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Key Studies in Nonmalignant Hematology: Independent Conference Coverage of ASH 2020

Hanny Al-Samkari, MD
Mark A. Schroeder, MD
Sujit Sheth, MD
Released: February 11, 2021

New Approaches to Treating Graft-vs-Host Disease

GVHD: Where Are We Now?

Mark A. Schroeder, MD:
GVHD can be either acute or chronic. In the last year, significant progress has been made in the treatment of acute GVHD; specifically, ruxolitinib has now been approved by the FDA for the treatment of steroid‑refractory acute GVHD in adults and pediatric patients older than 12 years of age.[28]

By contrast, effective treatment of chronic GVHD remains a major problem—it occurs in up to 70% of patients after allogeneic stem cell transplantation.[29-31] The standard of care is corticosteroids and approximately 50% of patients who develop chronic GVHD will respond. There are no standard second‑line therapies (due to an absence of large, randomized trials). Ibrutinib is approved by the FDA for second-line treatment of steroid‑refractory chronic GVHD, based on a phase II study in patients with severe oral and skin chronic GVHD.[32,33]

REACH3: Phase III Trial of Ruxolitinib vs Best Available Therapy in Steroid-Refractory Chronic GVHD

Mark A. Schroeder, MD:
At ASH 2020, promising data were presented from studies of 2 approaches with great promise for the treatment of chronic GVHD: JAK inhibition and ROCK2 inhibition.

Zeiser and colleagues[34] presented results from REACH3, a large phase III study of the JAK inhibitor ruxolitinib vs BAT in patients 12 years of age or older with severe steroid-refractory or steroid-dependent chronic GVHD and myeloid engraftment (N = 329). Patients were randomized to either ruxolitinib 10 mg twice daily or BAT (eg, photopheresis, infliximab, mycophenolate mofetil, rituximab) plus steroids in both arms, with or without a calcineurin inhibitor. In the primary efficacy period, patients were treated for 6 months. In the extension period, patients could be treated for up to a maximum of 156 weeks (~ 3 years). The primary endpoint was ORR at 6 months, with secondary endpoints including failure-free survival and modified Lee symptom score at 6 months.

REACH3: Baseline Characteristics

Mark A. Schroeder, MD:
Treatment arms were generally well balanced at baseline. The median age was approximately 50 years, approximately 60% of patients were male, and the majority of patients had moderate (41.2% vs 44.5%) or severe (58.8% vs 54.9%) chronic GVHD in the ruxolitinib arm vs the BAT arm, respectively.

Phase III REACH3 Study of Ruxolitinib in Chronic GVHD: ORR at Week 24

Mark A. Schroeder, MD:
In REACH3, the primary endpoint of ORR at 6 months was 49.7% in the ruxolitinib arm vs 25.6% with BAT (odds ratio: 2.99; P < .001). Most of these were PRs (43.0% in the ruxolitinib arm and 22.6% in the BAT arm). Of note, the median duration of response was not reached in the ruxolitinib arm vs 6.24 months in the BAT arm.

Phase III REACH3 Study of Ruxolitinib in Chronic GVHD: Other Efficacy Endpoints

Mark A. Schroeder, MD:
On average, the best ORR in the ruxolitinib group was 76.4% vs 60.4% in the BAT group (odds ratio: 2.15). In chronic GVHD, CRs are generally uncommon, and that was the case in the ruxolitinib arm of REACH3 (only 12% of patients). In addition to responses in chronic GVHD, symptoms were also improved by treatment with ruxolitinib, as measured by the modified Lee Symptom Scale: 24.2% of patients in the ruxolitinib arm had at least a 7-point reduction from baseline at 6 months vs 11.0% in the BAT arm (odds ratio: 2.62; P = .0011).

OS results were not included in this report from REACH3. As GVHD tends to be a more chronic and debilitating disease, changes in OS may not be evident early in a study.

