Prophylactic Rituximab After Allogeneic Stem Cell Transplantation Prevents Steroid-Requiring Chronic Graft-Vs.Host Disease

Abstract Abstract 214 There are no standard methods for the pharmacologic prevention of chronic GVHD (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Based on compelling biology implicating B cells in the pathophysiology of cGVHD and the utility of rituximab as therapy for established cGVHD, we performed a phase II trial of rituximab for the prevention of cGVHD after HSCT. Methods: 64 patients in remission without active GVHD received rituximab (375 mg/m2) at 3, 6, 9 and 12 months after HSCT. Related and unrelated donor recipients of 5/6 or 6/6 HLA-matched PBSCs were eligible. Prophylactic IVIG infusions were permitted at investigator discretion. Chronic GVHD severity was assessed by the requirement for systemic corticosteroids, with a historical rate of steroid-requiring cGVHD within 1 year of transplantation of approximately 60% at our institution. Results: 56 patients have been followed for at least 12 months from HSCT. One patient had a hypersensitivity reaction requiring treatment discontinuation and one patient was lost to follow-up, leaving 54 evaluable patients. The median patient age was 55 years (range 19 – 74); 25 were MRD recipients and 31 were URD recipients. 21 underwent myeloablative and 35 underwent reduced-intensity HSCT. Prior grade II-IV acute GVHD occurred in 6 patients (10.7%). Primary GVHD prophylaxis was sirolimus+tacrolimus (67.9%) or calcineurin inhibitor+methotrexate (32.1%), both without ATG. Overall, in the first year after HSCT there were 18 episodes of grade 3 toxicity and 8 episodes of grade IV toxicity without clear relationships to rituximab. There were 15 documented bacterial infections. Transient grade 3–4 neutropenia occurred in 11 subjects. 12 patients relapsed during the year after HSCT and 2 subjects died of non-relapse causes (pneumonitis and sepsis). The cumulative incidence of any cGVHD at 1 year from HSCT was 44.6%, however, the cumulative incidence of cGVHD requiring initiation of systemic corticosteroids was only 31.2%. When stratified by donor type, the incidence of all cGVHD and steroid-requiring cGVHD was 33.6 and 22.9% (MRD) and 52.3 and 37.0% (URD). Donor type, age, conditioning intensity, GVHD prophylaxis, donor gender or malignancy did not impact the incidence of cGVHD in a multivariable model. 8 additional patients required corticosteroids during the first post-transplant year for treatment of anorexia, pneumocystis pneumonia, pneumonitis or late acute GVHD. At 12 months, 50% of all patients had successfully discontinued all immunosuppressants and only 22.4% of all patients were on corticosteroids. Since anecdotally, myofascial and sclerodermatous cGVHD are treated effectively with rituximab, it is notable that only 1 patient had this subtype of cGVHD in contrast to the expected frequency of this manifestation of cGVHD in individuals not given rituximab. At 12 months from HSCT, relapse-free survival was 71.1% and overall survival was 88.6%. CD19+ B cells were very low during the first year post-HSCT, however patients without cGVHD demonstrated a trend toward enhanced B cell recovery at 6, 9 and 12 months from HSCT (6 months 0.58 vs. 0.28 × 106/L; 9 months 1.10 vs. 0.66 × 106/L; 12 months 1.09 vs. 0.76 × 106/L, all p=NS). Similarly, there was a trend for BAFF levels to be higher throughout the first year in patients without cGVHD (6 months 13.64 vs. 11.81; 9 months 12.30 vs. 9.57; 12 months 12.25 vs. 9.79, all p=NS). Among patients with cGVHD, there was a trend for BAFF levels to be higher in those who did not require systemic corticosteroids when compared to those that required steroids at 9 and 12 months (9 months 15.09 vs. 5.89 p=0.045; 12 months 11.86 vs. 7.14, p=0.25). 18 month B cell and BAFF data will be available at ASH. Conclusions. The use of rituximab at 3, 6, 9 and 12 months after allogeneic HSCT can reduce the rate of steroid-requiring cGVHD by up to 50% when compared with historical control data. The presence of enhanced B cell recovery, potentially related to higher BAFF levels found during the first year after HSCT, predicts freedom from cGVHD and a reduction in the severity of cGVHD among those affected. These data provide additional support for the hypothesis that B cells contribute to the development of cGVHD. A randomized trial should be performed to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

