A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and Exposition • December 5-8, 2020
Ruxolitinib vs Best Available Therapy in Patients With Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease: Primary Findings From the Phase 3, Randomized REACH3 Study
Chronic graft-vs-host disease (GVHD) occurs in approximately 30% to 70% of patients undergoing allogeneic stem cell transplant and is a leading cause of nonrelapse mortality and morbidity.1-3 The standard first-line therapy consists of systemic corticosteroids; however, 50% of patients become refractory to corticosteroids or dependent on their use.4,5 Presently, there is no standard second-line treatment and no large, randomized clinical studies have been successfully completed in this setting.
Zeiser and colleagues investigated the efficacy of ruxolitinib vs best available therapy among patients with corticosteroid-refractory chronic GVHD in the randomized, phase 3 REACH3 trial.6 Eligible patients were ages 12 years and older, had moderate or severe corticosteroid-refractory chronic GVHD, and had evidence of myeloid and platelet engraftment.
Patients were randomly assigned to receive either ruxolitinib 10 mg twice daily (n=165) or investigator’s choice of best available therapy (n=164).6 Patients receiving corticosteroids were permitted to continue this treatment alone or in combination with a calcineurin inhibitor. At week 24, patients in the best available therapy group were permitted to cross over to ruxolitinib if they progressed, had a mixed or unchanged response, developed toxicity to treatment, or experienced a chronic GVHD flare. The primary endpoint was overall response rate (ORR) assessed at week 24 using the National Institutes of Health (NIH) consensus criteria for response.7 Key secondary endpoints were failure-free survival and modified Lee Symptom Scale response at week 24.
Overall, the patients’ baseline characteristics were well matched with respect to age, sex, prior GVHD severity, corticosteroid-refractory criteria, stem cell source, donor type, and cytomegalovirus (CMV) status.6 As of data cutoff in May 2020, treatment was ongoing for 83 patients (50%) in the ruxolitinib group and 42 patients (26%) in the control group. Adverse events (17% vs 5%) and lack of efficacy (15% vs 43%) were the main reasons for treatment discontinuation. At week 24, 61 patients (37%) crossed over from treatment with best available therapy to ruxolitinib.
Zeiser and colleagues presented the primary analysis of REACH3. The study met its primary endpoint of ORR at week 24.6 Among patients treated with ruxolitinib, the ORR was 49.7%, which included a complete response rate of 6.7% (Figure 1). Among patients treated with best available therapy, the ORR was 25.6%, including a complete response rate of 3.0% (P<.0001 vs ruxolitinib).
Failure-free survival (defined as time to recurrence of the underlying disease, start of new systemic treatment for chronic GVHD, or death [whichever was earliest]) had not been reached with ruxolitinib compared with 5.7 months with best available therapy (P<.0001; Figure 2).6 Ruxolitinib reduced the risk of progression by 63%, with a clear separation of the failure-free survival curves noticeable within 2 months of initiating treatment. In addition, patients who received ruxolitinib through to week 24 experienced a greater improvement in symptoms, as demonstrated by the proportion of patients with a response at week 24 according to the modified Lee Symptom Scale (24% vs 11%; P=.0011).6
The best ORR was 76.4% with ruxolitinib compared with 60.4% with best available therapy.6 The median duration of best overall response, which represents maintenance of response, was not reached in the ruxolitinib arm vs 6.2 months in the best available therapy arm. The median duration of treatment was 41.3 weeks (range, 0.7-127.3) with ruxolitinib and 24.1 weeks (range, 0.6-108.4) with best available therapy.
Among patients treated with ruxolitinib, 57% developed a grade 3 or higher adverse event and 33% had a serious adverse event. These rates were 58% and 37%, respectively, among patients treated with best available therapy.6 The most common adverse events in the ruxolitinib arm were cytopenias, with grade 3 or higher anemia occurring in 13% vs 8%, thrombocytopenia in 15% vs 10%, and neutropenia in 9% vs 4%. Patients in the ruxolitinib arm had more adverse events leading to dose modifications (38% vs 16%) and treatment discontinuation (16% vs 7%).6 There was no significant difference in the occurrence of death between the treatment arms (19% vs 17%).
The most common type of infection was viral, which occurred in 34% of the ruxolitinib arm vs 29% of the best available therapy arm.6 There was no significant difference with respect to CMV infection or reactivation between ruxolitinib and best available therapy (6% vs 8%). Bacterial infections also occurred at a similar frequency (28% vs 26%), although there was a trend toward more fungal infections with ruxolitinib (12% vs 6%).
The investigators concluded that REACH3 is the first successful randomized phase 3 trial in adolescent and adult patients with chronic GVHD with an inadequate response to corticosteroids. Compared with best available therapy at week 24, ruxolitinib demonstrated a significantly higher ORR, significant improvement in failure-free survival, greater symptom score improvement, and a higher best ORR. The safety profile of ruxolitinib was consistent with previous observations, with anemia and thrombocytopenia being the most common adverse events. REACH3 is ongoing and will continue for a total of 3 years.
References
1. Arora M, Cutler CS, Jagasia MH, et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):449-455.
2. Lee SJ, Zahrieh D, Alyea EP, et al. Comparison of T-cell-depleted and non-T-cell-depleted unrelated donor transplantation for hematologic diseases: clinical outcomes, quality of life, and costs. Blood. 2002;100(8):2697-2702.
3. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579.
4. Axt L, Naumann A, Toennies J, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019;54(11):1805-1814.
5. Jaglowski SM, Devine SM. Graft-versus-host disease: why have we not made more progress? Curr Opin Hematol. 2014;21(2):141-147.
6. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study [ASH abstract 77]. Blood. 2020;136(suppl 1).
7. Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21(6):984-999.
