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Hematology 2021: Nonmalignant

CME

Key Studies in Nonmalignant Hematology: Independent Conference Coverage of ASH 2021

Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™

Released: March 01, 2022

Expiration: February 28, 2023

David Dingli
David Dingli, MD, PhD
Mark A. Schroeder
Mark A. Schroeder, MD
Sujit Sheth
Sujit Sheth, MD
CME/CE Information

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Abatacept for Steroid-Refractory cGVHD: Study Design

Mark A. Schroeder, MD:
Chronic GVHD (cGVHD) is typically managed and treated differently than aGVHD. Abatacept is a selective co-stimulation modulator that binds to CD80 and CD86 on antigen-presenting cells blocking the costimulation of T-cells through CD28.7

In preclinical models, CD28 blockade has been shown to prevent GVHD via control of T-cell activation.8 Abatacept recently received FDA approval in combination with a calcineurin inhibitor and methotrexate for the prevention of aGVHD in adults and pediatric patients 2 years of age or older undergoing hematopoietic stem cell transplant.9 In a phase I study in steroid-refractory cGVHD, abatacept was shown to improve responses in 44% of patients and to reduce prednisone use in more than 50% of responders, with no dose limiting toxicity.10

At ASH 2021, Koshy and colleagues11 reported data from a phase II study of abatacept in patients who underwent bone marrow or stem cell transplantation with myeloablative or reduced intensity chemotherapy and who developed steroid-refractory cGVHD (N = 39). Abatacept was given at 10 mg/kg every 2 weeks for 3 doses and then after 1 month, every 4 weeks for 3 doses. Patients with a CR or PR could continue on abatacept in a treatment extension phase. The primary endpoint was overall response rate (ORR).

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Abatacept for Steroid-Refractory cGVHD: Baseline Characteristics

Mark A. Schroeder, MD:
Median time from hematopoietic stem cell transplantation was 43 months (range: 6-173 months); the median previous treatments for cGVHD was 5 (range: 1-11); and the median age of patients enrolled was 62 years.

The graft source for patients enrolled in this study was primarily peripheral stem cells (89.7%); 17 and 22 patients had moderate and severe cGVHD at baseline, respectively; and most patients had primarily involvement of the skin (85%), joints (82%), eyes (69%), lungs (54%), and mouth (44%).

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Abatacept for Steroid-Refractory cGVHD: Response

Mark A. Schroeder, MD:
The ORR was 49% (all were PR). Disease progression occurred in 26% of patients, and investigators observed a significant and sustained reduction in prednisone use 1 month after starting abatacept therapy. Responses (CRs or PRs) were observed in several organs, most notably in the lungs (33%), eyes (23%), joints (21%), mouth (21%), skin (15.4%), and liver (15.4%). Disease progression was observed most notably in mouth (10%), skin (8%), and eyes and joints (5% each).

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Abatacept for Steroid-Refractory cGVHD: Safety

Mark A. Schroeder, MD:
The adverse event (AE) profile for abatacept in the phase II study was consistent with that of other therapeutics for cGVHD and included fatigue (grade 1, n = 1; grade 2, n = 4), neutropenia (grade 2, n = 5; grade 3, n = 2; grade 4, n = 2), and upper respiratory infections (grade 2, n = 3; grade 3, n = 1). Serious AEs possibly related to abatacept included lung infections (grade 3, n = 2; grade 4, n = 1); 1 patient death was reported in a patient with grade 4 hemolysis, respiratory failure, and hepatic failure associated with herpes simplex virus infection.

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Abatacept for Steroid-Refractory Chronic GVHD: Conclusions

Mark A. Schroeder, MD:
In the phase II study of abatacept in steroid refractory cGVHD the ORR was 49%, which was comprised solely of PRs. Of importance, the treatment was well tolerated and enabled some patients to taper steroids. Although there are numerous treatments available for the management of cGVHD, abatacept may be a worthwhile option to add to the treatment armamentarium.

Phase I/II Study of Anti‒CSF-1R Antibody Axatilimab in Heavily Pretreated Chronic Graft-vs-Host Disease

Mark A. Schroeder, MD:
Axatilimab is an antibody that blocks the CSF-1 receptor expressed on macrophages and inactivates subsequent signaling through the RAS and PI3K pathways (NCT03604692).12 In preclinical models, macrophages have been shown to play a critical role in the fibrotic cascade that occurs in cGVHD.13 Targeting of the CSF-1 receptor pathway in macrophages for the management of cGVHD is a novel concept because most other therapies target T-cells or B-cells. At ASH 2021, Lee and colleagues14 presented the results of a phase I/II study investigating axatilimab for patients with cGVHD after at least 2 previous systemic therapies.

