Second allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and donor changes in relapsed hematological malignancies after the first allogeneic transplant / 中华血液学杂志

Objective: The purpose of this study was to assess the safety and efficacy of a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced-intensity conditioning (RIC) in patients with hematological malignancies who had relapsed after the first allo-HSCT. Methods: Between April 2018 and June 2021, 44 patients with hematological malignancies (B-ALL 23, T-ALL/T-LBL 4, AML15, and MDS 2) were enrolled and retrospectively examined. Unrelated donors (n=12) or haploidentical donors (n=32) were used. Donors were replaced in all patients for the second allo-HSCT. Hematological and immunological germline predisposition genes and hematopoietic and immune function tests were used to select the best-related donor. Total body irradiation (TBI) /fludarabine (FLU) -based (n=38), busulfan (BU) /FLU-based (n=4), total marrow irradiation (TMI) /FLU-based (n=1), and BU/cladribine-based (n=1) were the RIC regimens used. For graft versus host disease (GVHD) prevention, cyclosporine, mycophenolate mofetil, short-term methotrexate, and ATG were used. Eighteen (40.9%) of 44 patients with gene variations for which targeted medications are available underwent post-transplant maintenance therapy. Results: The median age was 25 years old (range: 7-55). The median interval between the first and second HSCT was 19.5 months (range: 6-77). Before the second allo-HSCT, 33 (75%) of the patients were in complete remission (CR), whereas 11 (25%) were not. All patients had long-term engraftment. The grade Ⅱ-Ⅳ GVHD and severe acute GVHD rates were 20.5% and 9.1%, respectively. Chronic GVHD was found in 20.5% of limited patterns and 22.7% of severe patterns. CMV and EBV reactivation rates were 29.5% and 6.8%, respectively. Hemorrhage cystitis occurred in 15.9% of cases, grade Ⅰ or Ⅱ. The 1-yr disease-free survival (DFS), overall survival (OS), and cumulative recurrence incidence (RI) rates of all patients were 72.5% (95% CI, 54.5%-84.3%), 80.6% (95% CI, 63.4%-90.3%), and 25.1% (95% CI, 13.7%-43.2%), respectively, with a median follow-up of 14 (2-39) months. There were eight deaths (seven relapses and one infection). The rate of non-relapse mortality (NRM) was only 2.3%. The CR patients' 1-yr RI rate was significantly lower than the NR patients (16.8% vs 48.1%, P=0.026). The DFS rate in CR patients was greater than in NR patients, although there was no statistical difference (79.9% vs 51.9%, P=0.072). Univariate analysis revealed that CR before the second allo-HSCT was an important prognostic factor. Conclusion: With our RIC regimens, donor change, and post-transplant maintenance therapy, the second allo-HSCT in relapsed hematological malignancies after the first allo-HSCT is a safe and effective treatment with high OS and DFS and low NRM and relapse rate. The most important factor influencing the prognosis of the second allo-HSCT is the patient's illness condition before the transplant.

Allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders

BACKGROUND: The role of allogeneic hematopoietic stem cell transplantation for advanced indolent lymphoproliferative disorders remains to be established. OBJECTIVE: This paper aims to describe the results of allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders. METHODS: This article reports on 29 adult patients submitted to allogeneic transplantations from 1997 to 2010. RESULTS: Most had follicular non-Hodgkin lymphoma (n = 14) or chronic lymphocytic leukemia (n = 12). The median age was 44 years (range: 24-53 years) and 65% of patients were male. Only 21% had had access to rituximab and 45% to fludarabine. All had advanced disease (stage IV) with partial response or stable disease. Most underwent myeloablative conditioning n = 17 - 59%). In this scenario, refractory disease was observed in seven (24%) patients, the 100-day mortality rate was 17% (n = 5) and relapse occurred in four patients (18%). The main cause of death throughout the follow up was refractory disease in six of the 12 patients who died. Moderate and severe chronic graft-versus-host disease was frequent; about 41% of 24 patients analyzed. The overall survival rates and disease free survival at 42 months were 56.7% and 45.4%, respectively. According to Kaplan-Meyer analysis, the median time from diagnosis to transplant predicted the overall survival; however age, gender and conditioning regimen did not predict the prognosis. It was impossible to reach other conclusions because of the small sample size in this study. CONCLUSIONS: The role of allogeneic transplantations should be re-evaluated in the era of targeted therapy.

Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms

BACKGROUND: In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. METHODS: This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. RESULTS: Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. CONCLUSION: Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.

