Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia

Clofarabine is a novel purine nucleoside analogue with immunosuppressive and anti-leukemic activity in acute lymphoblastic and myeloid leukemia (AML, ALL). This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5?×?30 mg/m² IV) followed by a T cell replete haploidentical transplantation for AML (n?=?15) or ALL (n?=?3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78 % at day +30. The rate of acute graft versus host disease (GvHD) grade II–IV was 22 %, while chronic GvHD occured in five patients (28 %). Non-relapse mortality (NRM) after 1 year was 23 %. At a median follow-up of 19 months, estimated overall survival and relapse-free survival at 1 year from haploidentical HSCT were 56 and 39 %, respectively. Non-hematological regimen-related grade III–IV toxicity was observed in ten patients (56 %) and included most commonly transient elevation of liver enzymes (44 %), mucositis (40 %), and skin reactions including hand-foot syndrome (17 %), creatinine elevation (17 %), and nausea/vomiting (17 %). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allows successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors.     

Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood

The optimal therapy for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We therefore reviewed our institutional outcomes for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for advanced APL. Between 1986 and 2003, 12 allogeneic HSCTs (five related donor, seven unrelated donor) were performed for 11 patients (median age, 13 years) with relapsed (n = 8) or refractory (n = 3) APL. All patients engrafted, after a median of 18.5 days. Grade B-D acute graft-versus-host disease (GVHD) developed after five transplants (42%; 90% CI, 18-68%), and the cumulative incidence of chronic GVHD was 45% (90% CI, 19-71%). The cumulative incidence of overt relapse post-HSCT was 10% (90% CI, 0-28%). The overall 5-year survival was 73% (90% confidence interval (CI), 51-95%), with a median post-HSCT follow-up of 64 months. The Lansky/Karnofsky performance scores are 100% in six of eight survivors. In view of the low risk of subsequent relapse and favorable survival suggested by other reports and our own experience, we continue to recommend allogeneic HSCT for children with advanced APL for whom a suitably HLA-matched donor is identified.     

Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia

The prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) for refractory acute lymphoblastic leukemia (ALL) is very poor. To improve survival rates, we attempted to intensify the conditioning regimen with daunorubicin, vincristine, prednisolone, medium-dose etoposide, cyclophosphamide, and total body irradiation (DNR/VCR/PSL plus medium-dose VP/CY/TBI). Four patients in relapse or induction failure of B-precursor ALL without other complications underwent allogeneic HSCT. Initially, chemotherapy comprising DNR 60 mg/m(2) for 3 days, VCR 1.4 mg/m(2) for 1 day, and PSL 60 mg/m(2) for 3 days was administered, which was followed by medium-dose VP/CY/TBI; some modifications were made for individual patients. All patients achieved engraftment and complete remission after HSCT. Regimen-related toxicities were tolerable and no patient died within 100 days. Two patients were alive without disease on days 563 and 1,055. The third patient relapsed on day 951, while the fourth died on day 179 without disease. Our results indicate that intensified myeloablative HSCT should be considered for patients with refractory ALL.     

异基因造血干细胞移植治疗进展期难治性急性髓系白血病17例分析

目的研究异基因造血干细胞移植(allo-HSCT)治疗进展期难治性急性髓系白血病(AML)的临床疗效。方法收集2002年5月至2011年6月苏州大学附属第一医院血液科收治的17例未缓解期难治性AML患者,采用改良马利兰+环磷酰胺(12例)或全身放疗+环磷酰胺(5例)的清髓性预处理方案行allo-HSCT,采用环孢菌素A(CsA)加短程氨甲蝶呤(MTX)预防移植物抗宿主病(GVHD),部分患者加入霉酚酸酯(MMF)。结果 15例成功获得造血重建,中性粒细胞>1.0×109/L和血小板>20×109/L的中位时间分别为12.5(11～14)d和12.5(10～15)d。急性GVHD发生率为53.3%(8/15),可评估的9例中,5例发生慢性GVHD,均为局限性。移植相关病死率为29.4%(5例),移植后成功获得完全缓解的14例中6例血液学复发,其中2例合并髓外复发,复发率为42.9%。中位随访5(0～71)个月,至今有6例无病生存(DFS),2年DFS为35.3%。结论 Allo-HSCT治疗进展期难治性AML仍不失为一种有效的挽救手段,其中发生慢性GVHD的患者预后较好,而移植相关并发症及移植后复发是影响患者生存的主要因素。     

Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia

Background

Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia.

