scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia with Pre-Transplant Conditioning Using Fludarabine, Reduced-Dose Cyclophosphamide, and Low-Dose Thymoglobulin:Â Ksgct Prospective Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2101-2101
Author(s):  
Shinichi Kako ◽  
Yoshinobu Kanda ◽  
Makoto Onizuka ◽  
Nobuyuki Aotsuka ◽  
Kensuke Usuki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Reduced Dose ◽  
Company Limited ◽  
Otsuka Pharmaceutical

Abstract [Background] Allogeneic hematopoietic stem cell transplantation (HSCT) is a potent treatment to cure in patients with aplastic anemia (AA). However, an optimal pre-transplant conditioning remains unclear. The combination of high-dose cyclophosphamide (CY) and anti-thymocyte globulin (ATG) has been used as an effective conditioning, but cardiotoxity due to high-dose CY has been a major concern especially in patients with iron overload by excessive transfusion. In addition, the appropriate dose and timing of ATG use is another unsolved topic in HSCT for AA. Therefore, we performed a prospective study to assess the safety and efficacy of a conditioning regimen using fludarabine (Flu), reduced-dose CY, and low-dose thymoglobulin in HSCT for AA. [Methods] Patients with severe AA, aged between 16 and 65 years, who have an HLA-matched or 1-locus mismatched, related or unrelated donor were prospectively included. A conditioning regimen consisted of Flu 30mg/m2 for 4 days, CY 25mg/kg for 4 days, and thymoglobulin 1.25mg/kg for 2 days (days -4, and -3). In patients who underwent transplantation from unrelated and/or HLA-mismatched donor, 2 Gy of total body irradiation was added. Cyclosporine for an HLA-matched related donor or tacrolimus for the other donors, together with short-term methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Granulocyte-colony stimulating factor was used from 1 day after transplantation. Primary outcome measure was an overall survival at 1 year after HSCT. This study was approved by the Institutional Review Board of all the participating institutions. [Results] Twenty-eight patients were enrolled between 2011 and 2017, and their median age was 36 years (range: 18 - 61y). Sixteen patients were male. A median time from diagnosis to transplantation was 1858 days in patients who had previously received immunosuppressive therapy (IST) using ATG (n = 16) and 121 days in those who had not received IST (n = 12). Sixteen patients received graft form related donors including 1 HLA-mismatched donor, and 12 patients did from unrelated donors including 3 mismatched donors. Stem cell source was bone marrow in 27 out of 28 patients. All patients but one, who died early due to infection, achieved neutrophil engraftment at a median of 19 days after HSCT. Mixed chimerism (MC) was observed in 6 patients at day 30, and 3 out of those 6 patients achieved complete donor chimerism by day 90. On the other hand, MC was newly observed in additional 2 patients at day 90. Only one patient experienced secondary engraftment failure, and which developed with complete donor-type chimerism at day 99. No patients developed grade 2-4 acute GVHD. However, the cumulative incidence of chronic GVHD was 39.9 % at 1 year, and one third of them had extensive type. With a median follow-up period of 1727 days for survivors, overall survival rates (OS) were 96.4 % at 1 year and 82.8 % at 5 years (Figure 1). Cytomegalovirus (CMV) antigenemia was detected in 17 patients, but no patients developed CMV disease. A high Epstein-Barr virus (EBV)-DNA load (more than 1×104 copies/mL) was detected in 2 patients at day 60 and 1 patient at day 90. Neither developed EBV-lymphoproliferative disorder (LPD) within a year. However, another patient, in whom high EBV-DNA load was not detected within 90days after HSCT, developed EBV-LPD and died at three and a half years after HSCT. [Conclusion] HSCT for AA using Flu, reduced-dose CY, and low-dose thymoglobulin as a conditioning regimen was safe and effective. Relatively high incidences of MC and chronic GVHD need further improvement. (This study is registered with www.umin.ac.jp as UMIN000006071.) Disclosures Kako: Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Tanabe-Mitsubishi: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Taiho: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Otsuka: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Usuki:Ono Pharmaceutical: Speakers Bureau; GlaxoSmithKline K.K.: Research Funding; Janssen Pharmaceutical K.K: Research Funding; Sanofi K.K.: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Takeda Pharmaceutical: Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Mori:Astella Pharma: Honoraria; Shire Japan: Honoraria; Janssen: Honoraria; SHIONOGI: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Novartis Pharma: Honoraria; Celgene: Honoraria; Japan Blood Products Organization: Honoraria; Pfizer: Honoraria; CHUGAI: Honoraria; MSD: Honoraria; Eisai: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; MSD: Research Funding; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria.