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Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽

10.1182/blood-2019-122762 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3320-3320

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Javier Bolanos-Meade ◽

Richard J. Jones

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Prospective Trial ◽

Stopping Rules ◽

High Dose ◽

Gvhd Prophylaxis ◽

Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

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Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

Blood ◽

10.1182/blood.v128.22.831.831 ◽

2016 ◽

Vol 128 (22) ◽

pp. 831-831 ◽

Cited By ~ 1

Author(s):

Yvette L. Kasamon ◽

Ephraim J. Fuchs ◽

Marianna Zahurak ◽

Gary L. Rosner ◽

Heather J. Symons ◽

...

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Stopping Rules ◽

High Dose ◽

Stopping Criteria ◽

Gvhd Prophylaxis ◽

Grade 3

Abstract Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. Disclosures No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood-2021-149534 ◽

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.

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Posttransplant Cyclophosphamide Promote Naïve-Subset Dominant B Cell Recovery Coordinated with Early Treg Expansion; Implication of Reduced Risk of Pathogenesis into Chronic Gvhd

Blood ◽

10.1182/blood-2018-99-120081 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4566-4566

Author(s):

Miki Iwamoto ◽

Yusuke Meguri ◽

Takumi Kondo ◽

Hiroyuki Sugiura ◽

Shuntaro Ikegawa ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Chronic Gvhd ◽

Lymphocyte Subset ◽

Cell Recovery ◽

Haplo Group

Abstract Posttransplant cyclophosphamide (PTCy) is an effective prophylaxis for both acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We recently studied the immune reconstitution dynamics of each lymphocyte subset after PTCy-based transplant using murine haploidentical BMT model and reported that PTCy strongly promoted Treg-dominant T-cell reconstitution and stem cell-derived mature B-cell generation with broad BCR-diversity. We also found that the early reconstitution of Treg could contribute to promote naïve B cell emergence from bone marrow, indicating the T and B cell recovery might be mutually coordinated after PTCy-based transplant (Iwamoto et al, ASH2017). However, the detailed process of immune reconstitution in patients after haploidentical HSCT with PTCy has not been well studied. To address this issue, we here investigated the early dynamics of donor-lymphocyte subset chimerisms in patient after clinical PTCy-based haploidentical HSCT with comparing those in patients after low-dose ATG-based haploidentical HSCT and patients after cord blood transplantation. Laboratory studies were undertaken in 13 adult patients who received HLA-mismatched allogeneic graft; unrelated cord blood (n=5), and haploidentical related peripheral blood after ATG-based conditioning (n=5) and haploidentical related peripheral blood after PTCy-based conditioning (n=5). Blood samples were obtained before and at 1, 2, 4, 6 and 8 weeks after HSCT. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples by density gradient centrifugation and cryopreserved before being analyzed. After thawing, to analyze the subset-specific chimerism, PBMCs were stained with anti-HLA monoclonal antibodies and other subset-specific antibodies as follows: Pacific Blue conjugated anti-CD4, eFluor450 conjugated anti-CD3, PE-Cy7 conjugated anti-CD25, anti-CD14, APC conjugated anti-CD127, anti-CD56, and APC-eFluor780 conjugated anti-CD8a, anti-CD19. Gated lymphotes (CD4+Tcons, CD4+Tregs, CD8+T cells, B cells, NK cells, Monocytes) were analyzed their chimerism by flowcytometry. To examine the detailed phenotype of B cells, the expression of CD27, CD24, CD38 and IgD were tested. Flowcytometry-based method enables us to analyze the lymphocyte subset chemerism in the very early phase after HSCT. At 2 weeks after HSCT, our analysis revealed that CD4+Tcons, CD4+Tregs and CD8+T cells had already achieved complete donor chimerisms (>95% in all subsets) in patients after ATG-based SCT and had been approaching complete donor chimerisms (85.8%, 75.4% and 87.2%, respectively) in patients after CBT. In contrast, percentage of donor chimerisms of CD4+Tcons, CD4+Tregs and CD8+T cells after PTCy-based haplo-SCT was 73.5%, 59.6% and 59.2%, respectively, and those remained to be in the lower levels than other 2 groups. However, at 4 weeks after HSCT, all examined patients achieved complete donor chimerism of T cells, NK cells and Monocytes (>90%). At 8 weeks after HSCT, the number of B cells in PTCy-based haplo-group was higher than in ATG-based haplo-group (3494 vs 1901/mm3). Of note, B cell population in PTCy-based haplo-group at 8 weeks contained the significantly higher percentage of CD24+CD27-IgD+CD38+ transitional/naïve subset and the significantly lower percentage of CD24+CD27+IgD-CD38neg/dim activated/switched-memory subset when compared to B cell population in ATG-based haplo-group (59.9% vs 10.2%, 2.6% vs 21.5%, P<0.02 respectively), suggesting PTCy treatment might be associated with the favorable B cell reconstitution with naïve-subset dominant composition. Moreover, in patients after PTCy-based haplo-group, the percentage of activated/switched-memory subsets in B cell population at 8 weeks was inversely correlated with percentage of Treg in CD4 T cells at 4 weeks (P<0.05, r2=0.77). Taken together, consistently with our murine study, the current data from clinical samples again suggest that PTCy-based immune-modulation lead to coordinated T and B cell recovery, especially promoting naïve-subset dominant B cell recovery with help of the early expansion of Treg, which might reduce the risk of subsequent chronic GVHD. These data provide the important information for understanding the immunological reconstitution after PTCy-based haploidentical HSCT. Disclosures No relevant conflicts of interest to declare.

