scholarly journals De-Escalation of Ptcy Dosing in Matched Allogenic Transplants: A Single Institution Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4872-4872
Author(s):  
Haritha Ackula ◽  
Georgio Medawar ◽  
Caroline Cerio ◽  
Todd F. Roberts ◽  
Kapil Meleveedu
Keyword(s):  
Phase I ◽  
Cell Transplantation ◽  
Viral Reactivation ◽  
High Dose ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Post Transplantation ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Introduction The role of post-transplant cyclophosphamide (PTCy) in preventing acute GVHD (aGVHD) and chronic GVHD (cGVHD) has been well established in the haploidentical setting (Al-Homsi AS et al., Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(4):604-611). More recently, several studies are also supporting its use in matched related and unrelated donors (Williams L et al., Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation. Front Immunol. 2020;11(April):1-7). But as new emerging data are starting to show some toxicities from that regimen, a reevaluation of the optimal PTCy dose is highly valuable (Duléry R et al., Early Cardiac Toxicity Associated with Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation. JACC CardioOncology. 2021;3(2):250-259; Goldsmith et al., Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-3305). PTCy dose de-escalation in preventing GvHD was also evaluated in a phase I/II study (NCT03983850) with initial results indicating that de-escalation of PTCy (DL2, 25 mg/kg/day given in Days 3−4) may provide a feasible and effective approach in preventing severe aGvHD(McAdams MJ et al., Phase I Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Haploidentical Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies. Transplant Cell Ther Off Publ Am Soc Transplant Cell Ther. 2021;27(3): S9-S11). However, this was in the setting of haplo-identical transplants. Currently there are no studies that investigate the safety and efficacy of a lower dose of PTCy in matched allogenic transplants. Methods We retrospectively selected 37 consecutive patients who underwent transplant at our center from January 2017 to April 2021. Patients who received a mismatched or haploidentical transplants were excluded. 26 matched sibling or matched unrelated donor transplants were further analyzed. These were divided into 3 cohorts according to GVHD prophylaxis: cohort 1 (No-PTCy) received standard calcineurin inhibitor-methotrexate based GVHD prophylaxis (n=16), cohort 2 (PTCy-50) received PTCy at 50 mg/kg (D+3 and D+4) in combination other immunosuppressive drugs (ISD) (n=6), and cohort 3 (PTCy-25) received PTCy at 25 mg/kg (D+3 and D+4) in combination with other ISD (n=4). The reduced PTCy dosing was based on physician discretion due to various reasons (2 cardiac risk, 1 heavy pre-treatment, 1 unknown). Results Baseline characteristics are summarized in table 1. Median follow up for all survivors was 523 days (range, 97-1463) while it was shorter for PTCy cohorts at 152 days (97-534). There were zero grade 3 aGVHD in PTCy groups compared to 12.5% (2/16) in No-PTCy cohort (p=0.30). cGVHD was significantly lower in PTCy-50 and PTCy-25 as compared to No-PTCy (0/6, 0/4, 5/16 respectively, p=0.04). The 100-day treatment-related mortality (TRM) was significantly lower in PTCy-25 as compared to PTCy-50 and No-PTCy (0/4, 2/6, 2/16 respectively, p<0.001). There was no viral reactivation (EBV/CMV) in PTCy-25 as compared to 1/6 in PTCy-50 and 5/16 in No-PTCy (p=0.54). The length of hospital stay (LOS) for transplant and the median days for neutrophil recovery (NR) were shorter in PTCy-25 as compared to PTCy-50 and No-PTCy (25.5 days, 31 days and 28.5 days respectively for LOS, p=0.60; 15.5 days, 22 days and 17.5 days for NR, p=0.87). Although the overall survival (OS) seems to favor PTCy-25 (Figure 1), it is limited by short follow up. Conclusion De-escalating the dose of PTCy to 25mg/kg x 2 in GVHD prophylaxis regimens appears to be efficacious and safe in patients receiving matched allogenic transplant. Further prospective studies including a larger patient sample and longer follow-up is warranted to investigate lower PTCy dosing in matched transplants over the current standard dosing. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3285-3285
Author(s):  
Rebeca Bailén ◽  
Mi Kwon ◽  
Maria Jesus Pascual-Cascon ◽  
Anna Torrent ◽  
Christelle M Ferra ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cumulative Incidence ◽  
High Dose ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis

Blood ◽  
2021 ◽  
Author(s):  
Mahasweta Gooptu ◽  
Rizwan Romee ◽  
Andrew St. Martin ◽  
Mukta Arora ◽  
Monzr M. Al Malki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Failure ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Conditioning Regimens ◽  
Disease Free ◽  
Reduced Intensity ◽  
Grade Iii

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

A Phase I/II Trial Combining High-Dose Lenalidomide with Melphalan and Autologous Transplant for Multiple Myeloma: A Report of the Phase I Dose-Finding Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3146-3146
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Rebecca Silbermann ◽  
Robin Obryant ◽  
Lisa l Wood ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Progressive Disease ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Autologous Transplant ◽  
High Dose Melphalan

Abstract Abstract 3146 Background: High dose chemotherapy and stem cell transplantation (HDSCT) has been a standard of care for younger patients with adequate organ function since the early 1980s, due to its superiority over standard chemotherapy in prolonging disease-free and overall survival. Immunomodulatory agents, including thalidomide and lenalidomide, have significant single-agent activity and an additive effect when combined with melphalan. Preclinical data suggest an increased DNA damage and an anti-angiogenic effect with the combination. Additive clinical benefits were also observed when the 2 agents were used in combination in non-transplant settings. The antimyeloma effects of both agents are dose-dependent with myelosuppression being the dose limiting toxicity (DLT). This toxicity can be attenuated with stem cell rescue. Purpose: We conducted a phase I/II trial designed to evaluate the safety and efficacy of combining lenalidomide with high-dose melphalan as conditioning for autologous transplant for myeloma. The phase I portion of the study is complete and the results are reported in this abstract. Experimental Design: The enrolled patients included any patients with myeloma, regardless of the status of the disease, undergoing high dose melphalan for autologous stem cell transplantation. The melphalan dose was fixed (200 mg/m2) while the doses of lenalidomode were escalated from 50, 75, 100, and 150 mg/m2 administered orally days -7 to +2 of the transplantation. Dose escalation was based upon a 3+3 phase I design. DLTs were defined as grade ≥4, both hematologic and non-hematologic, occurring between days -7 to -2 which prevents subjects from undergoing stem cell transplantation, or grade 3 or 4 non-hematologic toxicity occurring after day -2 that does not resolve to a grade 2 or less by day +30 after transplantation, or delayed engraftment. The response was assessed at day +100 post transplantation using the International Myeloma Working Group criteria. Results: 13 patients participated in the phase I portion of the study from September 2010 to May 2012. Patients ages ranged from 42– 72 years (median 63 years). Seven patients were undergoing their first autologous transplant with 2 patients having had 2 lines of previous therapy and 5 having one line of therapy. Six patients were undergoing their second transplantationas salvage for control of progressive disease and all had more than 3 lines of prior therapy. At baseline, 5 patients had progressive disease, 1 had SD, 3 had PR, 3 had VGPR and 1 had CR as responses to their most recent lines of therapy. The median time for ANC and platelet engraftment was 10 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. The most common grade ≥ 3 adverse events were myelosuppression, neutropenic fever and electrolyte abnormalities, all of which are commonly observed with single agent high dose melphalan. Adverse events related to the study drugs were electrolyte abnormalities (hypokalemia, hyperkalemia and hypocalcemia), gastrointestinal side effects and rash, all of which were grade 1 to 2 and manageable without a delay or discontinuation of the study drugs. One patient died from disease progression prior to scheduled disease evaluation. One patient has not yet reached day +100 post transplant. Therefore, responses were evaluable for 11 patients. Three patients achieved stringent CR (27%), 3 CR (27%), 2 VGPR (18%), 3 PR (27%) and one had progressive disease (9%). The overall response rate was 91%, with 72% achieving VGPR or better. All patients had adequate count recovery and were able to initiate lenalidomide maintenance treatment by day +100 to +110 post transplantation. Conclusions: The use of high dose lenalidomide in conjunction with high-dose melphalan is well tolerated, with preliminary data suggesting that the combination is highly efficacious. DLT was not observed; therefore the recommended phase II dose is 150 mg of lenalidomide orally on days -7 to +2 in combination with melphalan 200 mg/m2. The phase II portion of this trial is ongoing in patients undergoing first HDSCT. Complete response at 3 months post transplantation is the primary end point. Disclosures: Off Label Use: Lenalidomide in myeloma transplant. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Influence of Graft Versus-Host Disease Prophylaxis Regimen On T-Cell Repertoire Diversity Following Reduced-Intensity HLA-Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3054-3054 ◽  
Author(s):  
Rachel B. Salit ◽  
Frances T. Hakim ◽  
Michael R. Bishop ◽  
Thea M. Friedman ◽  
Robert Korngold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Cell Repertoire ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Repertoire Diversity ◽  
Reduced Intensity

