Publications by authors named "Jean Yves Cahn"

171 Publications

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Division of Hematology/BMT, Mayo Clinic, Rochester, MN, USA.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.
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http://dx.doi.org/10.1038/s41409-021-01450-3DOI Listing
September 2021

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

Blood Adv 2021 Sep 21. Epub 2021 Sep 21.

University of Virginia, Charlottesville, Virginia, United States.

The role of haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariate analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) between haploidentical HCT using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD) , 7/8 HLA-matched UD, or umbilical cord blood (UCB) HCT. Comparing haploidentical to MSD HCT, OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher with MSD HCT. Compared to MUD HCT, OS, LFS, and relapse were not different but MUD HCT had increased NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD. Compared to 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR 1.38, P=0.01) and increased NRM (HR 2.13, P=<0.001), grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Compared to UCB HCT, late OS , late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001) and grade 3-4 aGVHD (HR 1.97, P<0.001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared to traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in CR.
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http://dx.doi.org/10.1182/bloodadvances.2021004916DOI Listing
September 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Aug 14. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
August 2021

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 09 16;56(9):2108-2117. Epub 2021 Apr 16.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425595PMC
September 2021

Conventional chemotherapy for acute myeloid leukemia in older adults: Impact on nutritional, cognitive, and functional status.

Eur J Haematol 2021 Jun 27;106(6):859-867. Epub 2021 Mar 27.

Clinical Hematology, Grenoble University Hospital, Grenoble, France.

Objectives: The impact of conventional treatment for acute myeloid leukemia (AML) on the nutritional, cognitive, and functional status of elderly patients is seldom studied. This assessment was performed in the context of the LAMSA 2007 trial.

Methods: The trial enrolled 424 patients with de novo AML. Among them, 316 benefited from geriatric assessment (GA) including nutritional, cognitive, and functional status and were scored according to Eastern Cooperative Oncology Group (ECOG) and sorror for the prediction of treatment toxicity, morbidity, and mortality. Patients were investigated at diagnosis for three times during follow-up.

Results: This study showed that AML and its treatment have no impact on cognitive (P = .554) nor functional status (P = .842 for Activity of Daily Living and P = .087 for Instrumental Activities of Daily Living). The nutritional status improved over time (P = .041). None of these three parameters at baseline, associated or not with ECOG and sorror scores, impacted survivals or toxicities.

Conclusions: The cognitive, functional, and nutritional status had no impact in this cohort of fit elderly AML patients without unfavorable cytogenetics. The GA tools used provided no additional information compared with ECOG and sorror scores, to predict toxicity, morbidity, or mortality due to intensive chemotherapy.
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http://dx.doi.org/10.1111/ejh.13624DOI Listing
June 2021

Risk factors of BK viral hemorrhagic cystitis in allogenic hematopoietic stem cell transplantation.

Transpl Infect Dis 2021 Mar 16:e13601. Epub 2021 Mar 16.

Department of Hematology, Bone Marrow Transplant Unit, CHU Grenoble Alpes, Grenoble, France.

Reactivation of BK virus (BKV) can occur during intensive immunosuppression such as in allogenic hematopoietic stem cell transplant (AHSCT) recipients for whom a systematic PCR urine test for BKV will be positive in 50% to 100% of patients. Only 5% to 40% will develop BKV hemorrhagic cystitis (HC). Thus, BKV PCR testing is useful to confirm a diagnosis of BKV-HC but not to predict its occurrence. The aim of this retrospective study was to ascertain the risk factors of developing BKV HC, mostly in patients receiving posttransplant cyclophosphamide. The study looked at data from Grenoble Alpes University Hospital included in the national retrospective register ProMISe, administered by the "Société Francophone de Greffe de Moelle et de Thérapie Cellulaire". Urine BKV PCR was performed when patients presented grade ≥ 2 hematuria with clinical symptoms of cystitis. BKV-HC was defined as an association of clinical symptoms of cystitis, grade ≥ 2 hematuria and BKV viruria > 7 log copies/ml. From January 2014 to January 2018, 168 AHSCTs were considered for analysis, of which 43 (25.6%) developed BKV-HC and 44.9% of the subgroup that received posttransplant cyclophosphamide. After logistic regression, the risk factors associated with BKV-HC were reduced to posttransplantation exposure to cyclophosphamide (OR 4.25, [1.66; 10.87], P = .02), age < 40 y (OR 3.85 [1.51; 9.80], P = .005) and corticosteroid therapy (OR 3.86, [1.59; 9.36], P = .003). Exposure to cyclophosphamide, younger age (<40) and corticosteroid therapy are potential risk factors for BKV-HC.
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http://dx.doi.org/10.1111/tid.13601DOI Listing
March 2021

Impact of early candidemia on the long-term outcome of allogeneic hematopoietic stem cell transplant in non-leukemic patients: an outcome analysis on behalf of IDWP-EBMT.