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A Study of Predictors of Clinical Outcomes and Healthcare Utilization in Children with Sickle Cell Disease Undergoing Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v126.23.528.528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 528-528 ◽

Cited By ~ 1

Author(s):

Prakash Satwani ◽

Ruta Brazauskas ◽

Staci D. Arnold ◽

Naya He ◽

Yimei Li ◽

...

Keyword(s):

Risk Factors ◽

Clinical Outcomes ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Disease ◽

Adjusted Cost ◽

Factors Associated ◽

Gvhd Prophylaxis ◽

Donor Type ◽

Hospital Days

Abstract Introduction: Current advances in allogeneic hematopoietic cell transplant (alloHCT) may warrant a paradigm shift in managing children with sickle cell disease (SCD). This study characterizes the clinical outcomes and health care utilization (HCU) of alloHCT for pediatric SCD. We hypothesize that early alloHCT will have improved clinical outcomes, and decreased HCU. Methods: The Center for International Blood and Marrow Transplant Research database was used to identify children 21 years or less with alloHCT for SCD in the United States. Patient data included comprehensive research forms (CRF) from 2000-13 and transplant essential data (TED) forms from 2000-11. CRFs provided clinical risk factors associated with overall survival, graft failure, grade III-IV acute GVHD, and GVHD related event free survival (GREFS) - the survival free of graft failure, chronic GVHD, or death. Risk factors included age, gender, performance status, year of alloHCT, prior SCD complications and therapy, CMV status, donor type, conditioning regimen, and GVHD prophylaxis. Due to low event rates and sample size, only univariate analysis of risk factors was performed. TED data was merged with Pediatric Health Information System (PHIS) inpatient data using a probabilistic merging algorithm to determine risk factors and clinical outcomes associated with HCU. Available PHIS adjusted cost data was used to determine the total adjusted cost for all inpatient admissions per patient per hospital day. To standardize these costs, the total adjusted cost per 30 hospital days was calculated for each patient and used as the primary HCU outcome. HCU outcomes were analyzed for the alloHCT year, day 0 to day +365. Results: CRF data for 161 patients showed an overall survival at 2 years of 90% (95% confidence intervals [CI] 85-95%): 96% (95% CI 89-100%) for related and unrelated cord blood transplant (CBT), 94% (95% CI 86-98%) matched siblings (MSD), and 74% (95% CI 54-90%) matched unrelated donors (MUD, p=0.002). All deaths occurred among children with pre-alloHCT complications of SCD, and deaths were due to organ failure (37.5%), infections (25%), GVHD (6.25%). Risk of death was significantly higher for children ≥10 years old (HR 21, p=0.003) and MUD compared to MSD (HR 5.88, p=0.005) but lower with cyclosporine A (CSA) GVHD prophylaxis versus FK506 (HR 0.33, p=0.031). 75% of deaths occurred before day +42. Cumulative acute GVHD incidence at day 100 was 14% (95% CI 9-20%)and was associated with age ≥10yrs (HR 2.63, p=0.035). Chronic GVHD incidence was 31% (95% CI 23-38%) at 2yrs, and factors associated were age ≥10yrs (HR 1.92, p=0.034), MUD vs MSD (HR 2.53, p=0.017), and CSA vs FK506 prophylaxis (HR 0.48, p=0.018). Chronic GVHD risk increased significantly after 2006 (HR 2.81, p=0.018). The 2yr GREFS was 64% (95% CI 56-71%). Age ≥10yrs (HR 2.2, p=0.005), MUD (vs MSD, HR 3.00, p=0.002) and CSA prophylaxis (vs FK506, HR 0.49, p=0.011) were significantly associated with this outcome. Among the 175 patients with combined TED and PHIS data, the median total adjusted cost was $117,393 per 30 hospital days per patient (range: $36,244-$515,640) during the alloHCT year with a median of 53 hospital days per patient (range: 16-304). Age ≥10yrs and HCU were not significantly associated (p=0.775). MSD had the lowest HCU compared to CBT and unrelated transplants (p<0.001). CBT and peripheral blood stem cells were associated with higher HCU compared to bone marrow (p=0.004). Increased HCU was associated with prior stroke (p=0.0004) and pain crises (p=0.0094) but not acute chest syndrome (p=0.2913). Overall SCD complication and severity indices correlated with increased HCU (p=0.052, p=0.0219, respectively). Conclusions: AlloHCT outcomes in children with SCD were linked to age and donor type suggesting that early alloHCT before age 10 years is preferred. Specifically, SCD severity and MUD alloHCT are associated with poorer outcomes and increased HCU. This supports the recommendation of early alloHCT, prior to onset of SCD complications, for children with SCD and an available MSD. Donor source and type had a significant impact on both outcomes and HCU. CBT outcomes were similar to MSD bone marrow; yet CBT had higher HCU suggesting additional analysis is needed to determine if the clinical benefit outweighs the cost. Further analysis is also needed to better understand and mitigate risk factors associated with poor outcomes and increased HCU following MUD alloHCT. Disclosures Arnold: Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program: Other: award. Hahn:NIH/NHLBI: Research Funding; Novartis: Equity Ownership.

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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 ◽

10.1182/blood-2019-131661 ◽

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.

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Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A Single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint

Blood ◽

10.1182/blood.v128.22.4574.4574 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4574-4574

Author(s):

Melhem Solh ◽

Lawrence E. Morris ◽

H. Kent Holland ◽

Scott R. Solomon ◽

Stacey Brown ◽

...

Keyword(s):

Competing Risks ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Chronic Gvhd ◽

