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.

Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL).@*METHODS@#CLAE regimen [cladribine 5 mg/(m2·d), d 1-5; cytarabine 1.5 g/(m2·d), d 1-5; etoposide 100 mg/(m2·d), d 3-5] followed by allo-HSCT was used to treat 3 R/R AL patients. The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state. After an interval of 3 to 5 days, followed by preconditioning regimen for allo-HSCT [fludarabine 30 mg/(m2·d), d -7 to d -3; busulfan 0.8 mg/kg q6h, d -6 to d -3 or d -5 to d -2. If the bone marrow hyperplasia was not active and the blasts were less than 10%, busulfan should be used for 3 days. If the bone marrow hyperplasia was active and the blasts were more than 10%, busulfan should be used for 4 days]. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prevention. After transplantation, the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients, and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation.@*RESULTS@#2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission, and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT, respectively. The two patients both relapsed 6 months after transplantation, then achieved complete remission by donor lymphocyte infusion, interferon, interleukin-2 and other methods, and disease-free survival was 2 years after transplantation. The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor, accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities. After morphological remission by induction chemotherapy, central nervous system leukemia was complicated. Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD. The patient relapsed 3 months after transplantation, and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy, however, he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD.@*CONCLUSION@#CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies: a prospective single-arm phase II study / 医学前沿

Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group (P = 0.03 and P = 0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%-86.7%) and 58.4% (95% CI: 41.9%-81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%-35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%-38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.

Chronic myeloid leukemia.

Chronic myeloid leukemia is one of the commonest hematological malignancies seen in clinical practice. It is the result of abnormal and excess cell proliferation due to de-regulated bcr-abl tyrosine kinase activity as a result of Philadelphia chromosome. The present article discusses the various options available to treat the disorder. Allogeneic stem cell transplant remains the gold standard and the only curative option. Hydroxyurea and Busulfan helps in controlling the total leukocyte count but fail to impact on survival. Interferon especially when combined with cytarabine is curative in minority of patients though a substantial number of patients achieve functional cure. Imatinib, a molecular targeted oral therapy, against bcr-abl tyrosine kinase is the latest addition to various treatment options. Early results appear very promising and can be considered as non- transplant standard of care.

Allogeneic blood stem cell transplantation in chronic myeloid leukaemia-chronic phase following conditioning with busulphan and cyclophosphamide: a follow up report.

BACKGROUND: Allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation remains the only modality of treatment that can eradicate a leukaemia clone in the majority of patients with chronic myeloid leukaemia (CML). However, the advent of the targeted molecule imatinib mesylate (formerly STI-571) against the bcr-abl chimeric protein in the disease has brought the issue of managing newly diagnosed CML patients, especially those with available donors, to the crossroads. Although the curative potential of this agent remains unknown, it can produce complete cytogenetic response in > 60% of newly diagnosed patients. METHODS: From May 1991 to October 2002, a total of 55 Ph+ CML-chronic phase patients received oral busulphan 16 mg/kg and cyclophosphamide 120 mg/kg i.v. as a conditioning regimen. All patients received human leucocyte antigen (HLA)-identical sibling donor haematopoletic stem cells--bone marrow in 41 patients (74.5%) and peripheral blood stem cells in 14 (25.4%). Post-transplant prophylaxis for graft-versus-host disease included a short course of methotrexate (on days +1, +3, +6 and +11) and cyclosporin till day +180 in 38 patients (69.1%), while a combination of cyclosporin and methylprednisolone was used in the remaining 17 (29%). RESULTS: At a median follow up of 48 months (10-144 months), 26 patients (47.3%) are alive. Early mortality (100-day) occurred in 17 patients (30.9%). Acute graft-versus-host disease developed in 37 patients (67.3%), and was grade IV in 6 of them. Chronic graft-versus-host disease developed in 17 patients (30.9%). Relapse occurred in only 2 patients (3.6%) till date. The leukaemia-free survival is 64.3% in the peripheral stem cell group, whereas it is 41.5% in the bone marrow recipient group. CONCLUSION: Allogeneic BMT appears to result in eradication of CML and ensure disease-free survival in about half the patients. However, efforts should be made to prevent graft-versus-host disease and minimize early mortality.

Reversal of marrow fibrosis in agnogenic myeloid metaplasia by allogeneic peripheral blood stem cell transplantation.

Agnogenic myeloid metaplasia (AMM) is a clonal hematopoietic stem cell disorder characterized by bone marrow fibrosis, extramedullary hemopoiesis, splenomegaly and a leukoerythroblastic blood picture. Current standard therapies using hydroxyurea, interferon, androgens or corticosteroids have not shown to prolong survival of patients with AMM. In this study, we performed a curative approach using an HLA-matched sibling as a donor for allogeneic peripheral blood stem cell transplantation (PBSCT) for a 45-year-old woman with AMM. Busulfan and cyclophosphamide were given as a conditioning regimen from day -7 to day -2 with cyclosporinA and methotrexate as post-transplant immunosuppressive therapy. Donor PBSCs were mobilized by G-CSF at 16 microg/kg/day for five days and transplantation was performed on March 2-3, 2000. The patient rapidly engrafted within 2 weeks after PBSC infusion without evidence of graft versus host disease. Her blood counts and bone marrow 2 years after transplantation were normal with full donor pattern by molecular analysis. In conclusion, marrow fibrosis can be reverted to normal by allogeneic PBSCT. Allogeneic PBSCT should thus be offered to AMM patients if an HLA-matched sibling is available. This report represents the first SCT for AMM in Thailand.

