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post‐transplantation. We screened 45 patients with chronic myelomonocytic leukemia (n = 39 patients, including seven with transformed‐acute myeloid leukemia), MDS/MPN unclassifiable (n = 5), and atypical BCR‐ABL1‐negative CML (n = 1) for mutations in ASXL1, CBL, NRAS, and TET2 genes by molecular genetics including a sensitive next‐generation sequencing (NGS) technique. In 36 patients, sufficient DNA was available for molecular analyses. In particular, TET2 and CBL mutations were screened applying amplicon deep sequencing. In 89% of cases, at least one mutation could be detected: ASXL1: n = 18 (50%); CBL: n = 7 (19%); TET2: n = 15 (42%); and NRAS: n = 11 (32%). Survival after AHSCT at 5 yr was 46% (95% CI 28–64%) and was not influenced by any mutation. After a median of 6 months after AHSCT in 33% of the patients, one of the molecular markers was still detectable, resulting in a higher incidence of relapse than in patients with undetectable mutations (50% vs. 15%, P = 0.04). In conclusion, pretransplant molecular mutation analysis can help to detect biomarkers in patients with MPN/MDS, which may be subsequently used as minimal residual disease markers after AHSCT.     

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.     

Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens

Conventional allogeneic stem cell transplantation (SCT) for myelodysplastic syndrome (MDS) is associated with excessive procedure-related mortality. The outcome following volunteer-unrelated donor (VUD) or sibling allogeneic SCT was therefore evaluated in 23 MDS patients conditioned with reduced-intensity regimens (fludarabine/busulphan/Campath-1H) because of advanced age (48 vs 37 years, P = 0.002) and/or co-morbidity (19 vs 3, P < 0.0001) which precluded conventional transplantation, and compared with 29 treated with standard protocols [busulphan/cyclophosphamide (Bu/Cy); Bu/Cy/total-body irradiation/Campath-1G]. Graft-versus-host disease (GVHD) prophylaxis comprised of cyclosporine/methotrexate. One hundred per cent donor engraftment (variable number tandem repeat analysis/cytogenetics/fluorescence in situ hybridization) was achieved in 18/19 (95%) evaluable patients receiving reduced-intensity regimens, although six (32%) have subsequently shown mixed chimaerism. Reduced-intensity conditioning was associated with significantly reduced duration of aplasia, less mucositis, fever, antibiotic, analgesia, parenteral nutrition use, less acute and chronic GVHD, and lower early procedure-related mortality [two (9%) vs nine (31%), P < 0.05]. Six patients relapsed (two standard, four reduced-intensity) and two (reduced-intensity) experienced late graft failure. The 2 year actuarial overall/disease-free survival (OS/DFS) was 48/39% in the reduced-intensity arm and 44/44% in the standard group. The 2 year non-relapse mortality was 31% and 50% respectively. In VUD recipients, OS was superior in the reduced-intensity arm (49%vs 34%). Predictors of DFS included good/intermediate-risk karyotype, low/intermediate-1 International Prognostic Scoring system score, human leucocyte antigen compatibility and attainment of complete remission. Our data demonstrates that VUD or sibling allogeneic SCT following reduced-intensity conditioning is feasible in high-risk MDS patients considered unsuitable for standard transplantation and is associated with comparable 3.5 year DFS to those receiving conventional regimens.     

Positive impact of chronic graft‐versus‐host disease on the outcome of patients with de novo myelodysplastic syndrome after allogeneic hematopoietic cell transplantation: a single‐center analysis of 115 patients

To evaluate the impact of graft‐versus‐host disease (GVHD) and prognostic factors for patients with myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (allo‐HCT), we retrospectively reviewed 115 patients with MDS or acute myeloid leukemia with multilineage dysplasia (AML‐MLD) after allo‐HCT at our center. Eighty one patients received reduced‐intensity conditioning (RIC) regimens, whereas 34 received myeloablative conditioning regimens. Although the RIC group was significantly older and included more patients with poor cytogenetic risk, no difference in 4‐yr overall survival (OS) was seen between the two groups. In a multivariate analysis, covariates associated with a worse OS were the French‐American‐British stage of refractory anemia excess blasts in transformation/AML‐MLD at peak, poor cytogenetic risk, bone marrow blasts of 20% or higher at HCT and the absence of chronic GVHD (cGVHD). By using semi‐landmark analyses, we found that the presence of cGVHD significantly improved OS in high‐risk patients or the RIC group. However, there was no difference in OS between those with and without cGVHD among low‐risk MDS patients. These findings suggest that the graft‐versus‐leukemia effect may be more beneficial in high‐risk patients who do not receive intensive preparative regimens.     

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial

Background

An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome.

Design and Methods

A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m² treosulfan and 5×30 mg/m² fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival.

Results

All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III–IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II–IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively.

Conclusions

Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01062490","term_id":"NCT01062490"}}NCT01062490