Reduced intensity allogeneic hematopoietic stem cell transplantation for MDS using tacrolimus/sirolimus-based GVHD prophylaxis

We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.     

Allogeneic stem-cell transplantation with fludarabine and 2-Gy TBI-based conditioning regimen for chronic hematological malignancy: a study of 25 consecutive patients and a literature review

We analyzed the outcome of 25 consecutive patients with chronic hematological malignancy who underwent allogeneic stem-cell transplantation conditioned with fludarabine (30 mg/m2/day, thrice) and total body irradiation (2 Gy). All patients received peripheral blood stem cells from an HLA-identical sibling donor. With a median follow-up of 769 days (range, 244 - 1231), the estimated 2-year overall survival (OS), event-free survival (EFS), transplantation-related mortality and relapse rates were 53%, 45%, 27%, and 39%, respectively. All patients had initial engraftment. Acute Grade II - IV graft-versus-host disease (GVHD) was recorded in 14 patients (56%), including 7 (28%) with Grade III - IV GVHD. Sixteen of the 23 patients (70%) who survived more than 100 days developed chronic GVHD. OS and EFS were adversely influenced by acute Grade III - IV GVHD (p < 0.001 and p = 0.033, respectively), but chronic GVHD seemed to favorably influence these two parameters (p = 0.03 and p < 0.001, respectively). Patients with full-donor chimerism at day 30 had lower relapse rates, as did those who received high-dose allogeneic CD8+ lymphocytes with their graft (p = 0.026). Collectively, these results provide a framework for refining nonmyeloablative conditioning, to improve outcome with an acceptable risk of GVHD.     

Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies.

PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H-containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.     

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.     

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55-66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m(2), n=5) or melphalan (100-150 mg/m(2), n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.     

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen

Background  As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM). Methods  We retrospectively compared the efficacy of a RIST regimen with FM with that of a conventional stem cell transplantation (CST) regimen. Eighty-two consecutive hematological patients who underwent allogeneic stem-cell transplantation (SCT) at our hospital were enrolled. Preparation for RIST consisted of 25 mg/m² fludarabine and melphalan 70 mg/m². The conventional regimen employed high-dose cyclophosphamide and total-body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis for RIST consisted of tacrolimus alone or in conjunction with short-term methotrexate for unrelated donors. Results  Of the 82 patients, 42 received the conventional CST regimen (median age, 35 years) and 40 received the RIST regimen (median age, 51 years). The probability of NRM was 17% (7/42) in the CST group and 8% (3/40) in the RIST group. Grade II to IV GVHD occurred in significantly more CST patients (38%) than RIST patients (28%). However, the overall survival was the same in the two groups (43%). Conclusion  The RIST regimen with FM incorporating tacrolimus and methotrexate demonstrated low TRM incidence and moderate control of GVHD and had efficacy comparable to that of the CST regimen, despite the advanced age of the RIST patient group.     

Alemtuzumab, fludarabine and melphalan as a conditioning therapy in severe aplastic anemia and hypoplastic myelodysplastic syndrome--single center experience

BACKGROUND: Allogeneic hematopoietic stem cell transplantation is the treatment of choice in young patients with severe aplastic anemia. The main causes of failure after this procedure are graft versus host disease, infections and graft failure, often exacerbated by large numbers of transfusions and prolonged disease duration before transplant. METHODS: We report the results of allografting following conditioning with fludarabine, alemtuzumab and melphalan in: five patients with severe aplastic anemia and one with hypoplastic myelodysplastic syndrome. All patients had matched sibling donors. Source of hematopoietic stem cell was: bone marrow-2, blood-3, bone marrow and blood-1. The age of recipients was 18-26 years. Four patients received their graft as the first line therapy and two after failure of cyclosporine and antithymocyte globulin treatment. Number of transfused units including red blood cells and platelets before transplantation was 8-100 (median: 22) and 10-32 (median: 11), respectively. All donors and recipients were CMV-seropositive. Conditioning consisted of: alemtuzumab 30 mg/d (day -7 to -5), fludarabine 30 mg/m(2) (days -7 to -3) and melphalan 140 mg/m(2) at the day -2. RESULTS: The time to granulocytes and platelets recovery was 15 and 25 days, respectively. All patients achieved full donor chimerism on day +60. Only two patients needed ganciclovir as preemptive therapy. Recurrent parvovirus B19 infection with pure red cell aplasia and acute viral B hepatitis was observed in one case. Pure red cell aplasia was successfully treated with immunoglobulins and cyclosporine discontinuation. With a follow-up of 16-39 (median: 29) months all patients are alive, and neither graft failure nor graft versus host disease, or any no other severe complications, was observed. CONCLUSIONS: Our study suggests that transplantation of hematopoietic stem cell using alemtuzumab, fludarabine and melphalan as a conditioning therapy is safe, inexpensive and effective treatment for patients with severe aplastic anemia, including multi-transfused adults having their disease for a long time.     