Follow-Up Analysis of KD025-213 (the ROCKstar study): A Phase 2, Randomized, Multicenter Study to Evaluate the Efficacy and Safety of KD025 in Patients With cGVHD
The serine-threonine kinase rho-associated kinase 2 (ROCK2) is 1 of 2 known isoforms of ROCK and plays a key role in immune diseases. ROCK2 inhibition rebalances the immune system by downregulating proinflammatory TH17 and increasing the generation of anti-inflammatory regulatory T cells.1 In addition, ROCK plays a critical role in the final common final pathway of fibrosis, regulating multiple profibrotic processes, including myofibroblast activation.2
Belumosudil (KD025) is a novel orally available small-molecule inhibitor of ROCK2 that targets both the immune and fibrotic pathophysiology of chronic GVHD.3 In a phase 2a study, treatment with belumosudil resulted in an ORR of 59% in patients with chronic GVHD who had received between 1 and 3 prior lines of systemic therapy.4 Belumosudil has since been granted breakthrough designation by the US Food and Drug Administration for patients with chronic GVHD who have been treated with at least 2 prior lines of therapy. This drug is undergoing investigation in the ROCKstar study (NCT03640481), a randomized, multicenter, open-label phase 2 trial.5
Cutler and colleagues presented a follow-up analysis of ROCKstar that enrolled patients ages 12 years and older who had received 2 to 5 lines of prior systemic therapy for active, chronic GVHD.5 Patients were randomly assigned to belumosudil at 200 mg administered once daily (n=66) or twice daily (n=66). Treatment continued until the patient developed clinically significant progression or unacceptable toxicity. Corticosteroid doses could be reduced after 2 weeks of belumosudil therapy at the discretion of the treating physician. The primary endpoint was ORR (assessed with the NIH chronic GVHD consensus criteria for response).
The ROCKstar trial fully enrolled patients in less than 10 months across 28 US sites. The baseline patient characteristics were evenly distributed among the 2 randomization cohorts. The median time from chronic GVHD diagnosis to enrollment was 28 months. Two-thirds of patients had severe chronic GVHD. Half of the patients had chronic GVHD that involved at least 4 organs.
Twelve months after the final patient enrolled in the study, treatment was ongoing in 49 patients, with a median treatment duration of 9.4 months in the daily treatment group and 11.8 months in the twice-daily treatment group.5 The treatment was discontinued by 43 patients in the daily group and 40 patients in the twice-daily group. Chronic GVHD progression and adverse events were the most common reasons for discontinuation of therapy.
The ROCKstar study met its primary endpoint, showing that belumosudil achieved clinically meaningful and statistically significant ORRs in both arms at the follow-up analysis.5 The ORR was 73% (95% CI, 60%-83%; P<.0001) in the once-daily group and 77% (95% CI, 65%-87%; P<.0001) in the twice-daily group. (This difference was considered statistically significant because the lower bound of the 95% CI exceeded 30%.) Seven patients achieved a complete response in all affected organs.
The responses occurred rapidly, with a median time to response of 4 weeks (the first assessment time point).5 The median duration of response was 50 weeks, and 60% of patients maintained responses for at least 20 weeks (Figure 3). Responses were also observed across all key subgroups, including those based on chronic GVHD severity, number of prior lines of systemic therapy, and number of organs involved at baseline. Organ-specific analyses demonstrated that patients receiving twice-daily belumosudil had slightly higher response rates for skin, eye, mouth, liver, and lower gastrointestinal (GI) disease than patients who received once-daily belumosudil. The response rates were also superior in patients with a shorter duration of chronic GVHD prior to study enrollment.
The data for both dosing arms were combined to provide a 1-year failure-free survival of 58% and a 2-year overall survival of 89%.5 The dose of corticosteroids was reduced for 64% of the patients, while 21% discontinued corticosteroid therapy. Similarly, the dose of calcineurin inhibitors was reduced for 45% of patients, and 22% discontinued therapy. There were clinically meaningful improvements in quality of life (defined as a 7-point reduction in the modified Lee Symptom Scale score), even among those patients considered to be nonresponders according to NIH criteria.
Overall, the safety profile of belumosudil was consistent with that expected in patients with chronic GVHD, with no noticeable differences between the 2 dosing regimens.5 The adverse events observed in the ROCKstar trial were similar to those reported in the initial belumosudil dose-escalation studies. The most common grade 3 or higher adverse events were pneumonia (8%), hypertension (6%), and hyperglycemia (5%). There were 8 deaths during the study (4 in each treatment arm), which were mostly related to infection and respiratory compromise.
The study investigators concluded that once- or twice-daily dosing of belumosudil at 200 mg was well tolerated and led to clinically meaningful outcomes and a high response rate (>70%) in patients with chronic GVHD. Responses were observed across key subgroups and organs with fibrotic disease. Pharmacokinetic and pharmacodynamic data are anticipated in 2021, and a pediatric cohort study is planned.
References
1. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014;111(47):16814-16819.
2. Riches DWH, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912.
3. Flynn R, Paz K, Du J, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154.
4. Jagasia M, Salhotra A, Bachier CR, et al. KD025-208: a phase 2a study of KD025 for patients with chronic graft versus host disease (cGVHD)—pharmacodynamics and updated results [ASH abstract 602]. Blood. 2018;132(suppl 1).
5. Cutler C, Lee SJ, DeFilipp Z, et al. Follow-up analysis of KD025-213 (the ROCKstar study): a phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in patients with cGVHD [ASH abstract 353]. Blood. 2020;136(suppl 1).
Biomarker and Safety Analyses of Patients With Steroid-Refractory Acute Graft-Vs-Host Disease Treated With Ruxolitinib or Best Available Therapy in the Randomized, Phase 3 REACH2 Study
Acute GVHD is driven by proinflammatory cytokines and chemokines. Inhibition of the Janus kinase (JAK) pathway by ruxolitinib may modulate such cytokines and prognostic markers of GVHD.1,2 In the phase 3 randomized REACH2 trial, once-daily ruxolitinib at a dose of 10 mg demonstrated superior efficacy over best available therapy in patients with corticosteroid-refractory acute GVHD. The ORR at day 28 was 62% with ruxolitinib vs 39% with best available therapy (P<.001), and the durable ORR at day 56 was 40% vs 22%, respectively (P<.001).3
In this first biomarker study conducted as part of a phase 3 randomized trial in acute GVHD, Socié and colleagues assessed whether baseline levels of proinflammatory cytokines and GVHD markers were prognostic for response and evaluated how these markers change throughout the treatment course.4 The investigators analyzed several proinflammatory cytokines (interleukin 6 [IL-6], IL-8, tumor necrosis factor alpha [TNF-α]), soluble receptors of cytokines (suppression of tumorigenicity [ST2], IL-2 receptor alpha, and TNF receptor superfamily member 1A [TNFRSF1A]), and tissue-specific markers for GI, liver, and skin GVHD (regenerating family member 3 alpha [REG3A] and hepatocyte growth factor [HGF]). More than 95% of randomized patients (295/309) in the REACH2 study were included in this biomarker analysis.