Bone Marrow Transplant 2021 07 29;56(7):1563-1572. Epub 2021 Jan 29.

Department of Pediatric Hematology and Oncology, Collegium Medicum UMK Torun, Bydgoszcz, Poland.

We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p < 0.0001), and 100-day OS was lower (HR 3.22, p < 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p < 0.0001, 28.2% vs.18.8%, p < 0.0001, and 25.3% vs. 27.2%, p = 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.
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http://dx.doi.org/10.1038/s41409-021-01212-1DOI Listing
July 2021

Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myelogenous Leukemia and Myelodysplastic Syndromes with Low/Intermediate but not High Disease Risk Index: A Center for International Blood and Marrow Transplant Research Study.

Transplant Cell Ther 2021 01 1;27(1):68.e1-68.e9. Epub 2020 Oct 1.

Division of Medical Oncology, Markey Cancer Center, University of Kentucky School of Medicine, Lexington, Kentucky.

Compared with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, disease-specific risk factors in AML/MDS can further inform when MAC and RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the Disease Risk Index (DRI) in 4387 adults (age 40 to 65 years) to identify the impact of conditioning intensity. In the low/intermediate-risk DRI cohort, RIC was associated with lower nonrelapse mortality (NRM) (hazard ratio [HR], .74; 95% confidence interval [CI], .62 to .88; P < .001) but significantly greater relapse risk (HR, 1.54; 95% CI, 1.35 to 1.76; P < .001) and thus inferior disease-free survival (DFS) (HR, 1.19; 95% CI, 1.07 to 1.33; P = .001). In the high/very high-risk DRI cohort, RIC was associated with marginally lower NRM (HR, .83; 95% CI, .68 to 1.00; P = .051) and significantly higher relapse risk (HR, 1.23; 95% CI, 1.08 to 1.41; P = .002), leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for patients with AML/MDS with low/intermediate-risk DRI, but with a similar benefit as RIC in high/very high-risk DRI. Novel MAC regimens with less toxicity could benefit all patients, but more potent antineoplastic approaches are needed for the high/very-high risk DRI group.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015679PMC
January 2021

Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS.

Blood Adv 2020 10;4(19):4748-4757

Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan.

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.
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http://dx.doi.org/10.1182/bloodadvances.2020002621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556156PMC
October 2020

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study.

Leukemia 2021 05 18;35(5):1291-1300. Epub 2020 Sep 18.

Clinical Hematology, Bordeaux University Hospital, Bordeaux University, Inserm 1035, Bordeaux, France.

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITD/NPM1 mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
May 2021

A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes.

Biol Blood Marrow Transplant 2020 11 8;26(11):2139-2146. Epub 2020 Aug 8.

Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609542PMC
November 2020

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.

Blood Adv 2020 07;4(13):3180-3190

Texas Transplant Institute, San Antonio, TX.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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http://dx.doi.org/10.1182/bloodadvances.2019001266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362362PMC
July 2020

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

(7)Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT.

J Clin Oncol 2020 06 4;38(18):2062-2076. Epub 2020 May 4.

Division of Clinical Hematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.

Purpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor.

Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, < .0071 in multivariable analysis and < .00025 in direct pairwise comparisons were considered statistically significant.

Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group.

Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.
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http://dx.doi.org/10.1200/JCO.19.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302955PMC
June 2020

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blood Adv 2019 12;3(24):4238-4251

Laboratoire d'Hématologie, CHU Estaing 1, Clermont-Ferrand, France.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.
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http://dx.doi.org/10.1182/bloodadvances.2019000647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929390PMC
December 2019

Pyoderma gangrenosum induced by lenalidomide in a case of multiple myeloma.

