Prevention and treatment of high-risk acute myeloid leukemia recurrence after allogeneic hematopoietic stem cell transplantation / 器官移植

Acute myeloid leukemia (AML) is a group of highly-heterogeneous clonal diseases. Chemotherapy and hematopoietic stem cell transplantation are considered as effective treatment for AML. For high-risk AML patients, allogeneic hematopoietic stem cell transplantation is an effective therapeutic option. However, some AML patients may still face the problem of disease recurrence after hematopoietic stem cell transplantation. A majority of recurrent patients cannot be effectively treated by chemotherapy or secondary transplantation, which is the main cause of death after allogeneic hematopoietic stem cell transplantation. Therefore, it is of significance to strengthen follow-up of AML patients after allogeneic hematopoietic stem cell transplantation and implement appropriate measures to prevent postoperative recurrence. In this article, the monitoring, drug prevention and cell therapy of recurrence after allogeneic hematopoietic stem cell transplantation in high-risk AML patients were reviewed, aiming to provide reference for improving clinical prognosis of high-risk AML patients undergoing allogeneic hematopoietic stem cell transplantation.

Predictive Role of Circulating Immune Cell Subtypes Early after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia

BACKGROUND AND OBJECTIVES: Cells of innate immunity normally recover in the first weeks to months after allogenenic hematopoietic stem cell transplantation (allo-HSCT). Their relevance in terms of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect is largely unknown. The predictive role of early recovery in the immune cells on acute GVHD and GVL effect after allo-HSCT was investigated in patients with acute leukemia who achieved the first complete remission. METHODS: Peripheral blood samples were taken at the median of 14 days (range, 12~29 days) after allo-HSCT. A cohort including 119 samples and characteristics of patients were analyzed. Immune cell populations were identified by flow cytometry. RESULTS: The median age was 49.0 years (range, 21~69) at transplantation. Univariate analysis showed that age less than 40 years old, lower frequencies of CD8+ T cells, invariant natural killer T (iNKT) cells, monocytic myeloid derived suppressor cells (M-MDSCs) and higher frequency of immature MDSCs were associated with occurrence of grade III–IV acute GVHD. Multivariate analyses showed that iNKT cells (hazard ratio (HR), 0.453, 95% CI, 0.091~0.844, p=0.024) and M-MDSCs (HR, 0.271, 95% CI, 0.078~0.937, p=0.039) were independent factors. Combination of higher frequencies of both cell subsets was associated with lower incidence of grade III–IV acute GVHD, whereas patients with lower frequency of iNKT cells and higher frequency of M-MDSCs showed significant higher probability of relapse. CONCLUSIONS: iNKT cells and M-MDSCs could be relevant cell biomarkers for predicting acute GVHD and/or relapse in acute leukemia patients treated with allo-HSCT.

Balance of ruxolitinib to anti-GVHD and GVL effect after allo-HSCT / 中华器官移植杂志

Objective To observe the anti-relapse and anti-graft versus host disease (GVHD) effects and side effects of ruxolitinib on patients who have relapsed leukemia after allo-hematopoietic stem cell transplantation (HSCT).Methods The clinical data of four patients sufferring from relapsed leukemia were collected and analyzed retrospectively.Three cases had a positive gene and 1 case had a extramedullary recurrence.All of them had serious GVHD involving multiparts,as the result of attenuating immunosuppressant aggressively.One case had central nervous system leukemia before allo-HSCT.Those patients were treated with ruxolitinib,according to the degree of GVHD,the treatment strategy and curative effect of GVHD,and the residual condition of original leukemia.Then,the degree of GVHD,the residual condition of original leukemia and the side effects of ruxolitinib were revaluated once a month after taking ruxolitinib.Results One case achieved completer remission (CR) and there partial remission (PR) in consideration of GVHD.Up to date,2 cases had no relapse in any level and 2 cases replased according to any of the results related to bone marrow aspiration.Conclusion Ruxolitinib is effective in patients with GVHD after allo-HSCT and doesn't influence GVL effect or increase the risk of relapse at the same time.Ruxolitinib doesn't have obvious side effects when treating GVHD.

