Safety and Efficacy of the mTOR Inhibitor Everolimus as Early Interventional Replacement for Calcineurin Inhibitors In Graft-Versus-Host Disease (GvHD) Prophylaxis After Allogeneic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2325-2325
Author(s):  
Herbert G. Sayer ◽  
Anne Klink ◽  
Thomas Schenk ◽  
Anne Treschl ◽  
Kristina Schilling ◽  
...  
Keyword(s):  
Research Funding ◽  
Mtor Inhibitor ◽  
Acute Gvhd ◽  
Solid Organ Transplantation ◽  
Immunosuppressive Drug ◽  
Solid Organ ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade 3

Abstract Abstract 2325 Background: The medical backbone of GvHD prophylaxis has been considered the use of a calcineurin inhibitor (CNI) like cyclosporine or tacrolimus in combination with methotrexate (MTX) or mycophenolate mofetil (MMF). The mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001, Certican®) is a novel immunosuppressive drug and beside sirolimus approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with CNI showed promising clinical effectiveness in innovative prevention strategies of acute GvHD after allogeneic stem cell transplantation (SCT). In this single centre retrospective analysis, we report the outcome on patients (pts), treated interventional with everolimus due to severe toxicity induced by CNI-based GvHD prophylaxis. Patients and Methods: Ten pts (3 acute myeloid leukaemias, 1 myelodysplastic syndrome, 1 acute lymphoblastic leukaemia, 4 Non-Hodgkin-lymphomas) underwent allogeneic blood SCT between 7/2007 and 3/2010. The median age was 51 years [range: 24–64] with 6 pts in advanced stages of their disease. Myeloablative conditioning was used in 3 pts (12 G TBI/120mg/kg cyclophosphamide (cyclo)] and reduced-intensity conditioning in 7 pts [5× treosulfan/fludarabine (flu), 1× busulfan/flu and 1× amsacrine/cytarabine/flu followed by 4 G TBI/cyclo]. HLA-matched family donors in 4 pts and unrelated donors in 6 pts donated on day 0 a median of 4.73 × 106 kg per bodyweight CD-34 positive stem cells. GvHD-prophylaxis consisted of standard CNI+MTX in 3 pts, CNI+MMF in 6 pts and CNI+MMF+MTX in 1 patient. Antithymocyte globulin as in vivo T-cell depletion was given in 7 pts as part of the reduced intensity conditioning regime. Results: Everolimus (0.75 mg Certican ® twice a day orally) was individual started after a median of 14 days [range: 6–16] after SCT. Primary reasons for stopping CNI (median day +10 [range 1–15]) were nephrotoxicity (CTC ≥ grade 3) in 7 pts and neurotoxicity (CTC ≥ grade 3) in 3 pts. Two pts received steroids in addition to everolimus temporally, 5 pts MMF and 3 pts steroids+MMF. The intended plasma therapeutic level of everolimus was 3–8 mg/l. All patients showed neutrophil engraftment on median day +18 [range: 8–20] and platelet engraftment on day +21 [range: 10–88]. Acute GvHD ≥ grade II (Glucksberg/Consensus NHI) occurred in 3pts (30%) (2× grade II, 1× grade III) or IBMTR-Index-Score ≥ B (2×B, 1×C). Chronic GvHD limited disease score grade I (Consensus NIH) was observed in 3 pts (n=1 overlap syndrome and n=2 de-novo cGvHD). Two out of 7 high risk pts for CMV reactivation developed viral activation. Until day +100 3 pts stopped interventional GvHD prophylaxis due to oral bleeding on day +46 (n=1) and assumed TMA on day +57/+64 (n=2). The period of everolimus administration was 140 days on average [range: 19–509]. As per August 2010 6 pts are alive resulting in a median cumulative overall survival of 58%. ALL-relapse had to be observed on day +312 in one patient. Fatal casualties occurred on day +19 by multiorgan failure (MOD), on day +103 by pneumonia, on day +211 by questionable pulmonary embolism and on day+ 411 by MOD and limited cGvHD. Conclusions: A delayed CNI-free GvHD-prevention strategy with the m-TOR inhibitor everolimus is feasible and efficacious in a series of patients after allogeneic SCT. The manageable toxicity profile in our cohort with pre-existing organ dysfunction at treatment onset mandates further evaluation of everolimus after SCT. A prospective multicentre phase II trial of everolimus as intended early replacement for CNI after SCT with a focus on tolerability is scheduled to start soon. Disclosures: Sayer: Novartis Pharma: Honoraria, Research Funding. Off Label Use: Everolimus -Certican (R)- is only approved as a immunosuppressive drug in solid organ transplantation. Hochhaus: Novartis: Consultancy, Research Funding.