Higher median baseline levels of the assessed proinflammatory cytokines, soluble cytokines, and tissue-specific GVHD markers were observed among patients exhibiting no response compared with patients who had a complete response (Figure 4).4 Higher biomarker levels at baseline were associated with a lower probability of response after adjusting for treatment. Patients with skin involvement at baseline had a higher probability of response, regardless of baseline biomarker levels. The presence of liver involvement and elevated IL-6, TNF-α, TNFRSF1A, REG3A, or HGF at baseline were associated with a lower probability of response. In contrast, GI involvement did not have a significant impact on biomarkers, which the investigators suggested is an area of interest for further research.
Von Bubnoff and colleagues reported additional safety data from the REACH2 study up to day 28.5 A total of 302 patients—152 in the ruxolitinib arm and 150 in the best available therapy arm—received at least 1 dose of study drug and were included in the safety analysis. The rates of adverse events (96% in the ruxolitinib arm vs 95% in the control arm) and serious adverse events (38% vs 34%) were similar between treatment arms. Adverse events leading to treatment discontinuation included anemia (2% in the ruxolitinib arm vs <1% in the control arm), thrombocytopenia (2% vs 0%), and pancytopenia (1% vs 0%). There were 15 deaths in the ruxolitinib arm (10%) and 17 deaths in the control arm (14%). The most common cause of death was acute GVHD. On-treatment deaths from acute GVHD were reported in 6% of the ruxolitinib arm vs 11% of the control arm.
The most frequent adverse events of any grade in the ruxolitinib arm were thrombocytopenia (50% vs 33%), anemia (30% vs 28%), and CMV infection/reactivation (26% vs 21%).5 Rates of adverse events of grade 3 or higher (78% vs 79%) and serious adverse events (38% vs 34%) were similar between ruxolitinib and the best available therapy. The most commonly reported serious adverse events were sepsis, CMV infection/reactivation, respiratory failure, and septic shock.
Rates of infections are shown in Figure 5. The most common infections were CMV infection/reactivation (23% vs 17%), sepsis/septic shock (5% vs 5%), and oral candidiasis (1% vs 3%).5 However, the difference in infection rates between the treatment arms was not considered significant. The median time to the first infection was 2.1 weeks with ruxolitinib vs 1.9 weeks with the best available treatment.
Up to day 28, the risk of developing an adverse event of special interest was similar between the treatment arms, with the exception of thrombocytopenia, which was higher with ruxolitinib.5 The risk of infection (CMV infection and sepsis/septic shock) was similar between the treatment arms. The investigators concluded that no new or unexpected safety issues were observed with ruxolitinib.
References
1. Zeiser R, Blazar BR. Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167-2179.
2. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12(6):443-458.
3. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810.
4. Socié G, Niederwieser D, Von Bubnoff N, et al. Biomarker analysis in patients (pts) with steroid-refractory acute graft-vs-host disease (aGVHD) treated with ruxolitinib (RUX) or best available therapy (BAT) in the randomized, phase 3 REACH2 study [ASH abstract 1519]. Blood. 2020;136(suppl 1).
5. von Bubnoff N, Butler JP, Wagner EM, et al. Safety analysis of ruxolitinib (RUX) vs best available therapy (BAT) in patients (pts) with steroid-refractory (SR) acute graft-vs-host disease (aGVHD) in the randomized phase 3 REACH2 study [ASH abstract 2440]. Blood. 2020;136(suppl 1).
Efficacy and Safety of Baricitinib in Refractory Chronic Graft-Versus-Host Disease: Preliminary Analysis Results of a Phase 1/2 Study
Baricitinib is an oral inhibitor of JAK1/2 that has shown therapeutic promise in preclinical models of GVHD.1 A single-arm, intrapatient dose-escalating phase 1/2 trial investigated the use of baricitinib in patients with severe, refractory chronic GVHD. The doses of baricitinib (1 mg, 2 mg, and 4 mg daily) were extrapolated from studies in patients with rheumatoid arthritis.
The trial enrolled 20 patients, who received baricitinib at 2 mg daily for 12 weeks. Patients with a dose-limiting toxicity switched to 1 mg daily for 24 weeks. Among patients with no dose-limiting toxicities, the dose remained at 2 mg daily (complete responders) or was escalated to 4 mg daily (partial responders and patients with stable disease or progressive disease) for a further 12 weeks. Patients receiving 4 mg daily who reported dose-limiting toxicities were required to switch to 2 mg daily until the 6-month primary endpoint. Patients who tolerated baricitinib and did not have disease progression were permitted to remain on therapy for a further 6 months.
The patients’ median age was 54 years.1 The median delay from chronic GVHD diagnosis to study enrollment was 3 years. Chronic GVHD involved a median of 4 organs (range, 2-6). The condition affected at least 3 organs in 75% of patients. Most of the patients (90%) had sclerotic skin involvement. At the time of study enrollment, 17 patients (85%) were receiving concurrent immunosuppressive therapy, with corticosteroids (n=12) and calcineurin inhibitors (n=5) being the most common treatments.
According to the pharmacokinetic analyses, the typical time to peak concentration of baricitinib was 2 hours, and the half-life of the drug was 6 to 7 hours.1 No significant exposure-response relationship was observed in this small study. No dose-limiting toxicities were reported, and 16 patients reached the 4-mg daily baricitinib dose.
The primary efficacy endpoint, ORR at 6 months as defined by the 2014 NIH chronic GVHD response criteria, was 65% (95% CI, 50%-85%).1 The best ORR at any time was 90%, and the median time to best response was 1.4 months (range, 1.4-6.3). Nine patients had reached the 12-month assessment, and 8 of these 9 patients had durable responses. Only 3 of the 9 patients progressed, at a median of 7.3 months (range, 6.9-11.9) following study drug discontinuation, with the remainder experiencing stable disease.
The highest rates of organ-specific response were observed in the lower GI tract (100%), joints/fascia (85%), and mouth (50%), whereas the lowest response rates were observed in the lungs (10%) and skin (0%).1 The investigators suggested that the lack of response for skin involvement was due to the fact that scleroderma is particularly challenging to resolve.
Treatment with baricitinib permitted 50% of study participants to taper their daily corticosteroid dose, by a median of 4 mg.1 Furthermore, treatment with baricitinib led to clinically meaningful improvement in patient-reported outcomes as measured by the Lee Symptom Scale in 7 of 14 patients evaluable at 6 months.
Holtzman and colleagues also reported treatment outcomes following long-term follow-up.1 The median failure-free survival was 20.6 months (range, 19 months to not reached; Figure 6). One-year and 2-year failure-free survival were 74% and 37%, respectively. Two out of 20 patients (10%) experienced relapsed malignancy, at a median of 5.2 months after discontinuing the study drug.