Composite Endpoint ◽

Allogeneic Hct ◽

Kaplan Meier ◽

Donor Type ◽

Grade 3

Abstract Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint Introduction The success of allogeneic HCT is based on long term survival, free of relapse or morbidity as commonly encountered when patients develop graft versus host disease (GVHD). The Bone marrow transplant clinical trials network (BMTCTN) recently incorporated a composite endpoint to determine success rate in ongoing clinical trials. The new composite endpoint of GVHD free, relapse free survival (GRFS) includes the factors of acute GVHD grade 3-4, relapse, death and chronic GVHD requiring systemic immunosuppression. As the decision to start patients on immunosuppression for chronic GVHD can be subjective and physician dependent, we elected to assess the success of allogeneic HCT using a more objective endpoint m-GRFS where the clinically significant negative events are acute GVHD grade 3-4, moderate-severe chronic GVHD, disease relapse and Death at 1 and 2-year post HCT. Methods Six hundreds and thirteen patients who underwent a first allogeneic HCT after a HLA-identical sibling (MRD, n=212), 10/10 matched unrelated donor (MUD, n=251) or T-replete haploidentical donor with post-transplant cyclophosphamide (HIDT, n=150) were included in this analysis. Patient, Disease and Transplant related variables were prospectively documented and obtained from our institutional database. The Kruksall-Wallis test was used to compare continuous variables and the Chi-squared test for categorical variables. OS, DFS and m-GRFS were estimated by the Kaplan-Meier (K-M) method. Log-log transformed confidence intervals for OS, DFS and GRFS were calculated. Comparison of m-GRFS between demographic subgroups and between clinical subgroups were evaluated using the log-rank test for the entire study period and using the Wald test for a select time point. Competing risks analysis was performed to disentangle the components of GRFS. Grade III/IV acute GVHD, mod-severe chronic GVHD, relapse and death were considered as competing risks and cumulative incidences of these endpoints were calculated. Patients were considered to have met the endpoint once any of the components occurred. Cox regression analysis was conducted to examine the impact of donor, demographic and clinical factors on the primary endpoint of modified GRFS. The proportional hazards assumption was checked by temporarily including and testing time-dependent variables and the variables in the final model passed the proportionality test. The adjusted GRFS for one characteristic was calculated as the average survival of the whole sample, assuming that everyone in the sample had this characteristic. Results The median follow-up was 50.2 months. Patients characteristics were as follows: median age 53 years (18-77), male 56%, reduced intensity/non-ablative 49%, AML 37%, ALL 13%, MDS/MPD 24%, bone marrow graft 19%, HCT-comorbidity index >=3 in 39%, and high/very high DRI 34%. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95%CI 32%-40%) and 28% (95%CI 25%-32%). The 2-year m-GRFS for MRD recipients was 30% (24-36%), MUD 24% (19-30%) and HIDT 33% (26-41%). The most common event at 2 years post HCT was chronic GVHD (39%) followed by relapse (31%), acute GVHD 3-4(20%) and death (10%). After adjusting for age, gender, diagnosis, conditioning intensity, donor type, cell source, HCT-CI, DRI , donor-recipient gender mismatch and year of transplant, the multivariate cox model on m-GRFS showed donor type, DRI risk , donor recipient sex mismatch and year of transplant to be significant predictors of m-GRFS (table 1). Patients who received a MUD had worse GRFS compared to MRD (HR 1.39, p=0.003) whereas HIDT had similar GRFS to MRD (HR 1.10, p=0.43). HIDT had better GRFS than MUD (HR 0.79, p=0.046). The adjusted 1- and 2- year m-GRFS showed donor type (MUD vs MRD), DRI, donor-recipient sex mismatch and transplant year to be associated with worse GRFS (table 2). Conclusions m-GRFS is a useful measure of transplant success. It appears to be significantly impacted by several modifiable factors including donor type, donor-recipient sex match and also by DRI. Adjusting donor choice and early referral of patients for transplant evaluation to improve DRI can potentially overcome the negative impact of these factors. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2021-148071 ◽

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.

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Improved Control of GvHD with Rabbit ATG, Rituximab and Bortezomib Among Pediatric Leukemia Patients after Tcrαβ/CD19-Depletion of Transplant from Matched Unrelated and Haploidentical Family Donors: A Single-Center Retrospective Analysis of Two Gvhd-Prophylaxis Regimens

Blood ◽

10.1182/blood.v128.22.3427.3427 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3427-3427

Author(s):

Zhanna Shekhovtsova ◽

Larisa Shelikhova ◽

Dmitry Balashov ◽

Elena Kurnikova ◽

Iakov Muzalevskyi ◽

...

Keyword(s):

Median Time ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Single Center ◽

Pediatric Leukemia ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Significant Difference ◽

