Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab

Alemtuzumab is a humanized monoclonal antibody directed against human CD52 with a strong lympholytic effect. We have performed unmanipulated hematopoietic stem cell transplantation (HSCT) from 2- or 3-locus-mismatched family donors in 14 patients using in vivo alemtuzumab. All achieved complete donor cell engraftment and grade III-IV acute graft-versus-host disease was observed in only one patient. However, eight of the 14 patients developed grade II-IV cardiac complications according to Bearman's criteria. Next, we retrospectively analyzed the records of 142 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. Among several factors that increased the incidence of grade II-IV cardiac complications with at least borderline significance, a multivariate analysis identified the cumulative dose of anthracyclines (P=0.0016) and the use of alemtuzumab (P=0.0001) as independent significant risk factors. All of the cardiac complications in the alemtuzumab group were successfully treated with diuretics and/or catecholamines. Patient selection and close monitoring of cardiac function may be important in HLA-mismatched HSCT using in vivo alemtuzumab.     

Successful treatment by donor lymphocyte infusion of adult T-cell leukemia/lymphoma relapse following allogeneic hematopoietic stem cell transplantation

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive hematologic neoplasm that has an extremely poor prognosis; however, this has improved following recent progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several clinical studies have shown that discontinuation of immunosuppressant therapy induces durable remission in a significant number of post-transplant relapsed patients, suggesting that ATLL may be susceptible to a graft-versus-leukemia effect. Here, we report two cases with ATLL who received donor lymphocyte infusions (DLIs) for relapse after allo-HSCT; one patient achieved complete remission (CR) after a single DLI, and the other suffered repeated relapses and was treated with chemotherapy and radiotherapy combined with a total of five rounds of DLIs. Both patients presented with exacerbation of the graft-versus-host disease after the DLIs, and remained in CR for 9 and 8 years, respectively. These data support the use of DLIs as an effective therapy to induce durable CR in the treatment of relapsed ATLL. In this study, we review previous reports and discuss the role of DLIs in the treatment of post-transplant relapsed ATLL.     

Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation

We studied the impact of risk stratification-directed interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD(-) after transplantation (Group A); 105 subjects were MRD(+), 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C). Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P = .001 and P = .002, respectively), but was not different from subjects in Group A (P = .269 and P = .688, respectively). Multivariate analyses confirmed that MRD state and modified DLI were significantly correlated with relapse (P = .000, odds ratio [OR] = 0.255 and P = .000, OR = 0.269) and DFS (P = .001, OR = 0.511 and P = .006, OR = 0.436, respectively). These data suggest that risk stratification-directed interventions with modified DLI in patients with standard-risk acute leukemia who are MRD(+) after transplantation may improve transplantation outcomes.     

Donor cell leukemia developing after hematopoietic stem cell transplantation for multiple myeloma

The development of secondary leukemia in donor cells after allogeneic stem cell transplantation is a rare event. We describe the occurrence of acute myeloid leukemia in donor cells 4 years after a stem cell transplantation for multiple myeloma. The multiple myeloma was relapsing at the time of the onset of acute myeloid leukemia. Secondary leukemia in donor cells after transplantation for multiple myeloma has not yet been reported.     

Immunomodulatory strategies for relapse after haploidentical hematopoietic stem cell transplantation in hematologic malignancy patients

Currently, human leukocyte antigen (HLA)-mismatched/haploidentical allografts have been validated as an alternative stem cell source for patients who have no immediate access to an HLA-matched related or unrelated donor. However, relapse remains a challenge after HLA-mismatched/haploidentical hematopoietic stem cell transplantation (HSCT) that is employed in the treatment of patients with hematological malignancies. In recent years, newly developed immunomodulatory strategies, which include prophylactic and therapeutic donor lymphocyte/natural killer (NK) cell infusion, donor selection based on NK alloreactivity/non-inherited maternal antigen (NIMA), immune reconstitution promotion, and application of exogenous cytokines, have made it possible to decrease the relapse rate and improve outcomes following haploidentical HSCT. Further elucidation of the underlying mechanisms that govern leukemia stem cell escape from immunosurveillance after haploidentical HSCT may broaden our understanding and lead to therapies that control relapse.     

