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Real-World Experience in Extracorporeal photopheresisfor adults with graft-versus-host disease
Asensi Cantó, P., Sanz Caballer, J., Sopeña Pell-Ilderton, C., Solís Ruiz, J., Lloret Madrid, P., Montaner Villalba, M., Facal Malvar, A., Chorão, P., Guerreiro, M., Balaguer Roselló, A., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
INTRODUCTION Extracorporeal photopheresis (ECP) has shown efficacy in graft-versus-host disease (GVHD). We aim to summarize eight years of real-world experience with off-line ECP in our institution, in order to validate this treatment schedule and analyze predictive factors. MATERIALS AND METHODS All consecutive adult patients with steroid-dependent or steroidrefractory GVHD receiving off-line ECP were included in this single center, retrospective study. ECP was performed with Spectra Optia®, processing one total blood volume, with a frequency of twice a week for acute GVHD and once a week for chronic GVHD, and tapered individually according to clinical response. Cumulative incidence of response, including complete responses (CR) and partial responses (PR), were compared among patients grouped by different baseline, apheresis and disease characteristics. RESULTS Between January 2015 and May 2022, 1382 ECP procedures were proposed for 82 patients. No incidents were reported in 97% of sessions. GVHD responded in 78% of patients (acute GVHD 57% CR and 4% PR, chronic GVHD 39% CR and 48% PR). Overall survival was statistically longer for acute GVHD patients responding to ECP than for those who did not (67.5% vs. 26% at one year, respectively; P = 0.037). Severity was an independent predictor of response in acute GVHD whereas the absence of mouth involvement and lower lymphocyte counts in the apheresis product correlated with a higher response in chronic GVHD. DISCUSSION This treatment schedule is effective for GVHD. Further investigation is required to identify ECP-specific predictive factors, as findings are not homogeneous among different studies.
PICO Summary
Population
Adults with steroid-dependent or steroid refractory GVHD from a single centre in Spain (n=82)
Intervention
Extracoroporeal photopheresis (ECP) with Spectra Optia®, processing one total blood volume, with a frequency of twice a week for acute GVHD and once a week for chronic GVHD
Comparison
None
Outcome
Between January 2015 and May 2022, 1382 ECP procedures were proposed for 82 patients. No incidents were reported in 97% of sessions. GVHD responded in 78% of patients (acute GVHD 57% complete response (CR) and 4% partial response (PR), chronic GVHD 39% CR and 48% PR). Overall survival was statistically longer for acute GVHD patients responding to ECP than for those who did not (67.5% vs. 26% at one year, respectively). Severity was an independent predictor of response in acute GVHD whereas the absence of mouth involvement and lower lymphocyte counts in the apheresis product correlated with a higher response in chronic GVHD.
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Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease
Al Malki, M. M., London, K., Baez, J., Akahoshi, Y., Hogan, W. J., Etra, A. M., Choe, H. K., Hexner, E. O., Langston, A., Abhyankar, S. H., et al
Blood advances. 2023
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Editor's Choice
Abstract
GVHD of the gastrointestinal (GI) tract is the main cause of non-relapse mortality following allogeneic HCT. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA 2/3 scores correlate with resistance to treatment and higher non-relapse mortality (NRM). We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA 2/3 GVHD. Seventy-five evaluable patients were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events (AEs) in more than 10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared to 150 well matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58%; P=0.67 and 48% vs. 48%; P=1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39%, P=0.80 and 46% vs 54%, P=0.48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high risk GVHD.
PICO Summary
Population
Adults with new onset high risk GvHD from 12 centres in USA (n=75)
Intervention
Natalizumab combined with corticosteroids (n=75)
Comparison
Matched controls from the MAGIC database whose primary treatment was corticosteroids alone (n=150)
Outcome
There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58% and 48% vs. 48%, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39% and 46% vs 54%, respectively).
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Phase II clinical trial evaluating Abatacept in patients with steroid-refractory chronic graft versus host disease
Koshy, A. G., Kim, H. T., Liegel, J., Arnason, J. E., Ho, V. T., Antin, J. H., Joyce, R., Cutler, C. S., Gooptu, M., Nikiforow, S., et al
Blood. 2023
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Editor's Choice
Abstract
Steroid-refractory chronic graft versus host disease (cGVHD) remains a significant cause of morbidity and mortality following allogeneic transplantation. Abatacept is a selective co-stimulation modulator, used for the treatment of rheumatologic disease, and was recently the first drug to be approved by the FDA for the prophylaxis of acute graft versus host disease. We conducted a Phase II study to evaluate the efficacy of Abatacept in steroid-refractory cGVHD (clinicaltrials.gov #NCT01954979). The overall response rate was 58%, with all responders achieving a partial response. Abatacept was well-tolerated with few serious infectious complications. Immune correlative studies showed a decrease in IL-1-alpha, IL-21, and TNF-alpha as well as decreased PD-1 expression by CD4+ T cells in all patients after treatment with Abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that Abatacept is a promising therapeutic strategy for the treatment of cGVHD.
