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Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.

ABSTRACT: At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease (GVHD) prophylaxis included post-HCT cyclophosphamide, tacrolimus, and mycophenolate mofetil. One patient died as a result of complications of fludarabine neurological toxicity. No neurological toxicity was observed in subsequent patients who received lower fludarabine doses and more intense postfludarabine dialysis. There were no cases of grade 2 to 4 acute GVHD and 1 case of moderate chronic GVHD by 12 months. One patient experienced relapse of multiple myeloma at 30 months after HCT and died 4 years posttransplantation. Overall, 4 of 6 patients remain alive, without disease relapse and with long-term renal rejection-free survival. This trial was registered at www.clinicaltrials.gov as #NCT01758042.

SUBMITTER: Chen YB

PROVIDER: S-EPMC6624971 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.

Chen Yi-Bin YB Elias Nahel N Heher Eliot E McCune Jeannine S JS Collier Kerry K Li Shuli S Del Rio Candice C El-Jawahri Areej A Williams Winfred W Tolkoff-Rubin Nina N Fishman Jay A JA McAfee Steven S Dey Bimalangshu R BR DeFilipp Zachariah Z O'Donnell Paul V PV Cosimi A Benedict AB Sachs David D Kawai Tatsuo T Spitzer Thomas R TR

Blood 20190531 2

At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease ...[more]

PMID: 31151984

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Project description:Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days-6 to-2) and cyclophosphamide (1,000 mg/m2/day) (days-5 to-4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8-55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35-120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95-12.51) × 108/kg and CD34 + cells 2.28 (0.75-5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10-20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.

Project description:PurposeHaploidentical and human leukocyte antigen (HLA)-identical sibling hematopoietic stem transplantation are two main ways used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, remarkable progress has been made in haploidentical allo-HSCT (HID-SCT), and some institutions found HID-SCT had similar outcomes as HLA-identical sibling allo-HSCT (ISD-SCT). To clarify if HID-SCT has equal effects to ISD-SCT in hematologic malignancies, we performed this meta-analysis.MethodsRelevant articles published prior to February 2017 were searched on PubMed. Two reviewers assessed the quality of the included studies and extracted data independently. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for statistical analysis.ResultsSeven studies including 1919 patients were included. The rate of platelet engraftment is significantly lower after HID-SCT versus ISD-SCT while there is no difference in neutrophil engraftment (OR = 2.58, 95% CI = 1.70-3.93, P < 0.00001). The risk of acute graft-versus-host disease (GVHD) is significantly higher after HID-SCT versus ISD-SCT (OR = 1.88, 95% CI = 1.42-2.49, P < 0.00001), but the relapse rate is lower in HID-SCT group (OR = 0.70, 95% CI = 0.55-0.90, P = 0.005). The incidence rates of overall survival (OS) and disease-free-survival/leukemia-free survival/relapse-free survival (DFS/LFS/RFS) after ISD-SCT are all significantly superior to HID-SCT (OR = 1.32, 95% CI = 1.08-1.62, P = 0.006; OR = 1.25, 95% CI = 1.03-1.52, P = 0.02). There is no significant difference in transplantation related mortality (TRM) rate after HID-SCT and ISD-SCT.ConclusionAfter myeloablative conditioning, patients receiving ISD-SCT have a faster engraftment, lower acute GVHD and longer life expectancy compared to HID-SCT with GVHD prophylaxis (cyclosporine A, methotrexate, mycophenolate mofetil and antithymoglobulin; CsA + MTX + MMF + ATG). Currently, HID-SCT with GVHD prophylaxis (CsA + MTX + MMF + ATG) may not replace ISD-SCT when HLA-identical sibling donor available.

Project description:BACKGROUND:Cardiovascular disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and kidney transplant (KT) patients. Compared with left ventricular (LV) ejection fraction (LVEF), LV strain has emerged as an important marker of LV function as it is less load dependent. We sought to evaluate changes in LV strain using cardiovascular magnetic resonance imaging (CMR) in ESRD patients who received KT, to determine whether KT may improve LV function. METHODS:We conducted a prospective multi-centre longitudinal study of 79 ESRD patients (40 on dialysis, 39 underwent KT). CMR was performed at baseline and at 12?months after KT. RESULTS:Among 79 participants (mean age 55 years; 30% women), KT patients had significant improvement in global circumferential strain (GCS) (p?=?0.007) and global radial strain (GRS) (p?=?0.003), but a decline in global longitudinal strain (GLS) over 12?months (p?=?0.026), while no significant change in any LV strain was observed in the ongoing dialysis group. For KT patients, the improvement in LV strain paralleled improvement in LVEF (57.4?±?6.4% at baseline, 60.6%?±?6.9% at 12?months; p?=?0.001). For entire cohort, over 12?months, change in LVEF was significantly correlated with change in GCS (Spearman's r?=?-?0.42, p?<?0.001), GRS (Spearman's r?=?0.64, p?<?0.001), and GLS (Spearman's r?=?-?0.34, p?=?0.002). Improvements in GCS and GRS over 12?months were significantly correlated with reductions in LV end-diastolic volume index and LV end-systolic volume index (all p?<?0.05), but not with change in blood pressure (all p?>?0.10). CONCLUSIONS:Compared with continuation of dialysis, KT was associated with significant improvements in LV strain metrics of GCS and GRS after 12?months, which did not correlate with blood pressure change. This supports the notion that KT has favorable effects on LV function beyond volume and blood pessure control. Larger studies with longer follow-up are needed to confirm these findings.

Project description:In the context of allogeneic transplant platforms, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents one of the latest and most promising curative strategies for patients affected by high-risk hematologic malignancies. Indeed, this platform ensures a suitable stem cell source immediately available for virtually any patents in need. Moreover, the establishment in recipients of a state of immunologic tolerance toward grafted hematopoietic stem cells (HSCs) remarkably improves the clinical outcome of this transplant procedure in terms of overall and disease free survival. However, the HLA-mismatch between donors and recipients has not been yet fully exploited in order to optimize the Graft vs. Leukemia effect. Furthermore, the efficacy of haplo-HSCT is currently hampered by several life-threatening side effects including the onset of Graft vs. Host Disease (GvHD) and the occurrence of opportunistic viral infections. In this context, the quality and the kinetic of the immune cell reconstitution (IR) certainly play a major role and several experimental efforts have been greatly endorsed to better understand and accelerate the post-transplant recovery of a fully competent immune system in haplo-HSCT. In particular, the IR of innate immune system is receiving a growing interest, as it recovers much earlier than T and B cells and it is able to rapidly exert protective effects against both tumor relapses, GvHD and the onset of life-threatening opportunistic infections. Herein, we review our current knowledge in regard to the kinetic and clinical impact of Natural Killer (NK), γδ and Innate lymphoid cells (ILCs) IRs in both allogeneic and haplo-HSCT. The present paper also provides an overview of those new therapeutic strategies currently being implemented to boost the alloreactivity of the above-mentioned innate immune effectors in order to ameliorate the prognosis of patients affected by hematologic malignancies and undergone transplant procedures.

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Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.

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Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.

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