Transplantation – Hematopoietic
Phase 2 RCT: Axatilimab Demonstrates Efficacy in Refractory Chronic GVHD by Targeting CSF1R-Dependent Macrophages
19 Sep, 2024 | 16:05h | UTCBackground: Chronic graft-versus-host disease (GVHD) is a significant long-term complication of allogeneic hematopoietic stem-cell transplantation, affecting approximately half of recipients and leading to substantial morbidity and mortality. Standard therapies often fail to induce durable responses in patients with refractory or recurrent disease. CSF1R-dependent monocytes and macrophages are key mediators of chronic GVHD, contributing to inflammation and fibrosis. Axatilimab, a CSF1R-blocking antibody, has shown promising activity in early studies.
Objective: To evaluate the efficacy and safety of axatilimab at three different doses in patients with recurrent or refractory chronic GVHD.
Methods: In this phase 2, multinational, randomized study (AGAVE-201), 241 patients aged ≥2 years with active chronic GVHD after at least two prior systemic therapies were randomized 1:1:1 to receive intravenous axatilimab at 0.3 mg/kg every 2 weeks (n=80), 1 mg/kg every 2 weeks (n=81), or 3 mg/kg every 4 weeks (n=80). Randomization was stratified by chronic GVHD severity and prior use of FDA-approved therapies (ibrutinib, ruxolitinib, or belumosudil). The primary endpoint was overall response rate (complete or partial response) within the first six cycles. The key secondary endpoint was a patient-reported reduction in symptom burden, defined as a decrease of more than 5 points on the modified Lee Symptom Scale (range 0–100).
Results: The overall response rate was 74% (95% CI, 63%–83%) in the 0.3 mg/kg group, 67% (95% CI, 55%–77%) in the 1 mg/kg group, and 50% (95% CI, 39%–61%) in the 3 mg/kg group, exceeding the predefined efficacy threshold in all groups. A clinically meaningful reduction in symptom burden was reported in 60%, 69%, and 41% of patients in the respective dose groups. Median time to response was less than 2 months across all groups. Organ-specific responses were observed in all affected organs, including skin, lungs, joints, and fascia.
The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade, such as elevations in liver enzymes and creatine kinase, which were not associated with clinical symptoms or end-organ damage. Periorbital edema occurred more frequently at higher doses. Adverse events leading to discontinuation occurred in 6% of patients in the 0.3 mg/kg group, 22% in the 1 mg/kg group, and 18% in the 3 mg/kg group. Serious infections were reported but were not dose-dependent.
Conclusions: Axatilimab demonstrated significant efficacy in patients with heavily pretreated recurrent or refractory chronic GVHD, with the highest response rates and best tolerability observed at the lowest dose tested (0.3 mg/kg every 2 weeks). Targeting CSF1R-dependent monocytes and macrophages may represent a novel therapeutic strategy in chronic GVHD.
Implications for Practice: Axatilimab offers a potential new treatment option for patients with chronic GVHD refractory to standard therapies, including those who have failed prior FDA-approved treatments. Clinicians should consider axatilimab as a therapeutic option while monitoring for transient laboratory abnormalities associated with CSF1R blockade. The lower dose appears to provide optimal efficacy with fewer adverse events.
Study Strengths and Limitations: Strengths include the randomized, multinational design and inclusion of patients with severe, refractory chronic GVHD who had received multiple prior therapies. Limitations include the lack of a comparator group, which may introduce outcome-reporting bias, and the small sizes of subgroups, limiting the generalizability of certain findings.
Future Research: Further studies are needed to confirm these results, assess long-term outcomes, and explore axatilimab in earlier lines of therapy and in combination with other treatments. Investigations into the use of axatilimab in other autoimmune diseases characterized by CSF1R-driven macrophage-mediated inflammation and fibrosis are also warranted.
RCT | Cyclophosphamide-based regimen enhances GVHD-free survival after hematopoietic stem-cell transplantation
27 Jun, 2023 | 13:54h | UTCSummary: The article details a phase 3 trial comparing the efficacy of two graft-versus-host disease (GVHD) prophylactic regimens in hematologic cancer patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT). The experimental group received cyclophosphamide–tacrolimus–mycophenolate mofetil, and the standard group received tacrolimus–methotrexate. The patients, a total of 431, underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched unrelated donor.
The primary end point was GVHD-free, relapse-free survival at 1 year. Results indicated a significantly higher incidence of this outcome in the experimental group (hazard ratio, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P=0.001). At 1 year, adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) in the experimental group, compared to 34.9% (95% CI, 28.6 to 41.3) in the standard group.
