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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

Immune Thrombocytopenia (ITP)

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Study Design

Hanny Al-Samkari, MD:
At ASH 2020, 2 key studies in ITP were reported. The phase III FLIGHT trial compared first‑line mycophenolate mofetil and corticosteroids vs standard steroid treatment in patients with newly diagnosed ITP (N = 120).[1] The current standard of care is high-dose corticosteroids, but these are associated with AEs, short and varied responses, and high relapse rates.[2,3] By adding the immunosuppressive agent mycophenolate mofetil (often used for steroid-refractory ITP[4]), it is hoped that the likelihood of durable remission following the first line of therapy can of first-line steroids can be improved.

In this open-label, randomized study, patients with ITP who were at least 16 years of age with a platelet count < 30 x 109/L and who required first‑line treatment were randomized to receive either mycophenolate mofetil 1 g twice daily orally plus a corticosteroid (dexamethasone or prednisone) or to corticosteroids alone. The primary endpoint was the time to treatment failure (platelet count < 30 x 109/L) as well as clinical need for second‑line treatment. The secondary endpoints were AEs, bleeding events, and patient‑reported outcomes. It is important to note that mycophenolate mofetil treatment in the study was designed to taper and stop at Month 6.

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Baseline Characteristics

Hanny Al-Samkari, MD:
The median age of patients enrolled on this study was approximately 55 years, and both treatment arms had relatively low platelet counts (< 8 x 109/L). Otherwise, baseline characteristics were relatively well balanced, including mean body mass index (29.7 and 27.8 kg/m2), hemoglobin levels (134.9 and 140.3 g/L), neutrophil (4.6 x 109/L and 4.8 x 109/L) and white blood counts (7.2 x 109/L and 7.4 x 109/L).

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Efficacy

Hanny Al-Samkari, MD:
In terms of the primary endpoint (time to treatment failure), significantly fewer treatment failures occurred in the combination arm vs the corticosteroid-alone arm (22% vs 44%, respectively; HR: 0.41; P = .0064). In addition, patients receiving mycophenolate mofetil were more likely to achieve platelet count of > 30 x 109/L following second-line treatment; for example, in patients with platelets > 100 x 109/L after first-line treatment, the response rate was 91.5% with addition of mycophenolate mofetil vs 63.9% with corticosteroids alone.

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Safety

Hanny Al-Samkari, MD:
No significant differences were seen in AE rates between arms. Approximately one quarter of patients developed an infection or infestation, only 4 cases of neutropenia were seen (all in the corticosteroid-only arm), and diarrhea or other gastrointestinal events affected 25% of patients in the steroid-only arm and 34% in the combination arm.

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Bleeding Events

Hanny Al-Samkari, MD:
Similarly, there was also no difference in rates of bleeding episodes, blood or platelet transfusions, use of tranexamic acid or IV immunoglobulin, or hospital admission. I think it is important to recognize that this study used a second treatment in addition to corticosteroids, but that AEs and bleeding events and rescue treatments were comparable between the 2 treatment groups.

FLIGHT: First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Patient-Reported Outcomes

Hanny Al-Samkari, MD:
Patient-reported outcome measures suggested that the quality-of-life scores were numerically worse in the mycophenolate mofetil plus steroid group vs the steroid-alone group (SF36: P = .012; FACIT-F: P = .05). However, quality-of-life differences were not statistically significant when a Bonferroni correction (P = .0033) was applied for multiple testing. Nevertheless, the numeric differences were provocative.

As previously mentioned, in the corticosteroid-alone arm, there was an unusually low rate of treatment failure. Generally speaking, adults with ITP receiving corticosteroids have higher failure rates than what was reported on this study.

FLIGHT Trial of First-line Mycophenolate Mofetil Plus Corticosteroids vs Corticosteroids in ITP: Conclusions

Hanny Al-Samkari, MD:
In summary, results from FLIGHT suggest that mycophenolate mofetil plus corticosteroids appears safe and effective in patients with ITP, including those older than 70 years (28%) or older than 75 years (16%). The combination was well tolerated with significantly lower rates of treatment failure than with corticosteroids alone.

I think the FLIGHT study is a very important study in ITP. I think that it is still unclear whether these findings will change the standard of care, and it will be important to review all of the results once the final publication is available. It would be nice to see longer-term remission data over the course of years to determine whether adding mycophenolate mofetil upfront results in a higher rate of durable drug free remission several years out. Those are the sort of outcomes measures that many of us are most interested in. In my opinion, the fact that there were no excessive additional toxicities with addition of mycophenolate is promising. It is not clear why there were lower quality-of-life scores for the combination group, and this is an important topic for additional study.