Donor Type

Abstract Introduction: Graft-versus-host disease (GvHD) remains to be a factor associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Bortezomib was shown in vitro to induce selective depletion of alloreactive T-lymphocytes, decrease the production of Th1 cytokines (Blanco et al. 2006), and to suppress the maturation and cytokine production by dendritic cells (Naujokat et al. 2007). Bortezomib was successfully used to prevent and treat GVHD in different settings (Al-Homsi et al. 2015; Koreth et al. 2015). As GvHD-prophylaxis agent Bortezomib was implemented since 2014 in aim to improve the results in a cohort of pediatric patients with acute leukemia who underwent HSCT from HLA-matched unrelated and haploidentical family donors after TCRαβ/CD19-depletion. Here we present the results of a retrospective comparison of two GvHD-prophylaxis regimens. Patients and methods: Between May 2012 and July 2016 eighty-one transplantation from 40 HLA-matched unrelated and 41 haploidentical donors were performed for children (56 boys and 25 girls with median age 9 years, range 0,6-23 years) with acute lymphoblastic (n=31) and acute myeloblastic (n=50) leukemia in complete remission. TCRαβ/CD19-depletion of HSC with CliniMACS technology was implemented in all cases. For all patients it was first allogeneic HSCT. The majority (93%) of the patients received Treosulfan-based condition regimen. Remaining 7% of patients received TBI-based conditioning regimen. Patients were divided retrospectively in two groups according to GvHD prophylaxis regimens. "Regimen 1" (n=35), which was used in 2012-2013 yrs.: horse ATG 50 mg/kg and post-transplant tacrolimus with short course of methotrexate. "Regimen 2" (n=46) started in 2014: rabbit ATG 5 mg/kg, rituximab 200mg/m2 and peri-transplant bortezomib 1,3 mg/m2 on days -5, -2, +2 and +5. The median dose of CD34+ cells in the transplant was 9 x106/kg (range 7-17), TCRαβ - 21x103/kg (range 1-305). Results: Groups differed significantly in regards to diagnosis: 57% of patients in "Regimen 1" had ALL, while most of the patients (78%) in "Regimen 2" were with AML (P= 0,002). Cumulative incidence of neutrophil and platelet engraftment at 30 days was 98% and did not differ between the groups. Median time to neutrophil and platelet engraftment was 14 days, (range, 9-33 and 9-25 days, respectively). Neutrophil engraftment was significantly faster among patients with "Regimen 2", 13 days vs. 16 days for patients with "Regimen 1" and CI of engraftment at day 30 after HSCT 98% (95% CI: 98%) vs. 94% (95% CI: 87-100, P<0,01). Overall cumulative incidence of acute GvHD II-IV grade was 23% (95% CI: 16-35); grade III-IV - 5% (95% CI: 2-13) and chronic GvHD - 18% (95% CI: 11-20). Cumulative incidence of acute GvHD II-IV was significantly lower within the group with "Regimen 2": 15% (95% CI: 7-30) vs. 34% (95% CI: 22-54), P=0,05. Amid patients with "Regimen2" there was one case of grade IV acute GvHD, most of the patients with grade II to IV developed visceral damage involving lower gut. "Regimen 2" was also more effective in prevention of chronic GvHD: CI at 1 year after HSCT was 7% vs. 31%, P=0,005. Only one patient with "Regimen 2" had extensive form of chronic GvHD. Median time of follow-up for survivors was 2 years (range, 0,3 - 4). Cumulative incidence of relapse at 2 years also differed between "Regimen 1" and "Regimen 2" groups, 31% (95% CI: 19-51) vs. 21% (95% CI: 11-39), respectively, though without statistical significance. TRM was 10% (95% CI: 5-20), without significant statistical difference between leukemia type, donor type or GvHD-prophylaxis regimens. EFS (event=death or relapse) at 2 years was 64% (95%CI: 53-75), OS - 69% (95%CI: 58-80). Statistically there was no significant difference in event-free or overall survival probabilities between leukemia type, donor type or GvHD-prophylaxis regimens Conclusion: In our retrospective single-center study we revealed that rATG, rituximab and bortezomib improve the control of acute and chronic GVHD in recipients of TCRαβ- depleted grafts in comparison to hATG, tacrolimus and methotrexate. Disclosures No relevant conflicts of interest to declare.

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Improved Survival of Patients Diagnosed with Severe (Grade 3-4) Acute GVHD or Severe NIH Grade Chronic GVHD in the Current Era Compared to Historic Controls

Blood ◽

10.1182/blood-2019-123230 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2006-2006

Author(s):

Asad Bashey ◽

Xu Zhang ◽

Lawrence E Morris ◽

H. Kent Holland ◽

Melhem Solh ◽

...

