scholarly journals Prospective, Multi-Center, Phase I Clinical Trial of PLX-R18 Placental Expanded Adherent Stromal Cells in Subjects with Incomplete Hematopoietic Recovery after Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3379-3379 ◽  
Author(s):  
Hillard M Lazarus ◽  
Leland Metheny ◽  
Tsila Zuckerman ◽  
Carolina Escobar ◽  
Joseph P. McGuirk ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Cell Transplantation ◽  
Stromal Cells ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Eligibility Criteria ◽  
Acute Radiation Syndrome ◽  
Hematopoietic Recovery ◽  
Grade 3

Abstract Background: Successful engraftment remains a challenge in hematopoietic cell transplantation (HCT) for some patients. Salvage approaches, including use of recombinant hematopoietic growth factors, cytokine therapy, CD34+-selected progenitor cell boosts, or second or subsequent HCT, are successful only in a minority of patients, and patients are exposed to prolonged blood products transfusions. With our successful pre-clinical rodent and Rhesus Macaques total body irradiation injury-induced marrow failure models (Metheny, Front Med 2018; Sher, Cell Transplantation 2018; Sher, Blood 2017), this prospective, multi-center, phase I clinical trial is evaluating the safety of PLX-R18 cells used to improve peripheral blood counts in patients who have experienced incomplete hematopoietic recovery after HCT. PLX-R18 cells are human placental-derived adherent stromal cells that are predominantly of fetal origin, expressing CD105, CD73 and CD29, and lacking surface expression of CD45, CD34, CD14, CD19, HLA-DR, CD31 (endothelial marker) and GlyA (erythrocyte cell marker). PLX-R18 also do not express HLA class II molecules (HLA-DP, DQ, and DR) and co-stimulatory markers (CD80, CD86, and CD40). PLX-R18 cells secrete MCP-1, IL-6, and IL-8 and had been shown to stimulate migration of bone marrow cells in vitro. Cells are grown ex vivo, under GMP conditions, using a 3-dimensional system, and are administered as several intramuscular (IM) injections. PLX-R18 cells already are approved for treatment of acute radiation syndrome (ARS) under an IND. Methods: This is a multi-center, open label, dose-escalation, phase 1 trial (ClinicalTrials.gov: NCT03002519). Eligibility criteria include patients age ≥18 years who underwent either an autologous (auto) or an allogeneic (allo) HCT but had incomplete hematopoietic recovery at 4 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8 g/dL and/ or neutrophil count (ANC) >1,000/µL and/or platelet count (Plt) (unsupported) >50,000/µL. Other eligibility criteria include ECOG performance status of 0-2, no evidence of underlying malignancy at time of enrollment, no active infection, and no evidence of grade 3-4 acute or severe chronic GvHD. The PLX-R18 cells, cryopreserved in DMSO and human serum albumin in Plasma-Lyte, are thawed and injected IM in multiple locations - half into the gluteus medius muscle on one side and half to the thigh muscles on the contralateral side. A total of 24 subjects are planned to be enrolled into 3 dose escalating cohorts: low (n=3) given 1 million cells/kg; intermediate (n=6) at 2 million cells/kg and high (n=15) dosed at 4 million cells/kg each. The assigned dose is given twice, 1 week apart; cohorts are recruited sequentially and progression to the next cohort is based on the safety assessment of its predecessor. Adverse event is graded using the CTCAE criteria of the NCI. As of July 2018, all 3 patients of cohort 1 were treated (with sufficient follow-up), as well as 3 out of the 6 subjects planned for the 2nd cohort, and data of the first cohort are presented herein. Results: Cohort 1 (low-dose) - 3 subjects (ages 43, 48 and 55 years old) who had an allo (n=2) or auto (n=1) HCT received two IM administrations of PLX-R18, 1 million cells/kg each within a 1-week interval. 67 Adverse Events (AEs) were recorded. 64.3% of the AEs were grade 1, 30.9% were grade 2, 3.6% were grade 3 and 1.2% were grade 4. One patient suffered from 3 Serious AEs (immune thrombocytopenic purpura, bacteremia and migraine), all assessed as not related to treatment. Most frequent related AE was transient injection site pain, experienced by all 3 patients. See patients' details and blood counts in the table and graphs. Conclusions: Treatment with PLX-R18 generally was well-tolerated and most frequent adverse events were injection site reactions, which were all reversible without sequelae. The trial continues to accrue patients and the next dosing cohort (intermediate dose) is at 2 million cells/kg. Upon completion, a larger phase II trial will be considered in the same indication using the optimal dose. Other potential uses include PLX-R18 therapy in Acute Radiation Syndrome, Bone marrow failure, and in HCT as a "pan" cytokine for rapid count recovery. Figure. Figure. Disclosures Lazarus: Pluristem Ltd.: Consultancy. Zuckerman:Cellect Biotherapeutics Ltd: Consultancy. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Fresenius Biotech: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceuticals: Research Funding. Rosen:Pluristem: Employment.

