Chronic Graft-Versus-Host Disease and Its Association with Treatment-Related Mortality, Relapse, Leukemia-Free and Overall Survival After Umbilical Cord Blood Transplantation (UCBT) In Children and Adolescents with Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 213-213
Author(s):  
Mary Eapen ◽  
Tao Wang ◽  
Joanne Kurtzberg ◽  
Stephanie J. Lee ◽  
Reggie Duerst ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Board Of Directors ◽  
Acute Gvhd ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
Related Mortality ◽  
Overall Mortality

Abstract Abstract 213 Chronic graft-versus-host disease (cGVHD) is the leading cause of late transplant-related mortality (TRM) after unrelated adult donor transplantation. However, limited, mild or moderate cGVHD may be associated with higher survival in part due to an association with lower relapse risk in adults with acute and chronic leukemia. While cGVHD rates are generally lower in children, we sought to determine the impact of cGVHD after UCBT on risk of relapse, TRM, leukemia-free survival (LFS) and overall survival (OS) as well as to identify risk factors for cGVHD after UCBT. Patients <18 years with acute lymphoblastic or acute myeloblastic leukemia transplanted with a single UCB unit after myeloablative conditioning between 1995–2007 who survived without recurrent leukemia for more than 3 months were eligible for analysis. Of the 657 patients, 59% were male, 26% were >10 years of age, 24% were transplanted in third remission or beyond, 74% were conditioned with TBI, 83% had pre-transplant anti-thymocyte globulin and 11% received tacrolimus, rather than cyclosporine, for acute GVHD prophylaxis. The cumulative incidence of cGVHD was 25% at 5 years with mild, moderate and severe disease in 91, 38 and 19 patients, respectively. cGVHD rates did not vary with donor-recipient HLA disparity. We constructed Cox proportional hazard-regression models to examine the effects of cGVHD on TRM, relapse, treatment failure (relapse or death; inverse of LFS) and overall mortality adjusting for age, disease, disease status, transplantation period, GVHD prophylaxis and donor-recipient HLA match. The risks of TRM (hazard ratio [HR] 9.33, p<0.0001), treatment failure (HR 2.96, p<0.0001) and overall mortality (HR 4.79, p<0.0001) were significantly higher in patients who developed cGVHD compared to those who did not develop cGVHD. In contrast to reports in adults transplanted with bone marrow or peripheral blood, mortality risk did not vary in those with mild, moderate or severe cGVHD after UCBT. Notably, relapse risk was not altered by the development of cGVHD (HR 0.73, p=0.38). In multivariate analysis, after adjusting for age and transplantation period, cGVHD risks were higher in patients who received tacrolimus (HR 3.12, p<0.0001) and in those with a prior history of grade 2 acute GVHD (HR 2.04, p=0.0001) or grade 3–4 acute GVHD (HR 5.51, p<0.0001) with a higher risk of cGVHD in patients with grade 3–4 versus grade 2 acute GVHD (HR 2.70, p<0.0001). These data suggest cGVHD of any severity has a markedly negative impact on survival after UCBT in children with acute leukemia without the associated graft-versus-leukemia effect previously reported for other stem cell sources. This analysis compels us to reevaluate our current acute GVHD prophylaxis strategies, including how tacrolimus is typically used, in an attempt to reduce the risk of cGVHD and its deleterious effect on LFS and OS after UCBT. Disclosures: Weisdorf: Genzyme: Research Funding; Hospira:Wagner:CORD:USE: Membership on an entity's Board of Directors or advisory committees; VidaCord: Membership on an entity's Board of Directors or advisory committees.

scholarly journals First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4885-4885
Author(s):  
Thomas A Gagliardi ◽  
Jordan Milner ◽  
Cassey Paula ◽  
Mehmet Ozkayank ◽  
Oya Levendoglu-Tugal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lung Biopsy ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Case Series ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD. Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172. Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved. Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option. Disclosures Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.