BTK Inhibitor Rilzabrutinib in ITP: Background

Hanny Al-Samkari, MD:
Rilzabrutinib is an oral, reversible, covalent BTK inhibitor that, unlike the currently approved BTK inhibitors used to treat lymphomas, does not appear to affect platelet aggregation and platelet function.[5,6] BTK inhibitors such as ibrutinib are potentially useful in ITP as they target the B-cells that are perpetuating the immune response. However, they also exhibit off-target effects that can lead to platelet dysfunction and impairment in platelet aggregation; the increased bleeding risk with ibrutinib is well documented.[7]

Although rilzabrutinib does affect more kinases than just BTK, it is much more selective than other BTK inhibitors overall and does not appear to affect platelet aggregation and function (preliminary studies).[6,8] Thus, rilzabrutinib is an optimal BTK inhibitor to evaluate in ITP for safety and efficacy.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Study Design

Hanny Al-Samkari, MD:
At ASH 2020, Kuter and colleagues[9] presented long-term extension results from an open‑label, dose‑finding, phase I/II trial of rilzabrutinib in adults with heavily pretreated, relapsed/refractory ITP (N = 53). Patients had received and responded to at least 1 previous treatment for ITP, did not have other treatment options, and had at least 2 platelet counts of < 30 x 109/L. Both primary and secondary ITP were allowed, as was stable treatment with corticosteroids and/or thrombopoietin receptor agonists.

In the initial dose-escalation phase, patients received rilzabrutinib 200 or 400 mg once daily or 300 or 400 mg twice daily, with the optimal dose identified as 400 mg twice daily. The primary endpoint in the dose-escalation portion was 2 or more consecutive platelet counts ≥ 50 x 109/L (or ≥ 20 x 109/L increase from baseline) without requiring rescue treatment. The endpoint of the long-term extension study presented at ASH 2020 was safety and durable responses in the 13 patients who received rilzabrutinib 400 mg twice daily and had platelet counts ≥ 50 x 109/L for at least one half of the final 8 weeks of treatment in the initial phase.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Baseline Characteristics

Hanny Al-Samkari, MD:
Baseline characteristics were fairly similar between the dose-escalation cohort and the long‑term extension cohort, with the exception that the long‑term extension patients had a shorter median duration of ITP than in the full‑dose escalation cohort (3.8 vs 6.0 years, respectively). The median baseline count in both groups was 17 x 109/L and more than 92% of patients had primary ITP. Patients in both cohorts had received many previous ITP therapies: a median of 6 previous treatments in the dose-escalation cohort (range: 1-53) and 5 in the long‑term extension cohort (range: 1-19). Approximately one quarter of patients had received a splenectomy.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Platelet Count Response

Hanny Al-Samkari, MD:
Despite being a heavily pretreated patient population, with very difficult–to-treat ITP, 16 of 38 patients (42%) in the dose-escalation cohort met the primary endpoint of 2 or more consecutive platelet counts ≥ 50 x 109/L. The rate of response clearly shows higher doses leading to a higher likelihood of response. Of importance, patients who did not respond to previous treatments, including thrombopoietin receptor agonists (n = 6), rituximab (n = 3), and fostamatinib (n = 1), responded to rilzabrutinib.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Response Characteristics

Hanny Al-Samkari, MD:
An important finding was that of the 38 patients initiating treatment with rilzabrutinib 400 mg twice daily, 53% achieved a platelet count ≥ 30 x 109/L by Day 8, which is a clinically relevant endpoint given that the vast majority of patients with ITP who have platelets above this threshold do not have issues with bleeding. Of importance, the responses were durable. Moreover, median platelet count for patients that crossed over from the initial phase of the study to the long‑term extension was 98 x 109/L. Responses achieved during the initial phase were maintained during the long‑term extension phase (n = 13), in which 6 patients were treated with single-agent rilzabrutinib and 7 received concomitant ITP therapy with corticosteroids and/or thrombopoietin receptor agonists.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Safety and Treatment Exposure

Hanny Al-Samkari, MD:
I want to highlight that, based on the presented data, rilzabrutinib 400 mg twice daily appears safe overall, with no treatment‑related bleeding or thrombotic events, and no high‑grade treatment‑emergent AEs. Any-grade treatment‑emergent AEs judged to be related to rilzabrutinib occurred in 47% of patients. As expected with drugs in this class, treatment‑emergent AEs included diarrhea, nausea, fatigue, and other abdominal‑related symptoms, but all were low grade and transient. The median treatment duration was 19.6 weeks in patients who received 400 mg twice daily, and combined with the main study the overall median treatment duration was 43.6 weeks.

Phase I/II Trial of BTK Inhibitor Rilzabrutinib in ITP: Conclusions and Takeaways

Hanny Al-Samkari, MD:
In this phase I/II trial, rilzabrutinib given at 400 mg twice daily yielded platelet responses of 42% in adults with ITP. Moreover, responses were observed regardless of splenectomy status or previous therapy and were rapid and durable.

My takeaway from this phase I/II study of rilzabrutinib, pending validation in later‑phase studies, is that rilzabrutinib appears to be a safe and efficacious oral option to manage patients with highly relapsed/refractory ITP who have few or no other available or appropriate treatment options. I think that this drug holds significant promise assuming, again, these results are borne out in later‑phase studies, such as the phase III LUNA3 trial, which is comparing rilzabrutinib to placebo in adults and adolescents with ITP.[10]

Finally, there are 2 other ongoing studies of interest in ITP that I am looking forward to: a phase I study of sutimlimab, a complement C1s inhibitor, in patients with multirefractory chronic ITP,[11] and a phase III study of efgartigimod, a neonatal Fc receptor antagonist in adults with primary ITP.[12]

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