Second unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia post-chemotherapy plus modified donor lymphocyte infusion / 医学前沿

Relapse is the main problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcome of a second allo-HSCT (HSCT2) for relapse post-HSCT has shown promising results in some previous studies. However, little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia (AL) post-chemotherapy plus modified donor lymphocyte infusion (post-Chemo + m-DLI) after the first allo-HSCT (HSCT1). Therefore, we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo + m-DLI in our center. With a median follow-up of 918 (457-1732) days, 26 patients (92.9%) achieved complete remission, and 2 patients exhibited persistent disease. The probabilities of overall survival (OS) and disease-free survival (DFS) 1 year after HSCT2 were 25.0% and 21.4%, respectively. The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1% ± 4.9% and 25.0% ± 8.4%. The cumulative incidences of relapse were 50.0% ± 9.8% and 53.5% ± 9.9% at 1 and 2 years post-HSCT2, respectively. Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2, and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2. Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo + m-DLI.

Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To explore clinical features and severity of chronic graft- versus- host disease (cGVHD) after chemotherapy plus donor lymphocyte infusion (Chemo-DLI) in a consecutive cohort of acute leukemia patients who were minimal residual disease (MRD) positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The global scoring system proposed by National Institutes of Health (NIH) Consensus Conference was used to identify the characteristics and severity of cGVHD in patients who MRD positive after Chemo-DLI. Results: 54 (59.3%) patients were diagnosed with cGVHD after Chemo-DLI, with the median time of onset of 70 (13-504) days. There were 6 cases (6.6%) of mild cGVHD, 21 cases (23.1%) of moderate cGVHD and 27 cases (29.7%) of severe cGVHD.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 15.1% (95%CI 1.1%-29.1%) , and 26.6% (95%CI 9.2%-44.0%) (χ(2)=18.901, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 19.9% (95%CI 8.1%-31.7%) , and 28.6% (95%CI 0.0%-65.0%) (χ(2)=18.307, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. cGVHD was not associated with non-relapse morality after Chemo-DLI. Probabilities of 5-year leukemia-free survival (LFS) after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 77.2% (95%CI 60.8%-93.6%) , and 64.9% (95%CI 45.7%-84.1%) (χ(2)=24.447, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year LFS after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 75.5% (95%CI 62.7%-88.3%) , and 42.9% (95%CI 1.8%-84.0%) (χ(2)=25.665, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. Probabilities of 5-year overall survival (OS) after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 87.9% (95%CI 74.7%-100.0%) , and 71.0% (95%CI 52.0%-90.0%) (χ(2)=9.517, P=0.009) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year OS after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 83.9% (95%CI 72.8%-95.0%) , and 51.4% (95%CI 6.2%-96.6%) (χ(2)=10.673, P=0.005) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. In multivariate analysis, patients receiving allo-HSCT in first complete remission stage and classical cGVHD after Chemo-DLI were associated with lower relapse risk and better survival. Conclusions: These findings highlight the close relation between cGVHD and the graft-versus-leukemia effect in patients who were MRD positive and received Chemo-DLI after allo-HSCT. However, overlap syndrome could not improve the clinical outcomes of these patients.

Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation / 医学前沿

The efficacy of salvage interferon-α (IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI) (n = 24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2-3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and > 2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