Second Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine Treosulfan Conditioning Regimen in Patients Previously Treated with Busulfan-Based Regimens; Myeloablation with Acceptable Toxicity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2255-2255 ◽  
Author(s):  
Avichai Shimoni ◽  
Avital Rand ◽  
Noga Shem-Tov ◽  
Izhar Hardan ◽  
Yulia Volchek ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose ◽  
Primary Malignancy ◽  
Hematopoietic Stem ◽  
Reduced Toxicity ◽  
Disease Free

Abstract Abstract 2255 Poster Board II-232 The prognosis of patients (pts) with leukemia who relapse after a prior autologous and or allogeneic hematopoietic stem cell transplantation (SCT) is dismal. A second allogeneic SCT can salvage some of these pts but myeloablative conditioning is associated with high rates of non-relapse mortality (NRM) in this setting and a relatively poor outcome. Reduced intensity conditioning allows reduction of NRM following a second SCT, but may be associated with a high relapse rate, mostly when leukemia is not in remission at the time of SCT. Similarly, allogeneic SCT for pts who develop secondary leukemia after a prior autologous SCT for a primary malignancy is associated with similar risks. The combination of fludarabine and treosulfan (FT) has been previously reported as a dose intensive myeloablative regimen with reduced toxicity and effective anti-leukemia capability, but its merit in second SCT is not defined. We explored a regimen consisting of fludarabine (total 150 mg/m2) and treosulfan (total 30-36 gr/m2) with the addition of ATG to recipients of unrelated or mismatched donor SCT, as a conditioning regimen for a second SCT. The study included 17 pts, 10 male, 7 female, median age 58 years (range, 20-70). Patient diagnosis at second SCT was AML (n=11), MDS (n=3), myelofibrosis (n=2) and CML in accelerated phase (n=1). The first transplant was autologous (n=6) or allogeneic (n=11). Autologous SCT was given for AML (n=3, 1 of them APL) or for a primary malignancy (lymphoma - 2, multiple myeloma -1). Second allogeneic SCT was given for relapse after a prior SCT or for secondary AML/MDS in the 3 pts having autologous SCT for lymphoma and myeloma. The Donor for the second SCT was an HLA-match sibling (n=6) or matched unrelated (n=11). In the 11 pts having a second allogeneic SCT after failure of a first allogeneic SCT the donor was the same donor in 3 transplants and a different donor in 8 transplants. The conditioning regimen for the first SCT contained high-dose intravenous busulfan (12.8 mg/kg) in 9 pts and reduced dose busulfan (6.4-9.6 mg/kg) in 5 pts. The three pts with primary lymphoma and myeloma were given BEAM and high-dose melphalan, respectively. The median time between the first and second SCT was 28 months (range, 3-48 months). Only 4 pts were in remission at the time of second SCT. Six pts were chemo-refractory and 7 pts were transplanted in untreated malignancy. Results: 12 pts engrafted with a median time to ANC > 0.5 × 109/L of 12 days (range, 9-38) and for PLT > 20 × 109 of 15 days (range, 11-44). Five pts died prior to engraftment, 3 of infections, 1 of cerebral hemorrhage and 1 of graft failure. There were no deaths related to organ toxicity (e.g. VOD or pneumonitis) and no late deaths due to NRM. Acute GVHD grade II-IV occurred in 2 pts, cumulative incidence 28%. Chronic GVHD occurred in 4 of 8 evaluable pts, cumulative incidence 57%. There were no deaths attributed to acute or chronic GVHD. The cumulative incidence of NRM was 30% (95%CI, 14-62). Three pts relapsed with a cumulative incidence of 25% (95%CI, 9-69). In all, with a median follow-up of 12 months (range, 1-59 months) the estimated 2-year overall and disease-free survival were both 45% (95CI, 17-73). Best results were achieved in the group of 8 pts having a second SCT form a second allogeneic donor; 5 pts are currently disease-free for a median of 18 months (range, 3-38), despite transplantation in advanced phase; 3 refractory to salvage chemotherapy and one in untreated relapse after the first SCT. The estimated 2 year survival in this group was 60%, a promising outcome in this setting. In conclusion, the fludarabine-treosulfan regimen is feasible for a second allogeneic SCT. NRM especially in the early post-transplant period is substantial, but can be expected in a group of heavily pretreated pts, many with active and refractory leukemia. The regimen has a promising anti-leukemia effect in this setting with a low recurrence rate, especially when using a different donor than in the prior transplant. The FT regimen can be considered a reduced toxicity myeloablative regimen that is feasible in pts given a prior transplant including pts previously given myeloablative doses of busulfan. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Resolution Donor/Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: The Italian Experience on Behalf of GITMO, IBMDR and Aibt

