HLA-Matched Related Hematopoietic Stem Cell Transplantation in Adolescents and Adults with Sickle Cell Disease: Comparison of Myeloablative Versus Non Myeloablative Approaches. Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) allowing a SCD-free survival over 95% among children with matched HLA-identical donor (Gluckman E. Blood, 2017; Bernaudin F. Haematologica, 2020). In adults, myeloablative HSCT is associated with more graft-versus host disease (GVHD) and higher toxicity (Cappelli B. Haematologica, 2019). More recent approaches using non myeloablative (NMA) conditioning regimen (3 gray (Gy) total body irradiation (TBI) plus alemtuzumab) followed by HLA-identical peripheral blood stem cells (PBSC) and post-transplant sirolimus appear safe in adults (Hsieh MM. JAMA, 2014), but incidence of graft failure might be higher than the one reported after myeloablative conditioning (MAC) (Alzahrani M. Br J Haematol, 2021). Here, we compare outcomes after MAC or NMA conditioning regimens in patients over 15 years old transplanted from a matched related donor (MRD). Patients and methods All consecutive patients transplanted for SCD from a MRD from January 2015 to October 2020 were eligible if they were over 15 years old and received a busulfan-based MAC conditioning regimen or a NMA conditioning regimen. Chimerism was studied by analyzing various polymorphisms after polymerase chain reaction (PCR) amplification of DNA obtained from whole blood cells. Rejection was defined as donor chimerism <5%. Event-free survival (EFS) was defined as the probability to be alive with blood donor chimerism over 20%. Results Thirty-four patients were included: 20 in the MAC and 14 in the NMA groups. Median age at transplant was 17 years (range 15-46) without difference between groups. Forty four percent of patients had a history of cerebral vasculopathy, 79% of recurrent vaso-occlusive crises and 76% of acute chest syndrome. ABO major incompatibility was present in 15% of patients. There was no difference in patient characteristics according to the conditioning regimen group except for pre-transplant cerebral vasculopathy, more frequently reported in the MAC group: 70% versus 6% in the NMA group (p<0.001). In the MAC group, conditioning regimen associated busulfan (12.8 mg/kg IV), cyclophosphamide (N=17) or fludarabine (N= 3) and anti-thymoglobulin (ATG, mostly 20mg/kg). Stem cell source was bone marrow and post-transplant immunosuppression combined cyclosporine and mycophenolate or methotrexate. In the NMA group, conditioning regimen associated 3Gy TBI and alemtuzumab (1mg/kg), followed by PBSC and post-transplant sirolimus. All patients engrafted and no secondary graft failure was observed. One MAC group patient died from GVHD. The 2-year overall and EFS were 95% (CI 95%: 85.9-100) in the MAC group (median follow-up of 39 months (range 8-63)) and 100% (CI 95%: 100-100) in the NMA group (median follow-up of 17 months (range 9-39)). Incidence of grade II-IV acute GVHD was 0% in the NMA group versus 20% in the MAC group (p=0.12). Incidence of chronic GVHD was 0% in the NMA group versus 25% in the MAC group (p=0.06). From the 27 patients with follow-up>12 months, 17/17 discontinued immunosuppressive therapy in the MAC group versus 8/10 in the NMA group. Hematopoietic recovery was faster in the NMA group with less platelet and red blood cell units transfused (Table). Throughout the follow-up, median donor chimerism was higher after MAC transplantation than after NMA transplantation: 98% (range 69-100) and 86 % (range 50-97) respectively at 1 year (p=0.017). Donor chimerism remained above 50% throughout the follow-up in all patients except 1 of the NMA group who displayed stable chimerism between 40 and 50%. All patients achieved HbS level close to the one of their donors. There was no difference between the 2 groups regarding occurrence of infections. MAC transplant was more often associated with hypertension, neurological complications, severe mucositis and need of enteral or parenteral nutrition. Moreover, duration of hospitalization was longer in MAC group: 54 days (range 39-192) versus 35 days in the NMA group (range 21-52) (p<0.001) (table). Conclusion In this series of adolescents and adults transplanted for SCD, the survival without SCD was excellent with a faster hematological recovery and a lower toxicity after NMA HSCT. Longer follow-up is required to confirm stable mixed donor chimerism and the cure of SCD after NMA approach. Figure 1 Figure 1. Disclosures Joseph: bluebird bio: Consultancy. Boissel: Servier: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Pondarré: ADDMEDICA: Honoraria.