Phase III REACH3 Study of Ruxolitinib in Chronic GVHD: Safety

Mark A. Schroeder, MD:
The AEs noted for patients treated with ruxolitinib were similar to what has been previously described in acute GVHD.[28] In REACH3, hematologic AEs were a concern, with anemia in 29.1% of the ruxolitinib arm (grade ≥ 3, 12.7%) vs 12.7% with BAT (grade ≥ 3, 7.6%), and thrombocytopenia in 21.2% of the ruxolitinib arm (grade ≥ 3, 15.2%) vs 14.6% with BAT (grade ≥ 3, 10.1%). As a result, more than one half of patients in the ruxolitinib arm underwent dose modifications or discontinued treatment.

Phase III REACH3 Study of Ruxolitinib in Chronic GVHD: Infections up to Week 24

Mark A. Schroeder, MD:
There was also a potential signal for increased fungal infections in patients treated with ruxolitinib vs BAT in this study (11.5% vs 5.7%, respectively), with a preponderance of grade 3 vs grade 1/2. Given this observation, patients receiving ruxolitinib need to be monitored for fungal infections, and prophylaxis against fungal infection should be considered in patients who are to be started on this therapy.

Phase III REACH3 Study of Ruxolitinib in Chronic GVHD: Conclusions

Mark A. Schroeder, MD:
The REACH3 study was the first successful randomized controlled trial for the treatment of patients with chronic GVHD who are failing steroids. Compared with BAT alone, the combination of BAT and ruxolitinib was associated with significantly improved ORR (49.7% vs 25.6%; P < .0001), failure-free survival (not reached vs 5.7 months; P < .0001), and symptom improvement (modified Lee Symptom Scale score of 24.2% vs 11.0%; P = .0011). In addition, safety was as expected, including anemia and thrombocytopenia in approximately one quarter of patients on the ruxolitinib arm.

Of note, all patients in this study had fewer than 2 lines of treatment for their chronic GVHD; that’s an important distinction compared with other studies presented at ASH 2020.[35] I think that ruxolitinib will ultimately be approved by the FDA for the treatment of steroid‑refractory chronic GVHD.

Phase I/II Study of JAK1/2 Inhibitor Baricitinib in Refractory Chronic GVHD

Mark A. Schroeder, MD:
A second JAK inhibitor, baricitinib, is also being investigated for chronic GVHD. At ASH 2020, Holtzman and colleagues[36] from the National Institutes of Health presented results from a single-arm, intrapatient dose-escalation phase I/II trial of baricitinib in patients with refractory chronic GVHD and 2‑7 previous lines of therapy (n = 20 of a planned N = 31).

Baricitinib was initially given at the dose of 2 mg once daily. If no dose-limiting toxicities were evident, responding patients were assessed in 3 months, whereas those with progressive disease received 4 mg once daily for 3 months. Dose-limiting toxicities at the 4-mg dose resulted in discontinuing treatment. If patients at the 2-mg dose level experienced dose-limiting toxicity, the dose was decreased to 1 mg daily for 24 weeks, and if not tolerated, treatment was discontinued.

Patients were assessed at 3 months and 6 months, with treatment continued for up to 1 year. The primary endpoint was ORR at 6 months and other endpoints included changes in the Lee Symptom Scale, pharmacokinetics, and safety.

Baricitinib in Refractory Chronic GVHD: Baseline Characteristics

Mark A. Schroeder, MD:
All 20 patients enrolled as of this presentation had severe chronic GVHD with a median of 4 previous lines of therapy. This is a distinction from REACH3, in which 58.8% of patients had severe chronic GVHD. The median age was 54 years and the population was 80% female; most (85%) had received concurrent immunosuppressive therapy at enrollment.

Baricitinib in Refractory Chronic GVHD: Responses

Mark A. Schroeder, MD:
Despite the heavily pretreated nature of these patients, the 6-month ORR was 65%, and the best ORR at any time was 90%. Responses were seen across organs, primarily in the lower gastrointestinal tract (100%), joints/fascia (85%), upper gastrointestinal tract (50%), and mouth (50%), with few responses in lungs (10%). Responses were durable, with 8 of 9 evaluable patients still responding at 12 months.