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4642-4642
Author(s):  
Alessandra Picardi ◽  
Nicoletta Sacchi ◽  
Valeria Miotti ◽  
Francesca Lorentino ◽  
Elena Oldani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hla Matching ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Grade 3 ◽  
Italian Origin ◽  
Advisory Role

Abstract Introduction: HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). To elucidate the effect and the potential identification of "permissive" and "non permissive" I and II class HLA mismatching (mm) loci on the early and long term transplant outcome, we conducted a retrospective/prospective observational analysis on 1789 patients transplanted with unmanipulated haematopoietic stem cells from a volunteer unrelated donor (URD). Methods Between January 2012 to December 2015, 1789 adult patients with a median age of 49 years (18-70) affected by haematological malignant diseases, performed an unrelated HSCT, coordinated by the Italian Bone Marrow Donor Registry (IBMDR). All patients have been typed by high resolution (HR) HLA typing for HLA-A/B/C/DRB1/DQB1 loci, at the start of the donor's search process. Patient and donor characteristics are shown in Table 1. As conditioning regimen and GVHD prophylaxis, 71% of patients received a myeloablative conditioning and 76% a combination of anti-Thymoglobuline, Cyclosporine and Metotrexate short course. Total Body Irradiation was part of conditioning regimen in 14% of cases and PBSC was used as stem cell source in 80% of transplants. Median follow for survivors was 38 months (1-76). Regarding to the allelic compatibility, 890 (50%) of donor/recipient (D/R) pairs were 10/10 HLA matched, 677 (38%) showed 1 mm for A, B, C, DRB1 or DQB1 in 249, 141, 173, 2 and 112 cases, respectively and 222 (12%) received HSCT from a 8/10 or less HLA matched donor. Results: Overall 90% and 79% of patients achieved PMN and PLTS engraftment within 30 and 90 days, respectively. Probabilities of 3-y Overall Survival (3-yr OS), Progression Free Survival (3-yr PFS), and Graft Relapse Free Survival (3-yr GRFS) were 52%, 42%, and 30%, respectively. The 3-y CI of Transplant Related Mortality (TRM) was 26%, with a 100-days CI of acute GVHD ≥2 of 26%, whereas the 3-yr CI of chronic GVHD was 30%, of which 10% extensive. Cox multivariate analysis showed that, compared to 10/10 HLA-matched HSCT, 9/10 and ≤8/10 HLA-matched HSCT were associated with worse outcomes in terms of OS (HR 1.16, p=0.04 and HR 1.3, p=0.007, respectively), GRFS (HR 1.2, p=0.005 and HR 1.2, p=0.07, respectively), TRM (HR 1.3, p=0.007 and HR 1.6, p<0.0001, respectively), grade 3-4 aGVHD (HR 1.8, p=0.0001 and HR 1.8, p=0.01, respectively) and cGvHD (HR 1.3, p=0.005 and HR 1.1, p=0.35, respectively). Notably, no significant differences occurred through the comparison between ≤8/10 and 9/10 matching. Univariate comparisons are shown in Figure 1. Moreover, in order to identify permissive and non permissive allelic mismatching, we analyzed the donor/recipient pairs with a single HLA mm with a frequency > 5%: the presence of A02:01 in the patient's HLA, after adjustment for HLA matching at the other loci and other clinical variables known to affect HSCT outcome, was associated with significant higher risk of TRM (HR 1.9, p= 0.03) and worst OS (HR 1.7, p=0.04). Patient's age > 49 years (p<0.0001), advanced disease stage (p<0.0001), presence of 1 or more co- morbidity according to the Sorror Hematopoietic Cell Transplant-Comorbidity Index (p=0.01) were associated with a hazard risk of 1.4, 2, 1.2 for OS and 1.6, 1.75, 1.4 for TRM. Moreover, the Italian origin of recipient and donor resulted in reduced grade 2-4 acute (HR=0.6, p=0.001) and chronic GVHD (p=0.002, HR=0.4). Finally, the Transplant Program expertise (>10 HSCT/year) is associated with reduced TRM (HR 0.8, p=0.0001), HSCT from female donor to male recipient was associated with higher risk of extensive cGvHD (HR 1.4, p=0.03), and CMV negative/negative status versus other combinations had protective effect on development of grade 3-4 aGVHD (HR 0.56, p=0.04). Conclusions: Our large cohort data of homogeneously treated 1789 URD transplants, show that 10/10 HLA matching remains a significantly favorable prognostic factor for OS, TRM, GRFS and acute/chronic GVHD, whereas there are no significant differences between 8/10 and 9/10 matching transplants. Moreover, the HLA A02:01 as single mm seems to play a "non permissive" role. Finally the Italian origin of recipient and donor is related to a reduced development of GVHD probably due to the matching of the extended MHC haplotypes in individuals of the same geographic origin. Disclosures Rambaldi: Amgen Inc.: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Omeros: Consultancy; Roche: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy. Vago:Moderna TX: Research Funding; GENDX: Research Funding. Patriarca:Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; MSD Italy: Other: Advisory Role.