scholarly journals Final Results of a Dual-Institution Phase I Clinical Trial of Targeted Marrow Irradiation (TMI) Intensification of Reduced-Intensity Fludarabine/Busulfan (Flu/Bu) Conditioning for Allogeneic Hematopoietic Cell Transplantation for Medically Frail Patients with High-Risk Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Naveed Ali ◽  
Ana Carolina Pires de Rezende ◽  
Folashade Otegbeye ◽  
Mariana Nassif Kerbauy ◽  
Brenda W. Cooper ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Board ◽  
Matched Sibling ◽  
Grade 3 ◽  
One Year ◽  
Reduced Intensity

Background Reduced-intensity conditioning (RIC) regimens provide insufficient disease control in patients with high-risk hematological malignancies who are ineligible for myeloablative hematopoietic cell transplantation (HCT) due to advanced age or comorbidities. RIC fludarabine/busulfan (Flu/Bu) is generally well tolerated, but is associated with high relapse rates. We hypothesized that intensification of RIC Flu/Bu with targeted marrow irradiation (TMI) would be feasible and improve outcomes in such patients. Methods This dose escalation phase I clinical trial incorporated 3+3 design with expansion. The primary endpoint was to estimate safety and feasibility of TMI combined with Flu/Bu. Secondary endpoints included transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Eligible patients were ≥ 18 years diagnosed with high-risk hematological malignancies who were not candidates for myeloablative HCT. The conditioning regimen consisted of TMI (dose levels: 3 Gy, 4.5 Gy and 6 Gy) delivered at 1.5 Gy/fraction in twice daily fractions on days -10 through -7, fludarabine (30 mg/m2) on days -6 through -2 and busulfan (AUC 4800 µM*minute) on days -5 and -4. Radiation was targeted to bone marrow and spleen using intensity modulated radiation therapy (IMRT) technique while minimizing injury to organs at risk. GVHD prophylaxis included tacrolimus and methotrexate for matched sibling and unrelated donors (UD), and tacrolimus, mycophenolate mofetil and post-cyclophosphamide for haploidentical donors. Antithymocyte globulin (ATG) was added for recipients of UD transplants. Dose limiting toxicity (DLT) was defined as engraftment failure, grade ≥ 4 mucositis and grade ≥ 3 other non-hematological adverse events (AEs) from day -10 to day +32. Results A total of 26 patients (median age 64 years [range, 25-76]; 61% females) were enrolled in two transplant centers (Table 1). Diagnoses included AML (n=15), MDS (n=5), T-PLL (n=2), CLL (n=1), DLBCL (n=1), multiple myeloma (n=1) and myeloproliferative disorder (n=1). Sixteen (61%) patients had intermediate/high HCT-comorbidity index and high/very high disease risk index (DRI). At the time of HCT, 19 (73%) patients had active or residual disease. Donors were UD (n=18), matched sibling (n=5) and haploidentical (n=3). All patients engrafted neutrophils (median, 16 days [range, 10-29]). Most frequent AEs were mucositis (65%), gastrointestinal toxicity (62%), hepatotoxicity (hyperbilirubinemia and/or increased transaminase levels) (65%) and fatigue (69%). Twenty-four grade ≥ 3 AEs occurred in 13 patients; 2 patients experienced reversible DLT (mucositis and hepatotoxicity) at 6 Gy TMI dose level. Additional escalation was halted and 6 Gy cohort was expanded. Only 1 patient experienced reversible hepatotoxicity in the expansion cohort. Grade II-IV and III-IV acute GVHD rates at day +100 were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. The 1-year cumulative incidence of chronic GVHD was 42% (95% CI, 24%-74%). The 1-year cumulative incidence of TRM and relapse was 8% (95% CI, 2%-32%) and 26% (95% CI, 13%-52%), respectively (Figure 1A). The overall TRM for 3 Gy, 4.5 Gy and 6 Gy cohorts was 25%, 12.5% and 12%, respectively. With a median follow up of 12.7 months (range, 1.1-36.8), 1-year DFS was 55% (95% CI, 34%-76%) and OS was 65% (95% CI, 46%-85%) (Figure 1B). One-year DFS was equivalent for patients transplanted in CR or with active disease (54% [95% CI, 14%-93%] vs 55% [95% CI, 29%-80%]; p=0.83) (Figure 1C). While no difference in DFS was observed between the 4.5 Gy and 6 Gy cohorts, the 3 Gy cohort was associated with inferior DFS (p=0.004) (Figure 1D). One-year DFS and OS for 6 Gy cohort was 58% (95% CI, 30%-87%) and 82% (95% CI, 59%-100%), respectively. Conclusion Intensification of RIC Flu/Bu with TMI is feasible, with low incidence of TRM in medically frail patients. Reversible mucositis and hepatotoxicity prevented dose escalation beyond 6 Gy. DFS and OS at 6 Gy are promising and deserve further investigation. Disclosures Malek: Janssen: Other: Advisory board, Speakers Bureau; Medpacto: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau.

