Liver graft-versus-host disease after donor lymphocyte infusion for relapses of hematologic malignancies post allogeneic hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is the commonest complication after donor lymphocyte infusion (DLI). In 19 patients undergoing DLI for relapses of hematologic malignancies post hematopoietic stem cell transplantation (HSCT), 11 developed GVHD, of whom nine had isolated liver involvement, and two had liver and skin involvement. The clinical diagnosis of liver GVHD was hepatitic in six patients (55%) and classical in five patients (45%). Patients with GVHD post-DLI showed a different clinical pattern when compared to a cohort of 106 cases of GVHD post-HSCT, in having significantly more isolated liver involvement (9/11 vs 17/106, P<0.001), and less skin (2/11 vs 80/106, P<0.001) and gut (0/11 vs 28/106, P<0.001) involvement. However, liver GVHD post-DLI and post-HSCT had comparable patient characteristics, underlying diseases, clinical subtypes (classical and hepatitic) and response to treatment.     

Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation

Donor lymphocyte infusions (DLI) are used to treat relapsed haematological diseases after allogeneic stem cell transplantation (SCT). We treated seven patients with DLI for indolent non-Hodgkin's lymphoma relapsed after SCT. In available blood and bone marrow samples, lymphoma cells were analysed by real-time quantitative polymerase chain reaction of t(14;18)-positive cells in follicular lymphoma, and by immunophenotyping in small lymphocytic lymphoma. Before DLI, three patients were treated with chemo- and/or radiotherapy, and one with rituximab. Evaluable responses to pre-DLI therapy were stable disease in one and partial remission (PR) in two patients. Six patients responded to DLI (complete remission (CR) in four and PR in two). After DLI, acute graft-versus-host disease (GVHD) occurred in 3/6 patients, classified as grade 2, whereas only limited chronic GVHD was seen (n=5). The four continuous CR are lasting for median 65+ (43-89) months. In the remaining patient, not responding to DLI, progressive disease was seen later on; chemotherapy followed by another DLI resulted in CR. In three cases, clinical responses to DLI could be substantiated by molecular or immunophenotypic analysis of lymphoma cells. We conclude that DLI is effective for treatment of indolent lymphoma relapsing after SCT.     

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.     

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‐derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation

Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell‐derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long‐term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.     

Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative approach for patients with myelodysplastic syndromes (MDSs). While a large proportion of HCT recipients become long-term disease-free survivors, recurrence of MDS remains the leading cause of mortality after HCT. The role of donor lymphocyte infusion (DLI) in patients with relapsed MDS after HCT is unclear. We report results among 16 patients treated with DLI for relapsed MDS after HCT at a single institution between March 1993 and February 2004. The cohort contained 10 men and 6 women with a median age of 49 (range, 22-67) years. CR with resolution of cytopenias and prior disease markers occurred in 3 of 14 patients who could be evaluated. Two patients survived without MDS for 68 and 65 months after DLI, respectively, but died with pneumonia. Grades II-IV acute GVHD and chronic GVHD occurred after DLI in 6 (43%) and 5 (36%) patients, respectively. All three responders developed grades III-IV acute GVHD and extensive chronic GVHD after DLI. Our results confirm prior reports that DLI can result in CR in some patients with recurrent MDS after transplant, but long-term survival is infrequent.     

Expansion of recipient‐derived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation

Donor chimerism (DC) analysis is an important marker in the hematopoietic stem cell transplant follow‐up. Here, we present evidence for a possible relationship of infectious complications and declines in DC. We analyzed the DC in patients experiencing cytomegalovirus (CMV) reactivation. In addition, in some patients chimerism analyses of T‐cell subsets were performed. CMV‐specific cytotoxic T‐lymphocytes (CMV‐CTL) were monitored using human leukocyte antigen‐restricted multimer staining. Interestingly, CMV reactivation was accompanied by changes in DC in 11 of 67 patients transplanted. For example, DC declined in a cord blood recipient, in both total leukocytes and CD4 and CD8 T‐cell subsets upon CMV reactivation. The latter was controlled after only 5 days through expanding CMV‐CTL of 96% recipient origin, according to chimerism analysis of CMV‐CTL (enriched beyond 50%). In another patient, transplanted after reduced‐intensity conditioning from a DQB1 mismatched, CMV seronegative donor, incipient CMV reactivation was completely aborted by CMV‐CTL of recipient origin. However, at the same time, mixed chimerism dropped from 51% to 0% donor type, resulting in late graft rejection. Our data indicate that chimerism analyses in subset populations lead to a better understanding of declining total leukocyte chimerism. Furthermore, recipient‐derived CMV‐CTL may be able to control CMV reactivation after reduced‐intensity conditioning. We speculate that autologous CMV‐CTL may be instrumental to overcome recurrent CMV reactivations, especially in patients transplanted from CMV‐seronegative donors. In addition, the expansion of recipient‐derived CMV‐CTL may contribute to both, graft failure or to conversion to full DC.     