Higher busulfan dose intensity does not improve outcomes of patients undergoing allogeneic haematopoietic cell transplantation following fludarabine, busulfan-based reduced toxicity conditioning

We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy‐five patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30 mg/m²/day, days ?7 to ?3), and 6 mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more‐intense conditioning with busulfan (130 mg/m²/day IV, days ?6 to ?3), fludarabine (40 mg/m²/day, days ?6 to ?3) and 6 mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen‐mismatched allografts. More patients in RIC group had high‐risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p = 0.003) and platelet engraftment (16 days vs. 11 days; p < 0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p = 0.004) and fungal infections (13.5% vs. 1.3% p = 0.01). For RIC and RTC groups rates of grades II–IV acute GVHD (34% vs. 40%; p‐value = 0.54), and chronic GVHD (45% vs. 57%; p‐value = 0.30) were not significantly different. In similar order at 1 year the cumulative‐incidence of non‐relapse mortality (NRM; 12% vs. 21%; p‐value = 0.21) and relapse rates (38% vs. 39%; p = 0.96) were not significantly different. Patients in RIC and RTC groups had similar 1‐year overall survival (61% vs. 50%, p = 0.11) and progression‐free survival (50% vs. 36%, p‐value = 0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/busulfan‐based RTC may be offset by higher early morbidity. Copyright © 2011 John Wiley & Sons, Ltd.     

Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML.

A total of 24 patients (median age 58; range, 27-71 years) with chronic myeloid leukemia (CML) in first chronic (CP1) (n=14), second chronic (n=4), or accelerated phase (n=6) who were not candidates for conventional hematopoietic cell transplantation (HCT), received nonmyeloablative HCT from HLA-matched siblings a median of 28.5 (range, 11-271) months after diagnosis. They were conditioned with 2 Gy total body irradiation (TBI) alone (n=8) or combined with fludarabine, 90 mg/m(2) (n=16). Postgrafting immunosuppression included cyclosporine and mycophenolate mofetil. All patients initially engrafted. However, 4 of 8 patients not given fludarabine experienced nonfatal rejection while all others had sustained engraftment. With a median follow-up of 36 (range, 4-49) months, 13 of 24 patients (54%) were alive and in complete remission. There were five (21%) deaths from nonrelapse mortality, one (4%) during the first 100 days after transplant. The proportions of grade II, III, and IV acute GVHD were 38, 4, and 8%, respectively. The 2-year estimate of chronic GVHD was 32%. The 2-year survival estimates for patients in CP1 (n=14) and beyond CP1 (n=10) were 70 and 56%, respectively. This study shows encouraging remission rates for patients with CML not eligible for conventional allografting.     

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.     

Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research.

PURPOSE: To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. RESULTS: Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. CONCLUSION: These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.     

Safety of autologous hematopoietic stem cell transplantation in patients with multiple myeloma and chronic renal failure.