Ann Hematol 2020 Feb 10;99(2):379-380. Epub 2019 Dec 10.

Department of Clinical Hematology, CHU Grenoble Alpes, Grenoble, France.

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http://dx.doi.org/10.1007/s00277-019-03846-0DOI Listing
February 2020

The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation.

Leukemia 2020 04 14;34(4):1144-1153. Epub 2019 Nov 14.

Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorobonne University, and INSERM UMRs 938, Paris, France.

Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD, n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD and MRD cohorts, respectively. In MRD patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD before allo-HCT.
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http://dx.doi.org/10.1038/s41375-019-0631-5DOI Listing
April 2020

Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study.

Biol Blood Marrow Transplant 2020 03 25;26(3):472-479. Epub 2019 Oct 25.

The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, Georgia.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358778PMC
March 2020

Influence of alternative donor type on early survival after hematopoietic stem cell transplantation for acute myeloid leukemia lacking a sibling donor.

Bone Marrow Transplant 2020 04 29;55(4):749-757. Epub 2019 Oct 29.

CHU (University Hospital) de Grenoble Alpes, Grenoble, France.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for acute myeloid leukemia. In the absence of an HLA-matched related or unrelated donor (MRD or MUD), the best alternative donor source remains controversial. Umbilical cord blood and haploidentical donors offer a shorter delay from indication to transplantation. This retrospective multicentre study of a French registry compares overall survival in the 18 months following registration in the absence of a MRD between four types of donors. Between 2012 and 2016, 1302 patients were transplanted using MUD (control, n = 803), mismatched MUD (n = 219), umbilical cord blood (n = 153) and haploidentical (n = 127) donors. Multivariate analyses were conducted for overall survival after registration, after transplant, and transplant-related mortality. After adjustment for variables, the type of donor did not influence any of the three end points. Our results confirmed the significant negative impact of longer time between registration and transplant: HR = 1.04 [1.02-1.06] (p < 0.0001). This indicates a positive correlation between better survival and shorter registration-to-transplantation wait time. In the absence of a sibling donor, the alternative stem cell source does not impact early survival in acute myeloid leukemia patients. The minimization of registration-to-transplantation time should be considered when weighing the alternative donor options.
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http://dx.doi.org/10.1038/s41409-019-0722-yDOI Listing
April 2020

Comparison of High Doses of Total Body Irradiation in Myeloablative Conditioning before Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 12 29;25(12):2398-2407. Epub 2019 Aug 29.

Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% CI, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI, .94 to 1.19; P = .36) for IH and .89 (95% CI, .76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304318PMC
December 2019

Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 11 6;25(11):2134-2142. Epub 2019 Jul 6.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous-allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.004DOI Listing
November 2019

Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report.

Clin Cancer Res 2019 08 28;25(16):5143-5155. Epub 2019 Jun 28.

Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).

Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.

Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high ( < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).

Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697588PMC
August 2019

Tumor microenvironment and clonal monocytes from chronic myelomonocytic leukemia induce a procoagulant climate.

Blood Adv 2019 06;3(12):1868-1880

Institute for Advanced Biosciences, INSERM U1209 and Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 5309, Grenoble Alpes University, Grenoble, France.

Chronic myelomonocytic leukemia (CMML) is a myeloid hematological malignancy with overlapping features of myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). The knowledge of the role of the tumor microenvironment (TME), particularly mesenchymal stromal cells (MSCs), in MDS pathogenesis is increasing. Generally, cancer is associated with a procoagulant state participating in tumor development. Monocytes release procoagulant, tissue factor (TF)-bearing microparticles. We hypothesized that MSCs and clonal monocytes release procoagulant extracellular vesicles (EVs) within the CMML TME, inducing a procoagulant state that could modify hematopoietic stem cell (HSC) homeostasis. We isolated and cultured MSCs and monocytes from CMML patients and MSCs from healthy donors (HDs). Their medium EVs and small EVs (sEVs) were collected after iterative ultracentrifugations and characterized by nanoparticle tracking analysis. Their impact on hemostasis was studied with a thrombin generation assay and fibrinography. CMML or HD HSCs were exposed to sEVs from either CMML or HD MSCs. CMML MSC sEVs increased HD HSC procoagulant activity, suggesting a transfer of TF from the CMML TME to HD HSCs. The presence of TF on sEVs was shown by electron microscopy and western blot. Moreover, CMML monocyte EVs conferred a procoagulant activity to HD MSCs, which was reversed by an anti-TF antibody, suggesting the presence of TF on the EVs. Our findings revealed a procoagulant "climate" within the CMML environment related to TF-bearing sEVs secreted by CMML MSCs and monocytes.
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http://dx.doi.org/10.1182/bloodadvances.2018026955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595258PMC
June 2019

Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.