Reduced Severe aGVHD and Improved Survival Using Post Transplant Cyclophosphamide/Tacrolimus/Methotrexate Graft Versus Host Disease Prophylaxis in AML Patients Receiving Myeloablative Fractionated Busulfan Conditioning Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3296-3296
Author(s):  
Uday Popat ◽  
Rima M. Saliba ◽  
Rohtesh S. Mehta ◽  
Amanda L. Olson ◽  
Julianne Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Similar Proportion ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods: Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P<0.001) and platelet engraftment by 9 days (22 vs 13 days; P<0.001) in the PTCy cohort. Full donor chimerism at day 30 was noted in 79% vs 28% in the PTCy and Tac/Mtx cohorts respectively, (P<0.001). Conclusion: As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Pfizer: Honoraria; Amgen: Research Funding; Jazz: Consultancy. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Qazilbash:Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

scholarly journals Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2141-2148 ◽  
Author(s):  
Junya Kanda ◽  
Masakatsu Hishizawa ◽  
Atae Utsunomiya ◽  
Shuichi Taniguchi ◽  
Tetsuya Eto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Leukemia ◽  
Graft Versus Host ◽  
Adult T Cell Leukemia ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.

scholarly journals Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 256-256 ◽  
Author(s):  
Uday Popat ◽  
Rohtesh S. Mehta ◽  
Roland Bassett ◽  
Amanda L. Olson ◽  
Julianne Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Very High

Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was &gt;3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (&gt; 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

The PTPN22 1858C/T Polymorphism Is Associated with the Development of Grade 3 to 4 Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation Following Nonmyeloablative Conditioning.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1969-1969
Author(s):  
Brian Kornblit ◽  
Tania Masmas ◽  
Soren L. Petersen ◽  
Hans O. Madsen ◽  
Peter Garred ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
Significant Difference ◽  
Grade 3 ◽  
Related Mortality

Abstract Graft-versus-host disease (GVHD) is a cause of considerable morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning. Genetic polymorphisms in various genes, associated with the immune system have been implicated in the development of GVHD. The PTPN22 gene encodes a lymphoid tyrosine phosphatase (LYP), which is involved in suppression of T-cell receptor signalling. The 1858 C→T polymorphism in PTPN22 entails an amino acid substitution that disrupts the suppressive function of LYP, rendering T-cells hyperresponsive. The 1858 T allele has been implicated in conferring increased susceptibility to various autoimmune diseases. As in autoimmunity, T-cell activation plays a key role in the development of GVHD. To asses the influence of the protein tyrosine phospatase N22 (PTPN22) 1858 C→T polymorphism on development of GVHD after allogeneic HCT following nonmyeloablative conditioning, 100 consecutive patient-donor pairs receiving allogeneic HCT with related (n=66) or unrelated (n=34) donors for hematological malignancies (HD=13, MM=14, CLL=12, NHL=17, MDS=18, AML=24, CML=2), between March 2000 and December 2005 at Rigshospitalet, Denmark, were genotyped. With a mean follow-up of 534 days (range 38–2324 days) the overall survival (OS), progression free survival (PFS), treatment related mortality (TRM) and relapse related mortality (RRM) were 59%, 50%, 25% and 17%. The C/T and T/T genotypes were present in 16% and 1% of the recipients, respectively, and in 17% and 1% of the donors. The overall cumulative incidence of grade 2–4 acute GVHD, grade 3–4 acute GVHD and extensive chronic GVHD was 67%, 24%, and 49%, with no significant difference between patients carrying the C/C or C/T and T/T genotype or donors carrying the C/C or C/T and T/T genotype. To assess a possible gene-dosage effect, the number of T-alleles in each recipient-donor pair was cumulated, and the cumulative incidence of grade 3–4 acute GVHD increased from 20% in recipient-donor pairs carrying no or one T-allele to 50% in recipient-donor pairs carrying two or more T alleles (p=0.04), while there was no significant difference in grade 2–4 acute GVHD (66% versus 80%; p=0.47) and extensive chronic GVHD (50% versus 42%; p=0,8) between groups. In the competing risk regression analysis, the recipient-donor pair genotype with 2 or more T-alleles was an independent risk factor (hazard ratio 3.0; 95% CI 1.2–7.5; p=0.022) for development of grade 3–4 acute GVHD, even after adjusting for baseline variables known to affect GVHD rates (donor type and sex-mismatch, patient and donor age, CD34+ cell dose, single HLA locus mismatch). Overall survival, PFS, TRM or RRM were not significantly different for recipient-donor pairs for any given combination of alleles. Furthermore, patients from recipient-donor pairs carrying two or more T-alleles were hospitalized for significantly more days (p=0.01) due to GVHD (median=15 days; range 0–63 d), than patients from recipient-donor pairs with no or one T-allele (median=0 days; range 0–104 d). Collectively, our data suggest, that the PTPN22 1858 C→T polymorphism, when present in both recipient and donor, is a risk factor for development of grade 3–4 acute GVHD after nonmyeloablative conditioning allogeneic HCT.