Download Full-text

Early Immune Reconstitution after Hematopoietic Stem Cell Transplantation for Adolescents and Adults with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147133 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3907-3907

Author(s):

Loïc Vasseur ◽

Florence Morin ◽

Corinne Pondarré ◽

Florian Chevillon ◽

Aude-Marie Fourmont ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Immune Reconstitution ◽

Normal Values ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Post Transplant ◽

Stem Cell Source ◽

Cell Source ◽

Adolescents And Adults

Abstract Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p < 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p < 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.

Download Full-text

Dendritic Cells Recovery and Chimerism after Reduced Intensity Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5341.5341 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5341-5341

Author(s):

Reza Tabrizi ◽

Francis Belloc ◽

Xavier Lafarge ◽

Virginie Perreau ◽

Krimo Bouabdallah ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Stem Cell ◽

Conditioning Regimen ◽

Mixed Chimerism ◽

Hematopoietic Stem ◽

Post Transplant ◽

Sibling Donor ◽

Donor Chimerism ◽

Reduced Intensity

Abstract The circulating dendritic cells (DC) are known to have an immunoregulatory role after allogeneic HSC transplantation, and recipient DC have been shown to be important in the development of GVHD in animal model. We studied the DC chimerism of 21 patients (pts) transplanted with reduced intensity conditioning regimen between January 2004 and August 2005. The blood was sampled at days -1, 15, 28 and 56 after transplantation. A series of 17 control normal bloods were also analyzed. DC were identified as ILT3-expressing cells negative for CD14. These cells were sorted by flow cytometry and chimerism was analyzed by PCR of Short Tandem Repeat motifs. Preliminary experiments showed that at least 500 sorted cells were necessary to perform chimerism analysis. Eight females and 13 males (median of age: 54 yrs; 25–61) were enrolled in the study. Diagnoses were 6 AML, 2 sAML, 1 MDS, 3 ALL, 6 MM, 2 NHL and 1 CML. Fifteen pts had high-risk disease. As conditioning regimen, all but 3 pts received cumulative dose of ATG (Thymoglobulin, Genzyme, Lyon, France) (2.5 mg/kg for sibling and 7.5 mg/kg for MUD), in addition to Busulfan 8 mg/kg and Fludarabine 150mg/m2. Eight pts received stem cells from a 10/10 MUD, 2 pts from 9/10 MUD, and 11 pts from sibling donor. For all but one patient, the stem cell source was blood. CsA alone was used for 11 pts, CsA with methotrexate for 8 pts and CsA with MMF for 2 pts. In the absence of aGVHD, the immunosuppressive therapy was tapered within 4 weeks (after day 28 in sibling donor and after day 90 for MUD). The kinetics of the absolute number of DC showed significantly lower count of circulating DC than in control samples at day -1, and a rapid increase, reaching normal values at day 15 post-transplant while the other leukocytes remained at a low value. To determine the origin of post-transplant blood DC, chimerism was analyzed on sorted DC. From 20 pts DC chimerism at day 15 was of full donor origin for 8 pts, mixed in 10 pts. Two pts had no detectable DC. At day 28 from 18 pts, only 4 pts had mixed chimerism. Of these 4 pts, 3 presented at day 56 a full donor chimerism and one patient died from relapse. For T cells at day 15, only one/17 pt had full donor chimerism, and one had no detectable circulating T cells. At day 28, 7/20 pts had full donor chimerism and one without detectable T cells. Only 2/17 had still mixed chimerism at 3 months. Six out of 21 pts relapsed and 3 died from relapse. Among these 6 pts, all but one reached full donor T cells, 3 had a full donor DC at day 28. Six pts from 21 had grade ≥ 2 aGVHD and 3 died from aGVHD. 7/17 evaluable pts had cGVHD. We didn’t found any correlation between DC chimerism and engraftment or relapse. At day 15, the median percentage of recipient DC was lower in pts who developed cGVHD (P<0.017) while it was higher in those with aGVHD (but p not significant). In conclusion, this study demonstrates that the circulating DC pool is rapidly reconstituted from both donor and recipient origins. Thereafter at day 28, donor engraftment of DC became predominant. The median of recipient DC was significantly higher in pts without cGVHD. An analysis on a larger series would be useful to determine if the chimerism in DC could be predictive for cGVHD.