Patients with multiple myeloma (MM) and chronic renal failure have generally been excluded from myeloablative therapy programs followed by hematopoietic stem cell support because of the potential increase in transplant-related morbidity and mortality. We here report our experience treating six MM patients with moderate to severe renal insufficiency, with autologous stem cell transplantation. One of these patients required chronic hemodialysis since the diagnosis of MM was made. Peripheral blood stem cell collection was performed with either cyclophosphamide 5.5-7 g/m2 + G-CSF, 5 microg/kg/day (patients 1-3, 5 and 6) or G-CSF, 15 microg/kg/day alone (patient No. 4). Four patients (Nos 1-4) received autotransplant as front-line therapy, while the last two patients were treated in relapse, which occurred following prior autologous stem cell transplantation in support of melphalan, 200 mg/m2 (No. 5) or maintainance therapy with alpha-interferon (No. 6). High-dose chemotherapy administered as preparation to transplant included busulfan 12 mg/kg + melphalan 80 mg/m2 (patients 1-3 and 6) or melphalan 80 mg/m2 alone (patients 4 and 5) in order to reduce mucosal damage. Following transplant, prompt and sustained recovery of hematopoiesis was documented in all the patients; 500 PMN/microI and 20000 platelets/microI were reached after a median of 13 and 14 days, respectively. None of the patients suffered from WHO grade 3-4 infectious complications. Transplant-related toxicity included grade 3-4 oral mucositis (patients 1, 4 and 5) and veno-occlusive disease (patient No. 3). Renal function either improved or remained stable throughout the transplant period. All the patients but one responded to therapy, three of them are progression free after 2, 15 and 26 months; two relapsed after 16 and 4 months and one died from cholangiocarcinoma 7 months after transplant, while still in remission. Although our experience is limited so far, these results appear promising and support the investigational use of myeloablative therapy in MM patients with chronic renal failure.     

High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma

High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) has improved response rates and survival for patients with multiple myeloma (MM). We report a single-institution experience using two conditioning regimens, busulfan, cyclophosphamide, and etoposide (BCV) or high-dose melphalan (HDM). Between July 1992 and August 2003, 110 patients with MM (median age=56.1) underwent HDC with ASCT using either BCV (n=62) or HDM (n=48) in sequential cohorts as the preparative regimen. Overall response rates, progression-free survival, and median overall survival were similar. BCV and HDM confer similar long-term outcomes with similar toxicity profiles as conditioning regimens prior to autologous stem cell transplant in patients with MM.     

Allogenic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution

The prognosis of patients relapsing after an autologous transplant (autoSCT) is very poor. Allogenic stem cell transplantation (alloSCT) offers the possibility of curing some of these patients, at the cost, however, of a high transplant related mortality (TRM). The aim of this study was to analyze the outcome of 14 consecutive patients with hematologic malignancies, from a single institution, who underwent alloSCT for progressive disease after autoSCT. Patients had relapsed at a median of 11.5 months (range 2-72) after autoSCT and they underwent alloSCT at a median of 25.5 months (range 7-73) from the first transplant. Ten patients received HLA-identical related peripheral blood progenitor cells, three patients underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related transplant. Conditioning regimens consisted of total body irradiation plus cyclophosphamide (n=5) or melphalan (n=1), or high-dose combination chemotherapy (n=8). Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Eight patients (57%) developed grade II-IV acute GVHD. All evaluable patients (n=6) presented extensive chronic GVHD. Overall survival at 1 year was 16% (median 3.5 months, 95% CI 0.7-10.3). Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7-11). Only one patient died of recurrent disease. Three patients remain alive and in complete remission at the time of this report (4, 20 and 20 months, respectively). In conclusion, alloSCT offers the possibility of a sustained control of the disease in some patients who relapse after an autoSCT. However, the procedure is associated with a high transplant-related mortality. Better results might be obtained by carefully selecting patients and by reducing the intensity of the preparative regimen.     

Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.     

氟达拉滨替代环磷酰胺的清髓性预处理化疗联合异基因造血干细胞移植治疗急性白血病的对照研究

目的 探讨氟达拉滨替代改良BuCy方案中环磷酰胺的预处理方案在异基因造血干细胞移植中的安全性及有效性.方法 对45例急性白血病患者进行异基因造血干细胞移植,其中23例采用改良BuCy预处理化疗,22例采用BuFlu方案（氟达拉滨每天40 mg/m2,用5d,来替代改良BuCy方案中的环磷酰胺）进行预处理化疗.移植均采用外周血造血干细胞移植.移植后观察比较两组预处理方案相关不良反应、植入、移植物抗宿主病（GVHD）、感染发生和长期随访下的无病生存情况.结果 除改良BuCy组1例患者死于预处理后脑出血,其余患者均获得成功植入.两组患者预处理不良反应发生率差异无统计学意义（P＞0.05）;BuFlu组患者病毒感染较改良BuCy组高（P=0.009）,而Ⅲ～Ⅳ度急性GVHD发生率较低[26.1％（6/23）比4.5％（1/22）,P=0.046].中位随访41个月,改良BuCy组非复发死亡4例（17.4％）,BuFlu组非复发死亡2例（9.1％）（P=0.665）.两组复发率分别为30.3％（7/23）和40.9％（9/22）（P=0.474）;5年总生存率分别为（55.1±l 1.9）％和（61.4±10.8）％（P=0.659）,无事件生存率分别为（44.5±12.1）％和（22.1±12.3）％（P=0.747）.结论 氟达拉滨替代改良BuCy方案中环磷酰胺的预处理化疗耐受性较好,严重GVHD发生率低,总生存率无明显差异.应用时应注意移植中感染及复发的风险.     

