The transplantation of stem cells from a matched unrelated donor (MUD) or a haploidentical mismatched related donor (MMRD) is a widely used variant of curative treatment for patients with primary immunodeficiency (PID). Currently, different strategies are used to reduce the risk of post-transplant complications and enhance immune reconstitution. We report the preliminary results of MUD and MMRD transplantation with TCRαβ/CD19 depletion in patients with PID (trial registered at www.clinicaltrials.gov as NCT02327351). Thirty-seven PID patients (median age, 2.6 years; range, .2 to 17) were transplanted from MUDs (n = 27) or haploidentical MMRDs (n = 10) after TCRαβ(+)/CD19(+) graft depletion. The median numbers of CD34(+) and TCRαβ(+) cells in the graft were 11.7 × 10(6)/kg and 10.6 × 10(3)/kg, respectively. Acute graft-versus-host disease (GVHD) was observed in 8 patients (22%), without a statistically significant difference between MUDs and MMRDs; 7 of these patients had grade II acute GVHD and responded to first-line therapy, whereas 1 patient had grade IV acute GVHD with transformation to extensive chronic GVHD. Primary and secondary graft failure (nonengraftment or rejection) was observed in 10 patients (27%), 9 of whom were treated with 1 alkylating agent in the conditioning regimen. All these patients were successfully retransplanted with different rescue protocols. Preliminary data on immune reconstitution were very encouraging. Most patients had significant numbers of T lymphocytes detected on the first assessment (day +30) and more than 500 T cells/μL, on day +120. Based on our preliminary data, no significant difference was seen between MMRD and MUD hematopoietic stem cell transplantation (HSCT). With a median follow-up period of 15 months, the cumulative probabilities of overall patient survival and transplant-related mortality were 96.7% and 3.3%, respectively. Based on the results, the ability to control the main post-transplant complications and the immune reconstitution rates are the main factors leading to successful outcome in patients with PID after TCRαβ(+)-depleted HSCT.
We evaluated the depletion of TCR-alpha/beta cells from the graft of children with high-risk AML, who received transplantation from unrelated (n = 20) and haploidentical donors (n = 13). The preparative regimen included treosulfan, melphalan, fludarabine and anti-thymocyte globulin. Grafts were PBSC engineered by TCR-alpha/beta and CD19 depletion. The graft contained a median of 9 × 10 6 /kg of CD34+ and 20 × 10 3 /kg of αβ-T cells. Post-transplant immune suppression included tacrolimus till day +30 and Mtx in 21 patients, tacrolimus in 5, Mtx in 2 and no prophylaxis in 5 patients. Sixteen patients received native or TCR-alpha/beta-depleted donor lymphocytes at a median of 47 (40-204) days. Median follow-up is 1.76 years. Primary engraftment was achieved in 33 patients (100%). Cumulative incidence of acute GvHD (aGvHD) grade 2-3 was 39 (26-60)%, half of them had skin-only aGvHD. Cumulative incidence of chronic GvHD was 30(18-50)%. Transplant-related mortality is 10(4-26)%. Event-free survival (EFS) is 60 (43-76)% and overall survival (OS) is 67(50-84)% at 2 years. In a subgroup of patients, who received transplantation in CR, EFS is 66 (48-84)% and OS − 72(53-90)% at 2 years. Our data suggest that TCR-alpha/beta and CD19 depletion is a robust method of graft manipulation, which can be used to engineer grafts for children with AML
Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantationrelated mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6*4; P ¼ 0.0067), HC (recipient CYP2B6*2; P ¼ 0.03) and VOD (donor CYP2B6*6; P ¼ 0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P ¼ 0.03), and recipient VDR TaqI with TRM and overall survival (P ¼ 0.006 and P ¼ 0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.
