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Hematology 2021: Nonmalignant

CME

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

Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™

Released: March 01, 2022

Expiration: February 28, 2023

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

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Paroxysmal Nocturnal Hematuria: Background

David Dingli, MD, PhD:
PNH is a rare, acquired hematologic disorder caused by somatic mutations in the PIGA gene in hematopoietic stem cells. PNH is characterized by severe hemolysis and life-threatening thrombosis via activation of the complement alternative pathway (AP).35 In part, PNH results from continuous low-level activation of the alternate complement pathway (coupled with the acquired loss of complement regulatory proteins on RBCs due to somatic mutations in PIG-A within hematopoietic stem cells) that leads to hemolysis. There is much interest in proximal complement inhibition to prevent intravascular and extravascular hemolysis in PNH. Inhibition of the alternate complement pathway may result in good disease control without extravascular hemolysis and perhaps be less immunosuppressive because the complement components are not depleted and the classical and lectin pathways still can be activated.

Iptacopan for PNH: Study Design

David Dingli, MD, PhD:
At ASH 2021, Jang and colleagues36 reported results from a randomized, open-label phase II study of iptacopan, a first-in-class, oral, selective inhibitor of factor B, a key component of the AP pathway, in 13 adult patients with PNH and active clone size ≥10%. In this study, patients with PNH and anemia were treated with iptacopan as part of either one of two cohorts: patients in Cohort 1 (n = 7) were treated with iptacopan 25 mg twice daily for 4 weeks (Period 1), 100 mg twice daily for 8 weeks (Period 2), and then 100 mg twice daily (Period 3: extension) for 1 to 4 additional weeks, as part of an extension program, tapered for 7 days at 25 mg then 20 mg for 7 days. In Cohort 2 (n = 6), patients were treated with iptacopan 50 mg twice daily during Period 1, 200 mg twice daily during Period 2, and 200 mg twice daily during Period 3, and then tapered as previously mentioned for Cohort 1. The primary endpoint was reduction of PNH-associated hemolysis, measured by reduction in LDH levels. Secondary objectives included dose response, reduction in markers of intravascular and extravascular hemolysis, improvement in hemoglobin, markers associated with risk of thrombosis, safety and tolerability, and pharmacokinetics. Interim analysis was conducted after 11 ongoing patients had completed 52 weeks of iptacopan treatment.

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Iptacopan for PNH: Baseline Characteristics

David Dingli, MD, PhD:
All patients had very active disease at the time of recruitment with a very-high mean LDH levels (range: 1946-2228 U/L) and mean hemoglobin levels well below 10.0 g/dL (range: 7.9-9.0 g/dL). The study population was Asians, but there is no reason to believe the results would be dissimilar to other non-Asian populations with PNH.

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Iptacopan for PNH: Reduction in LDH levels

David Dingli, MD, PhD:
Although the number of patients treated to date is small (N = 13), the results are very encouraging with substantial reductions in mean LDH levels from baseline ranging from -77% on Week 2 to -85% by Week 64 of treatment in Cohort 1, and up to -90% in Cohort 2. LDH levels were reduced by -60% or higher in all patients by Week 12 of treatment. Mean treatment duration in Cohort 1 (doses: 25-100 mg) was 62 weeks (range: 14-81), and in Cohort 2 (doses: 50-200 mg), duration was 54 weeks (range: 0-76).

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Iptacopan for PNH: Additional Outcomes

David Dingli, MD, PhD:
At the time of this report, 10 out of 11 patients still receiving treatment have maintained durable increase in hemoglobin levels, and all patients have become transfusion-independent since the start of iptacopan treatment. Study investigators also reported durable improvements in reticulocyte and bilirubin levels, abrogation of complement d3 deposition, and no thromboembolic events on study.

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Iptacopan for PNH: Safety Summary

David Dingli, MD, PhD:
Although the number of patients is small overall, the iptacopan appears to be safe and well tolerated. No thromboembolic events were reported on this study. Treatment-emergent AEs were mild to moderate, and there were no severe/serious treatment-emergent AEs. Treatment-emergent or drug-related AEs leading to discontinuation of the study drug occurred in 1 patient in Cohort 2. Most common treatment-emergent AEs in Cohort 1 included upper respiratory tract infection, pyrexia, oropharyngeal pain, and cough (28.6% for each). Most common treatment-emergent AEs in Cohort 2 included headache (50%) and blood alkaline phosphatase elevation (16.7%). There was 1 report of mild, self-limited breakthrough hemolysis in a patient who missed several doses of iptacopan.

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Iptacopan for PNH: Conclusions

David Dingli, MD, PhD:
The data in this interim report of iptacopan in patients with highly active PNH are very encouraging with respect to efficacy, safety, tolerability, and sustainability of the response. We probably need a larger cohort of patients and more quantitative data from this trial. Iptacopan is not yet approved for the management of patients with PNH, but these results do provide a glimpse of the future where patients may be offered an oral agent to treat their disease.

It is an exciting time in the field of PNH with several agents being studied, including for the first time oral agents like iptacopan that can potentially control the disease well and do so safely. We will need additional information on the risks of breakthrough hemolysis in patients who miss their doses or if the patient develops a concomitant acute condition that activates the complement pathway with the potential to increase the risk of breakthrough hemolysis. It would be important for investigators to develop a plan for how to treat the patient in that scenario due to the increased risk of thrombosis. We also need to determine whether concomitant anticoagulation is needed in patients treated with oral agents.

You recently attended the 2021 ASH annual meeting, and a colleague caring for patients with PNH asks you to share insight from the ongoing phase II study of iptacopan in adult Asian patients with active PNH, anemia, and active clone size ≥10%. Which of the following results will you mention was reported from that trial?
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