Effects of chemotherapy combined with donor lymphocyte infusion on chronic graft-versus-host disease and prognosis in minimal residual disease positive patients after allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective@#To explore clinical features and severity of chronic graft- versus- host disease (cGVHD) after chemotherapy plus donor lymphocyte infusion (Chemo-DLI) in a consecutive cohort of acute leukemia patients who were minimal residual disease (MRD) positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT) .@*Methods@#The global scoring system proposed by National Institutes of Health (NIH) Consensus Conference was used to identify the characteristics and severity of cGVHD in patients who MRD positive after Chemo-DLI.@*Results@#54 (59.3%) patients were diagnosed with cGVHD after Chemo-DLI, with the median time of onset of 70 (13-504) days. There were 6 cases (6.6%) of mild cGVHD, 21 cases (23.1%) of moderate cGVHD and 27 cases (29.7%) of severe cGVHD.The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 15.1% (95%CI 1.1%-29.1%) , and 26.6% (95%CI 9.2%-44.0%) (χ2=18.901, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. The 5-year cumulative incidence of relapse after Chemo-DLI was 61.9% (95%CI 45.3%-78.5%) , 19.9% (95%CI 8.1%-31.7%) , and 28.6% (95%CI 0.0%-65.0%) (χ2=18.307, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. cGVHD was not associated with non-relapse morality after Chemo-DLI. Probabilities of 5-year leukemia-free survival (LFS) after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 77.2% (95%CI 60.8%-93.6%) , and 64.9% (95%CI 45.7%-84.1%) (χ2=24.447, P<0.001) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year LFS after Chemo-DLI were 24.0% (95%CI 9.1%-38.9%) , 75.5% (95%CI 62.7%-88.3%) , and 42.9% (95%CI 1.8%-84.0%) (χ2=25.665, P<0.001) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. Probabilities of 5-year overall survival (OS) after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 87.9% (95%CI 74.7%-100.0%) , and 71.0% (95%CI 52.0%-90.0%) (χ2=9.517, P=0.009) in non-cGVHD, mild to moderate cGVHD, and severe cGVHD groups, respectively. Probabilities of 5-year OS after Chemo-DLI were 50.0% (95%CI 31.1%-68.9%) , 83.9% (95%CI 72.8%-95.0%) , and 51.4% (95%CI 6.2%-96.6%) (χ2=10.673, P=0.005) in non-cGVHD, classical cGVHD, and overlap syndrome groups, respectively. In multivariate analysis, patients receiving allo-HSCT in first complete remission stage and classical cGVHD after Chemo-DLI were associated with lower relapse risk and better survival.@*Conclusions@#These findings highlight the close relation between cGVHD and the graft-versus-leukemia effect in patients who were MRD positive and received Chemo-DLI after allo-HSCT. However, overlap syndrome could not improve the clinical outcomes of these patients.

Treatment and clinical outcomes of patients relapsing after allogeneic hematopoietic cell transplantation for myelodysplastic syndrome

BACKGROUND: Although allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment option for myelodysplastic syndrome (MDS), a substantial number of patients experience relapse. We reviewed the clinical outcomes of patients with MDS who relapsed after allogeneic HCT. METHODS: Thirty patients who experienced relapse or progression after allogeneic HCT for MDS between July 2000 and May 2016 were included in this retrospective analysis. RESULTS: The median time from HCT to relapse was 6.6 (range, 0.9–136.3) months. Donor lymphocyte infusions (DLIs) were administered to four patients: one achieved complete remission (CR) and survived disease free, while three did not respond to DLI and died. Hypomethylating agents were administered to seven patients: one who had stable disease continuously received decitabine, while six died without response to treatment. Six patients received AML-like intensive chemotherapy, and three achieved CR: two underwent second HCT and one DLI. One patient receiving second HCT survived without disease, but the other two relapsed and died. Three, four, and eight patients who did not respond to intensive chemotherapy, low-dose cytarabine, and best supportive care, respectively, died. One patient who underwent second HCT following cytogenetic relapse survived disease free. Median overall survival after relapse was 4.4 months, and relapse within 6 months after HCT was associated with shorter survival. CONCLUSION: Outcomes of MDS patients relapsing after allogeneic HCT were disappointing. Some patients could be saved using DLI or second HCT.

Sorafenib combined with chemotherapy and donor lymphocyte infusion as salvage therapy in patients with FLT3-positive acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation / 中华内科杂志

To explore the efficacy of sorafenib combined with chemotherapy and donor lymphocyte infusion (DLI) in patients with FLT3-positive acute myeloid leukemia (AML) relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Of the 14 patients relapsed after allo-HSCT,9 achieved complete remission after salvage therapy of sorafenib combined with chemotherapy and DLI,6 with complete molecular remission,2 with partial remission,and 3 with no response.With a median follow up of 220 (range,30-1 782) days after post-transplantation relapse,7 patients were still alive and 7 died.Salvage therapy of sorafenib combined with chemotherapy and DLI shows a decent therapeutic effect for FLT3-positive AML relapsed after allo-HSCT.