供者淋巴细胞输注治疗异基因造血干细胞移植后EB病毒相关的淋巴细胞增殖性疾病的疗效和安全性

目的 采用控制数量的供者淋巴细胞输注(DLI)治疗EB病毒(EBV)相关的淋巴细胞增殖性疾病(PTLD),观察其有效性和安全性.方法 2006年11月到2009年11月移植的患者,临床或病理诊断EBV相关的PTLD采用DLI治疗者纳入研究.采用COBE血球分离机应用淋巴细胞程序采集白细胞,首选原供者,次选直系亲缘供者,冻存外周血采集物(G-PB)与移植时输入的外周血干细胞(PBSC)组分相同.控制输入的单个核细胞(PBMC)在(0.5～1.0)×108/kg.原基础免疫抑制剂预防移植物抗宿主病(GVHD),观察疗效及其副作用.结果 PTLD患者9例,输注13例次,输入外周血PBMC 0.8(0.16～1.03)× 108/kg,CD3+T淋巴细胞4.2(1.6～5.7)×107/kg.7例半相合移植患者采用了原供者,有效率为7/7,完全缓解率为6/7,退热中位时间2(1～5)d,淋巴结缩小中位时间6(1～14)d;7例中6例发生GVHD,均为轻中度,得到控制.至今无病存活3例.2例非亲缘HSCT采用了半相合供者的外周血白细胞,仅获得短暂部分疗效.结论 在配型不合/半相合移植中,采用原供者控制细胞数量的DLI并免疫抑制剂预防GVHD治疗EBV相关的PTLD安全有效.最佳方案尚需进一步研究.     

Solid cancers after allogeneic hematopoietic cell transplantation

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.     

Analysis of chimerism in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation

Serial monitoring of chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) can be performed easily and rapidly using PCR-based assays analyzing informative tandem repeat genetic markers. Sequential analysis of individual chimerism status was performed in 34 patients who underwent myeloablative allo-HSCT using a commercial multiplex short tandem repeat (STR) kit. Mixed chimerism (MC) was found in 14 of the patients for more than one month. The incidence of MC seemed to be dependent on the type of disease or pretransplantation regimen. There was no significant difference in relapse rates between MC and complete donor chimerism (CC) in all patients. However, the relapse rate was significantly higher in MC than in CC among patients with acute leukemia. The severity of acute graft-versus-host disease (aGVHD) was significantly reduced in the patients with MC. Most of the MC patients with hematologic malignancies had transient mixed T-lymphoid chimerism, and CC was achieved within 6 months after HSCT in such cases. Patients with MC beyond 6 months after HSCT and patients with reappearance of autologous signals (MC after CC) may have an enhanced risk of relapse.     

Leukemia in donor cells after allogeneic hematopoietic stem cell transplant

The development of leukemia in donor cells after allogeneic hematopoietic stem cell transplant is an extremely rare event. We report here the case of a patient who developed myelodysplastic syndrome/acute myeloid leukemia, in cells of donor origin 3.5 years after related donor HSCT for refractory chronic lymphocytic leukemia and therapy-induced myelodysplastic syndrome. The origin of the leukemia was determined by analysis of minisatillite polymorphism tested on CD34(+) cells.     

Treatment of lymphoma relapses after allogeneic hematopoietic stem cell transplantation with intensive chemotherapy followed by infusion of hematopoietic stem cell from the original donor

Five lymphoma patients relapsed from allogeneic hematopoietic stem cell transplantation (HSCT). Three patients who received myeloablative conditioning had full donor chimerism at relapse, whereas two who received nonmyeloablative conditioning had partially or completely lost the graft. All received mini-BEAM [carmustine (BCNU), etoposide, cytarabine (AraC), melphalan], followed by infusion of HSC (four peripheral blood, one marrow) from the initial donor. Neutropenia and thrombocytopenia were brief, and full donor chimerism was established in all cases. There were four complete and one partial remissions. Graft-versus-host disease occurred in three cases, all with full donor chimerism at relapse. Two patients died subsequently of disease relapse or progression. Another two patients died from fungal infection, one of whom was still in remission at death. One patient had remained in remission 47 months after treatment. Mini-BEAM/HSC is an effective treatment for lymphoma relapses after allogeneic HSCT, but optimal strategies of remission consolidation and prevention of treatment-related complications are needed to improve outcome.     

Complete allogeneic hematopoietic chimerism achieved by a combined strategy of in utero hematopoietic stem cell transplantation and postnatal donor lymphocyte infusion

In utero hematopoietic stem cell transplantation (IUHSCTx) can achieve mixed hematopoietic chimerism and donor-specific tolerance without cytoreductive conditioning or immunosuppression. The primary limitation to the clinical application of IUHSCTx has been minimal donor cell engraftment, well below therapeutic levels for most target diseases. Donor lymphocyte infusion (DLI) has been used in postnatal circumstances of mixed chimerism as targeted immunotherapy to achieve a graft-versus-hematopoietic effect and to increase levels of donor cell engraftment. In this report we demonstrate in the murine model that a combined approach of IUHSCTx followed by postnatal DLI can convert low-level, mixed hematopoietic chimerism to complete donor chimerism across full major histocompatibility complex barriers with minimal risk for graft-versus-host disease (GVHD). Time-dated embryonic day 14 (E14) to E15 Balb/c (H-2K(d), CD45.2) fetuses underwent intraperitoneal injection of 5 x 10(6) T-cell-depleted B6 (H-2K(b), CD45.2) bone marrow cells. Chimeric recipients then received transplants at either 4 or 8 weeks of age with 1 of 3 doses (5, 15, or 30 x 10(6) cells) of donor congenic splenocytes (B6-Ly5.2/Cr, H-2K(b), CD45.1). The response to DLI was dose dependent, with conversion to complete donor peripheral blood chimerism in 100% of animals that received high-dose (30 x 10(6) cells) DLI. Only 1 of 56 animals receiving this dose succumbed to GVHD. This study directly supports the potential therapeutic strategy of prenatal tolerance induction to facilitate nontoxic postnatal cellular therapy and organ transplantation, and it has broad implications for the potential treatment of prenatally diagnosed genetic disorders.