Immunotherapy with natural killer cells: a possible approach for the treatment of Acute Myeloid Leukemia also in Brazil / Imunoterapia com células natural killer: um caminho possível para o tratamento da Leucemia Mielóide Aguda também no Brasil

SUMMARY The allogeneic hematopoietic stem cell transplantation (HSCT) can cure intermediate and high-risk acute myeloid leukemia. Even with the development of strategies to reduce HSCT toxicity, this is still a complex treatment with high morbidity and mortality. Knowledge of the graft versus leukemia effect of HSCT has prepared the way for the development of Adoptive Immunotherapy or in vitro expansion of activated lymphocytes without alloreactivity, with subsequent intravenous infusion. The infusion of genetically modified T lymphocytes and haploidentical natural killer cells has been tested as an alternative to HSCT with very interesting results worldwide and in Brazil, as we not only have the technology of in vitro expansion of clinical grade lymphocytes available, but also do it according to the Good Manufacturing Practices that have been determined internationally.

RESUMO O transplante de células-tronco hematopoéticas (TCTH) alogênico é curativo para leucemia mielóide aguda de risco intermediário e alto. Mesmo com o desenvolvimento de estratégias para minorar a toxicidade do TCTH, este ainda é um tratamento complexo com elevada morbi-mortalidade. O conhecimento sobre o efeito enxerto contra leukemia do TCTH pavimentou o caminho para o desenvolvimento da Imunoterapia Adotiva ou expansão in vitro de linfócitos ativados, sem alo-reatividade, com posterior infusão endovenosa. A infusão de Linfócitos T geneticamente modificados e de células Natural Killer haploidenticas tem sido testada como alternativa ao TCTH com resultados bastante interessantes no mundo e no Brazil já que não apenas dominamos a tecnologia de expansão in vitro de linfócitos em grau clínico, como o fazemos segundo as Boas Práticas de Manufatura determinadas internacionalmente.

Influence of the lentiviral vectors-mediated mouse genetic engineering Treg on GVHD and GVL effect after allogeneic bone marrow transplantation in mice / 中华器官移植杂志

Objective To explore the influence of the lentiviral vectors-mediated mouse genetic engineering regulatory T cells (Treg) infused after allogeneic bone marrow transplantation (alloBMT) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect in mice.Methods Lentivirus-mediated expression of Forkhead box P3 (Foxp3) transformed CD4 + CD25- T cells from Balb/c mice into engineered Tregs in vitro. An allo-BMT model of Balb/c→C57BL/6 mice was established. The recipients were given lethal X-ray total body irradiation before transplantation.Mice were randomly assigned into five groups and each group contained 10 recipients: (1) The recipients in radiation group were injected with 0.2 ml RPMI 1640; (2) The recipients in leukemia control group were injected with 5 × 106 donor bone marrow cells and 500 mouse T-cell leukemia/lymphoma cells (EL4 cells); (3) The recipients in transplantation control group were injected with 5 × 106 donor bone marrow cells and 5 × 106 splenocytes plus 500 EL4 cells; (4) The recipients in engineering Treg group were injected with 5 × 106 donor bone marrow cells, 5 × 106 splenocytes and 500 EL4 cells plus 5 × 106 genetic engineering Treg; (5) The recipients in empty vector control group were injected with 5 × 106 donor bone marrow cells, 5 × 106 splenocytes and 500 EL4 cells plus 5 × 106 empty vector-transduced CD4+ CD25- T cells. Survival time, clinical GVHD score or histopathological analysis (skin, liver and small intestine) were observed after allo-BMT. Chimerism of bone marrow cells from recipients survived for 60 days after transplantation was measured. Results The mean survival time in radiation group, leukemia control group, transplantation control group,engineering Treg group and empty vector control group was ( 10. 3 ± 1.5), (20. 7 ± 1.9), (26. 0 ±4.3), (49. 0 ± 17. 7) and (24. 4 ± 4. 1 ) days respectively. The survival time in engineering Treg group was significantly prolonged as compared with other groups as judged by the log-rank test (P＜0. 05).Histopathological analysis in several target organs (skin, liver and small intestine) confirmed the presence of severe GVHD in transplantation control group and empty vector control group. No histological signs of GVHD or leukemia were observed in recipients in engineering Treg group and clinical GVHD scores in this group were significantly decreased as compared with transplantation control group and empty vector control group. Conclusion Co-injection of genetic engineering Treg can efficiently prevent recipients from lethal GVHD without affecting GVL activity during allo-BMT in mice.