Baricitinib in Refractory Chronic GVHD: Safety

Mark A. Schroeder, MD:
Treatment with baricitinib in this heavily pretreated population was safe; study investigators noted that the majority of patients were able to be escalated to 4 mg. There were no dose-limiting toxicities or treatment-related grade 4 events on this study. That said, 11 (55%) patients had dose interruptions and 3 (15%) had dose reductions. Although no fungal infections were seen, baricitinib was associated with more leukopenia, with 30% of patients on this treatment developing neutropenia. Treatment discontinuation due to an AE was reported in 15% of patients, and early study discontinuation was reported in 9 patients (due to toxicity [n = 3], disease progression [n = 3], cataracts [n = 1], Epstein-Barr virus posttransplant lymphoproliferative disease [n = 1], and venous thromboembolism [n = 1]). The median time to discontinuation was 5.6 months.

Baricitinib in Refractory Chronic GVHD: Conclusions

Mark A. Schroeder, MD:
The take-home lesson from this phase I/II study of baricitinib is that there appears to be a class effect of JAK1/2 inhibition in the treatment of GVHD. Baricitinib appears to be well tolerated in patients with refractory, severe chronic GVHD with reasonable safety. Specifically, rapid and durable responses were seen in multiple organs with a 6-month ORR of 65%.

This study had a small number of patients, but 100% of them had severe chronic GVHD and 90% had sclerotic features. By contrast, in REACH3, 58.8% had severe chronic GVHD. Therefore, with the standard caveats about cross-trial comparisons, it is interesting that despite apparently worse overall disease severity, responses at 6 months in this baricitinib study were similar to that of ruxolitinib in REACH3.

As mentioned by Holtzman and colleagues, baricitinib may have a cytopenia profile compared with ruxolitinib. Baricitinib has potentially less thrombocytopenia, but perhaps more leukopenia than ruxolitinib. A potential benefit to baricitinib might be that there are few or no interactions with the CYP inhibitors, such as the azoles used to prevent fungal infections. In this small study, no fungal infections were seen, but REACH3 was much larger. Baricitinib can be given as a once-daily dose medication compared with ruxolitinib, which is given twice daily.

ROCKstar: Belumosudil Once or Twice Daily in Chronic GVHD

Mark A. Schroeder, MD:
The second important new approach to treating chronic GVHD that was presented at ASH 2020 is ROCK2 inhibition. ROCK2 plays a key role in immune diseases, as it is important for inflammatory signaling within the germinal center of lymph nodes. By inhibiting ROCK2 signaling, proinflammatory TH17 cells are reduced and T‑regulatory cells are increased.[37] Previously, belumosudil was shown to reverse profibrotic mediators.[38]

Cutler and colleagues[39] reported top-line results data from the phase II ROCKstar study of belumosudil, a ROCK2 inhibitor, in 132 patients 12 years of age or older with chronic GVHD after previous allogeneic stem cell transplantation and 2-5 previous lines of systemic therapy. Patients were randomized to 1 of 2 dosing schedules of belumosudil, given at 200 mg either once daily or twice daily. The primary endpoint was ORR 6 months (per the 2014 National Institutes of Health chronic GVHD consensus criteria). Secondary endpoints included safety, response duration, Lee Symptom Scale score, and survival.

Key baseline characteristics included a median age of 56 years and a median of 3 previous lines, and 67% of patients had severe chronic GVHD. More than one half had at least 4 involved organs, and nearly three quarters were refractory to their last line of systemic therapy.

ROCKstar: Subgroup Analysis of ORR

Mark A. Schroeder, MD:
The ORR for belumosudil was similar with once-daily vs twice-daily dosing: 73% vs 77%, respectively.

Similar to JAK inhibitors, CRs were unlikely in organs, with only 7 patients achieving a CR in all affected organs. However, unlike JAK inhibitors, ROCK2 inhibition yielded responses in organs with fibrotic disease. And, as with JAK inhibition, the Lee Symptom Score was improved with belumosudil in 42% of the daily group and 36% of the twice-daily group.[39]

The median time to response was 4 weeks, and the median duration of response was 50 weeks. Some patients required up to 40 weeks to respond, but eventually responses were seen in all organs. Responses to belumosudil were also observed in patients who had previous ibrutinib failure 78% (n = 74), or had previous ruxolitinib 68% (n= 38).