Design and Methods

Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplantation from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation. Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. Eighteen of these patients received post-grafting imatinib.

Results

With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%, respectively. The cumulative incidence of chronic graft-versus-host disease was 44%. Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall survival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remission and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first remission who received post-grafting imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of minimal residual disease at transplantation, the overall survival was 73%.

Conclusions

For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-myeloablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term survival. (Clinicaltrials.gov identifier: NCT0036738)     

异基因造血干细胞移植治疗高危恶性血液病

目的 分析HLA配型相合同胞供者异基因造血干细胞移植（allo-HSCT）治疗高危恶性血液病的疗效及影响疗效的相关因素。方法 回顾性分析90例有高危因素的恶性血液病患者,其中急性髓细胞白血病（AML）43例,急性淋巴细胞性白血病（ALL）28例,急性混合细胞性白血病（AHL）2例;移植前处于第1次完全缓解期（CR1）11例,均为Ph染色体阳性,第二次及以上CR期23例,未缓解／复发39例;骨髓增生异常综合征（MDS）-难治性贫血伴原始细胞增多或难治性贫血伴原始细胞增多一转化型17例。预处理方案采用全身照射加环磷酰胺（CY／TBI）方案11例,白消安加环磷酰胺方案79例。干细胞来源包括骨髓移植（BMT）27例,外周血造血干细胞移植（PBSCT）30例,BMT＋PBSCT33例;移植物抗宿主病（GVHD）预防采用经典环孢素A加短程甲氨蝶呤（MTX）。平均随访时间为15个月。结果 至随访终点,62．2％（56／90）存活,55．5％（50／90）无病存活,31．1％（28／90）复发。HSCT后预计4年累积总体生存率（OS）为45．5％,无病生存率（DFS）为34．9％。移植前处于CR、未缓解／复发和MDS患者HSCT后4年的累积0s分别为54．0％、28．2％和70．1％（P=0．027）。发生0～Ⅰ和Ⅱ～Ⅳ度GVHD的患者HSCT后的4年OS分别为57．6％和26．7％（P=0．015）,而患者性别、年龄、移植前有无脑膜白血病、预处理方案、干细胞来源均不是OS,DFS及复发的影响因素。多因素分析表明,移植前处于CR期者长期生存率明显提高,而ALL长期生存率明显低于AML／MDS。结论 对有高危因素的血液系统恶性肿瘤患者,选择allo—HSCT可使部分患者延长无病生存乃至根治。移植前处于CR期者长期生存率明显提高,ALL复发率明显高于AML／MDS。对于急性白血病挽救性治疗争取在取得CR后移植;对于MDS患者一经诊断,无需化疗,可尽早移植。     

Clinical research of high-risk and refractory acute myeloid leukemia with allogeneic hematopoietic stem cell transplantation therapy

目的 探讨异基因造血干细胞移植( allo- HSCT)治疗高危难治急性髓系白血病(AML)的疗效和移植时机.方法 选取allo-HSCT治疗的AML患者47例,其中高危AML 17例,难治AML20例,骨髓增生异常综合征(MDS)转AML10例.第1次完全缓解期(CR1 )23例,第2次完全缓解期(CR2)11例,未缓解进展期(NR)13例.接受同胞供者骨髓和(或)外周血干细胞移植16例,非血缘脐血移植31例.所有患者均采用清髓性预处理方案,环孢素联合霉酚酸酯预防移植物抗宿主病(GVHD).结果 47例患者46例(97.9％)获得植入,中性粒细胞绝对计数≥0.5×109/L和血小板≥20×109/L的中位时间分别为14.5(10 ～ 36)天和26(12-90)天.16例发生急性GVHD(34.8％),Ⅲ度以上4例.在可评估的39例患者中,10例出现慢性GVHD( 25.6％),复发6例(12.8％),移植相关死亡12例(25.5％),32例(68.1％)患者存活.高危难治AML患者CR1、CR2、NR期移植生存率分别为75.5％、72.7％和40.0％.MDS转AML患者CR和NR期移植生存率分别为0％和75.0％.结论 allo-HSCT有助于提高高危难治AML疗效,降低复发率,提高生存率,且最好在首次缓解期进行移植.对于MDS转AML患者可立即行allo-HSCT,无需等待化疗达完全缓解.     