scholarly journals Predicting Induction Toxicity with 7+3: Analysis of SWOG Trial S1203

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1403-1403 ◽  
Author(s):  
Megan Othus ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
Harry P. Erba ◽  
Roland B. Walter
Keyword(s):  
Clinical Trial ◽  
Research Funding ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Cell Counts ◽  
Increased Risk ◽  
Multivariable Models ◽  
Grade 3 ◽  
Baseline Covariates ◽  
Support Research

Abstract Background: Prior work has shown that multivariable models can have reasonably high accuracy in predicting early deaths (deaths within 28 days of starting induction, defined as treatment-related mortality [TRM]) following intensive AML chemotherapy. These models can be used to derive a TRM score reflective of the probability of TRM with intensive AML therapy, and such scores can be used to make informed treatment decisions and as explicit eligibility criteria in AML protocols. The degree to which non-fatal toxicities can be predicted is unknown. It is also not known which patient characteristics are most strongly associated with occurrence of non-fatal toxicities following induction chemotherapy. Here, we examined these questions using data from the most recent SWOG Phase III with a 7+3 arm. Patients and Methods: We analyzed 260 eligible patients randomized to the 7+3 arm SWOG trial S1203 who received the first cycle of protocol therapy. 7+3 was per contemporary standard when the trial was opened in 2012: 100mg/m2 cytarabine on days 1-7 and 90mg/m2daunorubicin on days 1-3. Toxicities were reported using CTCAE version 4.0. We used logistic regression models to model toxicity incidence and evaluated the predictive accuracy of the models with the area under the receiver operating characteristic curve (AUC). We note that AUC of 0.5 is what would be expected with random chance or using a coin flip to make a decision, while an AUC of 1 denoted perfect prediction. We evaluated the following baseline covariates (modeled quantitatively unless otherwise specified): age at study registration, gender, Zubrod performance status (0-1 versus 2-3), pre-study white blood cell counts (WBC), pre-study platelets, pre-study marrow blasts, secondary vs. de novo AML, cytogenetic risk, and NPM1+ and FLT3-ITD- versus other NPM1/FLT3-ITD status. For toxicities with lower incidence, the number of covariates included in multivariable models was proportionate to one covariate per 10-15 patients with a toxicity. Toxicities were reported using the contemporary CTCAE version 4.0. Only toxicities observed during the first cycle of induction are analyzed below. Results: We evaluated the incidence grade 3 or higher thrombocytopenia (n=180, 70%), infection (n=166, 64%), anemia (n=159, 61%), neutropenia (n=145, 56%), lymphopenia (n=92, 35%), electrolyte abnormalities (n=66, 25%), liver abnormalities (n=37, 14%), cardiovascular abnormalities (n=20, 8%), constitutional symptoms (n=19, 7%), skin abnormalities (n=18, 7%), mucositis (n=17, 7%), GI tract abnormalities (n=16, 6%), pulmonary abnormalities (n=14, 5%), pain (n=13, 5%), endocrine abnormalities (n=12, 5%), bleeding (n=12, 5%), neurologic abnormalities (n=10, 4%), nausea/vomiting (n=7, 3%), kidney abnormalities (n=4, 2%). In univariate models no individual covariate was a strong predictor of toxicity. Only 3 pairs of toxicity/covariate had an AUC > 0.65 [indicating modest predictive ability]: older age predicting increased risk of endocrine abnormalities (OR=1.08 [per year], p=0.06, AUC=0.67), higher baseline WBC predicting increased risk for bleeding (OR=1.26 per 1,000, p=0.36, AUC=0.67), and higher baseline HGB predicting increased risk of neurologic toxicity (OR=1.33 per g/dL, p=0.10, AUC=0.69). As incidence allowed, we evaluate multivariable models. Multivariable models had increased AUC compared to univariate models, but no multivariable model had an AUC larger than 0.70. Conclusion: These findings indicate that with the baseline covariates evaluated, we have a poor ability to predict commonly occurring grade 3 and higher toxicities that occur during the first cycle of 7+3 induction therapy for AML. These findings support the claim that randomization is necessary to compare toxicities between standard and investigational regimens. Moreover, assuming that trial eligibility criteria are often stringent in an attempt to minimize the occurrence of treatment toxicities in study participants, the lack of strong association between individual baseline characteristics and toxicities could be used to argue for less-stringent study inclusion criteria. Support: NIH/NCI grants CA180888 and CA180819 Disclosures Walter: Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Amgen Inc: Other: Clinical Trial Support, Research Funding; Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy.