Download Full-text

Transplant Outcomes with Fludarabine and Melphalan in High Risk AML Patients By Donor Types

Blood ◽

10.1182/blood-2020-134474 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Betul Oran ◽

Stefan O. Ciurea ◽

Rohtesh S. Mehta ◽

Amin M. Alousi ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Research Funding ◽

Conditioning Regimen ◽

Advisory Board ◽

Research Support ◽

Hematopoietic Stem ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Count Recovery

Background: Fludarabine and melphalan (FM) reduced intensity conditioning regimen has been widely used for allogeneic stem cell transplantation (allo-SCT) in AML patients not eligible for more ablative regimens. In this study, we looked into a contemporary group of high risk AML patients treated with FM and updated their outcome expectation by donor type. Methods: We included 292 AML patients who had first allo-SCT between January 2010 and December 2019 if their donors were haploidential (haplo, n=142) or matched related sibling (MSD, n=49) or matched unrelated donor (MUD, n=101) and their conditioning regimen was intravenous melphalan given as 100 mg/m2 or 140 mg/m2 in addition to fludarabine. Graft versus host disease (GvHD) prophylaxis was either tacrolimus and methotrexate (n=91) or tacrolimus with post-transplant cyclophosphamide (PTCy) +/- Mycophenolate mofetil (n=201). The primary outcome was relapse-free survival (RFS) defined as time to relapse or death whichever happened first. Secondary outcomes was overall survival (OS). Results: The median age was younger in haplo transplants compared with MDS or MUDs (50 vs. 63)(Table 1). There were more patients in first or second complete remission with count recovery (CR1/2) in haplo group compared with MSD (29%) and MUD (37%) but that did not reach significance (p=0.22). High risk disease risk by European Leukemia Net (ELN), advance group, was also distributed similarly between donor groups (21% in MSD, 32% in MUD and 24% in haplo, p=0.5). Hematopoietic comorbidity index (HCT-CI) >2 was frequent in all donor groups (43% in MSD, 46% MUD and 36% haplo, p=0.4). Hematopoietic stem cell source and GvHD prophylaxis differed by donor as expected; all haplo patients but 15 had bone marrow (BM, 89%) while 2% of MSD and 26% of MUD had BM. GvHD prophylaxis was PTCy in all haplo patients but half of the MUD patients (49%) and some of the MSD also received PTCy (20%). The median follow-up of 143 survivors was 24 months (range, 1 to 102 months). RFS at 2 years was 41.6% (95% confidence interval (CI) 35.5%- 47.6%) and OS was 48.6% (95% CI=42.1%-54.7%). Outcome estimates by donor types are presented in table 2. Considering the haplo patients were younger, we also analyzed RFS for older patients aged >50 and >60 separately (Figure). Causes of death was mostly relapse in all donor types; 54.2% in MSD, 40.4% in MUD and 44.7% in haplo. Cox regression model for RFS revealed that CR1/2 or CR without count recovery (CRi/p) were favorable prognostic variables compared with advanced disease (hazard ratio (HR)=0.35, 95%CI=0.25-0.51, p<0.001 and HR=0.65, 95%CI=0.44-0.96, p=0.03) but ELN adverse risk (HR=1.91, 95%CI=1.37-2.65, p<0.001) and HCT-CI>2 (HR=1.62, 95%CI=1.17-2.23, p=0.003) were poor prognostic markers. Age >50 was not a prognostic factor for RFS. Conclusion: FM remains to be an effective conditioning regimen that is leading to similar RFS after transplant with different donor types. Despite smaller sample size, even older haploidentical patients had RFS that was not significantly different compared with older MSD and MUD patients. However, relapse remains to be the major reason of failure in patients with high risk features including disease status not in CR with count recovery at allo-SCT and/or adverse ELN risk. Innovative strategies either with more ablative regimens or post-transplant maintenance or integration of cellular therapy options are needed to improve outcomes for those AML patients. Disclosures Oran: Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Mehta:Incyte: Research Funding; Kadmon: Research Funding; CSL Behring: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Pfizer: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board. Champlin:Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy.

Download Full-text

Reduced Intensity Hematopoietic Stem Cell Transplantation for Treatment of Class 3 Lucarelli Severe Thalassemia Patients.

Blood ◽

10.1182/blood.v108.11.5364.5364 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5364-5364

Author(s):

Suradej Hongeng ◽

Samart Pakakasama ◽

Ampaiwan Chuansumrit ◽

Nongnuch Sirachainan ◽

Thanyachai Sura ◽

...