An International Multicenter Comparative Analysis of Tacrolimus Plus Sirolimus with or without Antithymocyte Globulin As Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3142-3142
Author(s):  
Mohamed A. Kharfan-Dabaja ◽  
Rocio Parody ◽  
Janelle Perkins ◽  
Oriana Lopez-Godino ◽  
Lucia Lopez-Corral ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Infectious Complications ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis

Abstract Background: There is lack of consensus in regards to the optimal regimen for graft-versus-host disease (GVHD) prophylaxis in patients undergoing HLA-mismatched unrelated donor (MMUD) allografting. A regimen combining tacrolimus plus sirolimus (TAC-SIR) has been shown to be effective as GVHD prophylaxis in HLA-matched related (MRD) or matched-unrelated donor (MUD) allogeneic hematopoietic cell transplantation (HCT). Addition of antithymocyte globulin (ATG) has been shown to reduce incidence of acute GVHD but it is associated with a high rate of infectious complications. Here, we retrospectively compare post-transplant outcomes using TAC-SIR or TAC-SIR-ATG in 104 patients who underwent a MMUD allogeneic HCT between June 2008 and December 2014 at 5 Spanish and 1 transplant center (MCC) in the United States. Patients and methods: Forty-three (MCC=5, Spanish Centers=38) patients received TAC-SIR whereas 61(MCC=41, Spanish Centers=20) received TAC-SIR-ATG as GVHD prophylaxis for MMUD allogeneic HCT. Patient-, disease-, and transplant characteristics are summarized in Table 1. Results: The median follow-up (months) for all, TAC-SIR, and TAC-SIR-ATG patients were 29 (5-83), 27 (5-64), and 30 (6-83) months, respectively. Patients receiving TAC-SIR had faster platelets (12 vs. 15 days, p=0.005) but slightly slower neutrophil engraftment (16 vs. 15 days, p=0.037). Addition of ATG resulted in a lower incidence of acute GVHD (grade 2-4) (44% (95%CI=33-59%) vs. 67% (95%CI=55-83%), p=0.055) and over two-fold lower incidence, albeit not statistically significant, of moderate/severe chronic GVHD (17% (95%CI=10-30%) vs. 38% (95%CI=25-60%), p=0.086). Non-relapse mortality (NRM) (2-year) was two-fold higher, but not statistically significant, in the TAC-SIR-ATG group (TAC-SIR-ATG=35% (95%CI=24-50%) vs. TAC-SIR=17% (95%CI=10-35%), p=0.078) mainly attributable to a 3-fold higher number of non-relapse deaths attributed to infections (9 vs. 3). There was no difference in cumulative incidence of relapse (2-year) (TAC-SIR=28% (95%CI=17-46%) vs. TAC-SIR-ATG=26% (95%CI=17-41%), p=0.858) or in 2-year OS (TAC-SIR=56% (95%CI=40-72%) vs. TAC-SIR-ATG=47% (95%CI=34-60%), p=0.244) between the groups. These and other outcomes are summarized in Table 2. Conclusion: In MMUD allogeneic HCT, addition of ATG to TAC-SIR results in a lower incidence of grade 2-4 acute GVHD but does not improve OS. The two-fold higher 2-year NRM with addition of ATG is probably explained by a higher incidence of resulting infectious complications with in vivo T-cell depletion. While these results are intriguing, a prospective randomized study is certainly needed to confirm these findings.Table 1.Patient-, disease-, and transplant-related characteristics.VariablesCategoriesTAC-SIRTAC-SIR-ATGMCC (N=5)Spanish Centers (N=38)MCC (N=41)Spanish Centers (N=20)Median age (range), years53 (25-64)51 (17-69)52 (24-67)55 (30-68)Gender mismatch(Donor→recipient)F→M F→F M→M,F Missing1 1 3 07 5 25 110 13 18 02 0 10 8 HLA-mismatchA B C DRB1 Missing1 1 3 0 010 14 8 6 024 13 4 0 08 3 3 5 1DiagnosesALL AML CLL CML HL MDS MF MM NHL Other1 2 0 0 0 1 0 0 1 03 10 3 1 3 7 1 1 10 04 18 3 2 1 5 1 0 7 01 6 1 0 1 3 0 1 5 2Preparative regimenFLU-BU FLU-MEL3 218 2035 611 7CIBMTR riskNone Low Intermediate High0 2 1 20 24 2 121 13 15 120 18 2 0Cell sourceBM PBSC0 58 300 411 19Median CD34 cells (range) x106/recipient Kg body weight7.99 (4.08-10.0)6 (1.2-11.0)8.57 (2.81-23.01)6.08 (0.67-9.5)Recipient/donor