scholarly journals A Prospective Phase 2 Study Testing High Dose Post-Transplant Cyclophosphamide As Sole Ghvd Prophylaxis after Matched Allotransplant Using Baltimore-Based Reduced-Intensity Conditioning Regimens and PBSC As Source of Graft

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1812-1812
Author(s):  
Patrice Chevallier ◽  
Amandine Le Bourgeois ◽  
Alice Garnier ◽  
Pierre Peterlin ◽  
Yannick Le Bris ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Phase 2 ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Phase 2 Study ◽  
High Incidence ◽  
Grade 3

Abstract Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults. Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767. Results: The results of the first 27 first patients (males n=17 and female n=10; median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17. Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached. Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported here may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing. Disclosures Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.

scholarly journals Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1950-1950 ◽  
Author(s):  
Brian T Hess ◽  
Feng Gao ◽  
John F. DiPersio ◽  
Peter Westervelt ◽  
Ravi Vij ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Transplant Outcomes ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Transplant Patients ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution. Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method. Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%. Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

scholarly journals The Association between Transplant-Associated Thrombotic Microangiopathy and Calcineurin Inhibitor and Sirolimus Levels

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 814-814
Author(s):  
Ang Li ◽  
Qian V. Wu ◽  
Chris Davis ◽  
Stephanie J. Lee ◽  
Jingfei Dong ◽  
...  
Keyword(s):  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Time Varying ◽  
Drug Levels ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
The Impact ◽  
Trough Levels

Abstract Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). An ongoing debate is whether TMA is caused by acute graft-versus-host disease (GVHD) or calcineurin inhibitor (CNI)/sirolimus. Previous studies have not examined the impact of CNI/sirolimus average trough levels while accounting for the confounding effect of GVHD. In the current study, we examined the association between time-varying levels of CNI/sirolimus and the onset of TMA among 2105 adult allogeneic HCT recipients. Methods: We performed a retrospective cohort analysis of allogeneic HCT recipients during 2006-2015 at Fred Hutchinson Cancer Research Center who received CNI/sirolimus for GVHD prophylaxis. TMA (outcome) was ascertained and validated as previously described (Blood 130;Suppl:666). Acute GVHD (confounder) was defined and graded according to established criteria. Consecutive CNI/sirolimus trough levels (exposure) were obtained and interval values between checks were imputed via linear interpolation. We followed patients from the time of hematopoietic cell infusion until the onset of TMA and censored patients at day 100 or >1 week of missing drug levels. To examine the association between the "type" of immunosuppressant and TMA, CNI/sirolimus exposure over time was characterized as a discrete categorical variable (tacrolimus alone, cyclosporine alone, or sirolimus + CNI). To examine the impact of the "level" of immunosuppressant on TMA, CNI/sirolimus exposure was both defined as an average of the previous 7-day trough levels (continuous variable) as well as a discrete time-above-peak variable (binary variable for tacrolimus >15 ng/mL, cyclosporine >450 ng/mL, or sirolimus >10 ng/mL). Extended Cox regression models were built to examine the time-varying association between CNI/sirolimus exposures and TMA after adjusting for GVHD. Results: In the current study, 2105 adult allogeneic HCT recipients contributed 173,171 person-days and 150 cases of TMA. The median follow-up time was 94 days and trough blood levels were checked on average 3x per week. Initial GVHD prophylaxis regimen for patients included 54% on tacrolimus (n=1135), 40% on cyclosporine (n=837), and 6% on a combination of sirolimus + CNI (n=133). Nearly no one received sirolimus alone without CNI. Eight percent of patients (n=162) had at least one switch in the immunosuppression regimen within 100 days. The median (IQR) trough levels for tacrolimus, cyclosporine, and sirolimus were 9 ng/mL (7-12), 283 ng/mL (206-372), and 5 ng/mL (4-7), respectively. Acute GVHD developed in 64% of patients including 53% grade 2 (n=1115), 9% grade 3 (n=185), 2% grade 4 (n=52). In the analysis adjusted for both discrete time-varying CNI/sirolimus exposure and GVHD, higher grades of GVHD had strong associations with TMA (Table 1: grade 2 HR 2.24, P=0.001; grade 3 HR 12.38, P<0.001; grade 4 HR 26.04, P<0.001). While cyclosporine and tacrolimus had a similar risk for TMA (HR 1.23, P=0.230), sirolimus + CNI regimen was associated with a slightly higher risk compared to CNI alone (HR 1.76, P=0.051). In the analyses of individual drug levels adjusted by GVHD, higher trough levels of tacrolimus and cyclosporine (either as a linear average level or binary time-above-peak) were not associated with an increased risk of TMA (Table 2). However, higher sirolimus trough levels were associated with an appreciable risk of TMA (HR 1.44, P=0.001 for every 1 ng/mL increase in sirolimus average trough level; HR 3.23, P=0.164 for time above 10 ng/mL). Conclusion: In allogeneic HCT patients, acute GVHD was strongly associated with the onset of TMA independent of ongoing exposures of CNI/sirolimus. We did not find an association between CNI recipients (tacrolimus versus cyclosporine) or CNI levels and the risk of TMA. However, when combined with CNI, higher sirolimus trough levels were linearly associated with a higher risk for TMA. Limitations in this observational study include the inability to adjust for concomitant medications and conditions that might have altered drug levels and inability to adjust for target drug levels since recognized risk factors might have led clinicians to target higher drug levels due to higher risks of GVHD. These findings suggest that prevention and treatment of GVHD and avoidance of high sirolimus levels will decrease the risk of TMA. Disclosures Lee: Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Kadmon: Research Funding; Takeda: Research Funding. Garcia:Pfizer: Consultancy; Portola: Research Funding; Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Janssen: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Boehringer Ingelheim: Consultancy.