Ocurrencia de leucemia mieloide crónica y linfoma no Hodgkin en un mismo paciente: caso clínico / Simultaneous occurrence of chronic myeloid leukemia and non Hodgkin lymphoma: clinical case

Chronic myeloid leukemia is a myeloproliferative disorder caused by a clonal disturbance of the trunk cell and the accumulation of granulocytic series in the marrow, blood and other organs. We report a 63 years old male, carrier of a chronic myeloid leukemia whose clinical condition was complicated by the appearance of a T cell lymphoma. He was subjected to chemotherapy, that reduced the size of adenopathies and improved his general condition. Further studies are required to determine if there is a relationship between these two clinical entities

Serum vitamin E levels in patients of chronic myeloid leukaemia.

OBJECTIVE: To estimate vitamin E levels in sera of patients of chronic myeloid leukaemia (CML) before and after treatment with busulphan and hydroxyurea and to compare the levels with those in healthy controls. METHODS: The study was carried out in a total of 50 subjects (mean age 34 +/- 8.86 years; 25 were proved cases of CML and 25 were healthy controls. Vitamin E level was measured by spectrofluorometeric method. In patients of CML vitamin E level was estimated twice i.e. once when their total leucocyte count (TLC) was raised (i.e. before treatment) and then after treatment after bringing the TLC near normal. RESULTS: The mean serum vitamin E level in 25 normal healthy controls was 7.19 micrograms/ml and that in 25 patients of CML at presentation (before treatment) was 2.67 micrograms/ml. It increased to 3.61 micrograms/ml after treatment. CONCLUSION: The results show that patients of CML have a significantly lower (p < 0.001) level of serum vitamin E as compared to normal healthy adults and that the level of vitamin E increased significantly (p < 0.001) after treatment even without supplementing vitamin E.

Busulfán versus busulfán-interferón como terapia de mantenimiento en leucemia mieloide crónica / Busulfan versus busulfan-interferon as maintenance therapy in chronic myeloid leukemia

Se estudiaron 30 pacientes con el fin de evaluar la eficacia terapéutica y la toxicidad del interferón alfa-2b, asociado al busulfán, en el mantenimiento de la fase crónica con leucemia mieloide crónica de novo. Los pacientes recibieron busulfán hasta alcanzar la remisión hematológica completa, y se dividieron aleatoriamente en dos grupos: uno se mantuvo con busulfán el cual se administró cuando los leucocitos superaron los 5 x 10 9/L, y otro recibió interferón alfa a dosis de 5 millones UI SC tres veces por semana, agregándose busulfán cuando los leucocitos eran superiores a 15 x 10 9/L. El promedio de la duración de la fase crónica fue mayor en el grupo de busulfán-interferón, 31 vs 16 meses (p= 0.03) pero no hubo ningún caso de remisión citogenética. El interferón fue bien tolerado: ningún enfermo se eliminó por toxicidad del medicamento

Successful bone marrow transplantation in a Chinese boy with Wiskott-Aldrich syndrome.

We describe the successful use of HLA-compatible sibling bone marrow transplantation (BMT) in a 17-month-old Chinese boy in whom Wiskott-Aldrich syndrome (WAS) was diagnosed on the basis of eczema, thrombocytopenia, recurrent otitis media and abnormal immunological tests. The conditioning chemotherapy included 2 days' oral busulfan, 40 mg/m2/6 hours, and 2 days' intravenous cyclophosphamide, 60 mg/kg/day (BU2CY2). Complete hematological chimerism was achieved 3 weeks after transplantation. Eight months after his BMT the eczema has resolved, platelet count is normal, and he no longer has frequent infections. BU2CY2 as a preconditioning regimen gave complete lymphohematopoietic engraftment in this WAS patient with no evidence of graft-versus-host disease. The excellent clinical response of this patient and the inevitable fatal outcome of WAS support the opinion that where a histocompatible donor is available, BMT at the earliest opportunity is the best option. We believe this is the first case of successful BMT in a Chinese patient with WAS.