Keyword(s):

Stem Cell ◽

Survival Rate ◽

Hematopoietic Stem Cell Transplantation ◽

Conditioning Regimen ◽

Hla Antigens ◽

Mixed Chimerism ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Reduced Intensity

Abstract Approximately 80% of children with severe thalassemia (thal) were cured with hematopoietic stem cell transplantation (HSCT). However, initial reports suggested that a subset of patients (pts) had poorer outcomes, and were more likely to experience transplant-related mortality or recurrence. These were older pts who had evidence of organ damage from iron-overload and were classified as class 3 Lucarelli pts. One approach to reduce the mortality that has been tested in limited series is reduced intensity (RI) HSCT, which relies upon immunosuppressive rather than ablative pre-transplantation conditioning to facilitate engraftment of donor cells. We conducted RIHSCT in 8 severe thal pts with class 3 lucarelli. All were older than 10 yrs of age (median 12.5 yrs; range 10 – 18) and received blood more than 100 transfusions. Three pts had homozygous β thalassemia and 4 had β thalassemia/hemoglobin E. Five of these pts had splenectomy. The conditioning regimen; busulfan 12 mg/kg orally, iv. fludarabine 175–180 mg/m2, antithymocyte globulin (ATG) (Fresineus®) 40 mg/kg, was given in all pts. In addition, one pt (pt 2) also received thiotepa 10 mg/kg and single fraction total lymphoid irradiation (TLI) 500 cGY and one (pt 1) also received. TLI. All pts received hydroxyurea 20 mg/kg at least for 6 months prior to transplant in order to suppress erythroid expansion. Seven pts received peripheral blood stem cells (PBSC) from 6 HLA antigens matched siblings and 1 (Pt2) received T cell depleted PBSC by CD34+ selection from 4 HLA antigens matched mother. The median number of infused CD34+ cell was 9 × 106cells/kg (range 6.5 – 15 × 106). GvHD prophylaxis regimen was with cyclosporin or tracolimus and MMF. All pts can achieve full donor engraftment. Median time of neutrophil engraftment was 11 days (range 11– 14), and platelet was 14 days (range 12–24). Two pts did not have neutrophil count less than 0.5 × 109/L and four did not have platelet count less than 20 × 109/L. Four pts did not have acute GvHD, 3 had gr I and 1 had gr II. Only 1 pt had limited chronic GvHD. All pts had no major toxicity except pt 2 who developed CMV retinitis but it was resolved. The 2 yr thal free survival rate is 88% (95%CI: 39 %, 98 %) and the 2 yr overall survival rate is 100%. The median time of follow up was 10 months (range: 3 – 63). Currently, 6 pts had full donor chimerism, one had mixed chimerism and one had graft rejection. We would like to suggest that busulfan, fludarabine, and ATG together is the backbone of RIHSCT conditioning regimen for class 3 lucarelli pts. Since 2 (pt 7 and pt 8) out of three pts who did not have splenectomy prior to transplant, had mixed chimerism and one of these 2 pts finally had graft rejection, we, therefore, plan to add either another agent such as thiotepa or melphalan or TLI in our backbone RIHSCT conditioning regimen for the pts who do not have splenectomy prior to transplant in the future to achieve the sustainable engraftment. Donor chimerism study, Recent outcome, and Follow up time Pt Day + 15 Day + 30 Day + 60 Day + 100 Recent Outcome F/U time (months) M = mixed chimerism, F = full donor chimerism, L = loss of donor chimerism, A = alive, F/U = follow up, N/A = not applicable 1 M F F F A with F 63 2 F F F F A with F 47 3 F F F F A with F 39 4 F F F F A with F 12 5 F F F F A with F 8 6 F F F F A with F 7 7 F M L L A with L 4 8 F F M N/A A with M 3

Download Full-text

Sexual Life, Fertility and Ovarian Function in Women after Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽

10.1182/blood-2019-127371 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3301-3301

Author(s):

Forgeard Nathalie ◽

Matthieu Jestin ◽

Dominique Vexiau ◽

Florian Chevillon ◽

Régis Peffault de Latour ◽

...

Keyword(s):

Stem Cell ◽

Acute Leukemia ◽

Research Funding ◽

Ovarian Function ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reproductive Technology ◽