scholarly journals Graft Versus Host Disease (GVHD) after HLA-Mismatched Haploidentical Transplantation with Post-Transplant Cyclophosphamide Compared to Matched Unrelated Donor: Incidence, Distribution and Response to Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4541-4541
Author(s):  
Melhem Solh ◽  
Xu Zhang ◽  
Asad Bashey ◽  
Lawrence E Morris ◽  
H. Kent Holland ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Response To Treatment ◽  
Organ Distribution ◽  
Cox Models ◽  
Haploidentical Transplantation ◽  
Gvhd Prophylaxis ◽  
All Cause Mortality ◽  
Grade Ii ◽  
Grade 3

Unmanipulated T-cell replete HLA-mismatched haploidentical transplantation (haplo) with post-transplant cyclophosphamide (PTCY) is now widely used for patients lacking a suitably matched donor. The use of PTCY post haplo results in lower chronic GVHD rates compared to match unrelated donors (MUD) without PTCY. GVHD after PTCY in the haplo setting may have different presentation, response to treatment and impact on survival endpoints compared to a standard GVHD prophylaxis of calcineurin inhibitor plus MMF or methotrexate for MUD patients. To check for differences in GVHD presentation and response to treatment between MUD and haplo with PTCY, we assessed 394 consecutive patients who developed acute or chronic GVHD after receiving their first allogeneic transplantation (HCT) from a 10/10 HLA MUD (n=179) or a haplo (n=215) at our center between 2008 and 2017. Median follow up for survivors was 52.5 months. Our institution has prospectively documented onset, grading and therapy of patients with GVHD using a single dedicated practitioner since 2005. All haplo patients received standard GVHD prophylaxis of tacrolimus (days 5-180), MMF (stop day 35) and PTCY at 50mg/kg on days 3 and 4. Most commonly used GVHD prophylaxis for MUD patients were tacrolimus/methotrexate (68%) and tacrolimus/MMF (26%). MUD recipients were older (median age 56 vs 53 years, p=0.007), were more likely to be white (93% vs 58%, p<0.001), received mainly PBSC as graft source (76% vs 63%, p0.013) and had a higher HCT-comorbidity index (HCT-CI≥3, 64% vs 47%, p<0.001) compared to haplo recipients. The cumulative incidences for grade II-IV and III-IV aGVHD at day 180 post HCT were similar between both donor sources at 35% and 11% for haplo compared to 44% and 16% for MUD (p=NS). Haplo patients had lower cumulative incidence of mod-severe cGVHD at 22% versus 31% for MUD (p=0.026).The median times to onset of grade II-IV acute GVHD and moderate-severe chronic GVHD were: acute, 56 vs 49 days (p=0.19) and chronic 213 vs 280 days (p=0.011) for haplo versus MUD patients respectively. Among patients with grade II-IV acute GVHD, there was no significant difference in organ involvement between Haplo (n=101) and MUD (n=96) with skin being most commonly affected (74% haplo vs 71% MUD), Gut (70% haplo vs 69% MUD) and liver (14% haplo vs 17% MUD). For patients who developed chronic GVHD, organ involvement distribution is shown in table 1. Haplo patients had less involvement of the eyes (46% vs 75% for MUD, p<0.001) and of the joints/fascia (12% vs 36%, p=0.001). Among patients who developed grade II-IV acute GVHD, there was no difference in all-cause mortality (28% vs 19%, p=0.34) and being off immunosuppression at one 1 year (49% vs 51% p=0.80) between haplo and MUD recipients. Among patients who developed cGVHD, haplo recipients had similar all-cause mortality (22% vs 18%, p=0.89) but were more likely to be off immunosuppression at 2 years post HCT (63% vs 43% p=0.03) compared to MUD (figure 1). A cox model was conducted on survival and relapse endpoints where donor type was retained in all models. The fixed covariates tested in Cox models included age (<55, >=55), gender, race, diagnosis, regimen intensity, graft source (BM, PBSC), disease risk index (low/intermediate, high/very high), CIBMTR risk (low, intermediate, high), HCT-CI (0-2, >=3), CMV status, year of transplantation (2008-2012, 2013-2015, 2016-2017). The following variables were evaluated as time-dependent covariates in Cox models: all-grade cGVHD, moderate-severe cGVHD, severe cGVHD, grade 2-4 aGVHD, grade 3-4 aGVHD. Variables were selected if p values were less than 0.05. Developing grade 3-4aGVHD and severe chronic GVHD were both associated with worse OS, DFS and TRM (table 2). Both aGVHD and cGVHD were not significant factors for relapse. Our analysis reveals that compared to MUD, haplo transplant results in significantly lower incidence of moderate-severe chronic GVHD, faster cGVHD onset, different organ distribution and a higher chance of coming off immunosuppression. This data, added to prior publications from our center and others showing similar OS and DFS between MUD and haplo, enforces the notion that haplo transplant with PTCY is at least equivalent to MUD transplant. An ongoing BMTCTN 1702(CTRL-ALT-D) study will help answer assess this in a prospective fashion. figure 1: Chronic GVHD patients who are Immunosuppression free at 2 years Table 1: Organ Distribution of Chronic GVHD by Donor Type Disclosures No relevant conflicts of interest to declare.