Adverse events possibly related to treatment were reported in 85% of patients. The most common of these events were upper respiratory infection, hypophosphatemia, hypokalemia, neutropenia, and pneumonia. Six patients experienced grade 3 or higher adverse events that were possibly treatment-related. Eleven serious adverse events were reported in 6 patients. Five of these events were possibly drug-related, including hospitalizations for joint infection (n=1), cellulitis (n=2), and viral upper respiratory infection (n=2). Dose interruption was required in 11 patients owing to adverse events, and dose reduction was required in 3 patients owing to neutropenia (n=2) and myalgia (n=1). Nine patients discontinued treatment owing to toxicity (n=3), progressive disease (n=3), and other unrelated causes (n=3). The median time to study discontinuation was 5.6 months (range, 0.8-10.7). There were no relapses of malignancy or deaths during the study.
Given the interest in infectious complications in heavily immunocompromised GVHD populations, the investigators noted that cases of grade 1 viral reactivation of CMV (n=6), Epstein–Barr virus (EBV; n=7), and BK virus (n=5) were detected in the urine of patients.1 All cases were asymptomatic and self-limiting, and did not require therapy. There were 13 viral upper respiratory infections, mostly observed during the winter months. Several bacterial infections were observed, but there were no mycobacterial or fungal infections. Only 40% of patients received concurrent prophylaxis for fungal infections.
Reference
1. Holtzman NG, Im A, Ostojic A. Efficacy and safety of baricitinib in refractory chronic graft-versus-host disease (cGVHD): preliminary analysis results of a phase 1/2 study [ASH abstract 357]. Blood. 2020;136(suppl 1).
Phase 1 Study of Axatilimab (SNDX-6352), a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease After 2 or More Lines of Systemic Treatment
Ibrutinib is the only approved second-line treatment for patients with chronic GVHD and disease progression or an inadequate response during treatment with corticosteroids.1 Morbidity and mortality are high among patients who require second or subsequent lines of therapy. Therefore, there is an urgent need to develop novel agents to treat chronic GVHD.
Axatilimab is an immunoglobulin G4 monoclonal antibody directed against the colony-stimulating factor 1 (CSF-1) receptor. Inhibition of the anti–CSF-1 receptor is thought to deplete circulating nonclassical monocytes and tissue macrophage infiltration, and to reduce GVHD-associated tissue pathology.2 Axatilimab is currently being investigated in a phase 1/2 dose escalation/expansion clinical study in patients ages 6 years and older who have active, chronic GVHD.1 Additional inclusion criteria include a Karnofsky Performance Scale score of 60 or higher and prior treatment with at least 2 lines of therapy for chronic GVHD.
Fifteen patients were enrolled in the phase 1 dose escalation part. They received sequential treatment with intravenous (IV) axatilimab escalating from 0.15 mg/kg every 2 weeks to 3.0 mg/kg every 2 or 4 weeks.1 The objective of the phase 1 study was to determine the maximum tolerated dose and to assess the pharmacokinetic and pharmacodynamic properties of axatilimab. The phase 2 dose-expansion part will enroll up to 22 patients and assess the efficacy (ORR) of axatilimab dosed at 1 mg/kg every 2 weeks.
Arora and colleagues presented the findings of the phase 1 dose-escalation study.1 The median age at transplant was 60 years, with 47% of patients undergoing transplant with myeloablative conditioning and 60% receiving a transplant from a related donor. The median time from transplant to the development of chronic GVHD was 6.8 months, and the median delay to the first cycle of chronic GVHD treatment was 42 months. Half of the enrolled patients had chronic GVHD that affected at least 4 organs. Patients had received a median of 4 prior treatments, including ibrutinib (73%), ruxolitinib (60%), and belumosudil (33%).
Responses to axatilimab were observed across several organ systems (Figure 7), at all dose levels, and after prior treatment with ibrutinib, ruxolitinib, and belumosudil.1 Complete responses were seen in patients with mouth (5/9), esophageal (1/1), and lower GI involvement (1/1). Four out of 12 patients with eye involvement had a response, of which 50% were complete responses. Partial responses were seen in patients with involvement of the joints and fascia (6/11), lungs (2/5), and skin (4/10). In 1 patient with sclerodermatous chronic GVHD that was unresponsive to prior therapies, axatilimab dosed at 1 mg/kg every 2 weeks led to significant improvements within 2 months of treatment. In another patient, axatilimab dosed at 3 mg/kg every 2 weeks led to significant improvement in lower leg ulceration.
Axatilimab provided early symptom control in heavily pretreated patients with chronic GVHD (Figure 8). An ORR was reported in 57% of patients, and 36% achieved stable disease.1 The median time to response was 1.9 months (range, 1-11). Axatilimab also provided clinically meaningful improvements in quality of life, as shown by the median 9-point reduction in normalized the Lee Symptom Scale score across all patients. Sixty-seven percent achieved at least a 7-point reduction from baseline. One patient in the 3 mg/kg every 4 week cohort experienced an increase in the Lee Symptom Scale score and discontinued treatment after 3 cycles.
All of the patients experienced a treatment-emergent adverse event related to axatilimab therapy.1 Nine events of infection with pneumonia, conjunctivitis, gastroenteritis norovirus, influenza, lower respiratory tract infection, pseudomonas infection, and upper respiratory infection were reported in 6 patients, with 2 patients experiencing multiple events. No cases of CMV reactivation were reported.
Grade 3/4 treatment-emergent adverse events occurred in approximately 50% of patients, and primarily consisted of laboratory abnormalities (creatine kinase in 3 patients; increased aspartate aminotransferase in 2 patients) and pneumonia (in 2 patients). Among the 8 patients who discontinued treatment, 2 did so owing to disease progression (in the ≤1 mg/kg every 2 weeks dosing groups) and 1 owing to adverse events (in the 3 mg/kg every 2 weeks group).
According to pharmacokinetic and pharmacodynamic analyses, axatilimab follows a dose-dependent nonlinear elimination typical for a monoclonal antibody with target mediated drug disposition.1 Axatilimab is highly effective at selectively reducing levels of circulating monocytes, with an approximate 95% reduction in profibrotic nonclassical monocytes and a 60% to 75% reduction in proinflammatory intermediate monocytes.