Graft-versus-Leukemia Effect of Nonmyeloablative Stem Cell Transplantation

Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies and those with various complications who are not suitable for conventional myeloablative stem cell transplantation (CST). Various conditioning regimens differ in their myeloablative and immunosuppressive intensity. Regardless of the type of conditioning regimen, graft-versus- host disease (GVHD) in NST occurs almost equally in CST, although a slightly delayed development of acute GVHD is observed in NST. Although graft-versus-hematological malignancy effects (i.e., graft-versus-leukemia effect, graft-versus-lymphoma effect, and graft-versus-myeloma effect) also occur in NST, completely eradicating residual malignant cells through allogeneic immune responses is insufficient in cases with rapidly growing disease or uncontrolled progressive disease. Donor lymphocyte infusion (DLI) is sometimes combined to support engraftment and to augment the graft-versus-hematological malignancy effect, such as the graft-versus-leukemia effect. DLI is especially effective for controlling relapse in the chronic phase of chronic myelogenous leukemia, but not so effective against other diseases. Indeed, NST is a beneficial procedure for expanding the opportunity of allogeneic hematopoietic stem cell transplantation to many patients with hematological malignancies. However, a more sophisticated improvement in separating graft-versus-hematological malignancy effects from GVHD is required in the future.

Enhancement of Graft-versus-leukemia Effects by Mesenchymal Stem Cells in Mixed Chimerisim after a Murine Non-myeloablative Hematopoietic Stem Cell Transplantation / 대한혈액학회지

BACKGROUND: Mesenchymal stem cells (MSCs) may be useful for reducing graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The GVHD and a graft-versus-leukemia (GVL) effect are inversely related. We therefore wanted to determine whether MSCs can preserve the GVL effect following experimental allo-HSCT. METHODS: After non-myeloablative allogeneic hematopoietic stem cell transplantation (NM-HSCT) using C57BL/6 (H-2b)-->B6D2F1 (H-2b/d), some mice received donor lymphocyte infusion (DLI) for induction of GVL effects by virtue of complete chimerism (CC), while the other groups did not receive DLI with persistence of mixed chimerism (MC). All mice were inoculated subcutaneously with P815 tumor cells and were intravenously treated with either donor MSCs or diluents. RESULTS: Between the DLI-treated groups with CC, tumor-related deaths and tumor growths were comparable irrespective to the infusion of MSCs. On the contrary, among mice without DLI which showed MC, the administration of MSCs significantly delayed tumor-related deaths compared to those without the administration of MSCs (50-day percent survival, 54.5% vs. 18.1%, P=0.0225). In the MC animals, tumor growth seemed to be more delayed in the mice injected with MSCs than in the controls (P=0.09). Donor MSCs injection was associated with increased donor effector/memory CD62L- T cells in MC but not in CC. CONCLUSION: In spite of the observed immunosuppressive effects of donor MSCs, our results indicate that the GVL effects were not influenced by the injection of MSCs but that under a given condition such as MC, the injection of donor MSCs could result in enhanced GVL effects.

