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380 Serial Clinical and Biomarker Monitoring during Treatment Can Stratify Patients with Low Risk Gvhd

Program: Oral and Poster Abstracts
Type: Oral
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD and Immune Reconstitution: Monitoring, Understanding and Optimizing GVHD Interventions
Hematology Disease Topics & Pathways:
Research, Translational Research, Clinical Research, Study Population, Human
Saturday, December 7, 2024: 4:15 PM

Nikolaos Katsivelos, MD1*, Nikolaos Spyrou, MD1, Daniela Weber2*, Ingrid Vasova, MD3*, Francis A. Ayuk, M.D.4*, Hannah Choe, MD5, William J. Hogan, MD6, Zachariah Defilipp, MD7, Muna Qayed, MD8, Aaron Etra, MD1, Karamjeet S Sandhu, MD9, Sabrina Kraus10*, Timothy S. Olson, MD, PhD11, Elizabeth O. Hexner, MD, MSTR12, Paibel Aguayo-Hiraldo, MD13, Ran Reshef, MD, MSc14, Evelyn Ullrich, MD15, Tal Schechter-Finkelstein, MD16*, Carrie L. Kitko, MD17, Chantiya Chanswangphuwana, M.D.18*, Pietro Merli, MD19*, Yu Akahoshi, MD, PhD1,20*, Janna Baez1*, Gilbert Eng1*, Rahnuma Beheshti1*, Steven Kowalyk1*, George Morales1*, Ioannis Evangelos Louloudis, MD1*, Rachel Young1*, Ernst Holler, MD, PhD2*, Ryotaro Nakamura, MD21, James L.M. Ferrara, MD, DSc1 and John Levine, MD, MS1

1Icahn School of Medicine at Mount Sinai, New York, NY
2Internal Medicine III - Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
3Department of Internal Medicine 5, Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany
4Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital, Columbus, OH
6Division of Hematology, Mayo Clinic, Rochester, MN
7Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
8Emory University, Winship Cancer Institute, Atlanta, GA
9Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
10Division of Hematology, University Hospital of Wurzburg, Wurzburg, Germany, Würzburg, Germany
11Children's Hospital of Philadelphia, Philadelphia, PA
12Abramson Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA
13Cancer and Blood Disease Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA
14Division of Hematology & Oncology, Columbia University Medical Center, New York
15Experimental Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany, Frankfurt Am Main, Germany
16The Hospital for Sick Children, Toronto, ON, CAN
17Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN
18Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
19Department of Hematology-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
20Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
21Hematology and HCT, City of Hope National Medical Center, Duarte, CA

Background: The majority of patients respond to steroid treatment for graft-vs-host disease (GVHD), but the typically high doses and prolonged courses can cause substantial morbidity. GVHD can be classified at onset into two groups with significant differences in treatment response and non-relapse mortality (NRM) by clinical criteria (Minnesota risk) but the more favorable standard risk group still experiences high rates of treatment failure and NRM [MacMillan, BBMT 2015]. We previously validated a serum biomarker-based (ST2+REG3α) risk stratification system, MAGIC algorithm probabilities (MAPs), that can stratify patients both at initiation and during treatment into risk groups for treatment response and NRM [Hartwell, JCI Insight 2017, Srinagesh, Blood Adv 2019]. GVHD that is Minnesota standard risk and has a low MAP (i.e., Ann Arbor 1) at start of treatment represents a low risk group with >80% response rate to steroids and ~10% NRM [Etra, Blood 2023]. We hypothesized that serial monitoring of GVHD symptom severity and MAPs twice (days (d) 7 and 14) in patients with clinical and biomarker defined low risk GVHD could further stratify patients into clinically meaningful groups.

Methods: We retrospectively determined MAPs at d7 and 14 in 450 patients with low risk GVHD who participated in a prospective, multi-center, observational trial and were treated with systemic steroids between 2015-2023. MAPs <0.291 at days 7 and 14 were defined as low risk based on a previously validated threshold [Major-Monfried Blood 2018]. Clinical responses were scored as complete (CR), partial (PR), or non-response (NR) by standard criteria. Initiation of second line therapy was considered NR. Patients were categorized into three groups (A-C) based on clinical responses and MAPs at days d7 and 14. A: CR/PR by d14 and low MAP at both d7+14; B: stable or worse GVHD (NR) by d14 with low MAP at both d7 and 14; C: any response with a high MAP at d7 or 14. The endpoints were clinical response at day 28 (overall response rate, ORR=CR or PR), regardless of earlier response status, and 6-month NRM.