PICO Summary
Population
Adults with steroid refractory cGVHD from two centres in USA (n=39)
Intervention
Abatacept 10mg/kg intravenously for a total of 6 doses
Comparison
None
Outcome
The overall response rate was 58%, with all responders achieving a partial response. Abatacept was well-tolerated with few serious infectious complications. Immune correlative studies showed a decrease in IL-1-alpha, IL-21, and TNF-alpha as well as decreased PD-1 expression by CD4+ T cells in all patients after treatment with Abatacept.
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Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study
Miklos, D. B., Abu Zaid, M., Cooney, J. P., Albring, J. C., Flowers, M., Skarbnik, A. P., Yakoub-Agha, I., Ko, B. S., Bruno, B., Waller, E. K., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2200509
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Abstract
PURPOSE To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.
PICO Summary
Population
Patients 12 years and older with newly diagnosed moderate or severe chronic graft-versus-host disease (cGVHD) enrolled in the iNTEGRATE trial (n=193)
Intervention
Ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily (n=95)
Comparison
placebo plus prednisone (n=98)
Outcome
At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients
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Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-Versus-Host Disease
Gonzalez, R., Gaskill, E., Padilla, M., Pidala, J., Lazaryan, A., Perez, L., Khimani, F., Faramand, R.
Transplantation and cellular therapy. 2023
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Abstract
BACKGROUND Belumosudil is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic GHVD in patients who have failed two or more prior lines of systemic therapy. Although clinical evaluation of the pharmacokinetic (PK) effects of belumosudil (BEL) on other immunosuppressive (IS) agents has not been performed, in vitro data indicates belumosudil may have possible interactions with narrow therapeutic index drugs utilized in the treatment of GVHD such as tacrolimus, sirolimus, and cyclosporine through CYP3A and PGP interactions. Further evaluation of these potential interactions is warranted to optimize safety and effectiveness of these medications if combined with belumosudil. OBJECTIVE This study investigates the potential effects of BEL on sirolimus and tacrolimus levels when used concurrently by assessing changes in IS levels with addition of BEL. STUDY DESIGN This is a retrospective single center study of patients who started BEL while on tacrolimus and/or sirolimus between February 1(st) 2019 to February 1(st) 2023. Patients were included if they had IS levels at baseline prior to starting belumosudil and at least one subsequent level to assess changes over time. The primary endpoint was the concentration to dose (C/D) ratio analyzed before and after addition of belumosudil. Secondary endpoints included incidence of IS levels outside of therapeutic range (subtherapeutic or supratherapeutic) and mean dose changes over time. RESULTS Thirty-seven patients met eligibility criteria and are included in this analysis. Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with belumosudil had a statistically significant increase in C/D ratios (sirolimus: 160%, p <0.001; tacrolimus: 113%, p = 0.013) between pre-belumosudil and final post-belumosudil assessment. The C/D ratios for both tacrolimus and sirolimus continued to increase over several timepoints after initiation of belumosudil, indicating that multiple drug dose adjustments may be required. After belumosudil initiation,19% of tacrolimus and 57% of sirolimus levels were supratherapeutic. Despite dose adjustments, 27% of tacrolimus levels were supratherapeutic at both 2(nd) and 3(rd) assessments after starting belumosudil, while sirolimus levels remained 28% and 30% supratherapeutic respectively. Of twelve patients who discontinued belumosudil during study period, all (100%) returned to baseline C/D ratios, confirming that the C/D ratio change can be attributed to belumosudil. CONCLUSIONS Belumosudil impacts IS levels with clinical significance warranting dose adjustments of concurrent medications. A significant number of patients taking sirolimus with belumosudil had levels greater than 15 ng/mL during the study period, indicating potential risk for toxicity if this interaction is unmonitored. We recommend empiric dose reductions of 25% for tacrolimus and 25-50% for sirolimus when adding belumosudil, as well as close monitoring of IS levels during the initial weeks of belumosudil therapy. Future studies are warranted to better describe the impact of belumosudil on patients taking CYP3A inhibitors.