Blood Adv 2019 06;3(12):1826-1836

The Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival ( = .15), leukemia-free survival ( = .50), nonrelapse mortality ( = .16), relapse ( = .90), or grade II-IV acute GVHD ( = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.
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http://dx.doi.org/10.1182/bloodadvances.2019000050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595262PMC
June 2019

Inferior Outcomes with Cyclosporine and Mycophenolate Mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 31;25(9):1744-1755. Epub 2019 May 31.

Cancer Transplant Institute, Virginia G. Piper Cancer Center, Scottsdale, Arizona, USA; Arizona Oncology, Scottsdale, Arizona, USA.

Combination therapy with a calcineurin inhibitor (CNI), such as cyclosporine (CSA) or tacrolimus (Tac), and methotrexate (MTX) or mycophenolate mofetil (MMF) is a widely used approach to graft-versus-host disease (GVHD) prevention. Data on the comparative effectiveness of MMF compared with MTX are limited and conflicting, however. We analyzed data from the Center for International Blood and Marrow Transplant Research for adult patients undergoing first myeloablative hematopoietic cell transplantation (HCT) from an HLA-identical matched related donor (MRD; n = 3979) or matched unrelated donor (URD; n = 4163) using CSA+MMF, CSA+MTX, Tac+MMF, or Tac+MTX for GVHD prevention between 2000 and 2013. Within the MRD cohort, 2252 patients received CSA+MTX, 1391 received Tac+MTX, 114 received CSA+MMF, and 222 received Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute GVHD grade II-IV (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.24 to 2.20; P < .001) and grade III-IV (HR, 1.92; 95% CI, 1.31 to 2.83; P < .001) compared with Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR, 2.31; 95% CI, 1.73 to 3.09; P < .001) due to higher transplantation-related mortality (TRM) (HR, 4.03; 95% CI, 2.61 to 6.23; P < .001) compared with Tac+MTX. Within the URD cohort, 974 patients received CSA+MTX, 2697 received Tac+MTX, 68 received CSA+MMF, and 424 received Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade III-IV acute GVHD (HR, 2.31; 95% CI, 1.57 to 3.42; P <0001), worse OS (HR, 2.36; 95% CI, 1.67 to 3.35; P < .001), and higher TRM (HR, 3.09; 95% CI, 2.00 to 4.77; P < .001), compared with Tac+MTX and other regimens. Thus, this large retrospective comparison of MMF versus MTX in combination with CSA or Tac demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared with Tac+MTX.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039394PMC
September 2019

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 11;25(9):1875-1883. Epub 2019 May 11.

Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3 T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3 T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3 T cell dose cutoff of 14 × 10 cells/kg identified MSD/low CD3 (n = 223) and MSD/high CD3 (n = 1214), and a dose of 15 × 10 cells/kg identified MUD/low CD3 (n = 197) and MUD/high CD3 (n = 1102). On univariate analysis, the MSD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3 group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3 group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3 T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4 T cells, CD8 T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3 T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4 and CD8 T cell doses were not possible given our small sample size.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071947PMC
September 2019

The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT.

Ann Hematol 2019 Jul 16;98(7):1755-1763. Epub 2019 Apr 16.

Collegium Medicum UMK, University Hospital, Bydgoszcz, Poland.

It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.
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http://dx.doi.org/10.1007/s00277-019-03669-zDOI Listing
July 2019

Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation.

Exp Hematol Oncol 2019 28;8. Epub 2019 Mar 28.

1Institute for Advanced Biosciences, Université Grenoble Alpes, INSERM 1209, UMR CNRS 5309, Grenoble, France.

Background: Immune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation.

Case Presentation: The patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation.

Conclusions: Multi-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities.
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http://dx.doi.org/10.1186/s40164-019-0132-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437980PMC
March 2019
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