Combined Use of Multi-Day Doses of Palonosetron and Aprepitant with Low Dose Dexamethasone In Prevention of Nausea and Emesis Among Patients with Multiple Myeloma and Lymphoma Undergoing Autologous Hematopoietic Stem Cell Transplant (ASCT): A Pilot Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1335-1335
Author(s):  
Delva Deauna-Limayo ◽  
Omar Aljitawi ◽  
Siddhartha Ganguly ◽  
Sunil Abhyankar ◽  
Jo Wick ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Low Dose ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Combined Use ◽  
Delayed Cinv

Abstract Abstract 1335 High dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) is a standard of care therapy patients with multiple myeloma and relapsed/refractory lymphomas. Unfortunately, high dose chemotherapy used in the preparative regimen is considered highly emetogenic. In one study, only 20% of patients undergoing ASCT managed to remain emesis-free. The 5-HT3 receptor antagonist is considered the backbone of anti-emetic regimens in this setting. Despite the combined use of these agents with dexamethasone, only 47% of recipients would achieve emetic control. Palonosetron, a second generation 5-HT3 antagonist, is approved as a single 0.25 mg IV dose in prevention of acute emesis in highly emetogenic chemotherapy regimens. Aprepitant represents a new class of oral anti-emetic which targets the NK-1 receptor. It is effective for both acute and delayed onset emesis. Objectives and Methods: Patients undergoing ASCT for multiple myeloma (MM) and relapsed lymphoma at the University of Kansas Medical Center were offered this study. The primary objective was to assess emetic responses to prophylactic multi-day doses of palonosetron, aprepitant and low dose dexamethasone. Emetic responses were assessed by daily patient diaries and the Multinational Association for Supportive Care in Cancer Antiemetic Tool (MAT). Nausea was measured using a Nausea Visual Score (NVS) of 0 to 10 with score of 0 having no nausea. A “modified” Osoba module was used to assess quality of life (QOL); and non-hematologic toxicities were evaluated. Preparative regimens were MEL140-200 for MM and BEAM or BEAC +/− rituximab for lymphomas. Standard doses aprepitant 125/80/80 mg were administered on days - 3, - 2, - 1 for MM group, and days - 7, - 6, - 5 for lymphoma group. Low dose dexamethasone 4 mg IV and multi-day doses of palonosetron 0.25 mg IV were administered on days - 3, - 2, -1, and on days - 7 thru - 3 for the MM and lymphoma groups, respectively. In both groups, palonosetron was repeated on day + 3. Acute chemotherapy-induced nausea/vomiting (CINV) was defined as nausea and/or vomiting within 24 hours of chemotherapy. Delayed CINV was defined as nausea and/or vomiting after 24 and up to 72 hours after chemotherapy; and extended CINV as nausea and/or vomiting after 72 hours of chemotherapy. Emetic responses were defined as follows: Complete Control (CC) – no emetic episode in 24 hours, no rescue medications and NVS of ≤ 2.5; Complete Emetic Response (CR) – 0 emetic episode, no rescue; Major Emetic Response (MR) – 1–2 episodes; Minor Emetic Response (MR) – 3–5 episodes; Failure - >5 episodes. Results: Between October 2007 and January 2010, 20 patients were enrolled, of which 18 were considered evaluable, 9 MM and 9 lymphoma – both Hodgkin's and non-Hodgkin's lymphoma. There were 11 males and 9 females. Median age was 55 (range: 35–66). All patients achieved at least a major emetic response in the acute, delayed and extended phases. Acute CINV responses were achieved in all patients: CC 2/9 (22%) and MR 7/9 (78%) in MM patients and CC 2/9 (22%), CR 2 (22%) and MR 5/9 (56%) in lymphoma patients. Delayed CINV responses were achieved in all patients: CC 2/9 (22%), CR 1 (11%) and MR 6/9 (67%) in MM patients and CC 4/9 (44%), CR 1 (11%) and MR 4/9 (44%) in lymphoma patients. Finally, all patients achieved extended CINV responses: CC 1/9 (11%) and MR 8/9 (89%) in MM patients and CC 2/9 (22%) and MR 7/9 (78%) in lymphoma patients. Eight patients developed grade 2–3 non-hematologic toxicities (arrhythmia, infection, febrile neutropenia, gastric mucositis, abdominal pain, and hyponatremia) attributed to the preparative transplant regimen. Only the arrhythmia was felt to be possibly related to the study drugs. Data on QOL will be presented during the conference. Conclusion: The combination of multi-day palonosetron combined with aprepitant and low dose dexamethasone appear to be well tolerated and effective in achieving at least a major emetic response in 100% of patients with MM and lymphoma undergoing high-dose therapy and ASCT. These encouraging results should warrant further evaluation in a larger population of ASCT patients. Disclosures: Deauna-Limayo: Eiasi: Research Funding. Aljitawi:Eisai: Research Funding.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 970-970 ◽  
Author(s):  
Robert Chiesa ◽  
Junfeng Wang ◽  
Henric-Jan Blok ◽  
Benedicte Neven ◽  
Despina Moshous ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Engraftment Failure