Donor lymphocyte infusion is an effective therapy for relapsed Hodgkin lymphoma after reduced-intensity allogeneic hematopoietic stem cell transplantation

A 3-year-old boy with Hodgkin lymphoma relapsed only 2 months after completion of first-line therapy. He received reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT), but relapsed again. To treat the second relapse, donor lymphocyte infusions were performed four times. He showed no evidence of disease and his quality of life was maintained for 500 days after stem cell transplant. However, his condition worsened and he died 3 years and 3 months after onset. In high-risk patients fully intolerant to myeloablative regimens, RIC allo-HSCT followed by subsequent donor lymphocyte infusions must be considered an effective therapeutic approach.     

Donor lymphocyte infusion and methotrexate for immune recovery after T‐cell depleted haploidentical transplantation

CD34+ cell selection minimizes graft‐versus‐host disease (GVHD) after haploidentical donor stem cell transplant but is associated with slow immune recovery and infections. We report a Phase I/II study of prophylactic donor lymphocyte infusion (DLI) followed by methotrexate (MTX) GVHD prophylaxis after CD34‐selected haploidentical donor transplant. A prophylactic DLI was given between day +30 and +42. Rituximab was given with DLI for the last 10 patients. The goal of the study was to determine a DLI dose that would result in a CD4+ cell count > 100/µL at Day +120 in ≥ 66% of patients with ≤ 33% grade II‐III, ≤ 17% grade III, and no grade IV acute GVHD by Day +180. Thirty‐five patients with malignant (n = 25) or nonmalignant disease (n = 10) were treated after CD34‐selected haploidentical donor peripheral blood stem cell transplant. The DLI dose of 5 × 10⁴/kg met the CD4/GVHD goal with 67% of patients having CD4+ cells > 100/µL and 11% grade II‐IV acute GVHD. The cumulative incidence of chronic GVHD was 16%. Fatal viral and fungal infections occurred in 11%. The 2 year estimated overall survival was 69% and the relapse rate was 14% for patients in remission at transplant. There was no effect of NK alloreactivity on relapse. Nine of ten patients at the target DLI dose cohort of 5 × 10⁴/kg are alive with median follow‐up of 18 mos (range 6‐29). Delayed prophylactic DLI and MTX was associated with promising outcomes at the target DLI dose. This trial was registered at clinicaltrials.gov , # NCT01027702.     

Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis

The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n=61) or did not (n=27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P=0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P=0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P=0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P=0.025). Higher OS was associated with use of prophylactic GPBPCI (P=0.002), AML (P=0.027) and female sex (P=0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT.     

T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis

Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. “Haploidentical expert” centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes (“haploidentical regular”, “haploidentical expert” and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10⁻⁵) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program.     

High CD4/CD8 ratio in allografts predicts adverse outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic stem cell transplantation for chronic myeloid leukemia

HLA-mismatched/haploidentical hematopoietic stem cell transplantation (haplo-mismatched HSCT) has improved the outcome of chronic myeloid leukemia (CML) in patients without an HLA-matched donor. To further improve the treatment outcome of haplo-mismatched HSCT in CML, a modifiable prognostic factor needs to be found. The cellular composition of grafts obtained from 75 HLA-mismatched/haploidentical related donors was prospectively correlated with the outcome of patients with CML undergoing haplo-mismatched HSCT following a modified regimen of BU/CY 2 plus antithymocyte globulin. The concentration of T-cell subsets, CD14+, and CD34+ cells and their relative proportions were analyzed. In univariate analyses, disease-free survival (DFS) and overall survival (OS) conversely correlated with the CD4/CD8 ratio in primed bone marrow graft (G-BM) (p = 0.012 and p = 0.040); similarly, CD4/CD8 ratio in total grafts was also negatively associated with DFS and OS (p = 0.018 and p = 0.020). In multivariate analyses, a CD4/CD8 ratio in G-BM higher than the median value remained the only factor negatively affecting DFS (p = 0.030; 95% confidence interval [CI], 1.166–19.341). Expectedly, high CD34+ cell dose was associated with accelerated platelet engraftment (p = 0.009; 95% CI = 1.181–3.271) after controlling for a high risk of disease. No other clinical parameter was influenced by graft composition. Our results suggest that a high CD4/CD8 ratio in allografts may predict adverse survival in patients with CML undergoing haplo-mismatched HSCT. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Successful treatment of juvenile myelomonocytic leukemia relapsing after stem cell transplantation using donor lymphocyte infusion