CMV serologic status+/+ +/- -/- -/+ Missing1 2 2 0 018 16 2 2 018 14 7 2 07 6 0 0 7 Table 2. Post-transplant outcomes. Outcomes TAC-SIR TAC-SIR-ATG P-value Median days (range) to ANC>500/µL 16 (10-29) 15 (9-24) 0.037 Median days (range) to platelets engraftment 12 (6-26) 15 (0-50) 0.005 Cum incidence acute GVHD (grade 2-4) (at 100 day) 67% (55-83%) 44% (33-59%) 0.055 Cum incidence acute GVHD (grade 3-4) (at 100-day) 16% (8-32%) 10% (5-21%) 0.347 Chronic moderate or severe (at 2-year) 38% (25-60%) 17% (10-30%) 0.086 Cum incidence of NRM (at 100-day) 12% (5-27%) 13% (7-25%) 0.078 Cum incidence of NRM(2-year) 17% (10-35%) 35% (24-50%) 0.078 Cum Incidence of relapse (2-year) 28% (17-46%) 26% (17-41%) 0.858 EFS (2-year) 54% (38-69%) 38% (26-52%) 0.191 OS (2-year) 56% (40-72%) 47% (34-60%) 0.244 Disclosures Off Label Use: Sirolimus for GVHD prophylaxis. Perkins:PDL Biopharma: Research Funding. Falantes:Celgene: Honoraria. Valcárcel:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Seattle Regimen RIC-HSCT in Early-Phase Multiple Myeloma: A Multi-Centre Experience Demonstrating Very Low Treatment-Related Mortality and Rapid Graft-Versus-Myeloma Effect Associated with Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4355-4355 ◽  
Author(s):  
Michael J Shipton ◽  
David JM Routledge ◽  
Neil Bodagh ◽  
James Cavet ◽  
Eleni Tholouli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Graft Versus Host Disease ◽  
Early Phase ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction: The introduction of novel agentshas revolutionised the treatment of multiple myeloma, with improvements in survival of newly diagnosed and relapsed/refractory patients. However, despite these advances, the role for allogeneic haematopoietic stem cell transplantation (HSCT) in the treatment of these patients remains in question. Reduced-intensity conditioning (RIC) HSCT with Seattle regimen (30 mg/m2 fludarabine and 2 Gray total-body irradiation, TBI) for multiple myeloma has been reported to be an effective treatment with low upfront toxicity, and the potential for graft-versus-myeloma effect (Niederwieser D et al, Blood, 2003). Its use as part of tandem HSCT (autologous HSCT followed by RIC-HSCT) is associated with a treatment-related mortality (TRM) rate as low as 15% (Björkstrand B et al, J Clin Onc, 2011). However, data on survival following auto-HSCT/RIC-HSCT is inconsistent and no unifying consensus has been reached regarding the optimal timing of RIC-HSCT in the treatment algorithm. In this retrospective multi-centre study, we investigated the safety, tolerability and efficacy of RIC-HSCT in multiple myeloma patients in remission following previous auto-HSCT. Methods: A retrospective series was conducted for early-phase, high-risk myeloma patients who underwent RIC-HSCT following prior auto-HSCT in two tertiary transplant centres in Manchester in North West England, between November 2006 and July 2014. Results: Over the eight-year period, 42 myeloma patients (male n=29, female n=13) underwent Seattle-conditioned RIC-HSCT following prior auto-HSCT. 66.6% (n=28) were performed in tandem. Median age at RIC-HSCT was 52 years (range 41-65), and median β2-microglobulin at diagnosis was 3.1 mg/L (range 1.6-18.0). 16 patients had cytogenetics assessed at the time of diagnosis, of which loss of TP53 and translocation of chromosome 14 were most common. 37 patients (88.1%) had previously been exposed to immunomodulatory agents (IMiDs). 53.3% patients (n=24) were in first remission at RIC-HSCT, whilst 37.8% (n=17) were in second remission. 31.1% (n=14) of RIC-HSCTs were performed after second auto-HSCT following previous relapse and re-induction chemotherapy. 