Abstract Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

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

Blood ◽  
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.

scholarly journals Clinical Outcome Associated with Cytomegalovirus (CMV) Infection/Disease in CMV-Seropositive Adult Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3382-3382
Author(s):  
Regis Peffault De Latour ◽  
Patrice Chevallier ◽  
Didier Blaise ◽  
Aurore Clement ◽  
Thierry Allavoine ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
First Year ◽  
Unrelated Donor ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Infection Disease

Abstract Recipients of allogeneic hematopoietic stem cell transplant (HSCT) who have positive cytomegalovirus (CMV) serology are at increased risk for morbidity and mortality after HSCT. However, the exact correlation between early CMV infection and post-HSCT outcomes, notably relapse, is still a source of conflicting data, especially in the era of viral surveillance through polymerase chain reaction (PCR) and preemptive antiviral therapy. We thus decided to retrospectively investigate the clinical impact of early, post-HSCT CMV infection/disease, in a large multi-center cohort of French patients. All consecutive CMV-seropositive adults (≥ 18 years old) who received a first HSCT in 3 French centers between January 1st 2010 and December 31th 2014 were eligible. Cord blood transplantation or a second HSCT were not considered here, as these procedures are associated with a significantly higher risk of morbidity and mortality. Study data were primarily derived from existing electronic health records. The study was conducted in accordance with the Declaration of Helsinki. CMV infection/disease was defined by the initiation of a preemptive and/or a curative anti-CMV treatment in the presence of a CMV viremia detected by a quantitative PCR. The primary objective of this study was to assess the association between CMV infection/disease and overall mortality within the first-year post-transplantation. Secondary clinical endpoints addressed the association between CMV infection/disease and the following outcomes within the first-year of HSCT: graft failure, relapse of the underlying disease, non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host disease (GvHD), and the occurrence of infections other than CMV. Relapse was considered as a competing risk for non-relapse mortality, and death for other events of interest (relapse, incidence of acute and chronic GvHD, and occurrence of infections). Models were adjusted for disease type, disease status at HSCT, age at HSCT, sex, donor type, stem cell source, and conditioning regimen (MAC versus RIC, use of total body irradiation or anti-thymocyte globulin). Five hundred seventy-two patients (54.5% male, 71.2% with Karnofsky >90, and median age 54 years) met the inclusion criteria. Underlying diseases were acute leukemia (33.9%), lymphoid neoplasms (25.9%), and myelodysplastic/ myeloproliferative neoplasms (22.6%). The disease was generally in complete remission at the time of HSCT (56.5%) or stable at the time of HSCT (16.4%). The majority of patients had received a reduced intensity conditioning regimen HSCT (72.5%), and peripheral blood stem cells (71.3%). Donor type was as follows: HLA-matched unrelated donor, 34.1%; HLA-matched relative donor, 46.5%; mismatched unrelated donor, 16.3% and mismatched related donor, 3.10%. CMV infection/disease was observed in 227 patients (39.7%) at a median time of 39.5 days (range, 3-295 days) post-transplant. Overall survival rate as per Kaplan-Meier analysis was 70.9% at 1-year post-HSCT. After adjusting for significant risk factors and considering CMV infection/disease as a time-dependent variable in a Cox model, overall mortality at 1-year was significantly increased in patients developing CMV infection/disease (HR 1.86, [95%CI 1.16 - 3.00], p=0.011). The Fine and Gray competing risk model showed that CMV infection/disease during the first-year post-transplant was significantly associated with higher risk of infections other than CMV (HR 2.34, 95%CI [1.63 - 3.37], p<0.0001) and, consequently, an increased risk for NRM (HR 2.62, 95%CI [1.59 - 4.30], p=0.0001). We did not find any significant association between CMV infection/disease and acute or chronic GvHD, as well as with relapse. In this large cohort of 572 consecutive CMV-seropositive adults undergoing allo-HSCT, and who were monitored with a PCR-based strategy according to routine clinical practice, we identified that CMV infection/disease were significantly associated with an increased risk of 1-year overall and non-relapse mortality, related to higher rates of infections other than CMV. Therefore, post-HSCT CMV infection/disease seemed to be a major concern in the recent healthcare setting, affecting mortality and morbidity. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Clement:MSD: Employment. Allavoine:MSD: Employment. Tadmouri:ClinSearch: Employment. Blomkvist:ClinSearch: Employment.