scholarly journals Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 368-368 ◽  
Author(s):  
Glen A Kennedy ◽  
Siok-Keen Tey ◽  
Cameron Curley ◽  
Jason P Butler ◽  
Ashish Misra ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Acute Gvhd ◽  
Phase Iii ◽  
Control Group ◽  
Double Blind ◽  
Free Survival ◽  
Entire Cohort ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Background: IL-6 mediates graft-vs.-host disease (GVHD) in experimental models of allogeneic stem cell transplantation. The addition of a humanized anti-IL-6R mAb (Tocilizumab; TCZ) to standard GVHD prophylaxis has shown in promise in reducing the incidence of acute GVHD in two prospective phase I/II clinical studies. Aims: To determine the efficacy of TCZ in preventing grade II-IV acute GVHD in patients with acute leukaemia or myelodysplasia undertaking 8/8 matched related sibling (MSD) or matched unrelated donor (MUD) allogeneic HPCT after myeloablative (MAC) or reduced intensity conditioning (RIC) across five Australian transplant centers. Methods: 145 patients (50 MSD and 95 MUD) were randomly assigned to either placebo or TCZ (8mg/kg; max dose 800mg) on day-1 of conditioning. Patients and physicians were both blinded to treatment. RIC patients all received Flu/Mel (n=81, 56%) while MAC patients received Cy/TBI (n=46, 32%) or Bu/Cy (n=18, 12%). All patients received T-replete PBPC grafts, and standard GVHD prophylaxis cyclosporine and day 1 (15mg/m2), 3, 6 and 11 (10mg/m2) methotrexate. The primary endpoint was incidence of grade II-IV acute GVHD. A planned substudy analyzed the MUD cohort. Secondary endpoints included day 180 grade II-IV acute GVHD free-survival (GVHD-FS), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), time to engraftment and rates of infection. The study was powered to observe a 50% reduction in the incidence of grade II-IV acute GVHD at day +100 for the entire and MUD cohorts, assuming a 50-55% baseline in the control group. Competing risk (death) regression adjusted hazard ratio (HR) was estimated to evaluate the GVHD-related outcomes in TCZ vs. placebo groups. Results: With a median follow up of 746 days, the overall incidence of grade II-IV GVHD at day 100 for the entire cohort was 36% vs. 27% for placebo vs. TCZ respectively (HR: 0.69; 95% CI 0.38-1.26; p=0.23), and 45% vs. 32% (HR: 0.61; 95% CI 0.31-1.22; p=0.16) for the MUD subgroup. The incidence of grade II-IV GVHD at day 180 for the entire cohort was 40% vs. 29% for placebo vs. TCZ respectively (HR: 0.68; 95% CI 0.38-1.22; p=0.19), and 48% vs. 32% (HR: 0.59; 95% CI 0.30-1.16; p=0.13) for the MUD subgroup. The incidence of severe grade III/IV GVHD at day 100 for the entire cohort was similar, 13% vs. 14% for placebo vs. TCZ respectively (HR: 1.04; 95% CI 0.42-2.61; p=0.93), and 10% vs. 14% for the MUD subgroup (HR: 1.42; 95% CI 0.41-4.95; p=0.59). A trend to improved GVHD-FS was noted in the TCZ-treated MUD subgroup, 52% vs. 68% for placebo vs. TCZ treated (HR: 1.70; 95% CI 0.86-3.37; p=0.13). For the entire cohort, TRM occurred in 8% of placebo-treated vs. 11% of TCZ-treated patients respectively (HR: 1.37; 95% CI 0.48-3.96; p=0.56); Progressions were similar at 25% vs. 33% (HR:1.44; CI 0.78-2.63, p=0.24) and OS was 79% vs. 71% (HR: 0.69; CI 0.35-1.34, p=0.27). No significant differences were seen in these outcomes in the MUD cohort. Day to neutrophil engraftment was marginally delayed in TCZ-treated patients, with median time to neutrophil ≥0.5 of 15 days (range 11-24 days) vs. 18 days (range 9-35 days) for placebo vs. TCZ-treated patients respectively (95% CI 1.3-4.7; p=0.001). Time to platelet engraftment was also marginally delayed in TCZ-treated patients, with median time to plts≥20 of 16 days (range 9-36 days) vs. 19 days (range 11-389 days) (95% CI 0.4-5.6; p=0.022). The median time to neutrophil and platelet engraftment in TCZ-treated patients were each 2 days slower in the MUD cohort (p=0.016 and p=0.22 for neutrophils and plts respectively). Two TCZ-treated patients died beyond day 30 (at day 31 and 32) with incomplete neutrophil recovery. The incidence of 1 or more grade 3 or higher liver toxicity (LT) was similar between groups, occurring in 14% of placebo-treated patients vs. 15% of TCZ-treated patients respectively (OR: 1.14; 95% CI 0.45-2.88; p=0.79). Grade 2 or higher infection adverse events occurred in 64% of placebo-treated patients vs. 71% of TCZ-treated patients respectively (OR: 1.34; 95% CI 0.67-2.71; p=0.41). Conclusion: In a phase III randomized, double-blind trial, TCZ administered at D-1 showed non-significant trends to reduced incidence of grade II-IV GVHD and improved acute GVHD-free survival in recipients of HLA-matched MUD donors, but no improvements in long term-survival. Study power was compromised by lower rates of acute GVHD in the control group than anticipated. Disclosures Ritchie: Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Sanofi: Honoraria. Gottlieb:Novartis: Consultancy; AbbVie: Consultancy; University of Sydney: Employment; Merck: Consultancy; Gilead: Consultancy; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding. Paul:Novo Nordisk: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Hill:Roche: Other: Investigator driven trial funding; Pharamcyclics: Consultancy, Research Funding; CSL: Consultancy, Research Funding; Implicit Bioscience: Consultancy, Research Funding. OffLabel Disclosure: Use of Tocilizumab for the prevention of acute GVHD

scholarly journals Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2881-2881
Author(s):  
Benjamin Bouchacourt ◽  
Valerio Maisano ◽  
Ana Benzaquen ◽  
Angela Granata ◽  
Sabine Furst ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Advisory Committees ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Background: Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD. Patients and Methods: This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery. Results: 241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01). Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802). By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS. Conclusion: In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. Figure 1 Figure 1. Disclosures Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Natasia Rodriguez ◽  
Jasme Lee ◽  
Lisa Flynn ◽  
Fiona Murray ◽  
Sean Devlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Low Incidence