Autologous stem cell transplantation for advanced acute myeloid leukemia

We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (x10(6)/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.     

Factors influencing hematopoietic recovery after autologous blood stem cell transplantation in patients with acute myeloblastic leukemia and with non-myeloid malignancies

Factors influencing hematopoietic recovery (HR) after autologous blood stem cell transplantation (ABSCT) were analyzed in 73 patients with various non-myeloid malignancies (NMM), and in 58 patients with acute myeloblastic leukemia (AML). Peripheral blood stem cells were collected following mobilization with chemotherapy, granulocyte colony-stimulating factor (G-CSF), or chemotherapy plus G-CSF. The conditioning regimen used consisted of either chemotherapy alone (112 cases) or chemotherapy plus total body irradiation (19 cases). The median number of colony-forming units granulocyte-macrophage (CFU-GM) was similar in both groups of patients, with the median number of CD34(+) cells infused being higher in the AML group (5.4 vs 4 x 10(6)/kg; P = 0.03). Median time neutrophils >0.5 x 10(9)/l was 13 days in both groups, and median time to a platelet count >20 x 10(9)/l was longer in AML patients (14 vs 12 days; P = 0.01). In multivariate analysis, the only factors affecting neutrophil recovery in the NMM group were the CD34+ cell number (continuous model) and the CFU-GM dose (categorized model) infused, whereas for platelet recovery, previous chemotherapy also remained significant. In the AML group, the only factors significantly affecting the speed of neutrophil recovery were dose of CD34+ cells administered and the patient's age. As for platelet recovery, only the progenitor dose administered remained significant. In the NMM group, the most discriminating cut-off values for a rapid neutrophil and platelet recovery were 1.5 x 10(6) and 2.5 x 10(6) CD34+ cells/kg, respectively, and for AML patients these figures were 1.5 x 10(6) and 4 x 10(6) CD34+ cells/kg, respectively. Our results confirm the slower HR after ABSCT in AML, and highlight the importance of progenitor cell dose in accelerating HR after ABSCT.     

Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study

Using non-myeloablative conditioning, allogeneic hematopoietic stem cell transplantation (HSCT) was conducted in 43 ALL patients in a CR2. The median age of the patients was 19 years. Patients received oral busulfan 4 mg/kg/day for 2 days; i.v. cyclophosphamide 350 mg/m(2)/day for 3 days; and i.v. fludarabine 30 mg/m(2)/day for 3 days. Oral cyclosporin A 4 mg/kg was started and methotrexate 5 mg/m(2) was delivered on days 1, 3, 5 and 11. The median CD34+ cell dose received was 5.0 x 10(6)/kg. The medium time to achieve a granulocyte count above 0.5 x 10(9)/l was 14 days. Thirteen patients were alive 30-1050 days after the HSCT. The 3-year overall survival rate was 30%. Ten patients (23%) developed acute GVHD, whereas eight patients (18.6%) developed chronic GVHD. Thirty patients died between days 47 and 1050 after the HSCT, most of them (70%) because of an ALL relapse. One hundred-day mortality was 15%, whereas transplant-related mortality was 21%. These results are inferior to those obtained using the same allografting method in other leukemias, probably as a consequence of poor susceptibility to the graft-versus-leukemia effect of the ALL cells beyond first remission as compared with other hematological malignancies.     

Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma

Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n?=?111) or allogeneic (n?=?51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65 months in the autologous and allogeneic HCT groups, respectively (P?=?0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were >?60 years of age at HCT (P?=?0.017), higher score of HCT-specific comorbidity index at HCT (P?=?0.033), and receiving MCEC (ranimustine?+?carboplatin?+?etoposide?+?cyclophosphamide) regimen (P?=?0.017), while higher performance status at HCT (P?=?0.011) and longer interval from diagnosis to HCT (P?=?0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT.     