The investigators summarized that axatilimab demonstrated good tolerability and safety with clinical activity, as evidenced by a 57% response rate in a heavily pretreated patient population. Ongoing development of axatilimab will include a multicenter, randomized phase 2 study (AGAVE-201) that will evaluate the efficacy, safety, and tolerability of 3 doses of axatilimab in patients with recurrent or refractory chronic GVHD who have received at least 2 prior systemic therapies.3
References
1. Arora M, Jagasia M, Di Stasi A, et al. Phase 1 study of axatilimab (SNDX-6352), a CSF-1R humanized antibody, for chronic graft-versus-host disease after 2 or more lines of systemic treatment [ASH abstract 358]. Blood. 2020;136(suppl.1).
2. Alexander KA, Flynn R, Lineberg KE, et al. CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014;124:4266-4280.
3. ClinicalTrials.gov. A study of axatilimab at 3 different doses in patients with chronic graft versus host disease (cGVHD) (AGAVE-201). https://www.clinicaltrials.gov/ct2/show/NCT04710576. Identifier: NCT04710576. Accessed February 2, 2021.
A Single-Arm, Open-Label Phase 1 Study of Itacitinib With Calcineurin Inhibitor–Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GRAVITAS-119)
JAK 1 and 2, which transduce signals from multiple cytokine receptors, have been implicated in the pathogenesis of GVHD.1 Itacitinib is a potent, selective JAK1 inhibitor that has been administered to patients with acute GVHD in combination with corticosteroids as initial treatment.2,3
Choe and colleagues presented the findings of the GRAVITAS-119 single-arm, open-label, nonrandomized phase 1 study.4 The objective of this proof-of-concept study was to evaluate itacitinib in combination with calcineurin inhibitor–based regimens for prophylactic treatment of GVHD. The trial enrolled adult patients with hematologic malignancies who were candidates for reduced-intensity conditioning and peripheral blood stem cell transplant. Patients received itacitinib at a dose of 200 mg daily 3 days prior to transplant, in combination with tacrolimus/methotrexate (MTX; n=41) or cyclosporine/mycophenolate mofetil (MMF; n=24) with or without antithymocyte globulin (ATG). Itacitinib was reduced to 100 mg daily by day 90 and discontinued by day 180, unless patients required systemic GVHD treatment, experienced a relapse of a malignancy, developed unacceptable toxicity, or withdrew consent.
The median exposure to itacitinib was 140 days (range, 10-187), and 74% of patients received itacitinib for longer than 90 days.4 More patients in the cyclosporine/MMF arm (50%) than in the tacrolimus/MTX arm (27%) completed the 180-day trial protocol. Adverse events (17% vs 24%) and malignancy relapse (13% vs 20%) were the most common reasons for treatment discontinuation.
The patients’ median age was 65 years.4 Acute myeloid leukemia was the most common underlying hematologic malignancy, and most patients had an intermediate disease risk index at study entry. The investigators compared the baseline characteristics of patients who did not receive ATG (n=41) with those who received ATG (n=24). In the group without ATG, donors were matched related in 61% and matched unrelated in 37%. In the group with ATG, 46% of patients underwent a matched unrelated transplant, while 33% underwent a matched related transplant. The most common conditioning regimen was reduced-intensity busulfan/fludarabine (63% in the group without ATG and 30% in the group with ATG).
All patients achieved hematologic recovery (defined as both neutrophil and platelet recovery).4 All patients but 1 (99%) achieved the primary endpoint of hematologic recovery at day 28 (Table 1). One patient who had secondary myelofibrosis achieved neutrophil recovery on day 31. Overall, the median times to neutrophil and platelet recovery were 17 and 14 days, respectively, with no significant difference between patients receiving tacrolimus/MTX or cyclosporine/MMF.
Two patients experienced secondary graft failure, 1 during treatment with tacrolimus/MTX/ATG on day 65 and a second during follow-up after treatment with tacrolimus/MTX (approximately 4 months after the last dose of itacitinib). Both patients received transplants from matched unrelated donors and busulfan/fludarabine as a conditioning regimen.
The cumulative incidence of acute GVHD at day 180 was low; grade 3/4 acute GVHD occurred in 5% of patients treated without ATG and in 4% of patients treated with ATG.4 These rates compare favorably with historical data for calcineurin inhibitor–based regimens.5,6 One-year overall survival rates higher than 70% were observed in GRAVITAS-119.4 The cumulative incidence of moderate or severe chronic GVHD was 31% without ATG vs 10% with ATG. Relapse or progression at 1 year was reported in 28% vs 4%, respectively. The investigators noted that these findings should be interpreted with caution based on the small sample size and possible confounding factors, which included concomitant use of rituximab for EBV infection (n=7).
Most patients (88%) experienced at least 1 adverse event of grade 3 or higher.4 The most common hematologic adverse events were thrombocytopenia (49%), anemia (29%), leukopenia (29%), neutropenia (29%), lymphopenia (26%), and febrile neutropenia (12%). The most common nonhematologic adverse events were diarrhea (15%), hypertension (14%), hypertriglyceridemia (12%), hyperglycemia (11%), and stomatitis (8%). Fifteen patients (23%) experienced hematologic adverse events that led to dose modification and/or discontinuation, with thrombocytopenia (9%) being the most common.
Up to one-third of patients reported an infection of grade 3 or higher, with viral infections the most common. There were 11 reports of CMV infection (any grade); all occurred in cases when the donor and/or recipient had a positive CMV serostatus. Ten of these cases were reported as CMV viremia, 9 of which required antiviral treatment. One patient who received cyclosporine/MMF/ATG had a resistant CMV infection, and died from acute respiratory distress. There were no cases of post-transplant lymphoproliferative disorder. However, there were 16 deaths during the study, the primary causes being infection during treatment (n=2), and malignancy relapse (n=5) or infection (n=3) during follow-up.
References
1. Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123(24):3832-3842.
2. Schroeder MA, Khoury HJ, Jagasia M, et al. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Adv. 2020;4(8):1656-1669.
3. Zeiser R, Socié G, Schroeder MA, et al. GRAVITAS-301: a randomized, double-blind phase 3 study of itacitinib or placebo in combination with corticosteroids for initial treatment of patients with acute graft-versus-host disease [EHA abstract S256]. Hemasphere. 2020;4(suppl).
4. Choe H, Shah NN, Chevallier P, et al. A single-arm, open-label phase 1 study of itacitinib (ITA) with calcineurin inhibitor (CNI)-based interventions for prophylaxis of graft-versus-host disease (GVHD; GRAVITAS-119) [ASH abstract 356]. Blood. 2020;136(suppl 1).
5. Bolaños-Meade J, Reshef R, Fraser R, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6:e132-e143
6. De Jong CN, Meijer E, Bakunina K, et al. Post-transplantation cyclophosphamide after allogeneic hematopoietic stem cell transplantation: results of the prospective randomized HOVON-96 trial in recipients of matched related and unrelated donors [ASH abstract 1]. Blood. 2019;134(suppl 1).