Background. GVHD is a frequent complication within the 1st year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced intensity (RI) and non-myeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis, frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor (PI) that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, anti-tumor activity, and has a wide safety profile. We hypothesized that secondary GVHD prophylaxis using ixazomib, will facilitate CNI taper without increase in GVHD frequency and severity, maintaining graft-versus-tumor (GVT) effect, and a safety profile. Methods. We conducted an open label, prospective, single-center pilot study between 11/16 and 03/19. Eligible patients were &gt; 18 yrs old, had a hematologic malignancy treated with RI or NMA conditioning allo-HCT, received CNI-based GVHD prophylaxis, and were within day 100 to 150 post-HCT. Patients with active acute and/or chronic GVHD were excluded. Patients were treated with ixazomib 4 mg orally once weekly, each cycle consisting of 3 weeks on and 1 week off therapy, until completion of taper from prophylactic CNI or 1-year post-HCT was reached, whichever occurred first. Patients who developed grade II-IV acute GVHD, chronic GVHD, or died of transplant-related mortality (TRM) were deemed treatment failure. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade II-IV acute GVHD or chronic GVHD at 1-year post-HCT. Additional endpoints included TRM, relapse rate, survival analysis, safety evaluation, and immune reconstitution. Results. A total of 18 patients (median age of 58 yrs) were accrued in the study. The majority were male, had a diagnosis of NHL, and received RI conditioning (Table 1). All patients had a PBSC graft, and 16 (89%) were 10/10 HLA-matched. The median time for initiation of ixazomib was 141.5 days post-HCT. Fourteen patients had no GVHD during the study period. The 4 patients who developed GVHD had severe overlap syndrome (n = 2), mild de novo chronic GVHD (n = 1), and recurrent grade II acute GVHD (n = 1). Notably, patients with severe overlap syndrome had limited chronic GVHD involvement affecting the mouth and/or eyes, and the severity score was driven by acute manifestations affecting the skin and GI tract. Six patients successfully discontinued CNI and 4 patients were tapering immunosuppression close to the end of study at 1-year post-HCT. The cumulative incidence (CI) of grade II-IV acute and chronic GVHD at 1-year post-HCT was 25% (95%CI: 7.2-48.1) (Fig. 1A). No patients died during the study and therefore, the CI of TRM at 1-year was 0%, and only 1 patient had malignant relapse (NHL). The CI of PFS and the composite endpoint GVHD-free/relapse-free survival (GRFS) at 1-year were 83% (95%CI: 58-100) and 73% (95%CI: 49-100, Fig 1B), respectively. All patients experienced at least 1 TEAE of any grade. Most AEs were grade 1 or 2, with the most common being cytopenia and elevation in ALT/AST. Drug-related SAEs were reported in 9 patients and included neutrophil and decreased WBC. Seven patients required ixazomib dose reduction due to side effects, and 5 patients were removed from the study due to toxicity (1 neutropenia, 3 GI, 1 skin rash). Of those, 1 had subsequent GVHD by day 365 post-HCT. Immune recovery at 3, 6 and 12 months post-HCT was evaluated. There was a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution Fig 2. Conclusions. Secondary GVHD prophylaxis with ixazomib was associated with low incidence of recurrent and late acute and chronic GVHD within the 1st year post-HCT. This approach allowed CNI taper while preserving GVT effect without aggravating GVHD. No deaths occurred during the study period and the 1-year GRFS was high. Ixazomib was overall well tolerated and favored immune reconstitution post-HCT. Our findings support further development of this approach and provide a proof-of-concept for secondary GVHD prophylaxis. Disclosures Dahi: Kite: Consultancy. Giralt:TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding. Sauter:Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: 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; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ponce:Ceramedix: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3046-3046 ◽  
Author(s):  
Vincent T. Ho ◽  
Haesook Kim ◽  
Shuli Li ◽  
Corey Cutler ◽  
John Koreth ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Historical Cohort ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity

Abstract We have previously shown that the combination of tacrolimus and sirolimus (TAC/SIR) without methotrexate (MTX) is a safe and effective regimen for GVHD prophylaxis after myeloablative SCT. However, TAC/SIR has not been investigated in the RIC setting. We hereby report a prospective phase II trial testing TAC/SIR as GVHD prophylaxis after RIC SCT from matched related donors (MRD). All patients received fludarabine (FLU) 30 mg/m2 IV and intravenous busulfan (BU) 0.8 mg/kg IV daily × 4 days (day -5 thru day -2) as conditioning, followed by transplantation of filgrastim mobilized peripheral blood stem cells. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Tacrolimus and sirolimus were started on day-3, and doses were adjusted to maintain target serum trough levels 5–10 ng/ml and 3–12 ng/ml, respectively. Twenty-six patients have been transplanted, with a median age of 52 years (range 29–64 yrs). Diagnoses include NHL (8), AML (6), HD (5), CLL/SLL (3), CML (2), MDS (1), MM (1). Median CD34+ cells infused was 8.06 × 106 cells/kg (range: 2.96–38.0 × 106 cells/kg). All patients had sustained hematologic engraftment. Only 4 (15%) patients developed neutropenia below ANC 500, and 6 (23%) had platelet counts below 20K. One patient had late graft failure at 7 months post transplant. Grade II-IV acute GVHD incidence was 20%, with grade III-IV incidence of 12%. No hepatic VOD or thrombotic microangiopathy was observed. Day +100 transplant related mortality (TRM) was 0%. The cumulative incidences of TRM and relapse at 1 year were 4% and 38%, respectively. The cumulative incidence of chronic GVHD at 1 year was 74%. A high level (>90%) of donor-derived hematopoiesis was achieved in 68% by 1 month post transplant. Median donor chimerism at between day 20–50 post transplant was 93.5% (range 32%-99%), and 94% (range 22%-100%) at day 85–115. With a median follow-up of 13.5 months among survivors (range 5.5–19 months), progression-free survival (PFS) and overall survival (OS) at 1 year were 58% and 79%, respectively. Compared to a historical cohort of 47 MRD transplant recipients treated with the same FLU/BU conditioning regimen and using TAC/SIR ± mini-MTX (5 mg/m2 IV day +1,3,6) as GVHD prophylaxis, there was no statistical difference between TAC/SIR vs. TAC/SIR/MTX in the incidence of grade II-IV acute GVHD (20% vs 11%, p= 0.48), cumulative incidence of relapse at year (38% vs. 57%, p= 0.25), 1-yr PFS (58% vs. 41%, p= 0.33), or 1-yr OS (79% vs. 73%, p= 0.79). These results demonstrate that omission of mini-MTX is permissible, and that the combination of TAC/SIR alone as GVHD prophylaxis following reduced intensity conditioning with FLU/BU is associated with low rates of acute GVHD, TRM, and high levels of donor chimerism after MRD SCT.

Reduced Intensity Conditioning Combined with Post-Transplant Cyclophosphamide for Graft Vs. Host Disease Prophylaxis In Older-Aged or Medically Frail Patients with Advanced Hematological Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2341-2341
Author(s):  
Amin M Alousi ◽  
Borje S. Andersson ◽  
Rima M. Saliba ◽  