Allogeneic Hematopoietic Cell Transplantation from an HLA-mismatched Family Donor: The Current Status and Future

Traditionally, human leukocyte antigen (HLA)-mismatched hematopoietic cell transplantation (HCT) has been considered ill-advised in a routine clinical practice due to excessive serious post-transplant complications, such as graft failure, graft-versus-host disease, and prolonged immunosuppression resulting in increased fatal infections. Recent introduction of new HCT techniques, especially in the area of conditioning therapy, has improved outcomes of HLAmismatched HCT considerably. Using several regimens of reduced-intensity conditioning (RIC), it is now possible to perform allogeneic HCT in patients without HLA-matched donors in the family or in the registry from HLA-mismatched family donors. Furthermore, due to less rigorous nature of RIC therapy, elderly patients (up to 70 years of age) and patients who have been treated heavily especially with a previous HCT can also be treated. In this review, we gave a brief historical background for the development of allogeneic HCT, discussed rationale for the use RIC for HLA-mismatched HCT, and summarized trial results of HLA-mismatched HCT after RIC. Lastly, future areas of research regarding HLA-mismatched HCT were discussed.

Unrelated stem cell transplantation after reduced-intensity conditioning plus rituximab for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with CNS involvement / 소아과

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) with central nervous system (CNS) involvement is usually fatal unless stem cell transplant (SCT) is offered. However, SCT with conventional intensity conditioning is associated with high transplant-related mortality. We describe our experience with unrelated SCTs after reduced-intensity conditioning (RIC) for patients with EBV-HLH with progressive CNS disease. This approach was associated with minimal toxicities and might be an effective option in patients with EBV-HLH with progressive CNS disease. Moreover, the addition of rituximab to RIC appears to be safe and effective in suppressing EBV in the patients with EBV-HLH.

Allogeneic Stem Cell Transplantation for Patients with Advanced Hematological Malignancies: Comparison of Fludarabine-based Reduced Intensity Conditioning versus Myeloablative Conditioning

We compared the outcomes of allogeneic hematopoietic stem cell transplantation using reduced intensity and myeloablative conditioning for the treatment of patients with advanced hematological malignancies. A total of 75 adult patients received transplants from human leukocyte antigen-matched donors, coupled with either reduced intensity (n=40; fludarabine/melphalan, 28; fludarabine/cyclophosphamide, 12) or myeloablative conditioning (n=35, busufan/cyclophosphamide). The patients receiving reduced intensity conditioning were elderly, or exhibited contraindications for myeloablative conditioning. Neutrophil and platelet engraftment occurred more rapidly in the reduced intensity group (median, 9 days vs. 18 days in the myeloablative group, p or =grade II) occurred at comparable frequencies in both groups, while the incidence of hepatic veno-occlusive disease was lower in the reduced intensity group (3% vs. 20% in the myeloablative group, p=0.02). The overall 1-yr survival rates of the reduced intensity and myeloablative group patients were 44% and 15%, respectively (p=0.16). The results of present study indicate that patients with advanced hematological malignancies, even the elderly and those with major organ dysfunctions, might benefit from reduced intensity transplantation.

Pre-transplant Disease Status is Important for an Improved Outcome of the Second Stem Cell Transplantation in the Myeloma Patients Receiving the First Autologous Stem Cell Transplantation

BACKGROUND: Double autologous stem cell transplantation (ASCT) seems to be superior to a single ASCT, at least in the patients who did not achieve a 90% response after the first transplant. An allogeneic SCT with a dose-reduced conditioning regimen after ASCT and as part of the initial therapy, might be a feasible and highly effective approach. The aim of this study was to determine the prognostic factors that are associated with the outcome of multiple myeloma (MM) patients who had received a second transplant. METHODS: From April 1996 to December 2004, 38 MM patients, who had previously received high-dose melphalan (200 mg/m2) with autologous stem cell support, underwent a second transplant. Following the 1(st) ASCT, 24 patients received a second ASCT and 14 received a tandem reduced-intensity conditioning allogeneic stem cell transplantation (RIST) from their HLA-matched siblings. RESULTS: The 3-year estimated PFS and overall survival (OS) from the time of the first ASCT were 25.2% and 77.6%, respectively. The median PFS and OS were 26 months (95% CI, 23~29) and 60 months (95% CI, 44~76), respectively. The disease status (a CR vs. PR or less) at the second transplant was be the most powerful factor for improving the PFS (P=0.001, hazard ratio 5.8, 95% CI 2.1~16.1). CONCLUSION: Patients whose disease is sensitive to chemotherapy and who obtain a CR after a single transplantation might benefit the most from a second transplant.