scholarly journals Hematopoietic Cell Transplantation in Thalassemia and Sickle Cell Disease: Report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry: 2000-2017

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 168-168 ◽  
Author(s):  
Donatella Baronciani ◽  
Ariane Boumendil ◽  
Arnaud Dalissier ◽  
Javid Gaziev ◽  
Ardeshir Ghavamzadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Cord Blood ◽  
Cell Transplantation ◽  
Marrow Transplantation ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Board ◽  
Cell Disease

Abstract INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) is a diffuse curative option for transfusion dependent thalassemia (TDT) and sickle cell disease (SCD). To verify transplant activity, distribution, demography, policies and outcomes the Hemoglobinopathy Registry was established inside the European Group for Blood and Marrow Transplantation (EBMT). After a previous analysis limited to TDT for the 2000-2010 period data (BMT 2016; 51:536-41), we performed an updated report considering TDT and SCD patients transplanted in the last eighteen years (years 2000-2017). METHODS: Data on pediatric patients transplanted between Jan 1st, 2000 through Dec 31st, 2017 were extracted by the EBMT promise Hemoglobinopathy registry database. Only first transplants were considered. Data are expressed as median with range unless specifically indicated. Survival probabilities were calculated with the method of Kaplan and Meier and expressed as means and 95% confidence intervals (95%CI). Differences between survival probabilities were tested by means of the log-rank test. RESULTS: In the above-specified period 3856 consecutive pediatric patients affected by TDT (2936, 76%) or SCD (920, 24%) were transplanted in 166 HCT centers distributed in 36 countries in Europe, Asia and Africa. Median age at transplant was 7.2 years (range 0.48-17.9). 3342 (87%) transplants were performed on patients <14 years, 514 (13%) on patients aged 14-17.9 years. 2593 (67%) patients received transplant from an HLA identical sibling donor. Figure 1 reports pediatric transplant activity inside the EBMT showing an increased numbers of patients transplanted after year 2010. After a median follow up of 24 months, the 2 years overall survival (OS) and event-free survival (EFS) were 91% (95%CI 90-92) and 86% (95%CI 85-87) for the entire population. In TDT, OS and EFS were 90% (95%CI 89-92) and 84% (95%CI 82-85), respectively. In SCD, OS and EFS were 94% (95%CI 92-96) and 92% (95%CI 90-94), respectively. In both diseases no outcome difference was recorded on the basis of year of transplant (data not shown). Source of hematopoietic cells was bone marrow in 70% of TDT transplants and 81% of SCD transplants. In both diseases better results were recorded with the use of bone marrow versus peripheral blood [OS 91% versus 85% (P< 0.001); 95% versus 84% (P= 0.004) for TDT and SCD, respectively]. Similar results were recorded when EFS was analyzed. 176 patients received hematopoietic cells from single cord blood donors. Of them only 21 were from an unrelated donor. 119 patients received cord blood + bone marrow. Results of related HLA identical cord blood were similar to that of HLA identical related bone marrow (data not shown). Transplantation from an HLA identical sibling offered the best results in OS and EFS compared to other donor options (P< 0.001), both for TDT and SCD. Transplant results by donor type are reported in table 1. The threshold age for optimal transplant outcomes is confirmed 14 years, with OS 92% (95%CI 91-93), EFS 87% (95%CI 85-88) versus OS 85% (95%CI 82-89), EFS 81% (95%CI 77-85) ( P<0.001) comparing younger versus older patients in the entire populations. These differences were confirmed either in TDT and SCD. The two years incidence of cumulative extensive chronic graft versus host disease was 4.1% in TDT and 4.4 % in SCD (P=ns). CONCLUSIONS: Allogeneic HCT for TDT and SCD is a widely available curative approach; the procedure has been increasing and internationally performed during the years with excellent results. The emerging gene therapy approach will have to be compared to these well-established results. Disclosures Zecca: Chimerix: Honoraria. Forni:Novartis: Other: travel expenses, Research Funding; Celgene: Research Funding; Roche: Consultancy; Shire: Research Funding; Apopharma: Other: DSM Board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding; Cellgene: Consultancy. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Celgene: Honoraria, Other: Chair DMC.