34 patients (55.9%) had achieved at least a very good partial response (VGPR) prior to RIC-HSCT. RIC-HSCT was performed a median of 20 months (range 10-89) from diagnosis. Two patients (4.8%) required re-transplantation for failed engraftment, but subsequently engrafted following in vivo T cell-depleting regimens. Mortality at early and interim time-points was low relative to registry and trial series, with TRM of 2.4% (n =1) and 9.5% (n=4) at day 100 and 365, respectively. 37 patients (82.2%) experienced chronic graft-versus-host disease (GVHD). Chronic skin GVHD was observed in 21 patients (grade 1-2: n=20; grade 3-4: n=1); chronic gastrointestinal GVHD in four patients (grade 1-2: n=1; grade 3-4: n=3); chronic hepatic GVHD in six patients (grade 1-2: n=4; grade 3-4: n=2); chronic oral GVHD in 17 patients (grade 1-2: n=17); and chronic ophthalmic GVHD in five patients (grade 1-2: n=5). There was an association between GVHD and enhanced disease control, as complete response rates increased from 26.5% to 51.5% by day 100 post-RIC-HSCT. However, 22 patients (48.9%) eventually relapsed with a median time to relapse of 6.5 months. 13 patients remain in CR one year post-RIC-HSCT. Relapse was treated with escalating donor lymphocyte infusions (DLI, n=13) or IMiDs (n=16). Response to lenalidomide at relapse was potentiated, despite the majority of patients having prior exposure to IMiDs. The median length of follow-up from diagnosis was 27 months (range 1-90). Median overall survival (OS) has not been reached; OS at two years was 69.2% (Figure 1). Conclusions: In this retrospective series we demonstrate the feasibility of Seattle-conditioned RIC-HSCT in multiple myeloma. We observed a very low early TRM of 9.5% and presence of allo-immune disease control (graft-versus-myeloma effect), thereby augmenting IMiD efficacy. Chronic GVHD was prevalent and relapse occurred in a significant proportion of patients, but salvage with DLI and IMiDs highlighted the efficacy of the graft-versus-myeloma effect elicited by RIC-HSCT. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Disclosures Cavet: Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Speaker. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Gibbs:Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mesenchymal Stromal Cell (MSC) Compassionate Use in France in Treatment of Steroid-Refractory Graft-Versus-Host-Disease (GVHD) after Approval By the Expert Committee of Société Française De Greffe De Moelle Et Thérapie Cellulaire (SFGM-TC)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Lea Bosdure ◽  
Laurence Blanc ◽  
Nimrod Buchbinder ◽  
Valerie Coiteux ◽  
Gaelle Fossard ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Malignant Disease ◽  
Acute Gvhd ◽  
Expert Committee ◽  
Compassionate Use ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Hematopoietic stem cell transplantation is a well-established efficient therapy for hematological diseases, but Graft-Versus-Host Disease (GVHD) is a major and frequent complication encumbering its outcome despite the administration of calcineurin inhibitor based GvHD-prophylaxis. Corticosteroids represent the worldwide first line treatment, however in case of steroid refractory acute GVHD there is no consensus about a subsequent treatment although Ruxolitinib is subject to a phase III trial. Multiple molecules have been tried, most of them immunosuppressive, increasing the risk of deadly infections and transplantation-related mortality (TRM). Recent studies reported that mesenchymal stromal cells (MSC) infusion which have immune modulatory abilities might be effective and harmless in steroid or treatment-refractory GVHD (R-GVHD). In France, MSCs are considered as an Advanced Therapy Medicinal Product. For 4 years, its administration as a compassionate use is subject to approval by an expert committee from SFGM-TC before its validation by the French regulatory agency (ANSM). We retrospectively analyzed the demands for MSC use in France since 2011 for patients suffering from R-GVHD. We evaluated the response at day 28 (range 23-28) and at