PICO Summary
Population
Patients identified retrospectively from a single centre in USA who were taking tacrolimus or sirolimus (n=37)
Intervention
Belumosudil (BEL) in addition to tacrolimus or sirolimus
Comparison
None
Outcome
Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with belumosudil had a statistically significant increase in concentration-dose (C/D) ratios (sirolimus: 160%; tacrolimus: 113%) between pre-belumosudil and final post-belumosudil assessment. The C/D ratios for both tacrolimus and sirolimus continued to increase over several timepoints after initiation of belumosudil, indicating that multiple drug dose adjustments may be required. After belumosudil initiation,19% of tacrolimus and 57% of sirolimus levels were supratherapeutic. Despite dose adjustments, 27% of tacrolimus levels were supratherapeutic at both 2nd and 3rd assessments after starting belumosudil, while sirolimus levels remained 28% and 30% supratherapeutic respectively. Of twelve patients who discontinued belumosudil during study period, all (100%) returned to baseline C/D ratios, confirming that the C/D ratio change can be attributed to belumosudil.
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Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation
Keklik, M., Deveci, B., Celik, S., Deniz, K., Gonen, Z. B., Zararsiz, G., Saba, R., Akyol, G., Ozkul, Y., Kaynar, L., et al
Annals of hematology. 2023
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Abstract
Graft versus host disease (GvHD) remains a significant risk for mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). A growing literature supports successful applications of mesenchymal stromal cells (MSCs) for the treatment of steroid-refractory acute GvHD (aGvHD). However, there is limited knowledge about the effects of MSC treatment on late-acute GvHD (late aGvHD). In this article, we present our multicenter study on the safety and efficacy of MSC therapy for patients with steroid-refractory late aGvHD in comparison to those with aGvHD. The outcome measures include non-relapse mortality (NRM) and survival probability over a 2-year follow-up. The study includes a total of 76 patients with grades III-IV aGvHD (n = 46) or late aGvHD (n = 30), who had been treated with at least two lines of steroid-containing immunosuppressive therapy. Patients received weekly adipose or umbilical cord-derived MSC infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 10(6)/kg in the aGvHD group, and 1.64 (ranging from 0.85 to 2.58) × 10(6)/kg in the late aGvHD group. This was an add-on treatment to ongoing conventional pharmaceutical management. In the aGvHD group, 23 patients received one or two infusions, 20 patients had 3-4, and three had ≥ 5. Likewise, in the late aGvHD group, 20 patients received one or two infusions, nine patients had 3-4, and one had ≥ 5. MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively (p = 0.002). To our knowledge, our study is the first to compare the safety and efficacy of MSC infusion(s) for the treatment of steroid-resistant late aGVHD and aGVHD. There were no infusion-related adverse effects in either group. The response rate to MSC therapy was significantly higher in the late aGvHD group than in the aGvHD group. In addition, at the 2-year follow-up, the survival and NRM rates were more favorable in patients with late aGVHD than in those with aGVHD. Thus, the results are encouraging and warrant further studies to optimize MSC-based treatment for late aGVHD.
PICO Summary
Population
Adults with grades III-IV acute GvHD or late aGvHD from three centres in Turkey (n=76)
Intervention
People with grade III-IV acute GvHD received weekly adipose or umbilical cord-derived mesenchymal stromal cell (MSC) infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 10(6)/kg, plus standard care (aGvHD group, n=46)
Comparison
People with late acute GvHD received MSC infusions at a median dose of 1.64 (ranging from 0.85 to 2.58) × 10(6)/kg, plus standard care (late aGvHD, n=30)
Outcome
MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively.
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Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis
Servais, S., Baron, F., Lechanteur, C., Seidel, L., Baudoux, E., Briquet, A., Selleslag, D., Maertens, J., Poire, X., Schroyens, W., et al
Frontiers in immunology. 2023;14:1106464
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Editor's Choice
Abstract
INTRODUCTION Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. METHODS We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). RESULTS Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. DISCUSSION In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.
PICO Summary
Population
Adults with prolonged severe cytopenia and poor graft function (PGF) after allogeneic transplant in eight centres in Belgium (n=30).
Intervention
Single infusion of third-party donor mesenchymal stromal cells (MSC)
Comparison
None
Outcome
Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive.
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Extracorporeal photopheresis as graft-versus-host disease prophylaxis: a randomized controlled trial: Prophylactic extracorporeal photopheresis to prevent graft-versus-host disease
Ali, M. M., Gedde-Dahl, T., Osnes, L. T., Perrier, F., Veierød, M. B., Tjønnfjord, G. E., Iversen, P. O.