Sexual Life ◽

Hematopoietic Stem ◽

Post Transplant

Introduction Infertility is a major late effect after allogeneic hematopoietic stem cell transplantation (HSCT). Post-transplant complications such as graft versus host disease (GVHD) may also impact health-related quality of life. The aim of this study was to evaluate sequalae of disease and transplant on fertility, pregnancy wish, affective and sexual life in female recipients. Patients and methods This unicentric prospective study was conducted from 2014 to 2016 in Saint Louis Hospital (Paris, France). To be included, women had to be a) aged > 18 years with a minimal follow-up of 2 years after an allogeneic HSCT b) younger than 35 at HSCT c) in persistent complete remission of their hematological disease. In the first part of the study, data related to affective, sexual life and pregnancies were collected by self-reported surveys. Responses to open-ended questions were analyzed using a thematic analysis approach. The second part, restricted to patients younger than 40 years at inclusion, evaluated post-transplant ovarian function by hormonal dosages. The study was approved by an institutional review board. Premature ovarian failure (POF) was defined by amenorrhea and follicle stimulating hormone >25 IU/L. Sixty-three patients were included at a median age of 31.3 years [IQR, 24.9-37.3]: 58 completed the survey and 34 were evaluated for ovarian function. Only 8 patients had already had children before HSCT. Median age at HSCT was 23.4 years [IQR, 18.3-28]. Twenty-nine (46%) patients were transplanted for acute leukemia and 16 (25%) for aplastic anemia. Conditioning regimen was myeloablative (MAC) in 39 patients (62%), reduced (RIC) in 22 (35%) and sequential in 2 (3%). Seventeen patients (27%) benefited from a fertility preservation procedure (82% performed after 2004): ovarian tissue cryopreservation alone (n=7) or associated with oocyte cryopreservation (n=9) (missing data n=1). Thirty-two (51%) patients experienced chronic GVHD and 16 (44% of assessed patients) gynecologic GVHD. Results Fifty patients (86%) reported hypoestrogenism symptoms, mainly vaginal dryness (n=44, 76%) and hot flushes (n=32, 55%). Forty-four patients (76%) reported negative impact of transplant on their sexual life: 18 (31%) a decrease in libido, 17 (29%) experienced dyspareunia, 14 (24%) highlighted a relationship between physical sequelae and sexuality, and 19 (33%) reported a loss of self-confidence. Twenty-seven patients (47%) indicated that disease and treatments had decreased their desire for pregnancy, mainly for fear of relapse, disease transmission, and also due to negative self-representation. Most patients (n=56, 97%) were treated with hormone replacement therapy (HRT). Thirty-six patients (64%) temporarily interrupted their HRT. During this break, 14 (39%) experienced return of menses. POF was diagnosed in 25 of the 34 (74%) patients evaluated: 19/20 (95%) after MAC, 6/12 (50%) after RIC and none after sequential. Twenty-two patients (38%) expressed a desire for pregnancy after transplant; among them, 9 (41%) had a child. In the whole population, 13 patients (21%) got pregnant: 8 naturally (1 after MAC and 7 after RIC or sequential regimen) and 5 through assisted reproductive technology. Natural pregnancy occurred in 2.6% (1/39) of patients after MAC, 22.7% (5/22) after RIC and 100% (2/2) after sequential conditioning regimen. Four of these 8 patients were transplanted for aplastic anemia, 2 for acute leukemia, 1 for sickle cell disease and 1 for lymphoma. Among patients who benefited from assisted reproductive technology, 4 resorted to oocytes donation and one had classical in vitro fertilization. Finally, 3 women adopted children. A univariate logistic regression analysis was performed to evaluate the impact of age at transplant and at inclusion, conditioning regimen, disease and chronic GVHD on post-transplant outcomes. Table 1 shows variables significantly associated with POF, return of menses, pregnancy desire and natural pregnancies. Conclusion This study highlights the major physical and psychological impact of disease and transplant on affective, sexual, and reproductive outcomes in women. In this series, RIC and sequential regimens allowed for post-transplant ovarian function preservation in more than 50% of patients. Improvement of post-transplant fertility and management of treatment impact on sexual and affective life has to be a priority in long-term survivors of HSCT. Disclosures Peffault de Latour: Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Robin:Novartis Neovii: Research Funding. Michonneau:Neovii: Consultancy. Boissel:NOVARTIS: Consultancy.

Download Full-text

Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of the Francophone Society for Stem Cell Transplantation and Cell Therapy

Blood ◽

10.1182/blood-2018-99-111710 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3447-3447

Author(s):

Regis Peffault De Latour ◽

Matthieu Resche-Rigon ◽

Didier Blaise ◽

Johan Maertens ◽

Patrice Ceballos ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Research Funding ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Sibling Donor

