Conversion from calcineurin inhibitors to sirolimus in transplant-associated thrombotic microangiopathy
Clinical transplantation. 2020
Transplant-associated thrombotic microangiopathy (TA-TMA) is a specific complication of allogeneic hematopoietic cell transplantation with a multifactorial etiology. There is little evidence published regarding the efficacy and factors influencing the outcome of substitution of calcineurin inhibitors (CNIs) with other agentsas a widely accepted practice in this disorder; however, there are limited data on the options for immunosuppression manipulation (ISM). In our study we retrospectively analyzed outcomes of 45 patients with TA-TMA with ISM and substitution either with steroids (steroid group) or anmTOR inhibitor sirolimus (sirolimus group). In our study, sirolimus was associated with significantly better 1-year overall survival (HR 0.3, 95%CI 0.13-0.7, p=0.004)and faster time to normalization of LDH (HR 2.2, 95%CI 0.99-4.99, p=0.044).Replacing CNIs with sirolimus could be an effective option in patients with TA-TMA. A multicenter confirmatory study ofCNIs replacement with sirolimus is justified.
The timing of post-transplant cyclophosphamide administration in haploidentical transplantation: a comparative study on behalf of the ALWP of the EBMT
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Timing of immunosuppressive-drugs therapy used in combination with post-transplant cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (Haplo-HSCT) is not standardized. We evaluated the schedule of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on day +3 and +4 along with tacrolimus (group 1, n=215) or cyclosporine A (CSA) and mycophenolate -mofetil (MMF) from day+5 (group 2, n=170) or CSA+MMF from day 0 or 1 with PTCY on day +3 and +5 (group 3, n=124). Patients in group 3 were younger (median age 46 years, p=0.02), received bone marrow (77%, p<0.01) and a regimen containing thiotepa, fludarabine and busulfan (84%, p<0.01) more frequently. At 2 years, OS was 44%, 48% and 59% (p=0.15), LFS was 43%, 46%, and 53%, (p=0.05) and refined-GRFS (rGRFS) was 33%, 39% and 36% (p=0.02), in groups 1, 2 and 3, respectively. Grade II-IV acute GVHD was 25%, 39% and 18%, respectively (p<0.01), and chronic GVHD was 25%, 21% and 24% (p=0.50) for the 3 groups, respectively. Relapse incidence was 36%, 37% and 26%, (p=0.02) and NRM was 26%, 20% and 21% (p=0.35) for the 3 groups, respectively. On multivariate analysis, the early start of ISTimmunosuppression therapy at day+1 followed by PTCY was associated with a better LFS (hazard ratio (HR) 0.58, p=0.02) and an improved rGRFS (HR 0.62, p=0.02). In our study, timing of immunosuppression influences outcomes of haplo-HSCT with PTCY. The early starting of CSA+MMF with PTCY administered on day +3 and +5 improves LFS and rGRFS.
Patients with acute leukaemia undergoing haploidentical transplantation (n=509)
Post-transplant cyclophosphamide (PTCY) on day +3 and +4 along with tacrolimus (group 1, n=215)
Cyclosporine A (CSA) and mycophenolate -mofetil (MMF) from day+5 (group 2, n=170) or CSA+MMF from day 0 or 1 with PTCY on day +3 and +5 (group 3, n=124)
Patients in group 3 were younger (median age 46 years), received bone marrow (77%) and a regimen containing thiotepa, fludarabine and busulfan (84%) more frequently. At 2 years, OS was 44%, 48% and 59%, LFS was 43%, 46%, and 53%, and refined-GRFS (rGRFS) was 33%, 39% and 36%, in groups 1, 2 and 3, respectively. Grade II-IV acute GVHD was 25%, 39% and 18%, respectively, and chronic GVHD was 25%, 21% and 24% for the 3 groups, respectively. Relapse incidence was 36%, 37% and 26%, and NRM was 26%, 20% and 21% for the 3 groups, respectively. On multivariate analysis, the early start of ISTimmunosuppression therapy at day+1 followed by PTCY was associated with a better LFS (hazard ratio (HR) 0.58) and an improved rGRFS (HR 0.62).