Ectopic osteomyelogenous response to demineralized bone matriz implant in busulphan treated mice

Camundongos Swiss, fêmeas, (25-30 g; n = 100) receberam 4 injeçöes de bussulfano (20 mg/kg, ip) a intervalos de 15 dias (n = 100). Antes do tratamento e após 30, 60 e 90 dias, os animais deste e de um grupo controle (n = 15) foram avaliados quanto ao leucograma, taxa de hemoglobina e hematócrito por meio do sangue colhido por punçäo retroorbital. Sessenta dias após o início do tratamento, 60 animais sobreviventes do grupo tratado e 15 animais do grupo controle receberam implantes intermusculares de matriz óssea desmineralizada (MOD-10 mg). No 90§ dia (30 dias após o implante) foram sacrificados para exame histológico da medula óssea esternal (MOE) e da resposta osteomielogênica ao implante de MOD. Trinta dias após o início do tratamento observou-se leucopenia, com diminuiçäo do número de granulócitos, linfócitos e monócitos nos animais que receberam bussulfano. O hematócrito e a taxa de hemoglobina apresentaram-se diminuídos no 60§ dia. O exame histológico da MOE do grupo tratado revelou hipocelularidade, dilataçäo dos capilares sinusóides e reduçäo do número de megacariócitos (50 por cento). Os animais controle apresentaram 100 por cento de resposta positiva ao implante de MOD, havendo formaçäo de placas metaplásicas compostas por trabéculas ósseas contendo cavitaçöes preenchidas por células hematopoiéticas. Em 46,7 por cento dos animais tratados observou-se resposta osteomielogênica semelhante à do grupo controle, mas com hipocelularidade e maior componente de adipócitos; 25 por cento apresentaram resposta osteomielogênica tardia e incompleta com menor componente ósseo, maior componente cartilaginoso e ausência de células hematopoiéticas; nos 28,3 por cento restantes a resposta foi negativa

Study of hematopoietic progenitor cells in thalassemia after bone marrow transplantation.

The hematopoietic committed progenitor cells (BFU-E and CFU-GM) in blood and bone marrow were studied in thalassemic patients before and after bone marrow transplantation. Eighteen transplants were performed in 17 patients with thalassemia. Five were homozygous beta-thalassemia and 12 were beta-thalassemia/hemoglobin E disease. The age ranged from 1.2-14 years (median = 3.4 years). The conditioning regimen comprised busulfan 3.5-4 mg/kg/day for 4 days and cyclophosphamide 50 mg/kg/day for 4 days. Cyclosporin in combination with methotrexate were administered post transplant for GVHD prophylaxis. Before transplantation, BFU-E and CFU-GM in the blood of the patients were significantly higher compared with normal (p < 0.05) but were normal in the bone marrow. Only the CFU-GM in the bone marrow of the successful cases after transplantation recovered to the normal level at the first month through the 12th month whereas the BFU-E were low. Both CFU-GM and BFU-E in the blood were lower than normal after follow up to the 12th month. Inspite of the low number of progenitor cells, there was hematological recovery in the blood of the patients. It may be due to the capacity of the hematopoiesis react to stress which could be amplified the differentiation compartment or the shortened-transit time through the stem cell compartment.

Síndrome nefrótica por glomerulonefrite membranosa associada a leucemia mielóide crônica / Nephrotic syndrome due to membranous glomerulonephritis associated with chronic myeloid leukemia

Os autores relatam caso de um paciente que apresentou síndrome nefrótica quatro anos após o diagnóstico de leucemia mielóide crônica. A biópsia renal revelou lesöes características da glomerulopatia membranosa. Acreditamos que este represente o primeiro caso relatado na literatura da associaçäo entre leucemia mielóide crônica e glomerulopatia membranosa

Quimioterapia combinada en la leucemia granulocítica crónica / Chronic granulocytic leukemia combined chemotherapy

La Leucemia Granulocítica Crónica (LGC), es una enfermedad mieloproliferativa maligna que se presenta con mayor frecuencia de la tercera a la sexta década de la vida, teniendo un promedio de sobrevivencia de 36 meses (1,3,8,9).El tratamiento de elección es la administración de drogas alquelantes (Busulf n) y/o antimetabólitos.(1,3,10,11). El objetivo del presente estudio fue evaluar la efectividad, así como el tiempo de sobrevida, logrados con la quimioterapia, usando la asociación de Busulf n y 6-Mercaptopurina (6-MP) en pacientes con LGC. Al estudio ingresaron 31 pacientes durante el período de octubre de 1968 a diciembre de 1986, habiéndose dado ciclos de 1 a 7 veces, y con una duración que osciló entre 7 y 104 días. Se observó en todos los pacientes que la remisión se logró en un periódo m s corto al usar la asociación mencionada, que cuando se aplicó el tratamiento único con Busulf n, así como un periódo m s largo entre el diagnóstico inicial y la crisis bl stica. Bas ndonos en la experiencia previa con el uso de los citost ticos únicos, proponemos el uso combinado de estos dos medicamentos: Busulf n y 6-MP, para lograr la remisión al hacer el diagnóstico de LGC activa y las recaídas subsecuentes

Eritrocitoses: diagnóstico diferencial e tratamento / Erythrocytosis: differential diagnosis and treatment

O termo Eritrocitose significa aumento do número de glóbulos no sangue circulante como resultado de algum estímulo. No trabalho a seguir os autores fazem uma revisäo das principais causas de Eritrocitoses, incluindo o quadro clínico, a conduta diagnóstica e terapêutica