Abstract Background: Nowadays acute myeloid leukemia (AML) patients above the age of 60 years are often candidates for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, little is known about the outcomes of HSCT in this particular population, due to the low number of HSCT with robust follow-up, the heterogeneity between centers, as well as reports usually mixing AML and other diseases such as myelodysplastic syndrome. We used the database of the Francophone society for stem cell transplantation and cellular therapy to address this question in a large cohort of patients in a recent time period. Patients and methods: 1167 consecutive patients aged ≥60 years with AML in complete remission (CR), transplanted between January 1st 2006 and January 1st 2016, reported to ProMISe (Project Manager Internet Server), an internet-based system shared by 36 Francophone transplantation centers, were reviewed. Classical post-HSCT endpoints were studied such as engraftment, acute and chronic graft-versus-host disease (GvHD), non-relapse mortality (NRM), relapse rate, leukemia free survival (LFS) as well as overall survival (OS). Cytogenetic risk was assessed according to the European Leukemia Network 2017 for patients in first complete remission. Data were analyzed using proportional hazards models and proportional sub-distribution hazards models in presence of competing risks. Results: Patients' Characteristics are detailed in Table 1. The median age at HSCT was 62.9 years (Interquartile range -IQR 61.9-66.1). Patients aged ≥60 years but less of 65 represented 63.8% of the population with 68.2% of patients transplanted in the recent period (2011-2016). Most patient had de novo AML (91.6%), in first CR (76.9%) with intermediate risk (83.8%) according to ELN-2017 classification. A matched unrelated donor (MUD) was used in 45 % of transplants and the majority of patients received peripheral blood stem cells (83.7%). Half of the patients received fludarabine and 2 days busulfan as conditioning regimen. The majority of patients (70.9%) received anti-thymocyte globuline (ATG). Engraftment occurred in 1089 patients (93.3%; 95%CI, 91.9-94.8). Day 100 cumulative incidence of grade II-IV acute GVHD was 24.6% (15.7% grade II; 5.8% grade III; 3% grade IV). At last follow up, 378 patients had developed chronic GVHD (severe in 37.2% of them; 95%CI, 34.0-40.3). With a median follow-up of 3.5 years (95%CI, 3.1-3.7 years), overall survival (OS) and LFS probabilities at 3 years were 50.7% (95%CI, 47.7-54.0) and 44.8% (95%CI, 41.8-48.1), respectively. In multivariable analysis, the only factor associated with worse OS was the use of a mismatched unrelated donor compare to MUD [Hazard Ratio (HR): 1.35 (95% CI, 1.01 to 1.80), p=0.04]. At 3 years, relapse incidence was 34.4% (95% CI, 31.5-37.4). The use of a sibling donor compared to MUD [Sub-distribution Hazard Ratio (SHR): : 1.49 (95% CI, 1.19 to 1.87), p<0.001], poor risk AML in CR1 according to ELN classification [SHR: 1.49 (95% CI, 1.10 to 2.02), p=0.01], as well as the use of ATG in the conditioning regimen [SHR: 1.57 (95% CI, 1.21 to 2.05), p<0.001] were associated with a higher risk of relapse. During the study, 534 patients died (main causes of death was relapse, 53%); leading to a CI of NRM of 20.7% at 3 years (95%CI, 18.2-23.2). A karnofsky score above 90% [SHR: 0.74 (95% CI, 0.56 to 0.98), p=0.04] and the use of a sibling donor compare to MUD [SHR : 0.43(95% CI, 0.30 to 0.63), p<0.001] were associated with reduced NRM. Conclusion: With more than 3 years follow-up, which is long enough for our results to be considered to be robust, the use of a mismatched unrelated donor was the only factor associated with worse overall survival in this population of AML patients aged of 60 years or more. Relapse appeared as the first cause of death, independently related to AML ELN poor risk classification, but also to the use of a sibling donor and of ATG in the conditioning regimen. This study highlights the major role of alloreactivity in this particular population, where modulation of T-cell alloreactivity as well as donor choice should be urgently addressed in well-designed prospective trials. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Download Full-text

The Graft-vs-Host Hematopoietic Effect Generated after Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) Cures Patients with Severe PNH.

Blood ◽

10.1182/blood.v104.11.811.811 ◽

2004 ◽

Vol 104 (11) ◽

pp. 811-811

Author(s):

Yoshiyuki Takahashi ◽

S. Chakrabarti ◽

R. Srinivasan ◽

T. Igarashi ◽

A. Lundqvist ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Cell Transplantation ◽

Conditioning Regimen ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Post Transplant ◽