Observation curative effect of FLAG combination G-DLI for relapse of AML after allogeneic hematopoietic stem cell transplantation / 重庆医学

Objective To observe clinical curative effect of the FLAG regimen combined donor lymphocyte infusion after granulocyte colony stimulating factor(G‐CSF) mobilization(G‐DLI) ,for the acute myeloid leukemia (AML) of allogeneic Peripheral blood hematopoietic stem cell trans‐plantation (allo‐HSCT) after recurrence of hematology .Methods For the patients with recur‐rence after allo‐HSCT ,giving the FLAG regimen chemotherapy when the WBC dropped to the lowest point ,followed by giving G‐DLI that infusion peripheral blood stem cell from the original donors ,to observe curative effect and survival situation .And searched the literature review through the PubMed etc .Results Through FLAG regimen combined G‐DLI ,3 cases of relapse after transplan‐tation again obtained complete remission (CR) .Case 1 :disease‐free survival (DFS) was 13 month and overall survival(OS) was 23 months after G‐DLI .The patient has been the central recurrence and remission in bone marrow ,he was dead after 23 months due to multipleorgan function failure .He occurred Ⅱ acute GVHD in Skin and Ⅰ acute GVHD in liver after G‐DLI and obtained effective control ,not chronic GVHD .Case 2 :DFS and OS were 12 months and 13 months ,as bone marrow relapse again and giving up treat‐ment ,so died a month later .Respectively ,he has limitations chronic GVHD in skin after G‐DLI .Case 3:DFS was 16 months after G‐DLI since the disease‐free survival ,had limitations GVHD in skin that was control for given small dose of immunosuppressive drugs .Conclusion Joint FLAG scheme and G‐DLI may be one of the effective treatment of postoperative recurrence of allo‐HSCT .

Allogeneic hematopoietic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasms / 白血病·淋巴瘤

Objective To investigate the effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with intensified conditioning regimen followed by rapidly tapering immunosuppressants and sequential minimal residual disease (MRD)-guided donor lymphocyte infusion (DLI) post-transplantation on outcome of blastic plasmacytoid dendritic cell neoplasm (BPDCN).Methods Two cases of BPDCN from January 2009 to May 2011 in Nanfang hospital were diagnosed according to 2008 WHO classification of tumours of haematopoietic and lymphoid tissues.Case 1 initially presented with typical cutaneous involvement and was promptly diagnosed with CD+4CD+56LCA+TdT+CD+43 BPDCN by skin biopsy.Case 2 was recognized as acute lymphocyte leukemia and acute non-lymphocytic leukemia,which was diagnosed to BPDCN at recurrence through flow cytometry analysis.Total-body-irradiation plus cyclophosphamide based intensified conditioning regimen were followed by allo-HSCT from sibling donor.Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate.Anti-thymocyteglobulin was included additionally for haploid donor allo-HSCT.Multi-color labeling flow cytometry was performed to monitor MRD.Rapidly tapering of prophylactic immunosuppressants and sequential MRD-guided donor lymphocyte infusion (DLI) were performed to control relapse of primary malignancy.Results Two cases of BPDCN received allo-HSCT from sibling donor after intensified conditioning regimen.Both patients achieved complete remission and complete donor engraftment.Case 1 survived refractory acyclovir-resistant Epstein-Barr virus viremia benefiting from preemptive treatment with rituximab and DLI-induced grade Ⅳ acute GVHD,but died of thrombotic microangiopathy mixed with diffuse alveolar hemorrhage and sepsis on +243 days.Case 2 relapsed just 2 months after allo-HSCT despite DLI and rapidly tapering of CsA,died of sepsis followed by diffuse intravascular coagulation on +101 days.Conclusion BPDCN is characterized with typical cutaneous and/or bone marrow involvement with CD4+CD+56CD+123CD+43 blastic plasmacytoid dendritic cell and highly aggressive clinical course.Allo-HSCT seems to be a promising treatment for early phase of aggressive BPDCN aided with MRD monitoring and DLI,but it deserves more intensive researches to promote outcome of advanced staged BPDCN.

The efficacy and safety of donor lymphocyte infusion to treat Epstein-Barr virus associated lymphoproliferative diseases after allogeneic hematopoietic stem cell transplantation / 中华内科杂志

