Parsaclisib: The Precision Strike Against Relapsed Mantle Cell Lymphoma

Clinical results from the CITADEL-205 trial demonstrate promising outcomes for BTK inhibitor-naïve patients

Article Navigation

The Relapse Challenge

Mantle cell lymphoma (MCL) represents one of oncology's most cunning adversaries. Accounting for 5-7% of non-Hodgkin lymphomas, this aggressive cancer often responds to initial chemotherapy only to return with vengeance. For decades, patients facing relapsed or refractory (R/R) MCL had limited options – until the emergence of targeted therapies like Bruton tyrosine kinase (BTK) inhibitors. Yet approximately 30-50% of patients develop resistance or intolerance to these drugs, creating an urgent need for new therapeutic strategies 1 6 .

5-7%

of non-Hodgkin lymphomas are MCL

30-50%

develop resistance to BTK inhibitors

High

unmet medical need in R/R MCL

The PI3Kδ Advantage

At the molecular heart of MCL lies the phosphatidylinositol 3-kinase (PI3K) pathway – a critical signaling network that lymphoma cells hijack to fuel their uncontrolled growth and survival. The delta (δ) isoform of PI3K is particularly important in malignant B-cells, making it an ideal therapeutic target.

Precision Targeting
  • 10,000-fold greater selectivity for PI3Kδ vs other isoforms 3 9
  • IC50 of 1 nM against PI3Kδ 7
  • Optimized structure reduces off-target effects 9
Safety Advantages
  • Reduced liver toxicity compared to pan-PI3K inhibitors
  • Favorable tolerability profile
  • Manageable side effects with proper monitoring

Inside the CITADEL-205 Trial: A Clinical Breakthrough

Trial Design

Phase 2, open-label, multicenter study (NCT03235544) evaluating parsaclisib in 108 BTK inhibitor-naïve R/R MCL patients with 1-3 prior therapies 1 3 9 .

Innovative Dosing Strategy
Lead-in Phase

20 mg once daily for 8 weeks

Maintenance Phase

Randomized to either:

  • Daily: 2.5 mg once daily continuously
  • Weekly: 20 mg once weekly
Patient Characteristics
Median Age

72 years

High-Risk MIPI

55.2%

Refractory

43.5%

Efficacy Results: Striking Responses

Key Findings from Daily Dosing Group (n=77)

Response Data

Response Parameter Daily Dosing Group (n=77) All Patients (n=108)
Objective Response Rate (ORR) 70.1% (58.6%-80.0%) 68.5% (58.9%-77.1%)
Complete Response (CR) Rate 15.6% (8.3%-25.6%) 17.6% (10.9%-26.1%)
Disease Control Rate 90.9% 89.3%
Median Time to Response 8.1 weeks 7.9 weeks
Patients with tumor regression 95.7% 96%

Durability of Response

Parameter Daily Dosing Group All Patients
Median Duration of Response (DOR) 12.1 months (9.0-NE) 13.7 months (9.0-19.9)
Median Progression-Free Survival (PFS) 13.6 months (10.0-16.9) 11.99 months (8.3-16.9)
Median Overall Survival (OS) Not Reached Not Reached
12-Month OS Rate 78.5% 80%
Clinical Insight: Responses were remarkably rapid – 88.9% of responders achieved their response by the first assessment at week 8. Among evaluable patients, 84.8% achieved >50% reduction in target lesions from baseline, with a median change of -75.1% 1 4 9 .

Safety Profile: Manageable Challenges

Safety Management Insights
  • Diarrhea onset: Median 4.3 months; improved to grade ≤2 within 11 days with intervention
  • Dose modifications: 47.2% required interruption; 8.3% required reduction
  • Serious TEAEs: Occurred in 42.6% of patients
  • Low hepatotoxicity: Grade ≥3 transaminase elevation in only 3-4%

Safety Overview (All Patients)

Adverse Event All Grades (%) Grade ≥3 (%) Management Impact
Diarrhea 34.3 13.9 Leading cause of discontinuation
Neutropenia - 8.3 Required monitoring
Pyrexia 17.6 - Generally manageable
Constipation 13.0 - Supportive care effective
Any TEAE leading to discontinuation - 25.0 Mostly GI-related

Conclusion: Precision Medicine in Action

Key Advantages
  • High response rates (70.1% ORR) rivaling frontline therapies
  • Rapid action with most responses by first scan (8 weeks)
  • Durable control with median DOR >1 year
  • Manageable safety profile distinct from BTK inhibitors
Future Directions
  • Frontline potential in combination regimens
  • Biomarker development for patient selection
  • MRD monitoring to predict long-term outcomes 8
  • Alternative dosing strategies to optimize safety

"The future of oncology lies not just in newer drugs, but in smarter targeting. Parsaclisib's success stems from attacking cancer at its molecular weak point while sparing healthy tissues – a strategy increasingly defining modern cancer care."

References