Wendeline Botnick ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Phase Ii Trial ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Graft Vs Host Disease ◽  
Matched Sibling ◽  
Grade 3

Abstract Abstract 2341 Graft-vs-Host Disease (GVHD) remains a common complication following matched sibling and unrelated (MUD) donor hematopoietic cell transplant (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (Cy) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and Cy. Herein, we report the results of a phase II trial exploring a reduced intensity conditioning (RIC) regimen combined with post-transplant Cy in BM and peripheral blood (PB) HCT recipients. Methods: Fludarabine (Flu) was administered at a dose of 40mg/m2 over 1hr followed by intravenous Bu over 3 hrs targeting a daily AUC of 4,000 microMol-min on days −6 to −3. Recipients of MUD's received ATG on days −3 to −1 (total dose 4mg/kg). Cy was given as sole GVHD prophylaxis at a dose of 50mg/kg on days +3 and +4. Results: 31 pts with a median age of 62 yrs (range, 39–71) received a matched sibling (n=11) or unrelated donor (n=20) graft from BM (n=22) or PB (n=9) for the following diagnoses: AML/ MDS (n=25), CLL+MDS (n=2), CLL (n=1), NHL+MDS (n=1), NHL (n=1) and ALL (n=1). Disease status at the time of HCT was induction failure, relapsed and/ or chemotherapy-refractory disease in 23 pts with the remaining pts in high-risk CR1 (n=5), CR2 (n=2) or CR3 (n=1). The median co-morbidity score was 3 (range, 0–7) and 7 pts had a prior HCT (autologous n=4, allogeneic n=3). Median days to ANC > 0.5 × 109/L and platelet count >20 × 109/L were 17 (range, 13–38) and 24 (range, 11–57), respectively. Primary and secondary graft failure occurred in 1 and 2 pts, respectively. Mucositis (grade 2: n=19, grade 3: n=4) and hemorrhagic cystitis (grade 2: n=10, grade 3: n=4, grade 4: n=2) were the most common toxicities. Day 100 non-relapse mortality was 6% (95% CI, 2–25). The cumulative incidence (C.I.) of acute GVHD grades II-IV and III-IV was 56% (95% CI, 40–79) and 13% (95% CI, 5–33) which includes 4 cases of late acute GVHD. Rates of acute GVHD did not differ between PB or BM recipients (55% vs. 58%, p-value 0.9). C.I. of chronic GVHD was 11% (95% CI, 4–32). With a median follow-up of 10 months (range, 4–20), 1-yr overall and progression-free survival (PFS) was 56% (95% CI, 35–73) and 43% (95% CI, 21–63), respectively. For pts with AML/MDS, 1- yr PFS for pts in CR1, any CR and relapsed/refractory disease were: 100%, 66% (95% CI, 16–91) and 40% (95% CI, 20–60), respectively. Conclusion: This phase II trial of RIC with BU/Flu combined with post-transplant Cy was well tolerated and resulted in favorable survival and good disease-control in this high-risk, older-age population. Rates for acute GVHD appear comparable to historical rates with calcineurin-inhibitor based regimens, while rates for chronic GVHD appear to be lower. Rates for acute GVHD were similar for PB and BM grafts supporting the inclusion of PB grafts in future trials using post-transplant Cy as the basis for the GVHD prophylaxis regimen. Disclosures: No relevant conflicts of interest to declare.