Objective To analyse our series patients' data to assess its efficacy and safety of donor lymphocyte infusion (DLI) for Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorders (PTLD) after allogeneic hematopoietic stem cell transplantation (HSCT). Methods Patients received HSCT from November 2006 to November 2009 and diagnosed as EBV associated PTLD by pathological or clinical methods were enrolled in this study. Lymphocyte was prepared by COBE collector.Related haplo-donors were the alternative if the original donors was unavailable. A range of mononuclear cell (MNC) dose of (0.5-1.0) × 108/kg was designed and the expected number of T lymphocyte included was at level of 107/kg. Cyclosporine (CsA) trough concentration was kept in a therapeutic level. Results Nine patients with PTLD received DLI 13 times, the median number of PBMC infused was 0.8 (0.16-1.03) ×108/kg, CD3+T cell number was 4.2 (1.6-5.7) × 107/kg. Seven patients received peripheral blood mononuclear cells (PBMC) from original haplo-identical donors, with 7 response and 6 complete remission.Defervescence occurred after 2 ( 1-5 ) d, and adenopathy began to recover in 6 ( 1-14 ) d after the initial infusion of leukocytes. Graft versus host diseases (GVHD) occurred in 6 recipients out of 7 evaluable patients, and all were controlled successfully. Three patients survived for 38, 23 and 3 months after PTLD.Conclusion In this small series cases, infusion of controlled dose of lymphocyte from primary donor is an effective and safe therapy for EBV associated PTLD after mismatched/haploidentical HSCT while the optimal regimen needs to be further studied.

Influence of intra-bone marrow injection of donor lymphocytes upon the development of graft-versus-host disease / 中国免疫学杂志

Objective:To investigate the effect of donor lymphocyte infusion (DLI) by intra-bone marrow (IBM) or intravenous (IV) on the incidence of graft-versus-host disease(GVHD) after allogeneic peripheral hematopoietic stem cell transplantation (allo-PBSCT).Methods:Female C57BL/6 mice as recipients received total body irradiation (TBI) on day 0,followed by injection of peripheral hematopoietic stem cells from mobilized male BALB/c with granulocyte-colony stimulating factor (rhG-CSF),and DLI was performed via IV or IBM.The extent of GVHD was compared in recipients received allogeneic IBM-DLI with those received IV-DLI.The percentage of donor-derived cells and CD4~+CD25~+ regulatory T cells (Tregs) was detected by flow cytometry.14 days after DLI,the levels of IL-4 and interferon (IFN)-γ were tested by ELISA.Results:It was found that the frequency and severity of GVHD were reduced in IBM-DLI compared with that of IV-DLI (P＜0.01).7 days after transplantation,the percentage of H-2~d-positive cells was over 95% in all surviving transplanted mice;and 14 days after transplantation,the percentage of Tregs detected as CD4~+CD25~+ was significantly higher in recipients treated with IBM-DLI than those treated with IV-DLI(P＜0.01).Compared with that of the recipients in IBM-DLI group,the level of IL-4 was significantly decreased,while the level of IFN-γ were elevated in group IV-DLI (P＜0.01).Conclusion:IBM-DLI could induce the proliferation of Tregs and the Th polarizing to Th2,resulting in decreasing the incidence and alleviating severity of GVHD after allo-PBSCT.

Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia / Infusão de linfócitos do doador para o tratamento da doença residual mínima

Minimal residual disease (MRD) was monitored in 80 patients with acute lymphoid (ALL, n=44) or myeloid (AML, n=36) leukemia, undergoing allogeneic haemopoietic stem cell transplantations. MRD markers were IgH-VDJ and TCR gene re-arrangement for ALL, and Wilm's Tumor (WT1) expression for AML. The overall cumulative incidence (CI) of MRD was positive in 45 percent and the CI of hematologic relapse was 24 percent (36 percent in MRD+ vs. 16 percent in MRD patients, p=0.03). The median interval from transplant to first MRD positivity was 120 days and to hematologic relapse 203 days. Patients were divided in 3 MRD groups: MRD (n=44), MRD+ given donor lymphocyte infusions (DLI) (n=17) and MRD+ not given DLI (n=19): leukemia relapse rates in these 3 groups were 16 percent, 6 percent and 63 percent, respectively (p<0.0001); the actuarial 3-year survival rates were 78 percent, 80 percent and 26 percent (p=0.001). In multivariate COX analysis, the MRD group was predictor of relapse (p<0.0001) and survival (p=0.01), together with disease phase and chronic graft versus host disease. In MRD+ patients, DLI protected against relapse (p=0.003) and improved survival (p=0.01). In conclusion, MRD positivity post-transplant predicts leukemia relapse: however, when MRD+ patients are given DLI, their outcomes are comparable to MRD- patients.