Results: The median age of the study population was 54 years (range: 0-79); 19% of patients received PT-Cy for GVHD prophylaxis. Target organ involvement was skin ± upper GI (66%), lower GI (23%), isolated UGI (11%), and skin+liver (1%), and GVHD severity was grade I (35%), II (61%), and III (4%) at start of treatment. Patients in group A (n=310, 69%), clinical responders with low MAPs through day 14, had excellent d28 ORR (93%) and very low NRM (4%). GVHD in this group was considered ultra-low risk (ULR) and subset analyses revealed highly consistent d28 ORR and NRM, regardless of target organ severity, age (<18, 18-59, >60), HCT-CI score, conditioning intensity, and GVHD prophylaxis. Group B patients comprised clinical non-responders with low MAPs through day 14 (n=112, 25%); half of them responded by d28 and their NRM was low (8%), albeit double that of group A (p=0.079). Group C was small (n=28, 6%) and included both clinical responders (n=20, 4%) and clinical non-responders (n=8, 2%) who had at least one high MAP through day 14. Their d28 ORR was 54% but NRM increased four-fold (32%) and was significantly worse than patients who maintained low MAPs regardless of clinical response (p<0.001).

Conclusion: Serial monitoring by clinical response and biomarkers during the first two weeks of treatment identifies a small number of high risk patients whose GVHD is initially low risk (group C). This group experiences high NRM regardless of clinical response to steroid treatment and may benefit from treatment escalation. Patients with low risk GVHD who do not have an early clinical response to steroids but maintain low MAPs, (group B) have reasonably good long-term outcomes with standard treatment. Finally, serial monitoring identifies a very large subset of patients with ULR GVHD (group A) who respond exceptionally well to standard treatment and experience very low rates of 6-month NRM regardless of pre-transplant characteristics and GVHD prophylaxis. Such patients may benefit from treatment de-escalation strategies such as shorter courses of lower dose steroids, a strategy we are currently testing in a clinical trial (NCT05090384).

Disclosures: Weber: German Research Foundation: Research Funding; German Jose-Carreras Leukemia Foundation: Research Funding; Else-Kröner-Fresenius Foundation: Research Funding. Ayuk: BMS: Honoraria; Medac: Consultancy, Honoraria; Miltenyi Biomedicine: Consultancy, Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria. Choe: Orca Bio: Consultancy; Ironwood Pharmaceuticals, Inc.: Consultancy; REGiMMUNE: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Sanofi: Consultancy; Actinium: Consultancy. Defilipp: Incyte: Consultancy, Research Funding; Regimmune: Consultancy, Research Funding; Taiho Oncology: Research Funding; Sanofi: Consultancy; Inhibrx: Consultancy; PharmaBiome AG: Consultancy; Ono Pharmacuetical: Consultancy; MaaT Pharma: Consultancy; Forte Biosciences: Consultancy; Kura Oncology, Inc.: Research Funding. Sandhu: Autolus: Consultancy. Olson: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Elixirgen: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Medexus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Akari: Research Funding. Hexner: Disc Medicine: Consultancy. Reshef: Atara Biotherapeutics: Research Funding; Abbvie: Research Funding; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Quell Biotherapeutics: Consultancy; Sana Biotechnology: Consultancy; Autolus: Consultancy; TScan: Consultancy, Research Funding; Bayer: Consultancy; Sanofi: Research Funding; Allogene: Consultancy; TCR2: Research Funding; Takeda: Research Funding; Immatics: Research Funding; Gilead Sciences: Consultancy, Research Funding; Orca Bio: Consultancy; J&J: Research Funding; Synthekine: Research Funding; Cabaletta: Research Funding; CareDx: Research Funding; BMS: Research Funding; Precision Biosciences: Research Funding. Kitko: Incyte corp.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Merli: Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees. Akahoshi: Novartis: Honoraria. Nakamura: Helocyte: Research Funding; Omeros (ended): Consultancy; Maat Pharma: Research Funding; Sanofi: Consultancy; Mitarisan: Research Funding; Ono Pharmaceutical: Consultancy; Pfizer: Consultancy; Blue Bird (ended): Consultancy. Ferrara: Alexion: Consultancy; Realta: Consultancy; Medpace: Consultancy; Viracor: Consultancy, Patents & Royalties: GVHD biomarker patent; Allovir: Consultancy; Physician Education Resource: Consultancy; Sanofi: Consultancy; Bluebird Bio: Consultancy; Inhibrx: Consultancy; X4 Pharmaceuticals: Consultancy. Levine: Bluebird Bio: Consultancy; Editas: Consultancy; Forte Biosciences: Consultancy; Inhibrx: Consultancy; Maat Pharma: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; X4: Consultancy; Ironwood: Consultancy; Calliditas: Consultancy; Viracor: Patents & Royalties: GVHD biomarker patent.

*signifies non-member of ASH