Equivalent Survival Following Fludarabine/Melphalan Reduced Intensity Conditioning with or without Rabbit ATG As Part of GvHD Prophylaxis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1959-1959
Author(s):  
J. Mark Prichard ◽  
Samatha Muppidi ◽  
Christopher R Flowers ◽  
Jonathan L. Kaufman ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Donor Cell ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Abstract 1959 Introduction: Reduced intensity conditioning (RIC) prior to allogeneic transplantation allows donor cell engraftment with the maintenance of a graft versus malignancy effect. A recent CIBMTR registry study suggested worse outcomes for patients receiving anti-thymocyte globulin (ATG) as part of the conditioning regimen. To further study the role of ATG when added to a fludarabine and melphalan RIC regimen in the unrelated donor (URD) setting, we have retrospectively studied 76 consecutive patients with advanced hematologic malignancies who underwent URD transplantation. Comparisons were made between cohorts that did or did not receive ATG (given primarily for HLA disparity) for pretransplant graft vs. host disease (GvHD) prophylaxis. Pateints and Methods: Seventy six patients with advanced hematologic malignancies (43% CIBMTR high-risk) received fludarabine and melphalan (FluMel) conditioning with or without pre-transplant rabbit ATG 6 mg/kg as part of GvHD prophylaxis. Twenty five patients who received ATG (24 of whom received grafts from donors mismatched at 1 or 2 HLA loci) were compared with 51 patients who did not receive ATG (45 of whom received grafts from HLA matched donors with six donors mismatched at a single locus). The majority of patients received post-transplant tacrolimus with either methotrexate (MTX) or mycophenolate mofetil for GvHD prophylaxis. With the exception of HLA disparity, pre-transplant patient characteristics were similar between groups (Figure 1). Results: With median follow up of 481 days and 376 days for the ATG and no ATG cohorts, respectively, K-M overall survival estimates were similar, with 2 year OS of 62 vs. 47 percent, respectively, for the ATG vs no ATG groups (p=.34). On multivariate analysis, the inclusion of MTX in GvHD prophylaxis was favorably associated with overall survival (p=.004), and was associated with a significant reduction in the incidence of severe (gr 3–4) acute GvHD (p=.03). There were no significant differences in pre-transplant creatinine, age, or comorbidity index scores between patients who did or did not receive MTX. Conclusions: Fludarabine and melphalan RIC, with or without pre-transplant ATG, produced similar outcomes following URD transplantation, despite the fact that patients receiving ATG in this series were more likely to have received a HLA mismatched graft. The inclusion of MTX for GVHD prophylaxis resulted in less severe acute GVHD and better survival when compared with tacrolimus/MMF. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Kaufman:Merck: Research Funding; Keryx: Consultancy; Novartis: Consultancy; Onyx Pharmaceuticals: Consultancy; Millenium: Consultancy; Celgene: Research Funding. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Sinha:Celgene: Research Funding.

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