Reduced-intensity Umbilical Cord Blood Transplantation in Adult Acute Myeloid Leukemia: Report of Four Cases

The outcome after unrelated cord blood transplantation (CBT) is similar to that of matched unrelated bone marrow transplantation in children, and the results of CBT in adult patients has recently shown improvement. In addition, the use of reduced-intensity conditioning regimens for CBT has shown stable engraftment and reduced treatment-related mortality (TRM). From May 2005 to Jan 2006, four adult patients with acute myelogenous leukemia were treated with CBT after reduced-intensity conditioning at our hospital. The mean age of patients was 53.8 yrs, and all patients received 2 HLA antigen mismatched single unit cord blood. The infused mean cell dose was 2.85 x 10(7)/kg for total nucleated cells and 0.72 x 10(5)/kg for CD34+ cells. All patients had engraftment. The mean number of days to WBC and platelet engraftment was D+20.3 and D+60.3, respectively. There was no TRM within 100 days after transplantation. At the last follow up, three of the four patients were alive. One patient transplanted in first complete remisson is alive in remission at day 413, but the other patients transplanted in advanced disease all relapsed. Reduced-intensity CBT is a feasible approach in selected adult patients with acute myeloid leukemia.

Trasplante no mieloablativo de células progenitoras hematopoyéticas: Mitos y realidades / Non-myeloablative transplant of hematopoyetic precursor cells: Myth and reality

The feasibility of applying allogeneic cell -mediated therapy in conjunction with allogeneic hematopoietic cell transplantation following reduced -intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to perform such procedures on an outpatient basis as well to offer a valid option for cure to elderly individuals and patients with less than optimal performance status. Based on available experience, clinical application of this innovative therapy may open new horizons for the treatment of patients with leukemia, lymphoma, myeloma and other diseases. Many patients can now benefit from the advantages of immunotherapy mediated by alloreactive donor lymphocytes, while minimizing transplant-related toxicity and mortality. This kind of transplant is making real progress in the world of transplantation.

El trasplante alogénico no mieloablativo basa su efecto en la capacidad de los linfocitos del donador de erradicar a la enfermedad residual del paciente. El empleo de dosis reducidas de intensidad de radioterapia y/o quimioterapia permite su empleo en pacientes de edad avanzada y aún con comorbilidad. La poca toxicidad del procedimiento evita frecuentemente la hospitalización del paciente, se asocia a menor frecuencia de infecciones y de transfusiones, por ello el costo es sensiblemente menor e ideal para países pobres. Se ha utilizado con éxito desde hace ocho años y en nuestro país su aplicación es cada vez más frecuente. La utilidad principal se ha observado en leucemias crónicas y linfomas indolentes. En leucemia aguda mieloblástica en primera remisión también es útil, siendo menos efectivo en la leucemia aguda linfoblástica y los linfomas no-Hodgkin agresivos. También puede ser utilizado en niños y en pacientes con enfermedades benignas. El trasplante no-mieloablativo es una realidad en el área de los trasplantes.

Reduced Intensity Conditioning Regimen Followed by Allogeneic Peripheral Blood Stem Cell Transplantation for Acute Panmyelosis with Myelofibrosis

A 44-year-old male presented with a month history of exertional dyspnea and dizziness. A peripheral blood smear revealed a pancytopenia with 3% of blasts. We were not able to obtain a bone marrow aspirate, but a biopsy specimen showed hypercellularity, proliferation of trilineage cell lines (panmyelosis) with extensive myelofibrosis, and clusters of immature cells at the paratrabecular area. After remission induction therapy with idarubicin 12mg/m2 (D1-3) and cytosine arabinoside 100mg/m2 (D1-7), the bone marrow blast count was decreased, but the marrow fibrosis and pancytopenia persisted. Peripheral blood stem cell transplantation from his HLA-matched brother was performed after administering fludarabine 30mg/m2 for 5 days and busulfan 3.2mg/kg for 2 days. Early engraftment occurred and the bone marrow reticulin fibrosis disappeared. Full-donor chimerism was demonstrated at day 22 by performing short tandem repeats analysis and this was maintained for 1 year. The patient has survived 20 months after transplantation without any complication.

Allogeneic hematopoietic stem cell transplantation using reduced-intensity Bu/Cy conditioning for patients with hematologic malignancies / 中国实用内科杂志

Objective To explore the efficacy of allogeneic hematopoietic stem cell transplantation using reduced-intensity Bu/Cy conditioning for patients with hematologic malignancies.Methods Five patients with hematologic malignancies were treated by allogeneic hematopoietic stem cell transplantation using reduced-intensity Bu/Cy conditioning,which consisted of busufan3~4 mg/(kg?d) for 3 days,cyclophosphamide50 mg/(kg?d) for 2 days, Ara-C 2 g/(m~2?d) for 1 or 2 days,and CsA 3 mg/(kg?d) and mycophenolate mofetil 1 g/d 7 days before the transplantation.Results Five patients established successful engraftment and no severe complications occured.After a follow-up of median 10.5(3-22)months,five patients still survived without diseases.Conclusion Reduced-intensity Bu/Cy conditioning may reduce transplantation-related toxicities.Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning is a safe and effective option for the patients with hematologic malignancies.