From December 7 to 10, 2024, the 66th Annual Meeting of the American Society of Hematology (ASH) convened in San Diego, attracting global hematology experts to discuss groundbreaking research. During the conference, Dr. David J. Kuter from Massachusetts General Hospital, Harvard Medical School, presented the latest findings from the LUNA 3 study (Abstract #5), which explored the efficacy and safety of rilzabrutinib, an oral Bruton tyrosine kinase inhibitor (BTKi), in adult patients with previously treated primary immune thrombocytopenia (ITP). Hematology Frontier invited Prof. Kuter to share key insights from the study and discuss challenges in ITP treatment and the impact on patients' quality of life.1. Challenges in ITP Treatment for Adults
Hematology Frontier: ITP remains a challenging condition, especially in adult patients. Could you outline the primary hurdles in managing ITP in this population?
Dr. David J. Kuter: Primary immune thrombocytopenia (ITP) is one of the most common autoimmune bleeding disorders, characterized by immune-mediated platelet destruction and reduced platelet production. Historically, ITP was thought to primarily affect young women. However, our understanding has shifted, with the disease now being increasingly recognized across age groups, especially among older adults, where the incidence is rising.
Looking back, ITP treatment initially relied on splenectomy and long-term corticosteroid use. However, with advancements in medicine, a range of effective therapies targeting various aspects of ITP has emerged. Many of these treatments successfully elevate platelet counts to safe levels in most patients.
We are now entering a new phase of ITP management, with the advent of novel drugs and cutting-edge therapies that hold promise for achieving a true cure. Despite these advancements, significant challenges remain. Chief among them is finding a treatment strategy that not only raises platelet counts to safe levels and reduces bleeding risk but also improves patients’ quality of life.
2. Key Findings from the LUNA 3 Study
Hematology Frontier: What are the key outcomes from the LUNA 3 study on rilzabrutinib in adult ITP patients? How do these findings influence clinical practice?
Dr. David J. Kuter:LUNA 3 is a randomized, multicenter Phase III trial evaluating the efficacy and safety of rilzabrutinib versus placebo in adults and adolescents with persistent or chronic ITP. These patients had an average disease duration of 6–8 years and had failed an average of five prior therapies. The median baseline platelet count was 15,000/μL, far below the normal range of 150,000–450,000/μL.
The primary endpoint was sustained platelet response, defined as achieving a platelet count of at least 50,000/μL for at least 8 of the final 12 weeks during the 24-week blinded treatment period without rescue therapy. Among patients treated with rilzabrutinib, 65% achieved this response, compared to significantly fewer in the placebo group. Secondary endpoints included platelet response time, use of rescue therapy, fatigue scores, and bleeding symptoms.
The results were remarkable. Of the patients receiving 400 mg of rilzabrutinib twice daily, 29% met the primary endpoint, a significant improvement over placebo. Secondary outcomes also highlighted meaningful clinical benefits, demonstrating the potential of rilzabrutinib to transform ITP treatment.
3. Quality of Life Improvements in ITP Patients
Hematology Frontier: Beyond improving platelet counts, quality of life (QoL) is a critical aspect of ITP treatment. Did the study track improvements in bleeding symptoms, daily activities, or other QoL metrics? How did rilzabrutinib perform in these areas?
Dr. David J. Kuter:One of the primary goals of ITP treatment is to quickly elevate platelet counts to safe levels and reduce bleeding risks. What sets this study apart is its focus on quality-of-life outcomes. Rilzabrutinib not only improved platelet counts and reduced bleeding risks but also significantly enhanced patients’ quality of life, particularly by addressing fatigue, a common symptom among ITP patients.
This study was the first to analyze changes in fatigue caused by treatment. Patients who achieved the primary endpoint of sustained platelet response showed significant reductions in fatigue. Interestingly, even those with suboptimal platelet responses experienced improvements in fatigue, suggesting rilzabrutinib might exert additional benefits, possibly through its anti-inflammatory effects.
Overall, the study clearly demonstrated QoL improvements for these refractory patients. Importantly, if rilzabrutinib is used earlier in the disease course, these benefits could be even more pronounced.
4. Safety and Adverse Events of Rilzabrutinib
Hematology Frontier :BTK inhibitors are widely used in oncology but are often associated with risks like bleeding and infections. How does rilzabrutinib compare in terms of safety, and what adverse events were observed in the LUNA 3 trial?
Dr. David J. Kuter:BTK inhibitors have become a cornerstone in cancer therapy, but many existing options impair platelet function, leading to bleeding as a common complication. Rilzabrutinib was specifically designed to overcome these challenges. Unlike other BTK inhibitors, it does not affect platelet function and avoids complications like atrial fibrillation or other cardiac issues.
In the LUNA 3 trial, rilzabrutinib demonstrated a favorable safety profile. Mild diarrhea was reported in a small number of patients, but there was no observed increase in infection risk compared to the placebo group. While bleeding is often considered an adverse event in ITP trials, rilzabrutinib significantly reduced bleeding risk.
These findings highlight the safety and tolerability of rilzabrutinib, making it a promising candidate for ITP treatment.