Abstract Abstract 3054 Background: A clearly superior graft-versus-host disease (GVHD) prophylaxis regimen has not been established for patients undergoing reduced intensity allogeneic hematopoetic stem cell transplantation (HSCT) from matched unrelated donors (URD). Encouraging results have been reported with both the combination of alemtuzumab and cyclosporine (AC) and the regimen of tacrolimus, methotrexate, and sirolimus (TMS) in the URD setting. These two regimens work by biologically distinct mechanisms and may have markedly different effects on immune reconstitution. T-cell receptor (TCR) spectratyping analysis, which provides information on antigen receptor diversity, is a valuable method for monitoring post-transplant immune reconstitution. As part of a randomized pilot study, we prospectively assessed the effects of AC vs. TMS on TCR Vb repertoire diversity in patients undergoing reduced intensity HLA-matched unrelated donor transplantation. Methods: Twenty patients (median age 53 yrs; range 24–70 yrs) with hematologic malignancies received reduced intensity conditioning (fludarabine 30 mg/m2/day and cyclophosphamide 1200 mg/m2/day IV Day -6 to -3) followed by a 10/10 HLA-matched unrelated donor T-cell replete mobilized peripheral blood allograft. Patients were randomized to receive either: AC (n=10): alemtuzumab 20 mg/day IV over 8 hours Days -8 to -4 and cyclosporine starting at Day -1 with a 10% per week taper starting at Day +100 or TMS (n=10): tacrolimus and sirolimus starting at Day -3 with a 33% taper at Day +63 and Day +119 and methotrexate 5 mg/m2 IV, Days +1, +3, +6, and +11. Blood samples were collected from the donor and patient at baseline and the patient at 1, 3, 6 and 12 months post-transplant for TCR spectratyping analysis. All comparisons are based on an exact Wilcoxon rank sum test; p values < 0.01 were significant because of multiple comparisons. Results: Patients on the AC arm had significantly fewer T-cells on Day +14 compared with the TMS arm (median CD3+ = 1 cells/μl vs 356 cells/μl; CD4+ = 0 cells/μl vs 243 cells/μl; CD8+ = 0 cells/μl vs. 59 cells/μl; each p<0.0001); there was less disparity at Day +28 (median CD3+ = 45 cells/μl vs. 398 cells/μl; CD4+ = 36 cells/μl vs. 218 cells/μl; CD8+= 5 cells/μl vs 152 cells/μl; each p 0.002). By Day +100, lymphocyte recovery was not appreciably different between the two arms (median CD3+ = 242 cells/μl vs. 445 cells/μl (p = 0.095): CD4+ = 106 cells/μl vs. 212 cells/μl (p=0.28); CD8+ = 72 cells/μl vs. 135 cells/μl (p = 0.03). NK-cell recovery was slightly less in the AC vs. TMS arm at Day +14 (median NK = 27 cells/μl vs. 70 cells/μl; p = 0.01) and at Day +28 (median NK = 29 cells/μl vs. 150 cells/μl; p=0.02). There was no difference by Day +100 (median NK = 124 cells/μl vs. 88 cells/μl; p=0.31). B-cell reconstitution was negligible in both arms through Day +100. Assessment of CD4+ TCR Vb repertoire diversity by spectratyping demonstrated significantly lower diversity in patients receiving AC at 1 (p = 0.0003), 3 (p = 0.0003) and 6 (p=0.003) months post transplant compared with patients receiving TMS. CD8+ TCR spectratyping similarly revealed significantly reduced diversity in the AC arm at 3 (p = 0.001) and at 6 months (p = 0.003), and a trend toward significance at 12 months (p = 0.07). On each of the 2 arms, 2 of 10 patients developed acute Grade II-IV GVHD. Of the 5 patients on the AC arm who were seropositive for CMV, all 5 reactivated CMV by PCR within the first 60 days and reactivated 2–5 times in the first year. In contrast, only 3 of 5 seropositive patients reactivated CMV on the TMS arm and only one reactivated in the first 60 days. Conclusions: Two factors may have contributed to the loss of repertoire diversity in the AC arm. First, the alemtuzumab regimen may have severely depleted the infused donor T-cells. Second, stimulation by reactivating virus may have induced expansion of CMV-specific memory and effector T-cells, resulting in a skewed and oligoclonal T-cell repertoire. Especially in CD8+ T-cells, CMV has been shown to produce significant oligoclonal expansion (including CD4+: CD8+ ratio inversion). The loss of T-cell numbers and repertoire may in turn have contributed to the prevalence of early CMV reactivation. Thus, despite the similarities in frequency of acute GVHD in this small sample, it appears that these two commonly used GVHD prophylaxis regimens have very different effects on post-transplant immune reconstitution in the first 6 months after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