ROCKstar: Safety

Mark A. Schroeder, MD:
The safety profile for belumosudil was acceptable and as expected in patients being treated for chronic GVHD. Toxicities occurring in more than 20% of patients included fatigue (38%), diarrhea (33%), nausea (31%), cough (28%), and upper respiratory tract infections (27%). Grade 3 or higher AEs in ≥ 5% of patients, included pneumonia in 10 patients, hypertension in 8, and hyperglycemia in 6.[39] Two patients experienced reactivation of Epstein-Barr virus and cytomegalovirus. Eighty-nine (67%) patients experienced drug-related AEs and 7 (5%) experienced serious AEs.

There was a total of 8 deaths on study (4 at each dosing schedule). Deaths in once-daily dosing were attributed (1 each) to aspiration pneumonia, hemoptysis, multiple organ dysfunction syndrome/septic shock, or acute myeloid leukemia relapse. Deaths in the twice-daily dosing arm were attributed to cardiac arrest (n = 2), infection (n = 1), or respiratory failure (n = 1).

ROCKstar: Conclusions

Mark A. Schroeder, MD:
My take home from ROCKstar was that, in patients with chronic GVHD (67% severe) and 2-5 previous lines of systemic therapy, belumosudil achieved clinically meaningful results and was well tolerated with no new safety signals. High response rates (> 70%) were seen with both dose schedules, across all key subgroups and in all affected organ systems (including with fibrotic disease). Failure-free outcomes were highly encouraging with a 12-month rate of 58% and a median duration of response of 50 weeks. Encouragingly, responses were seen in patients failing previous ibrutinib or ruxolitinib. The AEs were notable due to the absence of cytopenias, unlike previous reports of JAK inhibitor therapy in chronic GVHD.

Thus, based on these 3 studies, there are now 2 novel investigational therapies for the treatment of chronic GVHD that we hope will be approved in 2021: JAK1/2 inhibition with ruxolitinib and ROCK2 inhibition with belumosudil.

JAK Inhibition in Acute GVHD: Background

Mark A. Schroeder, MD:
Finally, I will discuss acute GVHD, which is common after allogeneic stem cell transplantation, and until recently, there were no FDA-approved drugs for this disease. Ruxolitinib was approved for treatment of steroid‑refractory GVHD, based on data from phase II and then subsequent follow-up with randomized phase III data.[28] It is unknown whether JAK inhibition can be used to prevent GVHD from occurring. However, there is rationale for using JAK inhibitors early after transplant based on effects on T‑cell trafficking, as well as anti‑inflammatory and antigen‑presenting cell‑mediated effects. The main concern for using these drugs this early is effects on stem cell regeneration, given that JAK/STAT signaling is essential in mediating cytokine signaling in hematopoietic stem cells.

The use of a JAK inhibitor as prophylaxis for acute GVHD was the subject of 2 studies reported at ASH 2020. Pidala and colleagues[40] reported results from a small cohort of patients (n = 12) treated with pacritinib plus sirolimus and low-dose tacrolimus. In the larger GRAVITAS‑119 study, which is discussed next, itacitinib was evaluated as a prophylactic treatment for acute GVHD after allogeneic stem cell transplant.

Phase I GRAVITAS-119 of ITA Plus CNI: Study Design

Mark A. Schroeder, MD:
GRAVITAS 119 was a single‑arm, open‑label phase I study of the JAK1 inhibitor itacitinib plus a calcineurin inhibitor, as prophylaxis for GVHD in patients 18 years of age or older with hematologic malignancies who were candidates for reduced-intensity conditioning and/or allogeneic stem cell transplantation (N = 65).[41] Starting 3 days before transplantation, patients were treated with itacitinib 200 mg once daily plus tacrolimus/methotrexate or cyclosporine A/mycophenolate mofetil with or without antithymocyte globulin (ATG). At Day 90 after transplantation, itacitinib was decreased to 100 mg once daily for the next 90 days and then tapered. Patients were followed for 6 months for GVHD and OS.

The primary endpoint of this study was the percent of hematologic recovery at Day 28, defined as absolute neutrophil count (ANC) ≥ 500/mm3 for 3 consecutive measurements; platelets ≥ 20,000/mm3 and no platelet transfusion in the previous 3 days. Secondary endpoints included GVHD-free and relapse-free survival, transplant-related mortality, OS, acute and chronic GVHD, and safety.