Donor T Cells

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of hematopoietic stem cells characterized by RBC susceptibility to complement-mediated lysis. Infections related to neutropenia, bleeding associated with thrombocytopenia, and thrombosis all contribute to morbidity and mortality. Although allogeneic hematopoietic cell transplantation (HCT) can be curative, the high-risk of treatment-related mortality with myeloablative HCT precludes this approach for most patients with severe disease. We previously reported in vitro and in vivo data showing PNH cells could be killed by allo-reactive donor T-cells recognizing minor histocompatibility antigens expressed on both normal and GPI negative cells. Here we present updated data on a cohort of 11 patients with severe PNH who received a NST at the NHLBI from 5/99 through 6/2004. Eligibility included a diagnosis of PNH associated with one or more of the following :1) Transfusion dependence (n=9) 2) Prior thrombotic episodes (n=4) 3) Recurrent debilitating hemolytic crisis (n=7). Patients received a T-cell replete G-CSF mobilized blood stem cell transplant from an HLA-matched family donor following nonmyeloablative conditioning with cyclophosphamide (120mg/kg) and fludarabine (125mg/m2). Patients with a significant transfusion history had horse ATG (40mg/kg/day x 4) added to the conditioning regimen (n=9). CSA either alone (n=1) or combined with either MMF (n=4) or mini-dose methotrexate (n=6) was used as GVHD prophylaxis. The median % of GPI anchored protein negative neutrophils pre-transplant was 83% (range 13%–99%). Blood samples obtained post-transplant were analyzed by FACS to determine the percentage of persisting GPI negative neutrophils (CD15+/CD66b−/CD16−). Chimerism was also assessed post-transplant in T-cell and myeloid fractions by PCR assay of polymorphic short tandem repeats (STR). Neutrophil recovery occurred at a median 15 days (range 10–19). STR analysis revealed donor engraftment occurred in both myeloid and T-cell lineages in all patients. Self-limiting febrile hemolytic reactions associated with ATG administration (6/9 patients) and grade II-IV acute GVHD (n=5) were the most common complications associated with transplantation. With a median follow-up of 458 days (range 31–1917), all patients survive either in remission (n=8) or with declining GPI negative populations (n=3); GPI negative neutrophils were detected in all patients at engraftment but gradually declined until no longer detectable (<0.1%) in all 8 patients evaluable more than 100 days after transplantation, while 3 with shorter follow-up (days + 37, +51, +78) have persistent albeit rapidly declining PNH populations. The observation that GPI negative neutrophils populations decrease and ultimately disappear when myeloid chimerism transitions from mixed to full donor chimerism is consistent with PNH cells being eradicated through a graft-vs-host hematopoietic effect. None of the 7 patients with more than 1 year follow-up have had reoccurrence of their PNH clone. Conclusion: Alloreactive donor T-cells mediating graft-vs-host hematopoietic effects can immunologically eradicate PNH following NST. NST should be considered a viable and potentially curative option for patients with severe PNH.

Download Full-text

Influence of Lower Dose Antithymocyteglobulin As Conditioning Regimen on Viral Infection after Haploidentical Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.825.825 ◽

2016 ◽

Vol 128 (22) ◽

pp. 825-825 ◽

Cited By ~ 1

Author(s):

Ren Lin ◽

Yu Wang ◽

Fen Huang ◽

Zhiping Fan ◽

Shen Zhang ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Viral Infection ◽

Cell Transplantation ◽

Natural Science ◽

Research Funding ◽

Viral Infections ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Post Transplant

Abstract Background: Antithymocyteglobulin (ATG), used as conditioning regimen, can reduce graft-versus-host disease (GVHD) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Notwithstanding, immunosuppressive effect of ATG may increase the risk of viral infections after HSCT. To evaluate the effect of different doses of ATG on post-transplant viral infection, we conducted a multicenter prospective study to compare EBV and CMV infection in haplo-HSCT recipients receiving 7.5 mg/kg or 10 mg/kg ATG. Methods Between May 2013 and November 2015, 350 consecutive patients with hematological malignancies undergoing haplo-HSCT were randomized in 5 hospitals. One hundred and seventy-two patients received ATG with a total dosage of 7.5 mg/kg and 175 received 10 mg/kg ATG. Three patients did not received allocated intervention and transplantation due to leukemia relapse before transplant or toxicity of conditioning regimens. Results The cumulative incidence of EBV viremia on day 180 was 23.3±3.2% in 7.5 mg/kg ATG arm which was lower than that in 10 mg/kg arm (34.6±3.7%, P=0.037). CMV viremia were comparable in the two arms (7.5 mg/kg arm: 79.0±3.1% vs. 10 mg/kg arm: 76.9±3.2%, P=0.950). The incidences of CMV diseases were 0.6±0.6% and 2.4±1.2% in 7.5 mg/kg and 10 mg/kg arms, respectively (P=0.093). No difference in the incidence of post-transplant lymphoproliferative disorder (PTLD) was found between the two arms (2.4±1.2% in 7.5 mg/kg arm vs. 5.4±1.8% in 10 mg/kg arm, P=0.150). Besides, acute GVHD grade II to IV within 100 days occurred in 55 recipients with the incidence of 31.4% in 7.5mg/kg ATG arms and 45 recipients in 10 mg/kg arms with the incidence of 26.2% (P=0.279). The incidences of aGVHD grade III to IV were similar in the two arms (8.0% in 7.5 mg/kg arm: vs. 4.7% in 10 mg/kg arm, P=0.196). The 2-years overall survival were 69.5±4.7% and 69.4±3.9% for 7.5 mg/kg and 10 mg/kg group (P=0.540). Conclusion Compared with 10 mg/kg of ATG, the application of 7.5 mg/kg might reduce the risk of EBV infection after haplo-HSCT and not increase aGVHD. Disclosures Lin: National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding; National Natural Science Foundation of China 81400141: Research Funding.