Influence of Pre-Transplant Cytomegalovirus (CMV) Serostatus on Post-Transplant Viral Reactivation after Allogeneic Stem Cell Transplantation in Patients Receiving Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3864-3864
Author(s):  
Ravi K. Paluri ◽  
Racquel Shelton ◽  
Melissa Gazi ◽  
Lawrence S. Lamb ◽  
Ayman Saad ◽  
...  
Keyword(s):  
Viral Reactivation ◽  
Systemic Steroid ◽  
Unrelated Donor ◽  
Seronegative Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Group A ◽  
Considerable Morbidity ◽  
Cmv Reactivation ◽  
Donor Transplant

Abstract Introduction/Background Human cytomegalovirus (CMV) infection remains one of the major complications affecting the transplant outcomes as it is associated with considerable morbidity and mortality. Pre-transplant CMV serostatus is considered as an important determinant of CMV reactivation after allogeneic HSCT. In 2012 we started using post-transplant cyclophosphamide (post-CY) as GVHD prophylaxis for matched and mismatched unrelated transplant (CY 1 dose) and haploidentical transplant (CY 2 doses). In this study we compared the incidence of CMV reactivation based on donor and recipient pre-transplant serostatus in patients who received post-CY and who did not. Methods and Results Post-transplant CMV reactivation was analyzed in relation to donor/recipient CMV serostatus in 117 patients who underwent alternative donor transplant at UAB between 2009 and 2014. Donors were matched unrelated (94), mismatched unrelated (11) and haploidentical (12) (Table 1). The study patients had at least two months of follow up after the transplant. Graft source was peripheral blood and bone marrow stem cells in 95 (81%) and 22 (19%) patients respectively. Two doses of CY at 50 mg/kg/day was administered on days 3 and 4 following haploidentical and a single dose on day 3 following unrelated donor transplant as a part of GVHD prophylaxis in addition to mycophenolate mofetil (MMF) and tacrolimus. Serial weekly monitoring for CMV viremia was performed using a PP65 antigenemia testing or quantitiative polymerase chain reaction (PCR). Sixty-four (55%) patients received post-CY (group C), 37 (32%) patients received anti-thymocyte globulin (ATG, group A) and 16 (13%) patients received neither ATG nor post-CY (group N). Forty-seven (40%) patients were found to have reactivation of CMV. The majority (99%) in this group had CMV reactivation by day 60 and only 8 of them received more than 7 days of systemic steroid by the time of CMV reactivation. Analyses were performed including these cases. Conclusions have been the same with or without these cases. There have been no CMV diseases in this group. The risk of CMV reactivation appears to be higher in group C (48%) when compared to group A (27%) or group N (37%) but it was not significant (p=0.104). Once CMV reactivated, the peak values of CMV PCR were the same regardless of the group (11,173 copies/ml and 12,173 in group C and group A+N, respectively, p=0.949). If the recipient (R) is seronegative (-), transplant from a seronegative donor (D-) is associated with lower CMV reactivation (0/26 and 2/8 in R-D- and R-D+, respectively, p=0.009). However, if the recipient is seropositive (R+), CMV reactivation incidence tends to be the same whether transplanted from D- or D+ (10/19 and 35/64 in R+D- and R+D+, respectively, p=0.874). In the group C, R+D+ tends to have higher incidence of CMV reactivation than R+D- (24/36 vs 6/12 in R+D+ vs R+D-, respectively, p=0.302). (Table 2) Conclusion: Post-CY has higher risk of CMV reactivation when compared to other GVHD prophylaxis, but once CMV is reactivated the peak values of CMV-PCR have been the similar. In CMV seropositive post-CY patients, transplant from a seropositive donor tends to higher incidence of CMV reactivation rather than from a seronegative donor. This result contradicts to previous publication (Luznik et al, Blood. 2010 Apr 22; 115(16):3224-30.). Our GVHD prophylaxis used only one dose of CY for unrelated donor transplant as opposed to previous publication (2 doses), and also we used tacrolimus and MMF after day 5, which may have caused this difference. Our results warrant further investigation in the mechanism of CMV reactivation in post-CY patients. Table 1 Group CMV Reactivation Post Transplant N Y Count Count A B C 27 33 10 10 31 6 P=0.104 Table 2 Table 2. Disclosures Off Label Use: Cytoxan for GVHD prophylaxis.

Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2307-2307
Author(s):  
Sara Redondo Velao ◽  
Mi Kwon ◽  
Diana Champ ◽  
MJ Pascual Cascon ◽  
Pascual Balsalobre ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation (AHCT) in Post Infusion Cyclophosphamide (PIC) Era: The Switch from Anti-Thymocyte Globulin (ATG) to PIC for Graft Versus Host Disease (GVHD) Prophylaxis in AHCT from Alternative Donors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5720-5720
Author(s):  
Deniz Goren Sahin ◽  
Nurcan Özçelik ◽  
Tülay E Özçeli̇k ◽  
Mutlu Arat
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Cmv Status

Aim: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHCT). As GVHD prophylaxis regimen, post-transplant cyclophosphamide (Post-Cy) has been associated with less acute and chronic GVHD. Anti-Thymocyte Globulin (ATG), which is another GVHD prophylaxis regimen, could reduce the risk of chronic but not acute GVHD. Anti-thymocyte globulin (ATG) in association with a calcineurin inhibitor (CNI) and methotrexate or mycophenolate mofetil (MMF) is widely used in the setting of unrelated donor transplantation (UDT). Recent studies proned non-inferior results of haplotype matched donor transplantation (HMDT) using Post-Cy in comparison with UDT. However, there is no consensus about the optimal GVHD prophylaxis regimen or choosingwisely. Aim of this study was to compare the outcome of two GVHD prophylaxis regimens; Post-Cy used in HIDT or UDT and ATG used for unrelated donors in a single-cohort of consecutive transplant recipients. Material and Methods: Two hundred adult (17-72 years) patients who underwent HIDT and UDT with a minimum 100 days follow-up at Florence Nightingale Hospital Hematopoietic Stem Cell Transplantation Center between 2011 and 2017 were included in this study. Medical records of patients were reviewed retrospectively. Transplantation was performed in cases with high or very high DRI. HIDT was performed in 73 cases and UDT in 127 cases. One hundred eighty five out of 200 cases with a complete follow-up were included in the statistical analysis. Sixty-seven patients underwent HIDT with Post-Cy (Group 1), 97 patients with UDT receiving ATG (Group 2) and 21 with UDT receiving Post-Cy (Group 3). Patients who completed minimum 100 days post-transplantation follow-up were identified as eligible for survival analysis. Results: Median age of patients was 42.8±14.9 years. Percentage of male patients was 65.6%, 68% and 38% for HIDT with Post-Cy (Group 1), UDT with ATG (Group 2) and UDT with Post-Cy groups (Group 3), respectively, which is significantly different (p=0.03). Bone marrow was used in 58.2% patients as stem cell source in HIDT, contrary to UDT, which is below 1% (p<0.0001). Median follow-up time was 398 days. Patient characteristics (Table 1), were mainly similar, such as donor age, gender, recipient cytomegalovirus (CMV) status, Karnofsky performance status, conditioning regimens, median neutrophil and platelet engraftment time, engraftment failure, acute GVHD incidence and disease status at post-transplant D100. Since the incidence of donor CMV IgG was significantly higher due to regional reasons in HIDT group, CMV activation rate was also significantly higher in this HIDT (p=0.001). No significant difference was found in Kaplan-Meier survival analysis among the HIDT with Post-Cy, UDT with ATG and UDT with Post-Cy groups, even if they were classified according to primary disease, and post transplant 100th day disease status. Transplant related mortality at 30th and 100th days were similar among three groups. Also, donor CMV status (CMV IgG positivity or negativity) and CMV reactivation was not an important factor on survival (for donor CMV status p=0.307; for CMV reactivation p=0.274). Conclusion: We did not find any significant difference among three groups with regards to survival rate and acute GVHD development. Reactivation of CMV does not effect 100th day survival. These findings support our hypothesis that post-Cy infusion regimen is an important factor for higher survival rate rather than the donor type. We believe that post Cy infusion GVHD prophylaxis platform along with MMF and CNI is maturing, proved itself as a standard immune suppressive regimen for alternative donor transplantation. The related donor switch will be expectedly soon, and we have to wait for maturation of data both on related matched and alternative donor AHCT using post Cy infusion. Disclosures No relevant conflicts of interest to declare.