scholarly journals Pembrolizumab for the Treatment of Disease Relapse Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3415-3415 ◽  
Author(s):  
Justin Kline ◽  
Hongtao Liu ◽  
Tallarico Michael ◽  
Andrew S Artz ◽  
James Godfrey ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Myeloid Sarcoma ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Disease Relapse ◽  
Grade 3

Abstract Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD > grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade > 2 toxicity related to pem, or development of > grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

scholarly journals COVID-19 in Children Following Hematopoietic Cell Transplantation: A Multinational Study of the European Bone Marrow Transplantation Society (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2866-2866
Author(s):  
Diana Averbuch ◽  
Rafael De La Camara ◽  
Selim Corbacioglu ◽  
Malgorzata Mikulska ◽  
Jose Luis Piñana Sanchez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Median Time ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Immunosuppressive Drugs ◽  
Lung Pathology ◽  
Icu Admission

Abstract Introduction COVID-19 is usually a mild disease in immunocompetent children, with ~1% requiring intensive care unit (ICU) admission and &lt;0.1% mortality. Data on its course in children following hematopoietic cell transplantation (HCT) is limited. Methods Data on children following HCT who developed COVID-19 (diagnosed by positive SARS-CoV-2 PCR on respiratory tract samples) during 3.2020-4.2021 were prospectively collected by EBMT and GETH, including demography, HCT data, COVID-related manifestations, ICU admission and mortality. Factors associated with worse outcomes (ICU admission or mortality) were characterized. Results Sixty-two children (34 boys; median age 9; min-max; 0.7-17 years) were reported from 27 centers, 16 countries; 57 (92%) following allogeneic and 5 (8%) following autologous HCT. Underlying diseases were acute leukemia (23; 37%), inherited disorders (9; 15%), hemoglobinopathies (7; 11%), solid tumor (6; 10%), bone marrow failure (5; 8%), other malignant (8; 13%) and non-malignant (4; 6%) diseases. Five (8%) children had high blood pressure; 6 (10%) had underlying lung pathology. The median time from the most recent HCT to COVID was 5 months (min-max; 0-169). The stem cell source was bone marrow (33); peripheral (22) or cord blood (1). Among the patients with information available, 34 (62%) underwent in-vivo T cell depletion, 20 (33%) received corticosteroids, and 36 (60%) other immunosuppressant drugs(s) within two months prior to and after the COVID-19 episode. The presence of acute grade 2-4 or chronic graft versus host disease (GVHD) was reported in 12/54 (23%) and 8/51 (16%) children, respectively. Clinical presentation (n=57) included fever (28; 49%), cough (18; 32%), diarrhea (8; 14%), upper respiratory tract disease (as rhinorrhea, sinusitis, otitis, or pharyngitis; 12; 21%); six (10%) required oxygen to maintain oxygen saturation above 92%; 20 children (35%) were asymptomatic. The median time from symptoms onset to COVID diagnosis was 1 day (-43-40). Sixty-three percent