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Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation
Jiang, Z., Fan, Z., Zhang, T., Lin, R., Xu, H., Xu, N., Huang, F., Chi, P., Ou, X., Wang, Z., et al
British journal of haematology. 2024
Abstract
Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.
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Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Jullien, M., Guillaume, T., Le Bourgeois, A., Peterlin, P., Garnier, A., Eveillard, M., Le Bris, Y., Bouzy, S., Tessoulin, B., Gastinne, T., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
PICO Summary
Population
Adults with haematological malignancy, eligible for haploidentical transplant from a single centre in France (n=26)
Intervention
Increasing low-doses of IL-2 (5 days per week, 4 weeks) in combination with a single dose of zoledronic acid (ZA) to generate Vγ9Vδ2 T-cells early after h-HSCT (n=16)
Comparison
Haploidentical HSCT only (n=7)
Outcome
At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. Maximum tolerated dose was not reached.
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Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Locke, F. L., Filosto, S., Chou, J., Vardhanabhuti, S., Perbost, R., Dreger, P., Hill, B. T., Lee, C., Zinzani, P. L., Kröger, N., et al
Nature medicine. 2024
Abstract
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10(-9) for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10(-9) for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
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Donor Lymphocyte Infusion and Molecular Monitoring for Relapsed Myelofibrosis After Hematopoietic Cell Transplantation
Gagelmann, N., Wolschke, C., Badbaran, A., Janson, D., Berger, C., Klyuchnikov, E., Ayuk, F., Fehse, B., Kröger, N.
HemaSphere. 2023;7(7):e921
Abstract
Hematopoietic cell transplantation (HCT) is a curative approach for myelofibrosis patients, but relapse is a major cause of treatment failure. We investigated the effect of donor lymphocyte infusion (DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) after HCT. Patients received median of 2 (range, 1-5) cumulative DLI (total of 91 infusions). Median starting dose was 1 × 10(6) cells/kg, escalated by half-log ≥6 weeks if no response nor graft-versus-host disease (GvHD) occurred. Median time to first DLI was 40 weeks for molecular relapse versus 145 weeks for hematological relapse. Overall molecular complete response (mCR) at any time was 73% (n = 27) and was significantly higher for initial molecular relapse (88%) versus hematological relapse (60%; P = 0.05). The 6-year overall survival was 77% versus 32% (P = 0.03). Acute GvHD 2-4 occurred in 22% and half of the patients achieved mCR without any GvHD. All patients who relapsed from mCR achieved after first DLI could be salvaged with subsequent DLI, showing long-term survival. No second HCT was needed for molecular relapse versus 6 for hematological relapse. This comprehensive and largest study to date suggests molecular monitoring together with DLI as standard of care and a crucial approach to achieve excellent outcomes in relapsed myelofibrosis.
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Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant
Cao, X. Y., Zhang, J. P., Zhao, Y. L., Xiong, M., Zhou, J. R., Lu, Y., Sun, R. J., Wei, Z. J., Liu, D. Y., Zhang, X., et al
Frontiers in immunology. 2023;14:1191382
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Editor's Choice
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. METHODS A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. RESULTS The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). CONCLUSIONS Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who were minimal residual disease-positive after first transplant at a single centre in China (n=95)
Intervention
CAR-T therapy followed by consolidation allogeneic transplant, using a different donor
Comparison
None
Outcome
The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24) and OS(HR, 2.67, 95%CI, 1.24-5.74), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24).
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Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study
Gerbitz, A., Gary, R., Aigner, M., Moosmann, A., Kremer, A., Schmid, C., Hirschbuehl, K., Wagner, E., Hauptrock, B., Teschner, D., et al
Frontiers in immunology. 2023;14:1251593
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Editor's Choice
Abstract
INTRODUCTION Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. METHODS We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. RESULTS Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. DISCUSSION Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier NCT02227641.
PICO Summary
Population
Adults undergoing allogeneic transplant from a matched donor who was seropositive for cytomegalovirus (CMV) and Epstein-barr virus (EBV) and enrolled in the MULTIVIR-01 study in centres in Germany (n=33)
Intervention
A newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. (n=16; 9 received full treatment)
Comparison
Control (n=13)
Outcome
Central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation
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Efficacy of Azacitidine and Prophylactic Donor Lymphocyte Infusion after HSCT in Pediatric Patients with Acute Myelogenous Leukemia: A Retrospective Pre-Post Study
Booth, N., Mirea, L., Huschart, E., Miller, H., Salzberg, D., Campbell, C., Beebe, K., Schwalbach, C., Adams, R. H., Ngwube, A.