Summary:Pure red cell aplasia (PRCA) is a well-known although infrequent hematologic complication after allogeneic bone marrow transplantation. PRCA occurs in cases of major ABO-mismatch between donor and recipient and is believed to be due to inhibition of donor erythroid progenitors by residual host isohemagglutinins. We report a 10-year-old boy with post-hepatitis aplastic anemia (AA) who developed PRCA after HLA-matched familial peripheral blood stem cell transplantation (SCT) following conditioning with Cph 200 mg/kg + ATG 90 mg/kg. Granulocyte engraftment occurred on day +18, platelet engrafted on day +40, while reticulocytopenia at 0% persisted until day +118, and erythroid precursors were totally absent from bone marrow. After a single dose of rituximab 200 mg/m 2 administered on day +118 PRCA resolved and on day +132 the reticulocytes rose to 5.7%. On day +139 the Hb reached 137 g/l and the erythroid lineage in BM increased to 21%. We conclude that due to the rapid recovery from PRCA and lack of side effects, rituximab should be tried as firstline treatment of PRCA after allo-SCT. Bone Marrow Transplantation (2002) 30, 405-407. doi:10.1038/sj.bmt.1703668 Keywords: pure red cell aplasia; allogeneic stem cell transplantation; rituximab Pure red cell aplasia (PRCA) is an infrequent but wellrecognized complication of allogeneic bone marrow transplantation. Most cases of PRCA occur after transplantations with major donor-recipient ABO mismatch and are due to the long persistence of residual titers of natural recipient anti-A, 1 or very rarely, anti-B antibodies, 2 causing inhibition of donor erythroid progenitors. Additional risk factors include use of reduced intensity conditioning and immunosuppression with CsA in the post-transplant
Summary:Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m 2 , busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors. Fanconi anemia (FA) is a rare autosomal recessive syndrome of progressive marrow failure, constitutional physical abnormalities of skin, skeleton, kidneys, and cancer susceptibility. 1 FA cells are characterized by chromosomal instability and marked DNA hypersensitivity to crosslinking alkylating agents such as cyclophosphamide or platinum derivatives. 2,3 This hypersensitivity forms the basis for the confirmatory tests for FA with diepoxybutane (DEB), nitrogen-mustard, and others. Bone marrow failure remains the main cause of mortality among the FA patients, followed by complications of stem cell transplantation (SCT) and myeloid and nonmyeloid malignancies. Allogeneic hematopoietic SCT from unaffected sibling donors or suitably matched unrelated donors remains the only curative option for the correction of hematological abnormalities in FA patients. In the past, the use of highdose cyclophosphamide and ionizing radiation in preparative regimens often resulted in excessive organ toxicity and death in the early post transplant period. Low-doses of cyclophosphamide (20-40 mg/kg) combined with a 4-6 Gy of thoraco-abdominal or total body irradiation results in reduced toxicity and substantially improves the outcome for the FA patients transplanted from HLA-matched donors. 4 However, reduced doses of cyclophosphamide may not kill DEB-resistant naturally reverted T-lymphocytes, thereby increasing the risk of rejection in mosaic recipients of unrelated grafts (J Wagner, unpublished). Moreover, longterm follow-up clearly shows that these protocols are still associated with significant regimen-related toxicity and high risk of secondary malignant transformations. 5 More specifically, high incidence and severity of acute and chronic graft-versus-host disease (GVHD) in FA patients, who received cyclosporine alone as the GVHD prophylaxis, significantly contributed to transplantation-related morbidity and mortality, in addition favoring development of late epithelial cancers in irradiated patients. These obs...
We report a rare case of ovarian function recovery and pregnancy after hormone-replacement therapy (HRT) in the acute myeloblastic leukemia (AML) patient in third complete remission received hematopoietic stem cell transplantation (HSCT) with busulphan-based conditioning regimen. Successful engraftment of the donor cells and full donor's chimerism was achieved without the signs of leukemia. One year after HSCT the patient received a course of HRT as a treatment of hypergonadotropic hypogonadism. After 12 months of HRT the recovery of ovarian function was confirmed. Eight years after the HSCT spontaneous pregnancy occurred; heartbeat of the fetus was registered on week 7. Three weeks later a nonsevere vaginal bleeding occurred and the ultrasound examination showed a nondeveloping pregnancy. Genetic examination of the abortion material showed a full triploid genotype (69 XXX). To our knowledge this is a first case of ovarian function restoration and spontaneous pregnancy in a AML patient after multiple courses of high-dose chemotherapy and busulphan-based myeloablative conditioning for HSCT.
Трансплантация гемопоэтических стволовых клеток у пациентов с гемобластозами Обзор литературы В настоящее время методом спасения многих пациентов со злокачественными и незлокачественными гематологическими и иммунными заболеваниями является аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК). Улучшение выживаемости после ТГСК привело к возрастанию количества больных с отсроченными осложнениями, среди которых наиболее удручающими являются вторичные неоплазии. В плане их развития они представляют особую угрозу для детей, перенесших ТГСК. Это связано
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