of patients were hospitalized; 43% due to COVID. The proportion of children with neutropenia or lymphocytopenia (&lt;500 cells/mm 3) was 75% and 73%, respectively. Sixteen children (26%) had evidence of viral (n=10), bacterial (n=6) or fungal (n=2) coinfections. The median time from COVID diagnosis to the last follow-up in alive patients was 69 days (min-max; 2 - 294). Six (10%) children who developed COVID at a median 6.5 (min-max; 2- 16) months following allo-HCT (median age 6 years; 5 boys) required ICU care within a median 6 (min-max; -5-15) days after diagnosis. All of them were neutropenic, received steroids, and other immunosuppressive drugs at COVID diagnosis; 5 had undergone in-vivo T cell depletion; 5 were lymphocytopenic, 5 had GVHD (2 acute and 3 chronic); 3 received non-invasive and 2 invasive ventilation. Three children had viral or bacterial coinfections. Three children died. Six (10%) children (5 boys, median age 10.5 years; min-max; 4-13) who developed COVID at median 2 (min-max; 0-147) months following allo-HCT died within median 35 days (min-max; 5-54) after diagnosis. One had high blood pressure, and none suffered from underlying lung pathology. At the time of COVID, 3 were neutropenic, 2 lymphocytopenic; 4 had GVHD (2 acute, 2 chronic); 3 received steroids and 4 immunosuppressive drugs. Two had viral or bacterial coinfections. Five had positive SARS-CoV-2 PCR at the time of death. In 3, COVID was the primary cause of death. We compared nine children with the worse outcomes to 53 children with benign course. Among patients alive at 100-day post HCT, the probability of worse outcomes was higher in patients with vs. without chronic GVHD (Figure). No other significant differences were observed in demographic, underlying disease, and HCT-related characteristics. Compared to adults following HCT (Ljungman, Leukemia 2021), children had: - Shorter median time from HCT to COVID diagnosis, 5 vs 18 months; - Higher proportion of asymptomatic infections, 35% vs 9%; - Lower proportion of those who required oxygen, 10% vs 35%; - Lower all-cause mortality, 10% vs 29%. Conclusions Children following HCT with COVID-19 have a higher risk of ICU admission and mortality compared to immune competent children. The presence of chronic GVHD at COVID diagnosis was associated with worse outcomes. COVID course following HCT is milder in children compared to adults. Figure 1 Figure 1. Disclosures Averbuch: Takeda: Consultancy; Pfizer: Consultancy; GSK: Speakers Bureau. De La Camara: Roche: Consultancy; IQONE: Consultancy. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Mikulska: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Biotest: Speakers Bureau. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Lawson: Alexion: Honoraria. Kroeger: Neovii: Honoraria, Research Funding; Sanofi: Honoraria; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria. Styczynski: MSD, Pfizer, Giled, TEVA, Jazz, Novartis: Honoraria, Speakers Bureau. Ljungman: Takeda: Consultancy, Other: Endpoint committee, speaker; Enanta: Other: DSMB; Janssen: Other: Investigator; OctaPharma: Other: DSMB; Merck: Other: Investigator, speaker; AiCuris: Consultancy.

