Older patients with CLL and comorbidities: an option for treatment with immunotherapy without chemotherapy?

Fading stars and supernovas of immunotherapy

Chronic lymphocytic leukemia is the most common leukemia in Western countries. It typically affects older individuals, who often have one or more comorbidities at the time of diagnosis, limiting treatment options.

However, the last 10 years have introduced several new targeted immunotherapy drugs into clinical practice, significantly reducing treatment toxicity. One of them is obinutuzumab, and this article focuses on its use in combination with other medications for patients who cannot be treated with fludarabine-based regimens due to comorbidities or age. So, is the classic immunochemotherapy with obinutuzumab and chlorambucil still the right path, or has its star faded, giving way to new standards of care? This question was also posed by Croatian experts in their current review.

New horizons of treatment

The randomized clinical trial CLL11 with previously untreated older patients with comorbidities evaluated the effect of obinutuzumab in combination with chlorambucil, rituximab plus chlorambucil, and chlorambucil alone. The study showed the superiority of obinutuzumab over rituximab and chlorambucil. The combination of obinutuzumab and chlorambucil provided a clinically significantly higher chance of achieving complete or partial responses, along with prolonged overall survival. This study represented a significant contribution to clinical practice, demonstrating that chlorambucil monotherapy is outdated and should only be administered to very high-risk and otherwise ill older patients where the treatment goal is palliative symptom relief.

Chemoimmunotherapy with obinutuzumab + chlorambucil should only be given to patients with favorable genetic characteristics of the disease; it is unsuitable in the presence of del17p abnormality.

The combination of obinutuzumab and ibrutinib can bring significant benefits, especially for patients with high-risk genetic abnormalities. This was demonstrated by the pivotal iLLUMINATE study. However, it should be noted that this regimen does not involve a fixed duration of treatment, as ongoing ibrutinib monotherapy is necessary.

The combination of obinutuzumab and venetoclax is an alternative treatment approach with a fixed duration of 12 months. The CLL14 study demonstrated significantly longer progression-free survival and deeper disease remission (higher proportion of patients with undetectable minimal residual disease) with the venetoclax + obinutuzumab combination.

Obinutuzumab + acalabrutinib is another possible combination, whose effect is still being investigated.

Conclusion for practice

Is it possible to use immunotherapy without chemotherapy in the first line for patients with CLL and comorbidities? In the last 5 years, many patients have been prescribed ibrutinib monotherapy, but as shown, many discontinue treatment due to toxic effects. However, we also have at least two other possible immunotherapeutic regimens without chemotherapy, and potentially a third if studies with acalabrutinib show favorable results.

Newly available drugs allow similar treatment goals to be achieved for high-risk and vulnerable individuals as for younger patients. Nevertheless, further data from randomized controlled trials and real-world clinical practice are needed to clearly define the standard of care.

(eza)

Source: Milunovic V., Jakobac K. M., Rogulj I. M. et al. The fading star of obinutuzumab-chlorambucil regimen in patients with comorbidities with chronic lymphocytic leukemia – are we ready for chemo-free immunotherapy approach? Expert Rev Hematol 2020; 13 (7): 771−779, doi: 10.1080/17474086.2020.1775575.