Transplantation and cellular therapy. 2023
Abstract
Pediatric patients with acute myeloid leukemia (AML) who undergo allogeneic hematopoietic stem cell transplantation (HSCT) continue to have high rates of relapse. In 2018, Phoenix Children's Hospital started using post-HSCT maintenance therapy in patients with AML in attempt to decrease the number of relapses after HSCT. This therapy consisted of the hypomethylating agent azacitidine (AZA; 6 cycles starting on day +60) and prophylactic donor lymphocyte infusion (DLI; 3 escalating doses beginning after day +120). We aimed to compare 2-year leukemia-free survival (LFS) post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI and historical control patients who did not receive post-HSCT therapy. This retrospective pre-post study was conducted at Phoenix Children's Hospital and included patients with AML who underwent HSCT between January 1, 2008, and May 31, 2022. We compared LFS, overall survival (OS), and immune reconstitution patterns post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI (postintervention group) and historical control patients who did not receive this post-HSCT maintenance therapy (preintervention group). Sixty-three patients were evaluable. After excluding 7 patients who died or relapsed prior to day +60, 56 patients remained, including 39 in the preintervention group and 17 in the postintervention group. The median age at transplantation was 9.1 years in the preintervention group and 11 years in the postintervention group (P = .33). The 2-year LFS was 61.5% in the preintervention group, compared to 88.2% in the postintervention group (P = .06). The 2-year OS was 69.2% in the preintervention group and 88.2% in the postintervention group (P = .15). The rates of CD3(+)CD4(+) T cell and CD19(+) B cell recovery were faster in the preintervention group compared to the postintervention group (P = .004 and .0006, respectively). In this limited retrospective study, post-HSCT maintenance therapy using AZA and prophylactic DLI was well tolerated; however, its efficacy is yet to be fully determined.
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Comparison of Outcomes of Donor Lymphocyte Infusions With or Without Lenalidomide in Patients with Hematological Malignancies Post Allogeneic HSCT
Punatar, S., Murugaiyan, V., Kumbhalwar, K., Gokarn, A., Chichra, A., Mirgh, S., Nayak, L., Bonda, A., Jindal, N., Shirure, V., et al
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2023;39(1):40-49
Abstract
Outcomes with DLI alone for post-transplant relapsed hematological malignancies are poor especially in acute leukemias. Addition of immunomodulatory drugs to DLI may augment GVL effect. Use of lenalidomide with DLI to augment GVL has not been previously reported. This retrospective analysis was to compare the outcomes of DLI with or without lenalidomide. All consecutive patients who received DLI from 01/2010 through 01/2020 were included. DLIs were given without any immunosuppression. Lenalidomide, when used, was given continuously, starting with 1st or subsequent DLI. Patients who received lenalidomide were compared with those who did not. Event (hematological relapse or death) free survival (EFS) and overall survival (OS) were calculated from 1st DLI. Primary objective was to compare OS. Secondary objectives were EFS, CR rates, acute GVHD, lenalidomide toxicities and DLI related mortality (TRM). Total 61 patients received DLI-43 without and 18 with lenalidomide; all outcomes in the 2 groups were similar. There were 26 patients with HLA-A*24 and/or HLA-B*40. Among these, trend towards improvement in OS (median OS not reached vs. 8 months, 4 year OS was 62% vs. 32%, p = 0.1) and EFS (median 9 vs. 1 month, 4 year EFS 50% vs. 22%, p = 0.1) was seen with lenalidomide. Overall, there was no improvement in outcomes by adding lenalidomide to DLI. However, among patients with HLA*24 or B*40, there was a trend to improved survival with lenalidomide. Use of lenalidomide to augment the GVL effect of DLI warrants further exploration.
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Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study
Qi, S. S., Chen, Z., Du, Y., Sun, M., Wang, Z., Long, F., Luo, L., Xiong, H.
Pediatric blood & cancer. 2023;:e30659
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Editor's Choice
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. METHODS We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n = 46) and myelodysplastic syndromes (n = 8). RESULTS Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. CONCLUSIONS Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.
PICO Summary
Population
Children with high-risk myeloid neoplasms undergoing haploidentical peripheral blood transplant at a single centre in China (n=54)
Intervention
Post-transplant cyclophosphamide (PTCy) regimen for GvHD prophylaxis and prophylactic donor lymphocyte infusion (pro-DLI)
Comparison
None
Outcome
Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively.
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Magnesium enhances the graft-versus-tumor effect of donor lymphocytic infusion on hematologic malignancies
Wei, Y., Guo, J., Lu, N., Liu, Y., Wang, L., Wang, L., Bo, J., Li, H., Dou, L., Liu, D., et al
Hematological oncology. 2023
Abstract
Donor lymphocyte infusion (DLI) cures relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation through the graft-versus-tumor (GVT) effect. Although the important role of magnesium in enhancing immunity has been mentioned in studies, limited clinical data have explored how magnesium affects the efficacy of DLI. Besides, although laboratory data demonstrate that magnesium can enhance CD8(+) T cells effector function, whether magnesium regulates the tumor killing effect of peripheral blood mononuclear cells (PBMCs) remains to be explored. Here, for the retrospective study, we collected clinical data of relapsed patients receiving DLI and explored the relationship between different serum magnesium levels and patient outcomes. For in vitro studies, we investigated the effect of magnesium on the cytotoxicity of DLI cells which were PBMCs and preliminarily explored the mechanism. Eighty-one patients were enrolled in this study. It was found that the high post-DLI magnesium level was significantly associated with a higher incidence of complete remission (CR) or partial remission (CR/PR) and a higher possibility of survival. The magnesium level after DLI was an independent risk factor of overall survival. In vitro studies proved that increased magnesium enhanced the cytotoxic function of PBMCs on hematologic malignancies. Besides, magnesium modulated LFA-1 headpiece opening. When blocking the integrin-ligand interaction between LFA-1 and ICAM-1, the regulation effect of magnesium on PBMCs was weakened. Therefore, it was possible that magnesium regulated PBMCs effector function by stimulating LFA-1. These results show that serum magnesium levels affect immunological responses mediated by donor lymphocytes in hematologic malignancies.