scholarly journals Safety and Tolerability of Lurbinectedin (PM01183) in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2722-2722
Author(s):  
Kelly S. Chien ◽  
Christopher B. Benton ◽  
Ayalew Tefferi ◽  
José Rodríguez ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Committees ◽  
Genetics Research ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

scholarly journals Safety and Demonstrated Efficacy of Placenta-Derived Cell Therapy PLX-R18 in Subjects with Incomplete Hematopoietic Recovery Following Hematopoietic Cell Transplantation: A Phase I International Multi-Center Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Hillard Lazarus ◽  
Carolina Escobar ◽  
Leland Metheny ◽  
Joseph P. McGuirk ◽  
Tsila Zuckerman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Critical Level ◽  
Bone Marrow Failure ◽  
Optimal Dose ◽  
High Dose ◽  
Eligibility Criteria ◽  
Injection Site Reactions

Introduction: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT) while full engraftment remains a challenge in some recipients. Therapeutic approaches, such as recombinant hematopoietic growth factors, salvage only a minority of patients leaving affected patients at risk for recurrent infections and multiple blood products transfusions. PLX-R18 cells have been shown to mitigate bone marrow failure in rodent and non-human primate models. Further, these human placenta-derived mesenchymal-like adherent stromal cells secrete many cytokines after intramuscular (IM) injection that have been shown to stimulate growth and migration of bone marrow cells in vitro, e.g. MCP-1, IL-6, and IL-8. The initial results of the first cohort of this phase I trial were previously reported (ASH 2018 abstract 3379). Methods: Enrollment for this multi-center, open label, dose-escalation, phase I trial (ClinicalTrials.gov: NCT03002519) began in October 2017. Eligibility criteria included patients age ≥18 years who underwent either autologous (auto) or allogeneic (allo) HCT but suffered from incomplete hematopoietic recovery at least 3 months post-transplant, defined as failure to maintain either hemoglobin (Hb) &gt;8g/dL and/or neutrophil count (ANC) &gt;1,000/μL and/or platelet (PLT) count &gt;50,000/μL. Other eligibility criteria included no evidence of underlying malignancy at time of enrollment, no active infection and no evidence of grade 3-4 acute or severe chronic GvHD. Subjects were enrolled into 3 dose-escalating cohorts: low-dose at 1M cells/kg (n=3), intermediate-dose at 2M cells/kg (n=6), and high-dose at 4M cells/kg (n=10). The specified dose of PLX-R18 cells was injected IM in multiple locations and given twice, 1 week apart. Cohorts were recruited sequentially, and progression to the next cohort was based on the safety assessment of its predecessor. Adverse event grading used the NCI CTCAE criteria. As of July 2020, all patients in cohorts 1 and 2 (3 & 6 patients, respectively) and 10 patients in cohort 3 were treated. Data were analyzed using the lmerTest package (ver. 3.1.0) in R (ver. 3.6.1) to produce baseline-adjusted least square means. As study is in progress and data collection ongoing, not all subjects have data on all parameters for all time points. Results: Data on 19 subjects (29-75 yrs) with either allo (n=17) or auto (n=2) HCT are reported herein. Not all patients reached the 9 month time point. Four patients died while on study and 2 withdrew consent within the 1 year follow up period. All deaths and other severe adverse events (SAEs) occurred due to progression of primary disease and were assessed as not related by investigators and sponsor. Most frequent related AEs were injection-site reactions. The table summarizes number of patients who improved from below the critical level, as defined above, at day 0 to above the critical level for a sustained period. Only those patients that were below the critical blood levels at day 0 are shown. To date, the majority of such patients improved to above the critical level after treatment. For example, 9 patients had ANC &lt;1000/μL at day 0. Of the 4 patients for which data currently exists, all improved to ≥1000/μL at 9 months. The plots show changes in Hb, ANC and PLT up to 9 months following treatment. The dashed lines represent respective critical levels. Overall, there was improvement in the 3 parameters, with the greatest improvement observed in patients receiving the predicted optimal dose of 4M cells/kg. In this cohort, Hb levels increased from 9.29±0.5 to 13.19±1.2 (p=0.0019), ANC increased from 1.09±0.6 to 5.13±1.7 (p=0.018) and PLT increased from 45.7±10 to 175.9±28 (p=0.000012). Conclusions: Treatment with PLX-R18 is safe, well-tolerated and clearly effective in some patients. The most frequent AEs were reversible injection site reactions, all without sequelae. An overall improvement was observed in most patients, and among the high-dose cohort clinically impressive improvements in Hb, ANC and PLT were observed. The trial continues to follow up on patients. Upon completion, a large phase II trial, using the optimal dose, is considered for the same indication. Other attractive clinical areas for PLX-R18 therapy include acute radiation syndrome, bone marrow failure, aplastic anemia, myelofibrosis and with HCT as a "pan" cytokine to enhance rapid count recovery in all cells lines. Figure Disclosures Lazarus: Pluristem ltd: Consultancy. McGuirk:Astellas: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Ofir:Pluristem: Current Employment. Shani:Pluristem ltd: Current Employment. Rowe:Pluristem ltd: Consultancy.

Allogeneic Hematopoietic Cell Transplantation in Elderly Patients Aged 65 and Older: A Retrospective Analysis By the Complications and Quality of Life Working Party of the EBMT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 681-681 ◽  
Author(s):  
Grzegorz W. Basak ◽  
Isabel Sánchez-Ortega ◽  
Eric Beohou ◽  
Steffie van der Werf ◽  
Myriam Labopin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Elderly Patients ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Age Groups ◽  
Group I ◽  
Related Donor ◽  
Group Ii