scholarly journals Validation of Different Prognostic Scores in Allogeneic Hematopoietic Cell Transplantation in the Post-Transplant Cyclophosphamide Era

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3925-3925
Author(s):  
Maria Queralt Salas ◽  
Luis Gerardo Rodríguez-Lobato ◽  
María Suárez-Lledó ◽  
Nuria Martínez-Cibrian ◽  
Teresa Solano ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Operating Characteristic ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Prognostic Scores ◽  
Predictive Capacity ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has decreased the rates of this complication, resulting on an improvement of transplant-related toxicity and survival. Secondary to its efficacy, the use of PTCy has been almost universally integrated for allogeneic hematopoietic cell transplantation (alloHCT), independently of the selected donor source. Clinical decisions in alloHCT are supported by the use of prognostic scores for outcome prediction. However, capability of prediction by diverse scores can vary depending on their features and on the composition of the study cohort. Additionally, the continuous innovation on alloHCT techniques and practices leads to an ongoing need to update risk indices aimed at improving risk stratification of patients undergoing alloHCT. This study explores the predictive capacity of different prognostic scores routinely used in alloHCT, in a contemporaneous cohort of adults undergoing peripheral blood (PB) alloHCT using PTCy-based GvHD prophylaxis. METHODS Between 2014 and 2020, 230 consecutive adults with hematological malignancies underwent PB-alloHCT with PTCy-based GvHD prophylaxis at our Institution. Data related to Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), Karnosfky Performance Status (KPS), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) score, and Endothelial Activation and Stress Index (EASIX) were collected retrospectively. Complete information was available for 216 patients. Overall survival (OS) was considered the main outcome variable. Patients were grouped into two risk groups based on the optimal cut-off value for each score. In the case of EASIX, 1.578 was the most discriminating cut-off for OS. The score discrimination for OS was measured independently for each index using the receiver operating characteristic curve (AUC) calculated using receiver operating characteristic (ROC) curves, and determined at different time-points after alloHCT. RESULTS Of the 216 patients included, the median age was 52 years (range: 18-70), acute myeloid leukemia (36.1%) was the most prevalent baseline diagnosis, 42.1% of adults underwent reduced-intensity conditioning alloHCT, 69.4% received grafts from unrelated donors, and 23.0% from haploidentical donors. With a median follow-up of 22.6 months, 24.1% patients relapsed, and 2-y OS and non-relapse mortality were 67.3% and 19.9%. DRI, HCT-CI, KPS, and EASIX successfully grouped patients into higher and lower risk strata, supporting their use for risk classification. HCT-CI [(score&gt;3 (vs 0-3): HR 2.02, p&lt;0.01], DRI [High - Very High risk (vs Low - Int): HR 2.08, p&lt;0.01], and EASIX [&gt;1.578 (vs ≤ 1.578): HR 1.73, p&lt;0.02], maintained an optimal discrimination capacity during the entire post-transplant follow-up (median AUC ranges &gt; 55%). DRI was the most accurate prognostic index during the entire post-transplant period (median AUC ranges &gt; 60%). KPS score was found to be a useful predictor of mortality up to the first year after alloHCT and with the highest prognostic accuracy at 3 months (AUC 67.09%). HCT-CI score was found to present a better discrimination capacity once elapsed 6 months after alloHCT and with a peak of prediction capacity at 2 years (AUC 60.3%). EASIX, when measured at the pre-transplant evaluation, demonstrated to have acceptable predictive ability during the entire post-transplant period (median AUC &gt; 55%), and with a peak of prediction at 3 months (AUC 62.6%). The EBMT score had the lowest predictive capacity in our analysis (Figure 1). CONCLUSION: This study validates, for the first time, the risk stratification capacity for OS of DRI, HCT-CI, KPS, and EASIX in PB-alloHCT with PCTy-based prophylaxis. Interestingly, the prediction accuracy of the prognostic scores differed depending on the time-period. This result can be taken into consideration to enhance the applicability of these scores and refine the clinical decisions taken based on the information provided from their use in routine clinical practice. Figure 1 Figure 1. Disclosures Lozano: Terumo BCT: Honoraria, Research Funding; Macopharma: Research Funding; Grifols: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Esteve: Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

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