Comparison of Outcomes After Haploidentical Relative and HLA Matched Unrelated Donor Transplantation With Post-Transplant Cyclophosphamide Containing GVHD Prophylaxis Regimens
Results from the phase 2 BMT CTN 1203 trial suggested that a GVHD prophylaxis regimen based on post-transplant cyclophosphamide (PT-Cy) improved 1-year GVHD-free, relapse-free survival.1 It is unclear whether haploidentical donors are superior to matched unrelated donors when PT-Cy-containing GVHD prophylactic regimens are used. Gooptu and colleagues compared outcomes after haploidentical hematopoietic cell transplant and matched unrelated donor hematopoietic cell transplant among patients who received prophylaxis with PT-Cy.2 The study enrolled patients who underwent haploidentical cell transplant or matched unrelated donor hematopoietic cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The characteristics were well balanced between the patient groups. Age at transplant, sex, performance score, comorbidities, and CMV serostatus were similar. The study separately analyzed 1001 patients who received a myeloablative regimen and 1398 who received a reduced-intensity regimen. All patients who underwent haploidentical hematopoietic cell transplant and reduced intensity-conditioning matched unrelated donor hematopoietic cell transplant received PT-Cy, a calcineurin inhibitor, and MMF for GVHD prophylaxis. Among patients who underwent myeloablative conditioning and a matched unrelated donor hematopoietic cell transplant, 55% received PT-Cy, a calcineurin inhibitor, and MMF, while 45% received PT-Cy and a calcineurin inhibitor.
The study found that GVHD outcomes and overall survival were similar between haploidentical and matched unrelated donor transplant when PT-Cy was used in combination with a calcineurin inhibitor and MMF. The risk of grade 2 to 4 acute GVHD was lower among patients treated with the triplet regimen and haploidentical donor transplant compared with GVHD prophylaxis with PT-Cy plus a calcineurin inhibitor following a matched unrelated donor transplant. Among patients treated with less-intense conditioning regimens and GVHD prophylaxis with the triple combination regimen, nonrelapse mortality was 16% with haploidentical transplant vs 8% with matched unrelated donor transplant (P=.0008). The rate of disease-free survival was 55% in patients who underwent matched unrelated donor hematopoietic cell transplant vs 41% in those who underwent haploidentical hematopoietic cell transplant (P=.002). Overall survival was 67% vs 54%, respectively (P=.001; Figure 9).
The investigators concluded that among patients who received myeloablative conditioning and GVHD prophylaxis consisting of received PT-Cy, a calcineurin inhibitor, and MMF, the results were comparable between haploidentical related and matched unrelated transplants. In contrast, for patients who received less-intense conditioning regimens, disease-free survival and overall survival were higher after matched unrelated donor hematopoietic cell transplant compared with haploidentical hematopoietic cell transplant.
References
1. Bolaños-Meade J, Reshef R, Fraser R, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6(3):e132-e143.
2. Gooptu M, St. Martin A, Romee R, et al. Comparison of outcomes after haploidentical relative and HLA matched unrelated donor transplantation with post-transplant cyclophosphamide containing GVHD prophylaxis regimens [ASH abstract 76]. Blood. 2020;136(suppl 1).
Highlights in Chronic Graft-vs-Host Disease From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary
John F. DiPersio, MD, PhD
Virginia E. and Samuel J. Goldman Professor of Medicine
Chief, Division of Oncology
Director, Center for Gene and Cellular Immunotherapy
Deputy Director, Siteman Cancer Center
Washington University School of Medicine
St. Louis, Missouri
Presentations in graft-vs-host disease (GVHD) at the 62nd American Society of Hematology (ASH) meeting provided important information regarding treatments such as ruxolitinib, belumosudil, baricitinib, and axatilimab, as well as outcomes after haploidentical transplants vs unrelated donor transplants.
Ruxolitinib
Dr Robert Zeiser presented primary findings from the phase 3 REACH3 trial, which compared the Janus kinase inhibitor (JAK) ruxolitinib vs best available therapy in patients ages 12 years and older with corticosteroid-refractory or corticosteroid-dependent chronic GVHD.1 Several studies presented at the ASH meeting evaluated the role of various interventions for chronic GVHD. The REACH3 trial was the first and only randomized prospective study in this setting. It was an open-label trial. The trial randomly assigned patients with moderate or severe chronic GVHD to receive ruxolitinib at 10 mg orally twice a day (n=165) or best available therapy (n=164). Both treatment arms also included corticosteroids with or without a calcineurin inhibitor. The best-available therapy included many different kinds of treatments. The primary endpoint was efficacy (overall response rate [ORR]) at 24 weeks.
The difference was highly statistically significant in favor of ruxolitinib. The ORR at week 24 was 49.7% in the ruxolitinib arm vs 25.6% in the best available therapy arm (P<.0001). More important was an improvement in failure-free survival, which was not reached with ruxolitinib vs 5.7 months with best available therapy (P<.0001). The best ORR at 24 weeks was 76.4% with ruxolitinib vs 60.4% with best-available therapy.
The only notable complications in the ruxolitinib arm were thrombocytopenia and anemia; these events occurred more frequently with ruxolitinib than with best available therapy. Interestingly, there were no statistically significant differences in bacterial, viral, or fungal infections. This surprising finding suggests that the decrease in blood counts did not impact rates of infections.
The conclusion is that ruxolitinib is an effective therapy for patients with moderate or severe corticosteroid-refractory chronic GVHD. The superiority of ruxolitinib vs best-available therapy was highly statistically significant. The results of the REACH3 study provide hope that patients with progressive and severe corticosteroid-refractory chronic GVHD will benefit from ruxolitinib, which is a balanced JAK1/JAK2 inhibitor. The randomized design of this landmark study is important when interpreting the results and assessing their importance.
Belumosudil
Dr Cory Cutler presented preliminary results of the multi-institutional phase 2 ROCKstar study, which evaluated the ROCK inhibitor belumosudil.2 ROCK kinases are serine-threonine kinases that are important in immune inflammation and immune activation. They are activated by several different ligands and in multiple cell types. ROCK inhibitors downregulate specific downstream profibrotic mediators and profibrotic genes. Chronic GVHD is associated with fibrosis and scarring. The ROCKstar study is open-label. A downside is that the trial does not include a control group receiving a single therapy or best available therapy, but only randomly assigned patients to 2 different dosing schedules of the same drug, belumosudil (given once per day or twice per day). The trial enrolled patients with corticosteroid-refractory chronic GVHD who had received 2 to 5 lines of previous therapy for chronic GVHD. These treatments included ruxolitinib and ibrutinib, each reported in approximately one-third of patients. Half of the patients had been treated with more than 4 different therapies. The patient population could be considered a particularly high-risk group. The treatment arms consisted of belumosudil given at 2 different doses: 200 mg once a day or 200 mg twice a day. The trial is still ongoing.