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric malignancy. Hematopoietic stem cell transplantation (SCT) is the only curative approach. However, relapse after SCT remains the major cause of treatment failure. Unlike most other pediatric malignancies, JMML may be susceptible to a graft-versus-leukemia (GVL) effect, although, unlike chronic myeloid leukemia, reports of response to donor lymphocyte infusions (DLIs) remain scanty. This is the first report that describes the successful treatment of relapsed JMML with DLI in the absence of further chemotherapy and provides definite proof of a GVL effect in JMML.     

Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome

Donor lymphocyte infusion has become established as a salvage therapy for patients with hematological disorders relapsing after allogeneic bone marrow transplantation (BMT). The role of donor lymphocyte infusion for patients with myelodysplastic syndrome (MDS) remains to be established. Between July 1993 and October 2001, 14 patients with MDS relapsing after allogeneic BMT received DLI as salvage therapy. At the time of BMT, one patient had RA, nine had RAEB, of whom three were in CR after induction-type chemotherapy, two had RAEB-T, one had CMML and one had AML. Donors were HLA-matched siblings (n=12), HLA-matched other relative (n=1) and unrelated (n=1). At the time of relapse, the median marrow blast count was 9%. The median CD3+ cell dose administered was 6.3 x 10(7)/kg. With a median follow-up of 49 months, six patients were alive, of whom two were in CR after DLI alone and remained disease-free, two were in CR after a second BMT and two had active disease. Eight patients died of disease progression. Although DLI alone seems to be effective in a small number of patients with MDS, other treatment strategies, including prior debulking chemotherapy, deserve investigation.     

Genetically haploidentical stem cell transplantation for acute leukemia

Genetically haploidentical stem cell transplants have been performed for several decades, mostly for patients with advanced acute leukemia. Such transplants are an option for those patients who do not have a histocompatible sibling donor. The historical data have been disappointing due to graft-versus-host disease, engraftment failure and delayed immune reconstitution. Recent modifications and new technological developments have led to more encouraging clinical results. Haploidentical transplantation is immediately available to the majority of patients with acute leukemia and is an acceptable alternative to matched unrelated donor transplantation.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

目的 探讨供者粒细胞集落刺激因子(G-CSF)动员外周血干细胞输注对高危复发白血病患者单倍型移植后白血病复发的预防作用,评价其疗效及安全性.方法 对20例复发未缓解白血病患者在单倍型造血十细胞移植(HSCT)后给予预防性外周血干细胞输注,供者接受G.CSF 5～10μg·kg-1·d-1,分次注射,第5天采集外周血干细胞,在移植90 d后(+90 d)行第1次输注,30 d后4例患者行第2次输注,除1例第1次输注的单个核细胞数(MNC)为0.1×108个/kg外,其他患者均为0.2×108个/kg.外周血千细胞输注后观察移植物抗宿主病(GVHD)的发生、白血病复发率及患者长期生存的情况.结果 外周血干细胞输注后,中位随访25(4～印)个月,19例患者发生急性GVHD,其中Ⅲ度以上4例,累积发生率22.9%,均是接受2次输注的患者;可以评价的慢性GVHD13例,其中10例为局限性慢性GVHD.无患者因GVHD死亡.9例患者复发死亡,其余11例患者无病生存,其中4例慢性髓性白细胞、4例急性髓性白细胞(AML)、1例淋巴瘤性白血病、2例骨髓增生异常综合征转AML,Kaplan-Meier生存计算2年无病生存率为52.5%.结论 G-CSF动员外周血干细胞输注预防单倍型HSCT后白血病复发,效果显著,安全性较好.

Abstract：

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.