A doença residual mínima (DRM) foi monitorada em 80 pacientes com leucemia linfóide aguda (n=44) e mielóide aguda (n=36) que foram submetidos ao transplante alogênico de célula-tronco. Marcadores da DRM foram a IgH-VDJ e rearranjo do TCR para a LLA e expressão do Tumor de Wills (WT1) para LMA. A incidência acumulada global (IC) para a DRM foi positiva em 45 por cento e a IC para recaída hematológica foi 24 por cento (36 por cento na DRM+ versus 16 por cento na DRM-, p=0.03). O intervalo mediano entre o TMO e a primeira DRM positividade foi dia +120, e para a recaída hematológica, dia +203. Os pacientes puderam ser divididos em três grupos: DRM-(n=44), DRM+ onde foi dada a infusão de linfócitos do doador (ILD) (n=17) e DRM+ não dado ILD (n=19): a recidiva nos três grupos foi de 16 por cento, 6 por cento e 63 por cento, respectivamente (p<0.0001); a sobrevida em três anos foi 78 por cento, 80 por cento e 26 por cento (p=0.001). No modelo de Cox, o grupo de DRM foi preditor de recidiva (p<0.0001) e sobrevida global (p=0.01), juntamente com a fase da doença e a doença do enxerto contra o hospedeiro. Na DRM+, IDL protegeu contra a recidiva (p=0.003) e melhorou a sobrevida (p=0.01). Em conclusão, a positividade para a DRM pós-transplante prediz recidiva da leucemia. Entretanto, quando é dada a ILD ao paciente DRM+, a evolução destes pacientes é comparável aos pacientes DRM-.

Influência do imatinibe no resultado do TMO e sua eficácia no tratamento da recaída / The effect of prior exposure to imatinib on transplant outcomes and its effectiveness for relapse treatment

O mesilato de imatinibe (MI) tornou-se o tratamento de primeira linha para os pacientes com leucemia mielóide crônica (LMC). O transplante de células-tronco hematopoiéticas (TCTH) alogênico tem sido utilizado como tratamento de salvamento para os pacientes que são intolerantes ao MI, falham na obtenção da resposta citogenética completa (RCC) ou recidivam. A primeira parte desta revisão discutirá a influência do uso do MI pré-transplante nos resultados do transplante e o impacto da resposta subótima, ou perda da resposta, na sobrevida após o transplante, nos pacientes em fase crônica. A segunda parte discutirá o manejo da recidiva pós-transplante. A infusão de linfócitos (DLI) tornou-se o tratamento de escolha para os pacientes que recidivam após o TCTH. A resposta ao DLI é dose dependente e a dose de células efetivas é influenciada pela quantidade, pela fase da recidiva e pelo grau de histocompatibilidade entre doador e receptor. O MI é agora uma alternativa ao DLI para a obtenção da remissão, sem o risco da doença do enxerto contra o hospedeiro (DECH), e pode ser efetivo quando o DLI for ineficaz. O MI pode também ser utilizado em combinação com o DLI para aumentar as respostas. O MI é seguro e bem tolerado em combinação com o DLI. Os pacientes atingem a resposta molecular completa mais rápida, são capazes de parar o MI sem apresentar recidiva molecular e a sobrevida livre de doença é maior.

Imatinib mesylate (IM) has become the first-line therapy for chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly chosen as salvage therapy for patients who are intolerant of IM, fail to achieve a complete cytogenetic response (CCR) or relapse. The first part of this review will discuss the effect of prior exposure to IM on transplant outcomes and the impact of a poor or a loss of response at the time of transplantation on post-transplantation survival of patients who underwent transplantation in a chronic phase (CP). The second part will discuss the management of relapse disease after transplant. Donor lymphocyte infusion (DLI) has become the treatment of choice for patients who relapse. The response to DLI is dose-dependent and the effective cell dose is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility. IM is now an alternative to DLI as it can be used to achieve remission without graft-versus-host disease and may be effective when DLI has failed. It can also be used in combination with lower doses of DLI to maximize responses. IM is safe and well tolerated in combination with DLI, patients achieve molecular response more rapidly, are able to stop IM without recurrence of molecular disease and this treatment has a higher disease free survival rate after transplantation.

Donor Lymphocyte Infusions for Patients with Relapsed Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: a 10-year Experience of Seoul National University Hospital