Notably, patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall survival, disease-free survival, relapse, transplantation-related death, and engraftment did not show a substantial difference between the groups. These results suggest that cyclophosphamide–tacrolimus–mycophenolate mofetil may offer a more effective prophylaxis against GVHD in HSCT patients.
Article: Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis – New England Journal of Medicine (link to abstract – $ for full-text)
News Release: Study Sets New Standard for Graft-Versus-Host Disease Prevention After Stem Cell Transplant – Johns Hopkins Medicine
Commentary on Twitter
In this trial, 1-year GVHD-free, relapse-free survival after stem-cell transplantation was 52.7% in the cyclophosphamide–tacrolimus–mycophenolate mofetil group and 34.9% in the tacrolimus–methotrexate group. https://t.co/wCdvP1LChu
— NEJM (@NEJM) June 21, 2023
Consensus Paper | Primary prophylaxis of invasive fungal diseases in patients with hematological malignancies
23 Jun, 2023 | 13:23h | UTC
Review | Acute graft-versus-host disease
14 Jun, 2023 | 14:20h | UTCAcute graft-versus-host disease – Nature Reviews Disease Primers (if the link is paywalled, try this one)
Commentary on Twitter
Tissue damage resulting from allogenic hematopoietic cell transplantation conditioning regimens triggers cellular interactions and #inflammatory cascades that lead to acute #GraftVersusHost disease symptoms https://t.co/iHyUVoV75J pic.twitter.com/ob9X7zQWB8
— Nature Reviews Disease Primers (@DiseasePrimers) June 11, 2023
DNA sequencing may identify an increased risk of relapse in adults with AML prior to hematopoietic cell transplantation
13 Mar, 2023 | 14:47h | UTCDNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant – JAMA (free for a limited period)
Commentary on Twitter
Among patients w AML in first remission prior to allogeneic hematopoietic cell transplant, the persistence of residual variants in the blood at an allele fraction ≥0.01% was assoc'd w increased relapse & worse survival vs those w/o these variants. https://t.co/KCnaQ1NRXJ
— JAMA (@JAMA_current) March 11, 2023
Review | Management of adult patients with hematological malignancies in critical care
10 Feb, 2023 | 13:45h | UTCManagement of adult patients with haematological malignancies in critical care – Anaesthesia
Cohort Study | Risk of malignant neoplasms of the gastrointestinal tract after blood or marrow transplant
30 Jan, 2023 | 00:23h | UTCMalignant Neoplasms of the Gastrointestinal Tract After Blood or Marrow Transplant – JAMA Oncology (link to abstract – $ for full-text)
Commentary: Risk of Subsequent Gastrointestinal Tract Malignancies After Blood or Marrow Transplantation – The ASCO Post
Commentary on Twitter
Exposure to cytarabine, etoposide and anthracyclines & chronic graft vs. host disease increase risk of colorectal, liver & esophageal cancer after BMT, providing evidence for appropriate evaluation & management in high-risk populations. https://t.co/UENFM1UWRw
— JAMA Oncology (@JAMAOnc) January 23, 2023
ASCO Guideline | Management of fever and neutropenia in pediatric patients with cancer and hematopoietic cell transplantation recipients
24 Jan, 2023 | 14:28h | UTC
An investigational T-cell therapy shows promise against six viral infections common after stem cell transplants
13 Jan, 2023 | 13:10h | UTC
Joint consensus statement on the vaccination of adult and pediatric hematopoietic stem cell transplant recipients.
30 Nov, 2022 | 13:39h | UTC
Consensus Paper | Hematopoietic cell transplantation in the management of myelodysplastic syndrome.
29 Nov, 2022 | 14:11h | UTC
Systematic Review | Stem cell transplantation for systemic sclerosis.
1 Aug, 2022 | 12:10h | UTCStem cell transplantation for systemic sclerosis – Cochrane Library
Summary: Stem cell transplantation for the treatment of systemic sclerosis – Cochrane Library
Cohort Study | Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma.
5 Jul, 2022 | 11:39h | UTCNews Release: Mantle cell lymphoma treatment varies according to setting – Weill Cornell Medicine
Cohort Study: Burden of long-term morbidity borne by survivors of acute myeloid leukemia treated with blood or marrow transplantation.
29 Jun, 2022 | 10:56h | UTC
Commentary on Twitter
We must understand life after BMT better, what it MEANS for a patient surviving intensive but curative treatment. Kudos to this @JCO_ASCO paper but we need better designs: versus other treatments, in BMT cohorts!