Keyword(s):

Median Time ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Entire Cohort ◽

Donor Type ◽

Preparative Regimen ◽

Grade 3 ◽

Severe Grade

Severe (grade 3-4) acute GVHD (aGVHD) and NIH grade severe chronic GVHD (cGVHD) have historically been associated with poor survival. However, earlier diagnosis, improved treatment and supportive care, may result in an improvement in outcomes for patients recently diagnosed with severe GVHD compared to prior cohorts. Our institution has prospectively documented onset, grading and therapy of patients with GVHD using a single dedicated practitioner since 2005. We assessed 851 consecutive patients who received allografts at our center between 1/2005 and 12/ 2016 and identified 130 patients (15.3%) who developed severe aGVHD through Dec 2017 without prior relapse of malignancy. Characteristics were: median age 52.5, 51% male, race-81% white -17% black, diagnosis- AML 31% - MDS/MPD 20%- NHL/HL/CLL-23%, -ALL 11%, donor - MRD 21% - MUD 49% - haplo 30%, PBSC 78%, BM 17%, CBU 5%, preparative regimen MAC 44% - RIC/NST 56%, median time from BMT to onset of severe aGVHD was 49 days (7-376). Maximum grade = gd 3 (85%), gd 4 (15%), Median follow-up for survivors from date of onset was 59 months (23-155m). Survival estimates for the entire cohort from date of onset of grade 3-4 aGVHD at 1, 2 and 3 years were 62%, 49% and 47% respectively. Patients who developed severe aGVHD in 2016-2017 had significantly improved overall survival compared to patients who developed severe acute GVHD in prior years (2005-2015) -1 and 2 yr survival 86% & 79% vs 55% & 41% respectively, p=0.002 log-rank test, Fig 1). No significant differences were found between earlier cohorts. On multivariable analysis assessing the following variables: age, gender, race, diagnosis, donor type, cell source, regimen intensity, DRI, HCT-CI, CMV status, grade of aGVHD (3 vs 4), days from transplant to gd 3-4 aGVHD onset, year of development of severe acute GVHD (2016-2017 vs earlier) remained significant for survival (HR 0.36, p=0.018). Other significant variables were grade 4 vs 3 GVHD (HR 3.78, p<0.001) and DRI (high/very high vs low/intermediate, HR 1.84, p=0.011). For cGVHD we assessed 522 consecutive patients who underwent allografts between 4/2011 (start date of prospective documentation of NIH grade cGVHD )and 12/2016, and identified 146 (28%) patients who developed moderate to severe NIH grade chronic GVHD without prior relapse by Dec 2017 (85 severe, 61 moderate). Patient characteristics were: median age 53, 55% male, race-74% white -22% black, AML 40% - MDS/MPD 31%- NHL/HL/CLL-15%, -ALL 12% , donor - MRD 34% - MUD 40% - haplo 25%, graft- PBSC 82%, BM 18%, preparative regimen MAC 54% - RIC/NST 44%, median time from BMT to onset of moderate/severe cGVHD was 289 days (27-1364). Median follow-up for survivors from date of onset of moderate to severe GVHD was 48 months (19-94m). Estimated rates of survival from date of onset of moderate to severe cGVHD for the entire cohort at 1, 2 and 3 years were 82%, 73% and 71% respectively. For patients who developed severe cGVHD the corresponding survival estimates were 77%, 67% and 63%. No significant difference in post-onset survival was encountered when comparing patients developing moderate cGVHD in 2011-2013, 2014-2015 and 2016-2017. However, for severe cGVHD, 1 and 2 year estimated survival rates for the three cohorts were : 53% & 41%, 79% & 73% and 87% and 74% respectively (p=0.004 for 2011-2013 vs 2014-2015 but p=NS for 2014-2015 vs 2016-2017, Fig 2). On a multivariable analysis considering age, gender, race, diagnosis, donor type, graft source, regimen intensity, DRI, HCT-CI, and days from transplant to cGVHD onset, none of these variables was significantly associated with post-cGVHD survival. In the Cox model including year of onset of severe cGVHD, onset in recent years was linked to lower risk of mortality compared to onset in earlier years (onset 2014-2015 vs 2011-2013 - HR=0.34, p-0.012; onset 2016-2017 vs 2011-2013 - HR=0.28, p=0.006). These data suggest that survival of patients developing either severe aGVHD or severe NIH grade cGVHD has significantly improved in recent years compared to historical controls. More than two-thirds of such patients now survive two years from onset of severe GVHD. This must be taken into account when evaluating novel therapies for severe GVHD. Disclosures Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.

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