Clinical Outcomes of Fludarabine and Melphalan With an 800 cGy Total Body Irradiation Conditioning Regimen in Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionAllogeneic hematopoietic stem cell transplant with reduced-intensity conditioning is an effective therapeutic option for patients with refractory or relapsed aggressive non-Hodgkin lymphoma (NHL).Patients and MethodsWe retrospectively evaluated survival outcomes and the efficacy of our fludarabine/melphalan/total body irradiation (TBI) (FMT) regimen. A total of 89 patients had received the FMT regimen from 2007 to 2017.ResultsThe majority of patients (n = 81; 91%) belonged to the histologic subtype of aggressive NHL. The estimated 3-year overall survival and disease-free survival for the entire cohort during a median follow-up of 31 months were 47.1% (95% confidence interval, 36%-57%) and 45.4% (95% confidence interval, 35%-56%), respectively. The cumulative incidence rates of relapse and non-relapse mortality at 3 years were 33.1% and 13.8%, respectively. In analyses of risk factors affecting survival outcomes, chemosensitive disease status at transplant (hazard ratio [HR], 2.45; P = .010), delayed relapse after first-line chemotherapy (HR, 2.101; P = .009), no grade III to IV acute graft-versus-host disease (HR, 11.212; P < .001), and mild chronic graft-versus-host disease (HR, 0.448; P = .016) were independent significant predictors of favorable overall survival. Also, similar parameters were related to favorable disease-free survival. All non-hematologic toxicities occurred within 50 days after allogeneic hematopoietic stem cell transplant, and most of the adverse events were tolerable and manageable with a < 30% incidence.ConclusionOur FMT regimen shows favorable transplant outcomes with relatively low-risk toxicities, so it may be a promising strategy for patients with relapsed or refractory aggressive NHL.     

Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment

BACKGROUND: Thirty-three patients (median age 52; range 26-60) with acute myeloblastic leukemia (AML) were included in a pilot study of allogeneic stem cell transplantation (Allo-SCT) following a reduced-intensity conditioning (RIC). METHODS: Patients achieving first complete remission (CR1) were selected for their high-risk clinical and/or leukemic features. All patients received two courses of consolidation chemotherapy including one high-dose cytarabine course. Among them, 13 patients in addition received a high-dose melphalan course followed by autologous SCT. Then, all patients received an RIC Allo-SCT combining fludarabine, busulfan, and antithymocyte globulin. RESULTS: All patients engrafted had cumulative incidences of Gluksberg System Grade 2 acute and chronic graft-versus-host-disease (GVHD) of 24 (9-39%) and 64 (48-80%), respectively. Three patients died from nonrelapse causes (NRD) (cumulative incidence: 9%, 95% confidence interval (CI): 0-19) and 6 relapsed (cumulative incidence: 18%, 95% CI: 5-31). With a median follow-up of 18 months (range 7-52) after Allo-SCT, 26 patients are alive, of whom 24 remained in CR1 for a 2-year overall survival and leukemia-free survival (LFS) probabilities of 79 (range 61-90%) and 76 (range 59-87%), respectively. In a 'landmark' analysis starting on Day 100, the occurrence of chronic GVHD was associated with a lower relapse rate (0% vs. 44%: P = 0.007) and improved outcome (LFS; 95% vs. 53%, P = 0.007; overall survival, 95% vs. 61%, P = 0.05). CONCLUSIONS: We conclude that the sequential combination of intensive chemotherapy and allogeneic immunotherapy might offer relatively low NRD and leukemia relapse rates even in high-risk patients.     