Download Full-text

Outcome of Hematopoietic Stem Cell Transplantation in Children with Primary Hemophagocytic Lymphohistiocytosis: A Single Institution Experience Using Reduced Intensity Conditioning

Blood ◽

10.1182/blood-2020-142988 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Mohammed Essa ◽

Enas Basher ◽

Rodaina Abujoub ◽

Abdulrahman Alsultan

Keyword(s):

Stem Cell ◽

Graft Failure ◽

Conditioning Regimen ◽

High Rate ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Gvhd Prophylaxis

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for primary hemophagocytic lymphohistiocytosis (HLH). Conventional myeloablative conditioning regimen using busulfan, cyclophosphamide with or without etoposide was associated with high rate of transplant-related mortality (Horne et al. BJH 2005). Reduced intensity conditioning (RIC) is used in HLH to minimize transplant-related toxicities. The use of alemtuzumab, fludarabine, and melphalan in HLH was associated with low mortality; however, mixed donor chimerism and graft failure were frequent (Allen et al. Blood 2018). A recent report in 25 HLH patients who underwent HSCT from HLA matched donors using targeted busulfan (45-65 mg/L X h), fludarabine, and serotherapy resulted in adequate stable donor chimerism, no graft rejection, and no mortality (Felber et al. Blood Adv. 2020). In this study, we reviewed the outcome of 16 HLH patients who underwent HSCT from HLA matched donors using RIC. All patients were initially treated using HLH-2004 protocol. They subsequently underwent HSCT from 10/10 HLA matched related or unrelated donor using RIC regimens. We initially used AFM conditioning regimen that included alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) with or without thiotepa (10 mg/kg). GVHD prophylaxis included cyclosporine (CSA) and steroids. Given the high rate of low donor chimerism with AFM regimen, we subsequently used BF conditioning regimen that included busulfan (weight-based dosing for total of 16 doses) and fludarabine (160 mg/m2). Therapeutic drug monitoring of busulfan was performed. Thymoglobulin (10 mg/kg) was added in matched unrelated donor (MUD). GVHD prophylaxis included CSA and steroids in matched related donors (MRD) and CSA and methotrexate in MUD. Bone marrow was the stem cell source in all patients except one who underwent second transplant using peripheral blood stem cells. Supportive care was consistent among all patients. Defibrotide prophylaxis was administered to prevent sinusoidal obstruction syndrome (SOS). Donor chimerism <5% from whole blood or <20% in T-cell, graft failure, and death from any cause were considered as events. A total of 16 HSCT transplants were performed, 5 received AFM regimen and 11 received BF regimen. Patient and transplant characteristics are shown in Table. All patients had successful neutrophil and platelet engraftments. Among the five patients who underwent AFM conditioning, one patient with SH2D1A mutation is 8 years post transplant with stable full donor chimerism and another patient with PRF1 mutation who received AFM with thiotepa has stable sufficient donor chimerism 3 years post transplant. Both patients did not require donor leukocyte infusions (DLI). The remaining 3 patients had declining donor chimerism beyond the first year of transplant despite the frequent use of DLI, one of them had disease reactivation and underwent second HSCT using BF regimen. Event free survival (EFS) at 3 years was 60% and overall survival (OS) was 100%. Among the 11 patients who underwent BF regimen, 7 were transplanted using MRD and 4 MUD. The median cumulative area under the curve of busulfan was 64 mg/L X h (range, 56-73). Median donor myeloid chimerism was 97% (range, 83-100) and median T-cell chimerism was 78% (range, 40-93). One patient who underwent MUD had grade III acute GVHD and none had chronic GVHD. Two patients had mild SOS. There were no events among BF group with median follow up duration of 393 days (151-2080). The use of BF regimen in HLH was associated with excellent outcome and stable donor chimerism with no graft failure in comparison to AFM regimen. Longer follow up is needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.

Download Full-text