Abstract INTRODUCTION: Age is no longer a barrier to successful allogeneic hematopoietic cell transplantation (alloHCT). However, reports of alloHCT outcomes in elderly patients aged 65 years (yo) and older are limited. These patients are underrepresented in clinical trials and data usually come from relatively small series and subgroup analyses from the main indications, namely acute leukemia (AL) and myelodysplastic syndromes (MDS). Here, we sought to evaluate the feasibility and general outcomes of the alloHCT procedure in a large cohort of elderly patients reported to the EBMT. PATIENTS AND METHODS: All consecutive alloHCT in recipients 65 yo and older reported to the EBMT between 2000 and 2014 were included. Data collection and outcome analysis followed EBMT registry and statistical guidelines. RESULTS: A total of 6046 alloHCT, including 214 second or subsequent procedures, from 270 EBMT centers in 32 countries were identified: median age was 67 (65-84), 4914 were 65-69 yo (Group I) and 1132 ≥70 yo (Group II); 63% were male; 50% had AL, 37% MDS and/or myeloproliferative disorders (MPD), 8% chronic leukemia, 4% lymphoma, 1% bone marrow failure (BMF) and 0.6% plasma cell disorders. They underwent peripheral blood (91%), bone marrow (7%) or cord blood (2%) alloHCT from unrelated (68%), matched (28%) or mismatched related donors (4%). There was female to male sex mismatch in 19% and CMV mismatch in 34% of cases. T cell depletion was used as part of GVHD prophylaxis in 66% of patients. AlloHCT activity in elderly patients increased over the study period from 37 out of 6,413 in 2000 (<1%) to 1057 out of 15,765 in 2014 (6.7%; p <0.001). Neutrophil and platelet engraftment were achieved at median day +16 (IQR 13-20) and +15 (IQR 13-21), respectively, while 6% experienced primary or secondary graft failure. Grade II-IV acute GvHD was observed in 28% of patients, with stage 2-4 involvement of skin in 50%, gut in 28% and liver in 7% of aGvHD cases. Venoocclusive disease was reported in 2%. The incidence of transplant complications did not differ between age groups. Median follow up time for survivors was 13 months (0.2-175). Non-relapse mortality (NRM) was 27% [95%CI 26-28] at 1y and 35% [95%CI 33-36] at 3y and was significantly higher in Group II (29% at 1y and 39% at 3y) than in Group I (26% at 1y and 34% at 3y; p <0.01; Fig. 1A). Multivariate analysis contributing to NRM identified increased age, diagnosis of lymphoma, MDS/MPD or BMF, unrelated or mismatched related donor, sex mismatch female to male and transplantation from CMV negative donor to CMV positive patient, or between both CMV positive as independent prognostic factors (Table 1). Cumulative incidence of relapse was similar in both groups, 24% [95%CI 23-25] at 1y and 32% [95%CI 30-33] at 3y. Cause of death was transplant related in 53% of cases, relapse/progression in 39% and others in 8%, with no difference between age groups. Overall survival was 56.6% [95%CI 55-58] at 1y and 38.6% [95%CI 37-40] at 3y. It was significantly higher in Group I (57.3% at 1y and 39.5% at 3y) than in Group II (53.2% at 1y and 34.7% at 3y; p<0.001, Fig. 1B). Multivariate analysis of factors revealed increased age, diagnosis of lymphoma, unrelated or mismatched related donor, time from diagnosis to alloHCT >12 months, sex mismatch female to male and transplantation from CMV negative donor to CMV positive patient as independent risk factors affecting OS (Table 1). For the subset of alloHCT recipients ≥75 yo, NRM was 26% [95%CI 16-38] at 1y and 34% [95%CI 21-47] at 3y, and OS was 56% [95%CI 45-70] at 1y and 38% [95%CI 27-56] at 3y. CONCLUSIONS: Improved supportive care and less toxic preparative regimens make alloHCT feasible in elderly patients aged 65 yo and older. This study confirms the feasibility of alloHCT in a large-series of elderly patients, with acceptable NRM and OS at 1 and 3 years, including those with very advanced age of 75 yo and older. In addition, it identifies in the multivariate analysis factors that have an independent impact on the outcome of alloHCT in elderly patients. Undoubtedly, elderly alloHCT recipients in such a registry study are a highly selected population. This nevertheless further endorses the need to assess comorbidity and frailty beyond age in older alloHCT candidates to improve outcomes further. Studies to assess the benefit from alloHCT in elderly patients with particular diseases and indications for alloHCT are warranted. Disclosures Dreger: Novartis: Consultancy; Gilead: Speakers Bureau; Gilead: Consultancy; Novartis: Speakers Bureau; Janssen: Consultancy; Roche: Consultancy. Montoto:Roche: Honoraria; Gilead: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

scholarly journals Chimerism of bone marrow mesenchymal stem/stromal cells in allogeneic hematopoietic cell transplantation

Chimerism ◽  
2013 ◽  
Vol 4 (3) ◽  
pp. 78-83 ◽  
Author(s):  
Yasuo Miura ◽  
Satoshi Yoshioka ◽  
Hisayuki Yao ◽  
Akifumi Takaori-Kondo ◽  
Taira Maekawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Stromal Cells ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation
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