马利兰+氟达拉滨预处理异基因造血干细胞移植治疗白血病的临床研究

目的:探讨马利兰+氟达拉滨（Bu/Flu）预处理方案异基因造血干细胞移植治疗白血病的临床疗效。方法:30例患者中,急性淋巴细胞白血病（ALL)12例,急性髓系白血病（AML）12例,其中1例为MDS转化,慢性粒细胞白血病（CML）6例;其中急性白血病未缓解或复发状态下移植6例,CML加速期患者1例。供者干细胞为G-CSF动员后采集的HLA配型全相合或一个位点不合的同胞（21例）或非血缘（9例）外周血造血干细胞,有1例成人ALL患者接受HLA配型相合的双份脐带血移植。预处理方案包括:注射用马利兰3.2mg/(kg·d)×3-4d,氟达拉滨30mg/(m2·d)×4-6d,同胞不全相合和非血缘移植患者加用兔抗人胸腺细胞免疫球蛋白（ATG）2.5mg/(kg·d)×3d。输注外周血单个核细胞数7.73（0.36-16.0）×108/kg,CD34+造血干细胞数3.26（0.77-17.6）×106/kg。用环孢素+短疗程甲氨喋呤或环孢素+吗替麦考酚酯预防移植物抗宿主病（GVHD）。采用DNA短串联重复序列多态性（STR）分析方法鉴定供者干细胞植入情况。结果:29例患者重建造血,检测外周血白细胞STR-DNA证实均为100%完全供者植入,1例非血缘全相合患者未植入于短期内死亡外,其余患者为完全供者型,植入率为96.7%。血缘相关HSCT和非血缘相关HSCT白细胞植活的中位时间分别为11（8-17）d和13(9-15)d;血小板植活的中位时间分别为13（7-22）d和14(8-25)d。出现急性GVHD 14例,占46.7%,其中I-II度10例（33.3%）,III-IV度者4例（13.3%）;6例发生慢性局限性GVHD,发生率为20.0%。随访1-66个月（中位时间20个月）,总体生存率（OS）为63.3%,无事件生存率（DFS）为51.7%。结论:Bu/Flu预处理方案移植治疗白血病相关并发症轻,有很好耐受性和较好疗效,是值得推广应用的预处理方案。     

Myeloablative treatments for multiple myeloma: update of a comparative study of different regimens used in patients from the Spanish registry for transplantation in multiple myeloma

After a previous analysis that did not detect clear differences in the results of three conditioning regimens used for autologous stem cell transplantation (ASCT) in patients from the Spanish Registry for Transplant in Multiple Myeloma (MM), we have updated the registry, including a larger number of cases and a fourth conditioning regimen with a longer follow-up. We evaluate 472 MM patients treated with 200 mg/m2 melphalan (MEL200), 135 patients treated with 140 mg/m2 melphalan plus total body irradiation [(MEL140 + TBI)], 186 patients treated with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL) and 28 patients treated with 14 mg/kg busulphan followed by cyclophosphamide 120 mg/kg (BUCY). There were no significant differences in respect to either transplant related death or haematological recovery, regardless of growth factor use, between the four conditioning programs. Nevertheless, hospitalization time with MEL200 was less than with BUMEL when growth factors were used (19+/-9 vs. 25+/-9 days, P = 0.009) and less than with MEL140 + TBI without growth factors (20+/-8 days vs. 27+/-9 days, P = 0.002). In patients with measurable disease at ASCT (non-complete remission [CR]), BUMEL achieved a 51% CR vs. 43%-31% in the other groups (P = 0.007). The response rate for patients in partial remission (PR) at ASCT was 100% with BUMEL vs. 93%-86% in the other groups (P between 0.02 and 0.0007). The median overall survival (OS) for the BUMEL group was 57 months (95% confidence interval [CI]: 51-78) as compared to 45 (CI: 36-64) months for the MEL200 group and 39 (CI: 28-72) months for the MEL140 + TBI and BUCY groups. The median event free survival (EFS) was longer in the BUMEL group [30 (CI: 22-44) mo] than in the MEL200 [22 (CI: 18-26) mo], BUCY [23 (CI: 11-50) mo] or MEL140 + TBI groups [20 (CI: 15-29) mo]. Nevertheless, the differences in OS and EFS did not reach statistical significance in either the univariate analysis or the multivariate analysis adjusted with other high prognostic weight factors. As in the initial study, differences in regards to the anti-myeloma effect of the conditioning regimens are not conclusive. However, the better response rates associated with the favorable tendency in outcome achieved with BUMEL, continue to justify further prospective studies.