Allogeneic Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia / 소아과

PURPOSE: The purpose of this study was to evaluate the outcome of children with juvenile myelomonocytic leukemia(JMML) treated with allogeneic hematopoietic stem cell transplantation(allo- HSCT). METHODS: Eleven JMML patients aged 8-39 months underwent allo-HSCT. The sources of grafts were unrelated donors(n=7), HLA-matched siblings(n=3) and an HLA 1-antigen mismatched familial donor. All patients had received chemotherapy +/- 13-cis-retinoic acid(CRA) before transplant, and CRA was used, posttransplant, in six patients. RESULTS: Only three patients were in complete remission(CR) at the time of transplantation. Initial chimeric status revealed complete donor chimerism(CC) in five patients, mixed chimerism(MC) in five and autologous recovery(AR) in one. One patient with MC having persistent splenomegaly eventually turned to CC and CR after rapid tapering of cyclosporine, combined with daily use of CRA. An AR case relapsed shortly after transplant but was rescued with second, unrelated cord blood transplantation. Ultimately, six patients are alive, event-free, with a median follow-up of 15.5 months posttransplant. All three deaths occurred in patients who failed to achieve CC, leading to disease progression. CONCLUSION: We suggest that graft-versus-leukemia effect play an important role and CRA a possible role in posttransplant leukemic involution in JMML. In patients whose leukemic burden is still high with MC after transplant, early tapering of immunosuppressants and introduction of CRA might provide a chance of a cure for some patients.

Nonmyeloablative stem cell transplantation / 영남의대학술지

Allogenic hematopoietic stem cell transplantation is one of the effective therapy for several hematologic malignancies. Transplantation preparative regimen is designed to eradicate the patient's underlying disease and immunosuppress the patient adequately to prevent rejection of donor's hematopoietic stem cells. so, Conventional myeloablative preparative regimens with high-dose chemotherapy or radiotherapy are related to high rate of morbidity and mortality. however, It has become clear that the high-dose therapy dose not eradicate the malignancy in some patients, and that the therapeutic benefit of allogenic transplantation is largely related to graft-versus-leukemia/graft-versus-tumor (GVL/GVT) effect. An new approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow GVL/GVT effects to developed. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly and those with comorbidities that preclude high-dose chemoradiotherapy.

Nonmyeloablative stem cell transplantation / 영남의대학술지

Allogenic hematopoietic stem cell transplantation is one of the effective therapy for several hematologic malignancies. Transplantation preparative regimen is designed to eradicate the patient's underlying disease and immunosuppress the patient adequately to prevent rejection of donor's hematopoietic stem cells. so, Conventional myeloablative preparative regimens with high-dose chemotherapy or radiotherapy are related to high rate of morbidity and mortality. however, It has become clear that the high-dose therapy dose not eradicate the malignancy in some patients, and that the therapeutic benefit of allogenic transplantation is largely related to graft-versus-leukemia/graft-versus-tumor (GVL/GVT) effect. An new approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow GVL/GVT effects to developed. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly and those with comorbidities that preclude high-dose chemoradiotherapy.

The Effect of Bone Marrow Mesenchymal Stem Cells on Graft Versus Host Disease and Survival Rate After Allogeneic Bone Marrow Transplantation / 中国医师杂志

Objective To observe the effect of bone marrow mesenchymal stem cells (BMMSC) on graft versus host disease (GVHD) and survival rate after allogenic bone marrow transplantation (allo-BMT) in acute lymphocytic leukemia (ALL) mice. Methods In the experimental group, both bone marrow cells and BMMSC obtained from donor mice were transplanted into the recipient mice injected with leukemia cells five days ago, and in the control group, the mice was injected with bone marrow cells alone. The impact of BMMSC on the quantity of CD 4 + and CD 8 + T cells after allo-BMT was evaluated by flow cytometry. The general manifestation and pathological changes of GVHD were observed. The survival time of recipient mice was recorded. Results BMMSC could decrease the quantity of CD 4 + T cells, increase CD 8 + T cells number, delay GVHD, and obviously increase the survival time in the mice treated with allo-BMT(P

Clinical Analysis of Allogeneic Bone Marrow Transplantation at Tsuchiura Kyodo General Hospital / 日本農村医学会雑誌

