This study shows that obinutuzumab in combination with ibrutinib as a frontline treatment for older or unfit CLL patients, is safe, well-tolerated, and effective. Moreover, it successfully explores the possibility of fixed-duration ibrutinib in a subset of patients with deep and sustained responses.
Our safety data is encouraging, with lower rates of infusion-related reactions observed with the IG-regimen (obinutuzumab plus ibrutinib) in comparison to the CLL11 study (obinutuzumab plus chlorambucil). Our overall IRR rate was 19% vs. 65%, and only 3% of patients had grade 3–4 IRR vs. 20% in the CLL11. None of our patients required hospitalization or discontinuation of obinutuzumab therapy due to IRR or any other causes, while 10% of the patients withdrew from the CLL11 study due to IRR.(5) Additionally, the iLLUMINATE study (obinutuzumab plus ibrutinib) found a similar safety profile to ours (overall IRR rate of 25%, and 3% grade 3–4 IRR).(7)
Our correlative analyses show how ibrutinib abrogates the release of cytokines such as IFN-γ, and TNF-α which have shown to be responsible for the clinical manifestations associated with IRR.(13, 14) Importantly, we found that patients with IRR showed a higher peak of CCL3 and CCL4. These chemokines are associated with tumor burden, poor prognosis, and release of other inflammatory factors that contribute to the survival of CLL cells.(15, 16) Moreover, the downregulation effect on cytokine/chemokine release and IRR did not seem to impact the response of patients to either ibrutinib or obinutuzumab. Our data suggest that the underlying mechanism responsible for the blockade of immune modulators is most likely ibrutinib and its BTK mediated inhibition of critical pathways responsible for immune activation.
The overall safety profile of the IG-regimen was consistent with the known profiles of the individual drugs, with no new adverse events identified. The most frequent grade 3–4 adverse events were neutropenia, thrombocytopenia, and hyperglycemia. Our high rate of hyperglycemia is likely due to the intravenous administration of glucocorticoids as premedication.
Regarding efficacy, our investigator assessment showed an overall response rate of 100%, and 9 out of 32 patients (28%) had a CR. These results are comparable with the independent review committee-based assessment in the iLLUMINATE study (88% and 19%, respectively). However, we recognize the potential limitations of our study, including the sample size and single-arm design. We observed a rate of uMRD in the bone marrow of 12.5%, in comparison with the 20% observed in the iLLUMINATE study and the 19.5% in the CLL11 trial. However, in the CLL11 study, the uMRD rate used a denominator of the number of patients from whom a result was, rather than the total number of patients treated. Also, in the iLLUMINATE trial some uMRD occurred in patients with partial (including nPR) responses, while we only systematically assessed MRD in patients with CR.
Our study included an innovative design, in which patients maintaining a CR response at 3-year follow up were recommended to stop ibrutinib. The rationale for this design is that patients with sustained CR could have similar outcomes with interruption of ibrutinib therapy, decreasing the risk of adverse events, serious complications, toxicities, in addition to reducing the financial burden that is associated with long-term ibrutinib management. This hypothesis is supported by observations in which patients that discontinued ibrutinib due to side effects had better outcomes than those that stopped therapy because of disease progression.(17, 18)
At a median follow up of 35.5 months, overall ibrutinib discontinuation in our study was at 41%. This discontinuation rate is higher than the iLLUMINATE study (30%, median follow up of 31 months) (7) but is lower than pooled clinical trial analyses (51%, median follow up of 40 months) (19) and real-world data (41%, median follow up 17 months) (20). Of notice, in our study only three patients (9%) discontinued ibrutinib during the first 18 months.
The response status at the time of discontinuation appears to determine the long-term outcome of patients that discontinue ibrutinib. In our trial, five patients with sustained CR decided to discontinue ibrutinib, and at the time of this report, they have been on clinical follow-up for up to 10 months without signs of disease progression. Additionally, 8 patients with PR have discontinued ibrutinib, and only 2 have disease progression. Overall, in our cohort, patients that stop ibrutinib for any reason (n = 13) have a longer time-to-progression, that exceeds historical data (13.5 months vs. 2.7 months) with a median follow-up time of 8 months after ibrutinib discontinuation, and a median time to progression that hasn't been reached. (17)
We acknowledge that our study has limitations that prevent a direct comparison with historical data on ibrutinib discontinuation. However, our data after discontinuation of ibrutinib is highly encouraging in comparison to the real-world studies that report 2.7 months as the median time to next therapy among patients who stopped ibrutinib (6.5 months for those who stopped ibrutinib due to toxicity versus 0.3 months for those who stopped due to disease progression—CLL progression or Richter's transformation.(17) Additional data regarding progression after ibrutinib discontinuation in patients with sustained remission is limited, and studies such as the CAPTIVATE trial (NCT# NCT03462719) will help to confirm whether ibrutinib, in combination with other agents, could induce deep responses that allow patients to discontinue long-term treatment without compromising disease-free survival.
Overall, we show that the combination of ibrutinib and obinutuzumab as first-line treatment in CLL patients that either refuse or were considered unsuitable for standard chemoimmunotherapy is safe, highly effective, and induces deep responses associated with uMRD. The IG-regimen was associated with a lower rate of infusion-related reactions, abrogation in the release of associated cytokines/chemokines, and sustained remissions despite ibrutinib discontinuation. Our observations are encouraging and warrant confirmation in long-term prospective studies.