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

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.

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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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No Influence of Peripheral Blood CD34+ and CD3+ Graft Cell Counts on Outcomes after Reduced-Intensity Conditioning Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2018-99-112453 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4577-4577

Author(s):

Alice Garnier ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Amandine Le Bourgeois ◽

Alix Duquesne ◽

...

Keyword(s):

Board Of Directors ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Cell Content ◽

Post Transplant ◽

Cell Counts ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

Blood ◽

10.1182/blood.v120.21.4200.4200 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4200-4200 ◽

Cited By ~ 2

Author(s):

Amin M. Alousi ◽

Rima M Saliba ◽

Julianne Chen ◽

Borje S Andersson ◽

Issa Khouri ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Control Group ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Matched Sibling ◽

And Control

Abstract Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (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 and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

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

Blood ◽

10.1182/blood.v110.11.3046.3046 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3046-3046 ◽

Cited By ~ 1

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.

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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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Peritransplant Ruxolitinib Administration is Safe and Effective in Patients with Myelofibrosis: a Pilot Open-Label Study

Blood Advances ◽

10.1182/bloodadvances.2021005035 ◽

2021 ◽

Author(s):

Haris Ali ◽

Ni-Chun Tsai ◽

Timothy Synold ◽

Sally Mokhtari ◽

Weimin Tsai ◽

...

Keyword(s):

Chronic Gvhd ◽

Pilot Trial ◽

Conditioning Regimen ◽

Kidney Injury ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Open Label ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade 3

We report results of our prospective pilot trial (NCT02917096) evaluating safety/feasibility of peri-transplant administration of ruxolitinib for myelofibrosis treatment. Primary objectives were to determine the safety and identify maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was given at two dose levels (DL) of 5 and 10mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus GVHD prophylaxis. We enrolled 6 and 12 patients in DL-1 and DL-2, respectively. Median age at transplant was 65 years (range:25-73) for all patients. Per DIPSS, 4 patients were at high and 14 were at intermediate risk. PBSCs was the graft source from a matched sibling (n=5) or unrelated (n=13) donor. At each DL one patient developed DLTs: Grade 3 cardiac and GI with Grade 4 pulmonary in DL-1 and Grade 3 kidney injury in DL-2. All patients achieved engraftment. Cumulative incidence (CI) of acute GVHD grade 2-4 and 3-4 were 17% (95% CI: 6-47) and 11% (95% CI: 3-41), respectively. CI of 1-year chronic GVHD was 42% (95% CI: 24-74). With the median follow-up of 22.6 months (range:6.2-25.8) in surviving patients the 1-year overall and progression free survival were 77% (95% CI: 50-91) and 71% (95% CI: 44-87), respectively. Causes of death (n=4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results showed that peri-HCT ruxolitinib was safe and well-tolerated with the MTD determined as 10 mg BID, associated with dose-dependent PK and cytokine profile. The early efficacy data are highly promising in this group of high-risk older patients with MF.

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Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

Cell Transplantation ◽

10.1177/0963689720965900 ◽

2020 ◽

Vol 29 ◽

pp. 096368972096590

Author(s):

Chutima Kunacheewa ◽

Weerapat Owattanapanish ◽

Chutirat Jirabanditsakul ◽

Surapol Issaragrisil

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Peripheral Blood ◽

Chronic Gvhd ◽

Survival Rates ◽

Free Survival ◽

Graft Versus Host ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Matched Sibling

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% ( P = 0.251) and 29% versus 43% ( P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% ( P = 0.859), and the 5-year disease-free survival rates were 52% and 52% ( P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD.

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

Blood Advances ◽

10.1182/bloodadvances.2019000050 ◽

2019 ◽

Vol 3 (12) ◽

pp. 1826-1836 ◽

Cited By ~ 27

Author(s):

Armin Rashidi ◽

Mehdi Hamadani ◽

Mei-Jie Zhang ◽

Hai-Lin Wang ◽

Hisham Abdel-Azim ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Calcineurin Inhibitor ◽

Chronic Gvhd ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Conditioning Intensity ◽

First Complete Remission ◽

Acute Myeloid

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

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

Blood ◽

10.1182/blood.v116.21.214.214 ◽

2010 ◽

Vol 116 (21) ◽

pp. 214-214 ◽

Cited By ~ 1

Author(s):

Corey Cutler ◽

Lixian Sun ◽

Haesook Kim ◽

Stefanie Sarantopoulos ◽

Bhavjot Bindra ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

First Year ◽

Cell Recovery ◽

Systemic Corticosteroids ◽

Gvhd Prophylaxis ◽

Donor Type ◽

Grade 3

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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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 ◽

10.1182/blood.v116.21.2325.2325 ◽

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.

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