Recently, allogeneic bone marrow transplantation (allo-BMT) has been established for the treatment of hematological disorders. Fifteen patients had recieved allo-BMT at Tsuchiura Kyodo General Hospital as of April 1999. In this paper, we analyzedthe results and the problems of allo-BMT at our institution. The mean age of patients was 29.2years. Seven patients had AML, 5 ALL, 1 CML, 1 non-Hodgkin's lymphoma and one had severe aplastic anemia. Bone marrow donors were all HLA-identical siblings. Most of the patients were conditioned with a combination of busulfan or totalbody irradiation, cyclophosphamide and etoposide. To prevent GVHD, cyclosporine A and methotrexate were mainly used. Patients with acute GVHD were 4 and patients with chronic GVHD were only two. Three grade I patients with acute GVHD and all with chronic GVHD did not require therapy. In spite of small numbers of transfused cells, no cases of transplant rejection were found. All these engrafted patients achieved a WBC≥1×10<SUP>3</SUP>μl after a median of 19.5days and a Plt≥5×10<SUP>4</SUP>/μEl after a median of 38.1days. Five of the 14 engrafted patient relapsed in a median of 6.7months and all died in a median of 9.6months. Eight are alive in complete remission for 0.2 to 39.4 months (median 21.7months). For the improvement of the disease-free survival rate after allo-BMT, the prevention of relapse and prophylaxis of GVHD and infection are important. At our institution, especially the former is important. The conditioning regimens were stronger than usual but acute and chronic GVHD was very mild, therefore GVL would be weak. If prophylaxis of GVHD is weaken and mild GVHD ans GVL occur frequently, relapse will be prevented and better results will be obtained.

Donor Leukocyte Infusion as Treatment for Relapsed Leukemia after Allogeneic Bone Marrow Transplantation : Graft-versus-Leukemia Effect / 대한혈액학회지

BACKGROUND: Donor leukocyte infusion (DLI) is an effective therapy for patients who relapse with leukemia after allogeneic bone marrow transplantation (BMT). This is due to the fact that the immune reactivity of infused allogeneic lymphocytes on relapsed leukemia cells plays a major role in the control of leukemia. However, severe graft-versus-host disease (GVHD) and pancytopenia compromise the success of this treatment in a substantial number of patients. METHODS: To evaluate the effect of DLI, we surveyed 6 BMT centers regarding their use of DLI for relapsed leukemia after BMT. Detailed forms were used to gather data regarding the original BMT, relapse, response to DLI, complication and survival. Reports of 11 patients were consequently available for analysis. RESULTS: Five (83.3%) of 6 patients with chronic myeloid leukemia (CML) achieved complete remission (CR) [time-to-CR; 116 (27~180) days after DLI], and currently 4 are alive in CR (49~436 days). Five patients (83.3%) developed GVHD, and 2 developed pancytopenia which was related to DLI. In acute leukemia, all patients received salvage chemotherapy prior to DLI. Only 1 of 3 patients with acute lymphoblastic leukemia (ALL) who had early relapse achieved CR, but durable remission was not yet confirmed (62+ days). Both 2 patients with acute myeloid leukemia (AML) achieved CR, and their CR durations were 242+ and 326 days after DLI, respectively. CONCLUSION: This study demonstrates that DLI can exert considerable effects against myeloid forms of leukemia, especially in CML. Further investigations of separating GVHD from the graft- versus-leukemia effect and finding more effective anti-leukemia approaches on acute leukemiaare necessary to improve the current DLI limitations.

Influence of interleukin-11 on graft versus host disease and graft versus leukemia after allogenic bone marrow transplantation in acute lymphoblastic leukemic junior rats / 实用儿科临床杂志

Objective To study the influence of interleukin-11 (IL-11) on graft versus host disease(GVHD) and graft versus leukemia(GVL) after allogenic bone marrow transplantation and related mechanism in acute lymphoblastic leukemic(ALL) junior mice.Methods The impact of IL-11 on CD4 and CD8 T cell after transplantation was evaluated by flow cytometry;it was observed that the GVHD pathology chance of internal after transplatation in ALL junior mice;the survial time after transplantantion was recorded;the level of tumor necrosis factor-?(TNF-?) which evidently related to GVHD was evaluated by ELISA.Results IL-11 could decrease the quantity of CD4 T cell and increase CD8 T cell;IL-11 could obviously increase the survival time and decrease the level of TNF-?. After ALL junior mice transplatated,IL-11 could delay and relieve GVHD.Conclusion IL-11 can alleviate GVHD and retain the effect of GVL after allogenic bone marrow transplantation.