BACKGROUND: Donor lymphocyte infusion (DLI) has been established as a salvage therapy for patients with relapsed leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). However, its benefit can be limited by the development of graft-versus-host disease (GVHD) or marrow aplasia. METHODS: We retrospectively analyzed the data from 39 patients that received DLI for relapsed leukemia after HLA-matched, related HSCT between 1995 and 2005 at Seoul National University Hospital. RESULTS: The diagnoses were CML (n=8), AML (n=19) and ALL (n=12). Ten patients had received non- myeloablative HSCT (AML=9, ALL=1). Complete remission after DLI was achieved in 6 (75%) cases with CML, 5 cases (29%) with AML and 5 cases (41%) with ALL. The two-year progression-free survival was 60% in CML patients, but 8.1% in non-CML patients (P=0.01). In addition, better overall survival (OS) was shown in CML patients than in non-CML patients (2-year OS, 68% in CML; 10% in non-CML, P=0.01). The durable remission for more than three years after DLI was confirmed in five patients (one AML patient for 88 months, one ALL patient for 54 months, three CML patients for 38, 47 and 53 months). Acute GVHD (> or =Grade II) developed in 14 patients (35.9%). Prolonged marrow aplasia (neutrophil count <500/micro L, platelet count <20,000/micro L) developed in fourpatients (10.3%). CONCLUSION: DLI was the effective salvage therapy for relapsed CML after allogeneic HSCT, whereas limited effects were shown for AML and ALL with durable remission in only a few patients.

Effect of Donor Lymphocyte Infusion for a Patient with Isolated Knee Joint Relapse of Acute Lymphoblastic Leukemia after Allogeneic Bone Marrow Transplantation / 대한혈액학회지

Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT) in the absence of marrow involvement is a rare event, and the mechanisms underlying the selective involvement of extramedullary sites remain undefined. These might be due to relapse in sanctuary sites where the leukemic cells are resistant to preparative regimen, or a stronger graft-versus-leukemia effect in the marrow as compared with peripheral tissues. We report an adult ALL patient who experienced isolated extramedullary relapse in the right pretibial soft tissue and knee joint 42 months after allogeneic BMT. He was treated with localized radiotherapy followed by systemic chemotherapy and donor lymphocyte infusion. After treatment, he is currently well with no evidence of leukemia recurrence for 12 months.

A Case of DNA Chimerism Analysis as a Marker of Donor Lymphocyte Infusion / 대한혈액학회지

Donor lymphocyte infusion (DLI) has some benefit effects as graft-versus-leukemia effect, reducing the relapse of leukemia and inducing of a complete remission. But it has also a graft-versus-host-disease (GVHD) effect. So it is required a proper marker test when DLI is performing. The DNA chimerism analysis can be a marker test in DLI. Variable number of tandem repeats (VNTR) are highly polymorphic DNA markers in the human genomic DNA and used as primers of DNA chimerism analysis. A 43-year-old male who had been diagnosed acute myelogenous leukemia was transplanted with allogeneic peripheral blood stem cells. The initial chimerism analysis showed complete chimerism but it changed to mixed chimerism after 7 months of transplantation. We predicted the relapse of leukemia and performed DLI. The patient could obtain the complete chimerism after DLI. We report a case of chimerism analysis which was useful to predict the relapse of leukemia and perform the DLI.

Allogeneic Peripheral Blood Stem Cell Transplantation with Stepwise Donor Lymphocyte Infusions in Mantle Cell Lymphoma Relapsed after Autologous PBSCT / 대한혈액학회지

Mantle cell lymphoma (MCL) is a distinctive clinicopathologic entity and represents 5~10% of all non-Hodgkin's Lymphoma (NHL). The median survival of patients with MCL is only 3 years, and none of the available conventional chemotherapy regimens appear curative. Encouraging results have been reported with high dose chemotherapy with stem cell transplantation for its treatment. Particularly, alloSCT appears to induce durable remission via graft-versus-lymphoma (GVL) effect. Donor lymphocyte infusions (DLIs), by virtue of graft-versus-tumor effect, have been shown to induce remissions in leukemia that recurs after alloSCT. But GVL effect of DLI has not been clearly established in NHL. We describe a patient with relapsed MCL shortly after high dose chemotherapy with autoSCT who was successfully treated with alloPBSCT. The patient presented with diffuse GI and spleeninvolvement at the time of alloPBSCT. The patient received Bu/Cy/VP-16 as preparative regimen followed by alloPBSCT. The patient received cyclosporin and methotrexate as GVHD prophylaxis. Prednisone was added after grade II GVHD. The patient had partial response by D+64. To enhance GVL effect, the patient received G-CSF primed DLI serially at D+64 and D+92. Grade IV GVHD developed 19 days after 2nd DLI and was partially controlled with a combination of cyclosporin, prednisone and mycophenolate mofetil. Clinical complete remission was observed at D+112, and maintained till last follow-up day (D+515). Our findings suggest that alloSCT and stepwise DLIs may offer a curative approach to MCL.