GRAVITAS-119: Hematologic Recovery

Mark A. Schroeder, MD:
In GRAVITAS-119, all patients achieved hematologic recovery. The median time to ANC recovery was approximately 17 days, which is as expected with a reduced intensity conditioning allogeneic stem cell transplantation. The median time to platelet recovery was 14 days. Both ANC and platelet recovery were achieved by Day 28 in 98.5% of patients, with the remaining patient reaching ANC recovery on Day 31.

GRAVITAS-119: Secondary Endpoints

Mark A. Schroeder, MD:
With the caveat of small numbers, in this reduced intensity conditioned population of patients, there was a low incidence of grade III/IV acute GVHD, reported at approximately 5% of patients in both the ATG and no-ATG groups. At 1 year, rates of moderate to severe chronic GVHD were lower with ATG, at 10.4% vs 31.3% without ATG. Of note, the combined rate of GVHD and relapse-free survival was 23.1% with no ATG vs 60.9% with ATG. The 1-year OS estimate was also similar between groups, at 74.3% with no ATG vs 82.6% with ATG.

Relapse or progression at 1 year, given the small numbers, is hard to interpret but did not seem to be affected in this reduced intensity conditioned cohort.

GRAVITAS-119: Grade ≥ 3 AEs Regardless of Causality

Mark A. Schroeder, MD:
The most common grade ≥ 3 hematologic AEs seen on this study included thrombocytopenia (49.3%), anemia (29.2%), and decreased blood counts (29.2%). Eight patients (12.3%) developed grade ≥ 3 febrile neutropenia.

Grade ≥ 3 nonhematologic events included diarrhea (15.4%), hypertension (13.8%), and hypertriglyceridemia (12.3%), which is a class effect of JAK inhibition. AEs led to dose modifications or discontinuation in approximately one quarter of patients (23.1%). 

Phase I GRAVITAS-119 of ITA Plus CNI: Infections

Mark A. Schroeder, MD:
One concern regarding JAK inhibition after allogeneic stem cell transplant is an increased risk of infections. Reassuringly, in this small study, there did not appear to be an increased risk of viral, bacterial, or fungal infections with itacitinib. However, all-grade cytomegalovirus infections were seen in 6 patients without ATG and in 5 patients with ATG.

GRAVITAS-119: Graft Failures

Mark A. Schroeder, MD:
All patients had primary engraftment, but 2 had secondary graft failure and had to undergo a second transplant: 1 patient with myelodysplastic syndrome had received a previous transplant with an 8/8-matched unrelated donor, and 1 patient with acute lymphoblastic lymphoma had received a previous transplant with an 8/8-matched related donor.

GRAVITAS-119: Conclusions

Mark A. Schroeder, MD:
The take-home lesson from the phase I GRAVITAS-119 study is that the JAK1 inhibitor itacitinib plus calcineurin-based regimens can be safely given as prophylaxis for GVHD after a reduced-intensity conditioning allogeneic stem cell transplant. Preliminary data from this study suggest that there might be a reduced incidence of severe acute GVHD, as the incidence was approximately 5% by Day 180 after transplantation.

The occurrence of secondary graft failure in 2 patients is concerning, despite being expected for matched unrelated donor transplants with reduced intensity conditioning. Further follow-up will be needed.

GVHD at ASH 2020: Summary

Mark A. Schroeder, MD:
At ASH 2020, 2 new therapies were presented for chronic GVHD: the JAK1/2 inhibitor ruxolitinib and the ROCK2 inhibitor belumosudil. Ruxolitinib will likely be approved for upfront steroid refractory chronic GVHD. Belumosudil will likely be approved for GVHD after 2 or more lines of therapy. Belumosudil has an effect on sclerotic disease, and its AE profile is different than JAK inhibitors with fewer cytopenias and potentially lower risk for infections. Of importance, responses have been seen after ruxolitinib failure.

Regarding acute GVHD, JAK inhibition appears safe as prophylaxis in patients receiving reduced‑intensity conditioning allogeneic stem cell transplantation, with promising initial results showing low rates of grade 3/4 acute GVHD.

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