the last follow-up and its safety. Eleven demands were validated by both expert committee and ANSM, 8 patients (pts) received ex-vivo expanded MSCs, 1 pt refused the therapy, 1 infusion was postponed due to COVID-19 related sanitary crisis and the last 1 didn't receive MSCs due to relapse. Among pts who received MSCs, median age was 6 years (2-69), sex ratio was 0,6. All pts underwent their first HSCT for either malignant disease (62,5%) or non-malignant disease (37,5%). Four pts were transplanted from sibling donor, 2 pts from mismatched unrelated donors and 2 pts from haplo-identical donors. Stem cells source was bone marrow for 4 pts, peripheral blood stem cells for 3 and cord blood for 1. Donors median age was 28,8 years (0-49,5), 1 male had a female donor. Six pts got a myeloablative conditioning regimen (TBI-based for 2). All pts received a ciclosporin-based (CSA) GVHD prophylaxis (CSA alone, n=1; CSA + Mycophenolate Mofetil (MMF) or Methotrexate, n=7). Five pts had ATG. Six pts were suffering from acute GVHD, while 2 from extensive chronic GVHD (cGVHD). All 6 pts with acute GVHD presented a grade III or IV, refractory to corticosteroids and at least 2 other lines of GVHD therapy. All but one had a multipolar GVHD with at least 2 affected organs. Five pts were still taking corticosteroids, and six were taking additional immunosuppressive molecules (Tacrolimus, Ruxolitinib, Etanercetp, Inolimomab, MMF) at time of MSC infusion. Five pts received German commercialized MSCs (Obnitixâ, MEDAC, Germany; see Bader et al, 2018), 2 get mother's derived MSCs (not the initial donor), and 1 from a third-party donor. A median of 4 infusions were administered (1-4), once a week for 4 weeks. Mean single dose of MSCs was 1.23.10e6/kg (range: 0,86 - 3). No toxicity was reported except for 1 pt who experienced anaphylactic reaction within minutes, leading to the interruption of infusion (mother's derived MSCs prepared with fetal bovine serum where all other preparations were performed with platelet lysate). The median time from GVHD onset to first MSC infusion was 135 days (63-457). Overall response rate was 86% (6/7) at the first and at the last evaluation with 1 complete response (CR) and 5 partial responses (reduction of at least one grade of at least one affected organ). One pt did not respond and the last 1 was not evaluable due to anaphylactic reaction. Both were suffering from cGVHD. Among the seven pts who received complete MSC infusions, median follow-up was 1,5 months (1,1-18,5) due to premature TRM, overall survival (OS) at six months was 33,3%. Five pts died, all of them from a transplantation-related cause: GVHD n=2, severe infections n=3. Literature reported better outcomes lately, Bader and al, 2019 reported a 64% OS at 6 months and 51% of CR at last follow up. Those disparities might be explained by a delayed treatment after GVHD onset (135 days versus 28 days) and a median of 3 (2-10) therapies after receiving corticosteroids before MSC infusion due to difficulty to obtain MSCs in France. Besides, we included patient suffering from R-cGVHD. Regarding those results, MSC efficacy and safety should be confirmed in a proper clinical trial. Figure Disclosures Rubio: Neovii: Research Funding; Novartis: Honoraria; MSD: Honoraria; Gilead: Honoraria; Medac: Consultancy. Dalle:Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

Evaluating Gvhd Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haplo-Identical Setting: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Mindy Hsiao ◽  
Preet M. Chaudhary ◽  
George Yaghmour
Keyword(s):  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
Board Of Directors ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
End Points ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
Haplo Group

Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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