A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis
Acta haematologica. 2020;:1-8
INTRODUCTION This prospective study evaluated a calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis regimen of ruxolitinib in combination with post-transplant cyclophosphamide (PTCy). Patents and Methods: Twenty patients with primary or secondary myelofibrosis were prospectively enrolled. Reduced intensity conditioning was performed, followed by allogeneic stem cell transplantation from related (n = 7) or unrelated (n = 13) donors. GVHD prophylaxis included only PTCy and ruxolitinib (45 mg) from day-7 to day-2, and 15 mg from day+5 to day+100. This trial was registered at www.clinicaltrials.gov as #NCT02806375. RESULTS Primary engraftment was documented in 17 patients. One patient experienced primary graft failure and 2 died before engraftment. Eleven patients demonstrated severe poor graft function (SPGF), which required ruxolitinib dose reduction. The regimen was well tolerated, with grade 3-4 non-haematological toxicity in 30%, viral reactivation in 45%, and severe sepsis in 15% of patients. The incidence of acute GVHD grade II-IV was 25%, grade III-IV GVHD was 15%, and moderate chronic GVHD was 20%, with no severe cases. Only 2 patients required systemic steroids. Haematological relapse was documented in 1 patient. Two-year non-relapse mortality was 15%, 2-year overall survival was 85%, and 2-year event-free survival was 72%. CONCLUSION GVHD prophylaxis with PTCy and ruxolitinib is associated with low toxicity, good acute and chronic GVHD control, and low relapse incidence. However, the relatively high rate of SPGF should be taken into account. SPGF could possibly be mitigated by ruxolitinib dose reduction.
Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults
Bone marrow transplantation. 2020
Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.
Adult and paediatric patients with steroid refractory GVHD, 32 acute, 42 chronic (n=75)
Ruxolitinib at a starting dose of 10 mg bid for adults and children with weight >40 kg and 0.15 mg/kg bid for children with a weight less than 40 kg.
The overall response rate (ORR) was 75% in acute GVHD and 81% in chronic. Overall survival was 59% in acute group and 85% in chronic. The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%) in acute form and high disease risk score in chronic (65% vs 90%). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR, survival, and toxicity.
High prevalence of CD3, NK, and NKT cells in the graft predicts adverse outcome after matched-related and unrelated transplantations with post transplantation cyclophosphamide
Bone marrow transplantation. 2019
The predictive value of graft composition and plasma biomarkers on the outcome of allogeneic HSCT is well known for conventional GVHD prophylaxis based on calcineurin inhibitors with or without antithymocyte globulin. Currently, there is limited data whether these results could be translated to post transplantation cyclophosphamide (PTCy). The prospective extension cohort of NCT02294552 trial enrolled 79 adult patients with acute leukemia in CR. Twenty-six received matched-related bone marrow (BM) grafts with single-agent PTCy and 53 received unrelated peripheral blood stem cell graft (PBSC) with PTCy, tacrolimus, and MMF. The grafts were studied by the flow cytometry, and plasma samples were analyzed by ELISA. In the cluster and major component analysis, we determined that transplantation from donors with high content of CD3, NKT, and CD16-CD56 + subpopulations in the PBSC grafts was associated with poor immunological recovery and compromised event-free survival (50% vs. 80%, HR 2.93, p = 0.015) both due to increased relapse incidence and non-relapse mortality. The significant independent predictor of moderate and severe chronic GVHD was the high prevalence of and iNKT, Vbeta11, and double-positive cells in the PBSC grafts from young donors (HR 2.75, p = 0.0483). No patterns could be identified for BM grafts and for plasma biomarkers.
Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT
Bone marrow transplantation. 2018
Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 +/- 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 +/- 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.
Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide
Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post-transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-gamma and TNF-alpha in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-gamma (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-gamma after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN-gamma in GVHD patients after PTCy was different from previously reported after conventional prophylaxis. Copyright © 2017 Elsevier Ltd. All rights reserved.
Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis
Annals of Hematology. 2017;96(6):935-942
A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19-0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
Graft-versus-Host Disease Prophylaxis in Unrelated Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil
Biology of Blood & Marrow Transplantation. 2016;22(6):1037-42
Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA-matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event-free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno-occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG-based prophylaxis. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.