FABC预处理异基因造血干细胞移植治疗难治未缓解急性白血病临床研究

目的观察FABC预处理异基因造血干细胞移植治疗未缓解急性白血病(AL)患者的疗效及安全性。方法收集2005年11月至2010年8月广东省人民医院采用FABC预处理方案进行异基因造血干细胞移植治疗18例难治未缓解AL患者。观察造血恢复、植入率、急慢性移植物抗宿主病发生率、移植相关病死率、复发、总存活率和无病存活率及预后因素分析。结果所有患者均于移植后14～21 d获得完全供者植入,中性粒细胞>0.5×109/L和血小板>20×109/L中位时间分别为12(7～72)d和13(7～60)d;急性移植物抗宿主病(GVHD)及慢性GVHD累积发生率分别为50%和73.3%。中位随访10.5(3.1～66.6)个月,移植相关病死率5.6%(1/18),复发率为36.8%(7/18)。1年的预期总生存(OS)率和无病生存(DFS)率分别是(58.9±13.2)%和(53.6±15.5%)。COX逐步回归模型分析显示,慢性GVHD是DFS独立有利因素。结论 FABC预处理异基因造血干细胞移植是治疗难治性未缓解AL安全有效的方法。     

Autologous peripheral hematopoietic stem cell transplantation in leukemia

Six cases of acute leukemia patients were treated with APHSCT and the clinical results were satisfactory. The preparatory marrow ablative chemoradiotherapy regimen before APHSCT was same as that for autologous bone marrow transplantation (ABMT). The number of mononuclear cells infused to restore the hematopoietic function ranged from 1.65 to 2.92 x 10(8)/kg and these cells yielded 0.17 to 2.26 x 10(4)/kg CFU-GM. The hematopoietic and immunological function of patients returned to normal level 25 to 38 days after APHSCT; the recovery was faster than that of ABMT and FLT. One patient each died of recurrence of leukemia and fungi septicemia 90 and 70 days after transplantation respectively, whereas the other four patients have survived for 9, 8, 4, and 2 months respectively.     

Allogeneic hematopoietic cell transplantation with reduced-intensity conditioning following FLAMSA for primary refractory or relapsed acute myeloid leukemia

Patients with primary refractory or relapsed acute myeloid leukemia (AML) have a dismal prognosis. We report a retrospective single center analysis of aplasia-inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients. Two-year event-free survival and overall survival (OS) were 26 and 39 %, respectively. Risk stratification according to cytogenetic and molecular genetic markers showed superior survival in patients in the intermediate-1 risk group (2-year OS 70 %) compared to the intermediate-2 risk (2-year OS 34 %, p?=?0.03) and adverse risk (2-year OS 38 %, p?=?0.06) group. The use of HLA-matched versus HLA-mismatched donors had no significant influence on survival (p?=?0.98). Two-year OS in the elderly subgroup defined by age ≥60 years was 31 % compared to 46 % in the group of younger patients <60 years (p?=?0.19). Cumulative incidence of non-relapse mortality at 2 years adjusted for relapse as competing risk was 20 % for patients <60 years and 26 % for older patients (p?=?0.55). Chronic graft-versus-host disease was associated with a statistically significant superior survival (p?<?0.01). FLAMSA-RIC followed by allogeneic HCT enables long-term disease-free survival in primary refractory or relapsed AML even in the elderly patient population.     

Role of allogeneic and autologous hematopoietic stem cell transplantation in acute myeloid leukemia

Most younger patients with acute myeloid leukemia will enter remission of disease. Prevention of relapse is now the central therapeutic issue. A number of factors predict the risk of relapse, the most powerful of which is cytogenetics. Both allogeneic and autologous transplantation have been extensively used as remission consolidation, but intensive chemotherapy has also provided improved results such that the choice of consolidation treatment is not clear. Recent prospective trials of allogeneic and autologous transplantation with careful analysis have not always shown a survival benefit, although both approaches have significantly reduced relapse risk. In analysis where relapse risk is taken into account based on cytogenetics, there is little evidence of the benefit of transplantation in good-risk patients, partly because patients in this group who relapse can then undergo successful salvage therapy. The results are still uncertain in standard-risk patients, so transplantation should continue to be used in the context of a trial. Poor-risk patients have a higher failure rate after transplantation, and for these patients novel approaches are required.