Life's gray, not categorical…#bmtsmhttps://t.co/E4YQV4LzoN pic.twitter.com/P7bMWXMTB5— Nico Gagelmann (@NicoGagelmann) June 23, 2022
Under a https://creativecommons.org/licenses/by-nc-nd/4.0/ license
Bring it on: Top five antimicrobial stewardship challenges in transplant infectious diseases and practical strategies to address them.
29 Apr, 2022 | 10:51h | UTC
Commentary on Twitter
??Review Article @ASHE_Journal
Bring it on: Top five antimicrobial stewardship challenges in transplant infectious diseases and practical strategies to address them #IDTwitter #medtwitter #TwitteRx #MedEd https://t.co/ToPLQXtC4r pic.twitter.com/pZQWWb3ZSx— Antibiotic Steward Bassam Ghanem?? (@ABsteward) April 28, 2022
Under a http://creativecommons.org/licenses/by/4.0/ license
Pre-transplant EASIX (endothelial activation and stress index) may predict the hazard of sepsis after allogeneic stem cell transplantation.
19 Apr, 2022 | 02:04h | UTCPre-transplant EASIX and sepsis after allogeneic stem cell transplantation – Intensive Care Medicine
Commentary on Twitter
? Endothelial complications major causes of mortality post alloSCT. Pre Tx Endothelial Activation & Stress IndeX EASIX (basic lab data characterizing Tx-associated thrombotic microangiopathy) powerful marker of #sepsis, dysfunctional endothelial response.https://t.co/FRGUGT8L78 pic.twitter.com/VF2wTLCHaM
— Intensive Care Medicine (@yourICM) April 18, 2022
A single-arm study evaluated Naive T-Cell depleted peripheral blood stem-cell grafts for the prevention of chronic graft-versus-host disease.
19 Jan, 2022 | 08:22h | UTCNaive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease – Journal of Clinical Oncology
Commentary: New graft strategy may improve outcomes for blood stem cell recipients – University of Pittsburg
RCT: Maribavir for refractory Cytomegalovirus infections with or without resistance post-transplant.
7 Dec, 2021 | 08:37h | UTC
ASH 2021 guidelines for stem cell transplantation in patients with sickle cell disease.
14 Oct, 2021 | 09:53h | UTCNews release: ASH Releases New Clinical Practice Guidelines on Stem Cell Transplantation in Sickle Cell Disease
Commentary: ASH Issues Guideline on the Use of HSCT for Sickle Cell Disease – HealthDay
FDA authorizes additional Covid-19 vaccine dose for certain immunocompromised individuals – Other fully vaccinated individuals do not need an additional vaccine dose right now.
16 Aug, 2021 | 01:22h | UTCCommentaries:
CDC, FDA recommend COVID booster for immune-compromised – CIDRAP
FDA authorizes additional dose of Covid-19 vaccine for the immunocompromised – STAT
Covid booster: US approves third jab for the immunocompromised – BBC
CDC Panel Recommends 3rd Vaccine Dose For Immunocompromised People – NPR
6 Things To Know If You’re Immunocompromised And Considering A 3rd Shot – NPR
CDC recommends third Covid-19 vaccine dose for certain immunocompromised people – CNN
Commentary on Twitter
The Infectious Diseases Society of America (IDSA) supports the @FDA and @CDCgov's decision to authorize a supplemental vaccine dose for immunocompromised patients.
Read our statement: https://t.co/odzzSgIxnY pic.twitter.com/4PZfUwpjhM
— IDSA (@IDSAInfo) August 13, 2021
RCT: Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease.
16 Jul, 2021 | 10:37h | UTC
Review: Care for the organ transplant recipient on the intensive care unit
8 Apr, 2021 | 08:36h | UTCCare for the organ transplant recipient on the intensive care unit – Journal of Critical Care
Review: Post-Transplant Pregnancy and Contraception
23 Mar, 2021 | 02:10h | UTCPost-Transplant Pregnancy and Contraception – Clinical Journal of the American Society of Nephrology
Short review: Acute CV complications of hematopoietic stem cell transplantation
18 Feb, 2021 | 02:40h | UTCAcute CV Complications of Hematopoietic Stem Cell Transplantation – American College of Cardiology
Cohort study: Long-term clinical outcomes of hematopoietic stem cell transplantation in 210 patients with multiple sclerosis
25 Jan, 2021 | 01:15h | UTCLong-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis – Neurology (link to abstract – $ for full-text)