There are several limitations to this study. With 66 patients in each arm, it is relatively small, although reasonably sized for a study of chronic GVHD. The study also lacked a control arm comparing belumosudil with best available therapy.
At 12 months of follow-up, the ORRs were 73% in the once-daily arm and 77% in the twice-daily arm. Response rates were similar for patients who were or were not refractory to their previous lines of systemic therapy (73% vs 74%, respectively). The response was relatively similar among patients with a longer or shorter duration of chronic GVHD before enrollment (68% vs 82%, respectively). The duration of response was approximately 36 weeks, and the median duration of response was 50 weeks. At 24 months, the overall survival was 89%.
Symptoms improved, as measured by Lee Symptoms Scores, in approximately one-third of patients, which is difficult to document in studies of chronic GVHD. It was possible to reduce the calcineurin dose in a quarter of the patients, and two-thirds of patients were able to reduce their dose of corticosteroids. The drug was relatively well tolerated at both doses. The most common side effects were fatigue, diarrhea, and nausea, which are also commonly seen in patients with chronic GVHD who are not receiving treatment.
The rates of response and overall survival are impressive, particularly in this group of heavily pretreated patients. The duration of response was similar to that seen in the REACH3 trial of ruxolitinib,1 although comparisons cannot be drawn because the patient populations in the studies were different. The REACH3 trial had a better design because it included a control arm.
Baricitinib
The National Institutes of Health conducted a small phase 1/2 study evaluating baricitinib in patients with refractory chronic GVHD.3 Baricitinib is structurally similar to ruxolitinib, with balanced JAK1/JAK2 inhibition and an almost identical IC50. Baricitinib is approved for the treatment of patients with rheumatoid arthritis. It is now being tested in patients with COVID-associated inflammatory disorders because it has a unique ability to inhibit one of the enzymes (AAK1) that is important for COVID-19 internalization and viral replication. This study treated 20 patients. The dose of the drug was escalated to 4 mg when possible.
The 6-month ORR was 65%.3 The rate of 1-year freedom from progression was 74%, which is similar to that seen with ruxolitinib in the REACH3 trial and belumosudil in the ROCKstar study.1,2 Several of the patients who responded had to discontinue treatment. Treatment was relatively safe, with few side effects. There was no evidence of viral reactivation or significant infections. There was some decrease in blood counts.
Axatilimab
Dr Mukta Arora presented results of a small, multi-institutional phase 1 study evaluating axatilimab, a CSF-1R monoclonal antibody.4 The CSF-1 receptor is the receptor for macrophage CSF. In mouse models, when the macrophages that express the CSF-1 receptor are genetically or pharmacologically eliminated early after transplant, the mice develop worse GVHD.5,6 When these macrophages are eliminated late after transplant, then GVHD is diminished. The macrophages that are present early after transplant are of host origin, and they suppress the immune response. Later after transplant, those macrophages are now of donor origin, and they become proinflammatory. The theory is that inhibiting these proinflammatory macrophages reduces GVHD. Because treatment of chronic GVHD occurs late after transplant, the thought is that the macrophages present provide a proinflammatory environment, and that inhibiting them through an antibody that targets the CSF-1 receptor—which is differentially overexpressed on macrophages—will reduce GVHD.
The trial enrolled only 15 patients. In the phase 1 portion, axatilimab is being administered in a dose-escalated manner in individual patient cohorts. A phase 2 expansion phase is evaluating axatilimab given at 1 mg/kg every 2 weeks. Up to 22 patients will be treated in the expansion phase. The primary endpoint is the ORR.
Treatment was well tolerated. There were no major infectious complications. The response rate was 57%. Patients with esophageal disease, lower gastrointestinal disease, and mouth disease had good responses. Responses were lower among patients with lung disease, skin disease, joint disease, and fascial disease. Half of the patients had received ibrutinib and ruxolitinib, and 3 had received the ROCK inhibitor belumosudil. Clinical responses were durable in some of the patients, although the follow-up was not long.
A notable aspect to this study is that treatment appeared to particularly benefit patients who had sclerodermatous disease with ulcers. These patients historically are difficult to treat.
Outcomes After Haploidentical Transplants vs Unrelated Donor Transplants
A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) compared outcomes after haploidentical transplants vs unrelated donor transplants using post-transplant cyclophosphamide (PT-CY) prophylaxis for GVHD.7 A conundrum in the transplant setting is how to select a donor for transplant now that haploidentical donors are an option. Most of the studies thus far have shown relatively similar outcomes for unrelated donor transplants and haploidentical stem cell transplants. The haploidentical transplants have been a mixture of bone marrow and stem cell infusions, which can lead to complicated interpretations. Most of the unrelated donor transplants consisted of peripheral blood stem cells. This study evaluated the impact of PT-CY on the outcomes of patients undergoing transplant from matched unrelated donors (MUDs).
In those patients (both MUD and haploidentical) receiving myeloablative conditioning, the relapse rates for these groups were relatively similar. The nonrelapse mortality between the groups was also relatively similar overall, consistent with smaller studies comparing outcomes of patients undergoing unrelated vs haploidentical transplant. The rates of acute and chronic GVHD were similar between the haploidentical group and the MUD groups. There were no real differences in rates of GVHD relapse, nonrelapse mortality, and overall survival. One difference was that in the myeloablative setting, the use of calcineurin inhibitors as GVHD prophylaxis with PT-CY for MUD transplants was associated with an increased risk for GVHD compared with the use of calcineurin inhibitors plus MMF. Patients undergoing a myeloablative transplant with a MUD should receive the triple combination of calcineurin inhibitors, MMF, and PT-CY. The outcomes associated with this myeloablative regimen are very similar among patients with an HLA-matched unrelated donor vs those undergoing a haploidentical transplant. When possible, myeloablative regimens are increasingly preferred because they are associated with a reduction in relapse compared with reduced-intensity regimens. Reduced-intensity regimens are associated with a higher rate of relapse. Therefore, in patients with high-risk acute leukemias, outcomes were similar in those undergoing a MUD vs a haploidentical transplant when the procedure includes a myeloablative regimen consisting of PT-CY, a calcineurin inhibitor, and MMF. When MMF was omitted, there was a higher rate of acute GVHD in the unrelated donor setting, so this approach is not recommended. This regimen was not tested in the haploidentical setting because all of these patients always receive the 3 drugs together.
For patients undergoing reduced-intensity transplant, a MUD is favored over a haploidentical transplant. Rates of disease-free and overall survival were higher after MUD HCT compared with haploidentical transplant. Compared with haploidentical HCT, acute and chronic GVHD risks did not differ between the treatment groups. However, nonrelapse mortality was lower after MUD-HCT, which led to higher disease-free and overall survival. There was also a slightly increased delay in neutrophil engraftment when haploidentical donors were compared with MUD transplants, which resulted in increased rates of fungal infections compared with matched unrelated donor transplants.
Conclusions
The studies evaluated drugs with different biologies: inhibition of JAK1/JAK2, inhibition of serine-threonine kinases called ROCK kinases, and inhibition of the CSF-1 receptor pathway. The best-designed study is the REACH3 trial of ruxolitinib because it was controlled, prospective, and randomized.1 It is difficult to assess chronic GVHD, so randomized studies are particularly important. One drawback to the studies in chronic GVHD of the ROCK inhibitor baricitinib and the CSF-1R inhibitor is that they were open-label and lacked a placebo or best available therapy arm as a comparator group. It is understandable that patients who are doing poorly would not want to receive a placebo. The reality, however, is that it is difficult to identify improvement because of inherent biases among patients, nurses, and physicians. Objective measures of response are not quantitative.
A challenging aspect of chronic GVHD is treatment of bronchiolitis obliterans and progressive pulmonary insufficiency. This debilitating toxicity does not appear to improve with any of these treatments. Even in studies of agents with response rates of 70%, improvement in pulmonary function was negligible. A small Chinese study evaluated ruxolitinib in patients with bronchiolitis obliterans, but the results were unconvincing.8
One approach to the treatment of lung toxicity would be to use JAK inhibitors as prophylaxis. Late intervention might prevent further progression or modestly mitigate toxicities. However, the events leading to chronic GVHD occur within the first few days of transplant, although it may take weeks, months, or even years before they are manifest. Therefore, management of chronic GVHD might benefit from earlier administration of all of these agents. Our group and others have published preclinical data supporting this strategy.9
Early interventions would also affect acute GVHD. The 2 treatments that are associated with the most significant reproducible reduction in chronic GVHD are thymoglobulin and post-transplant cyclophosphamide.10,11 These interventions are administered in the immediate post-transplant period, thereby blocking early events that might initially trigger both acute and chronic GVHD.
The studies reviewed here are evaluating interventions that are administered long after the disease has already been established. Thus, it may be difficult to reverse the pathology, and perhaps the best that can be expected is to halt the progression of chronic GVHD. One study presented at the ASH meeting, the phase 1 GRAVITAS-119 study, evaluated a prophylaxis regimen consisting of itacitinib, a JAK1-specific inhibitor, combined with calcineurin.12 Results were presented for 64 patients who received a prophylaxis regimen consisting of itacitinib with tacrolimus and methotrexate or with cyclosporine and MMF (per institutional practice). The data from this study are too early to draw firm conclusions. At 180 days, the rate of grade 2 to 4 acute GVHD was surprisingly low (14.3%) and the rate of grade 3 to 4 acute GVHD was also reduced (6.5%).
I anticipate that early intervention with various approaches will have the most significant impact on the outcome of patients undergoing allogeneic stem cell transplant. Prophylaxis can limit early expansion of alloreactive T cells and minimize damage. Less damage will lead to fewer cases of acute and chronic GVHD.
Disclosure
Dr DiPersio is a consultant and/or a member of advisory committees for RiverVest, Bioline, and Incyte. He has received research support from NeoImmuneTech, MacroGenics, Bioline, and Incyte. He is an employee of and receives a salary from Washington University. He has an ownership investment in Magenta and Wugen.
References
1. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study [ASH abstract 77]. Blood. 2020;136(suppl 1).
2. Cutler C, Lee SJ, DeFilipp Z, et al. Follow-up analysis of KD025-213 (the ROCKstar study): a phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in patients with cGVHD [ASH abstract 353]. Blood. 2020;136(suppl 1).
3. Holtzman NG, Im A, Ostojic A. Efficacy and safety of baricitinib in refractory chronic graft-versus-host disease (cGVHD): preliminary analysis results of a phase 1/2 study [ASH abstract 357]. Blood. 2020;136(suppl 1).
4. Arora M, Jagasia M, Di Stasi A, et al. Phase 1 study of axatilimab (SNDX-6352), a CSF-1R humanized antibody, for chronic graft-versus-host disease after 2 or more lines of systemic treatment [ASH abstract 358]. Blood. 2020;136(suppl 1).
5. Hashimoto D, Chow A, Greter M, et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J Exp Med. 2011;208(5):1069-1082.
6. Terakura S, Martin PJ, Shulman HM, Storer BE. Cutaneous macrophage infiltration in acute GvHD. Bone Marrow Transplant. 2015;50(8):1135-1137.
7. Gooptu M, St. Martin A, Romee R, et al. Comparison of outcomes after haploidentical relative and HLA matched unrelated donor transplantation with post-transplant cyclophosphamide containing GVHD prophylaxis regimens [ASH abstract 76]. Blood. 2020;136(suppl 1).
8. Huang H, Zhao Y, Ouyang G, et al. Salvage therapy with low-dose ruxolitinib led to a significant improvement in bronchiolitis obliterans syndrome in patients with cGvHD after allogeneic hematopoietic stem cell transplantation [ASH abstract 2394]. Blood. 2020;136(suppl 1).
9. Choi J, Cooper ML, Staser K, et al. Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia. 2018;32(11):2483-2494.
10. Kröger N, Solano C, Wolschke C, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374(1):43-53.
11. Prem S, Atenafu EG, Al-Shaibani Z, et al. Low rates of acute and chronic GVHD with ATG and PTCy in matched and mismatched unrelated donor peripheral blood stem cell transplants. Eur J Haematol. 2019;102(6):486-493.
12. Choe H, Shah NN, Chevallier P, et al. A single-arm, open-label phase 1 study of itacitinib (ITA) with calcineurin inhibitor (CNI)-based interventions for prophylaxis of graft-versus-host disease (GVHD; GRAVITAS-119) [ASH abstract 356]. Blood. 2020;136(suppl 1).