scholarly journals Bortezomib, Melphalan and Low Dose TBI Conditioning for Patients Undergoing Autologous Stem Cell Transplantation for Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2267-2267
Author(s):  
Francis K Buadi ◽  
Morie A. Gertz ◽  
Betsy R. Laplant ◽  
Alese Halvorson ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Research Funding ◽  
Low Dose ◽  
Conditioning Regimen ◽  
High Dose ◽  
Phase 2 ◽  
Conditioning Therapy ◽  
High Dose Melphalan ◽  
Dose Levels

Abstract Background: Autologous stem cell transplantation is an integral part of myeloma therapy for patients who are able to undergo the treatment. While high dose melphalan has remained the typical conditioning regimen for ASCT in MM, recently there have been efforts to enhance the conditioning therapy by adding newer drugs to melphalan. Addition of bortezomib as well as carfilzomib have been attempted in phase 2 trials. Previous studies have shown that the combination of melphalan and total body irradiation (TBI) is an effective conditioning regimen. Pre-clinical studies have shown that bortezomib can sensitize MM cells to radiation, and based on this finding, we designed a clinical trial to examine the feasibility of combining low dose TBI with a combination of melphalan and bortezomib. Patients and Methods: The primary goal of the phase 1 study was to determine the maximally tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose TBI as part of conditioning chemotherapy in patients undergoing an ASCT for MM. The secondary goals were to examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with MM and to determine the progression free rate at 1 and 2 years. Patients eligible to receive full dose melphalan conditioning regimen for ASCT were included as long as they had no more than 2 prior regimens and had not received a prior transplant. An accelerated design that was later converted to a standard 3+3 cohort design was used for dose escalation. Three patients were treated at a given dose level combination and observed for at least 36 days to assess toxicity. Melphalan 80 mg/m2 was given days -4, -3, with bortezomib at increasing doses given on day -5, -2 along with TBI of 200 cGY given on the same days of bortezomib, timed after bortezomib administration. Stem cells were infused day 0. Results: Eleven patients were enrolled; 6 were males, and the median age was 60 years. Median time from diagnosis was 5.4 months (range 3.4-7.0). Four dose levels were explored with increasing doses of bortezomib (0.7 mg/m2 to 1.6 mg/m2). No dose limiting toxicities were observed. The dose levels and the best response after ASCT are as shown in the Table. The overall response rate was 100%, including 7/11 with a CR or sCR. With a median follow-up of 12.5 months, two patients have progressed; median OS was not reached. Toxicity was mostly hematologic, with other AEs being grade 3 or less and attributable to the conditioning therapy. All patients engrafted their counts adequately. Conclusion: The combination of melphalan, bortezomib, and low dose TBI is a safe conditioning regimen in patients with MM with good efficacy. The regimen should be further examined in the phase 2 setting. Table Table. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Noxxon: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

Sign in / Sign up

Export Citation Format

Share Document