ASH 2017 | Combination of ibrutinib and rituximab in CLL provides quicker, more durable response, but doesn’t yield better PFS 

On Sunday December 10^th, 2017 during an oral abstract session at the 59^th Annual meeting American Society of Hematology (ASH), Jan Burger of MD Anderson Cancer Center in Houston, Texas, on behalf of his colleagues, presented results from a phase II study, in which they sought to determine if the combination of ibrutinib and rituximab (IB+R) can better control chronic lymphocytic leukemia (CLL) compared to ibrutinib (IB) alone (NCT02007044).

This abstract (#427), “Randomized Trial of Ibrutinib Versus Ibrutinib Plus Rituximab in Patients with Chronic Lymphocytic Leukemia,” was presented during Oral Session: 642. “CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL Through Combinations of Novel Agents and Antibody.” In the summary below, data from the live session at ASH is used and therefore may supersede information in the pre-published Abstract.

Highlights

• While median time to achieve CR was significantly shorter in IB+R patients compared to IB, this did not translate to superior PFS
• Minimal residual disease (MRD) was significantly lower in IB+R vs IB patients

Treatment

• Patients were randomized to receive IB (n= 102) or IB+R (n= 104)
  • Relapsed CLL
  • Treatment naïve patients with high-risk disease (del17p or TP53mutation, n=27)
• IB patients:
  • 420 mg PO daily, until adverse events, disease progression, or death precluded further therapy
• IB+R patients:
  • rituximab during the first 6 months of treatment (375 mg/m² weekly during the first 4 weeks [cycle 1], then monthly for cycles 2-6), plus IB
• Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), safety, and tolerability

Efficacy

• 188 patients were evaluable for response assessment, including ORR, complete response (CR) and partial response (PR)
  • IB ORR: 98%; IB+R ORR: 100%
  • IB CR: 20 (21%); IB+R CR: 26 (28%)
  • IB PR: 72 IBR (77%); IB+R: 68 (72%)
• MRD was significantly lower in IB+R vs IB patients (17.1%, P = 0.002)
• Median time to normalization of the absolute lymphocyte count (ALC, ≤4.0 K/uL) was significantly shorter in IB+R vs IB patients (3.0 vs. 8.9 months, P < 0.001)
• Median time to achieve CR was also significantly shorter in IB+R treated patients (11.5 months, vs1 months in the IB patients; P = 0.032)
  • No significant difference in PFS between the patients treated with IB and IB+R during the observation period of time (91.2% vs4%, P = 0.788)

Safety

• Among the 56 patients that came off study (23 from IB, and 33 from IB+R), side effects and/or toxicities were the most common cause for therapy discontinuation (n = 28)
• Death was reported in 5 patients, causes of which were renal failure, cerebral hemorrhage, bowel perforation with colon hematoma, pneumonia, and respiratory failure
• 8 patients had disease progression (5 IB, 3 IB+R), with disease transformation reported in 3 patients
• Discontinuation due to second malignancies was reported in 6 patients with colorectal cancer, liposarcoma, melanoma, pleomorphic sarcomatoid tumor, and 2 cases of new-onset CML
• Most frequently reported related adverse events (AE) were similarly distributed in both arms, including arterial hypertension, neutropenia, diarrhea, and atrial fibrillation

While the addition of rituximab to ibrutinib in relapsed and high-risk CLL patients did not improve PFS, it’s hard to ignore the rapid and durable nature observed in these patients. While these results won’t change the current treatment paradigm (with single-agent ibrutinib standard-of-care), this finding may bear additional investigation. What’s more, some may choose to explore the option of adding rituximab to ibrutinib for patients whom a faster response is paramount.