Patients with active cGVHD received escalation doses of axatilimab (0.15 mg/kg, 0.5 mg/kg, 1.0 mg/kg, and 3.0 mg/kg) as 30-minute infusion every 2 weeks (doses 0.15 mg/kg to mg/kg) or every 4 weeks in a subset of patients receiving the 3.0 mg/kg dose. The selected phase II dose that was accepted for expansion was 1.0 mg/kg. The primary endpoint for the phase II was ORR by 2014 NIH criteria for cGVHD.15

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Axatilimab in cGVHD: Baseline Characteristics

Mark A. Schroeder, MD:
Patients enrolled in this study were heavily pretreated with a median of 4 previous therapies (range: 1-11) overall; 65% of patients had received myeloablative transplantation and most patients had ≥4 organs involved (65%). Most patients in this study previously had received treatment with ibrutinib (65%), approximately half had previous ruxolitinib, and 20% previously had been treated with belumosudil.

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Axatilimab in cGVHD: Response

Mark A. Schroeder, MD:
The ORR was 72% at the 1.0 mg/kg dose (n = 25) and 50% at the 3 mg/kg dose (n = 6). The median time to response was nearly one month. Finally, the median time on treatment was 6.7 months (range: 0.9-26.7) at the 1.0 mg/kg dose and 7.7 months (range: 2.8-17.5) at the 3.0 mg/kg dose, respectively.

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Axatilimab in cGVHD: Response by Organ System

Mark A. Schroeder, MD:
Responses were seen across all organs involved with a 100% response rate seen in the lower and upper gastrointestinal track (n = 4, each), 53% in mouth (n = 17), and 50% in esophagus (n = 6).

Of the 32 patients at the 1.0 mg/kg dose or the 3.0 mg/kg dose, many experienced responses in difficult-to-treat organs, including the lungs (33%, n = 15), skin (11%, n = 28), and joints and fascia (66%, n = 24).

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Axatilimab in cGVHD: Treatment-Emergent AEs

Mark A. Schroeder, MD:
In general, axatilimab was well tolerated. Investigators reported elevation in transaminases enzymes (AST, ALT, lipase, and amylase), which were mostly of grade 1/2 and were believed to be secondary to axatilimab binding to Kupffer cells in the liver. In addition, there was no evidence of end organ damage and no evidence of myositis or pancreatitis—despite some reports of elevations in amylase and lipase. Finally, there was no signal for increased grade 3/4 AEs or increased risk of infections in this setting.

Overall, 4 patients discontinued axatilimab treatment due to AEs (creatine phosphokinase elevation; periorbital edema; hypersensitivity; and fall).

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Axatilimab in cGVHD: Axatilimab in cGVHD: Infection Rates

Mark A. Schroeder, MD:
Upper respiratory tract infections (18%) were the most common types of infections with axatilimab, as would be expected with this patient population. Other infections reported for the overall population included cellulitis (10%), pneumonia (5%), pseudomonas infection (5%), urinary tract infections (5%), and COVID-19 infection (3%). Reactivation of cytomegalovirus or Epstein-Barr virus were not noted in the study.

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Axatilimab in cGVHD: Lee Symptom Scale

Mark A. Schroeder, MD:
Most of patients had a clinically meaningful improvement in symptoms as measured by the Lee symptom score (LSS). The median change in LSS was -7.8 points (range: 3.1-37.6); 16 (53%) LSS-evaluable patients achieved a 7.0-point reduction from baseline. Finally, improvement in LSS was seen irrespective of response by NIH consensus criteria.

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Axatilimab in cGVHD: Conclusions

Mark A. Schroeder, MD:
The results of the phase II study of axatilimab presented at ASH 2021 are encouraging and suggest that this drug may fill a void for the effective treatment of cGVHD in patients who have failed several prior therapies, including ruxolitinib, ibrutinib, or belumosudil. Furthermore, it is encouraging that responses were seen in otherwise difficult-to-treat organs of cGVHD, namely the lungs and the skin. Finally, axatilimab is being advanced to phase II study in a larger cohort of patients where 3 doses of axatilimab (0.3 mg/kg, 1.0 mg/kg, and 3.0 mg/kg Q2W) will be studied (NCT04710576).

Pratta and colleagues reported data from 2 prospective trials evaluating longitudinal plasma samples in patients with acute GVHD (aGVHD) to investigate biomarkers predictive of survival identified in the UMN study cohort and validated in REACH1 study cohort. According to that report, high levels of which biomarker(s) was significantly associated with rapid fatal outcome in both cohorts and could potentially be assessed in patients being treated with ruxolitinib?
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