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for many patients diagnosed with hematological malignancies. A major obstacle is graft-versus-host disease (GvHD) causing significant morbidity and mortality. Extracorporeal photopheresis (ECP) is an increasingly applied GvHD treatment, partly due to its favourable safety profile. In contrast, the use of ECP in preventing GvHD is sparse, and randomized controlled trials (RCTs) are lacking. OBJECTIVE We therefore conducted a RCT to assess if ECP applied post-transplant, could prevent the development of GvHD within the first year of transplantation. STUDY DESIGN We enrolled 157 patients (18-74 years) with a hematological malignancy receiving first allo-HSCT: 76 randomized to the intervention group and 81 to the control group. ECP was initiated directly upon engraftment and was planned twice weekly for two weeks, then once weekly for four weeks. GvHD, relapse, and death were analyzed with Cox regression analysis. RESULTS During the first year, 45 patients in the intervention and 52 control patients developed GvHD (HR=0.82, 95% CI 0.55-1.22, P=0.32). There were no differences in acute or chronic GvHD or its organ distribution in this intention-to-treat RCT. A per-protocol analysis revealed a significant difference in GvHD between the intervention (per-protocol; n=39 of 76) and the control group (n=77), 46% vs 68%, respectively, (HR 0.47, 95% CI 0.27-0.80, P=0.006). Relapse occurred in 15 patients in the intervention group and in 11 patients among the controls (HR=1.38, 95% CI 0.64-3.01, P=0.42). GvHD-free relapse-free (GRFS) survival, event-free survival, overall survival and non-relapse mortality did not differ significantly between the two study groups. No significant difference in immune reconstitution between the two study groups was revealed. CONCLUSION This first intention-to-treat RCT, investigating ECP as GvHD prophylaxis in allo-HSCT for hematological malignancy does not support the use of ECP as adjunct to standard drug-based GvHD-prophylaxis. This trial was registered at www. CLINICALTRIALS gov as #NCT03204721.
PICO Summary
Population
Adults with a haematological malignancy receiving first allo-HSCT in a single centre in Norway (n=157)
Intervention
Extracorporeal photopheresis (ECP) therapy, 8 sessions over 6 weeks in addition to standard GvHD prophylaxis (n=76)
Comparison
Standard GvHD prophylaxis (n=81)
Outcome
During the first year, 45 patients in the intervention and 52 control patients developed GvHD (HR=0.82, 95% CI 0.55-1.22). There were no differences in acute or chronic GvHD or its organ distribution in this intention-to-treat RCT. A per-protocol analysis revealed a significant difference in GvHD between the intervention (per-protocol; n=39 of 76) and the control group (n=77), 46% vs 68%, respectively, (HR 0.47, 95% CI 0.27-0.80). Relapse occurred in 15 patients in the intervention group and in 11 patients among the controls (HR=1.38, 95% CI 0.64-3.01). GvHD-free relapse-free (GRFS) survival, event-free survival, overall survival and non-relapse mortality did not differ significantly between the two study groups. No significant difference in immune reconstitution between the two study groups was revealed.
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A phase 2 study of Interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract
Ponce, D. M., Alousi, A. M., Nakamura, R., Slingerland, J., Calafiore, M., Sandhu, K. S., Barker, J. N., Devlin, S. M., Shia, J., Giralt, S. A., et al
Blood. 2022
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Editor's Choice
Abstract
Graft vs. host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, Interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating safety and efficacy of a novel recombinant human Interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD (NCT02406651; https://clinicaltrials.gov/ct2/show/NCT02406651). The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. 19/27 patients (70%; 80% CI: 56-79) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This work was supported by funding from Evive Biotech., The Society of Memorial Sloan Kettering Cancer Center, and the National Institutes of Health.
PICO Summary
Population
Adults with newly diagnosed lower gastrointestinal acute GvHD (n=27)
Intervention
F-652, a novel recombinant human Interleukin-22 dimer, in combination with systemic corticosteroids
Comparison
None
Outcome
The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. 19/27 patients (70%; 80% CI: 56-79) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis.
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10.
FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GVHD After Two or More Prior Lines of Systemic Therapy
Przepiorka, D., Le, R. Q., Ionan, A., Li, R. J., Wang, Y. H., Gudi, R., Mitra, S., Vallejo, J., Okusanya, O. O., Ma, L., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022
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Abstract
On July 16, 2021, the Food and Drug Administration approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025-213, which included 65 patients with chronic GVHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% (95% CI: 63, 85); 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI: 1.2, 2.9), and 62% (95% CI: 46, 74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.
PICO Summary
Population
Patients in six centres in the USA with chronic GvHD who had received 2-5 prior lines of therapy (n=65)
Intervention
Belumosudil 200 mg daily
Comparison
None
Outcome
The overall response rate through to Cycle 7 Day 1 was 75% (95% CI: 63, 85); 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI: 1.2, 2.9), and 62% (95% CI: 46, 74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension.