Treating CLL in the Age of COVID-19

Javier L. Munoz, MD, MBA

Although the magnitude of COVID-19 is enormous, one group of patients was particularly affected: those whose chronic lymphocytic leukemia (CLL) may have been poorly monitored at the height of the pandemic. Javier L. Munoz, MD, MBA, director of the Lymphoma Program at Mayo Clinic in Phoenix, Arizona, discussed best options and timing for treating CLL now and beyond the pandemic in a presentation during the Association of Community Cancer Centers 38th (Virtual) National Oncology Conference.¹

“Patients can die with CLL, not from CLL,” Munoz said. “But that’s not a universal rule.” Given the different phases of dormancy and active malignancy, CLL treatment is complicated. “We have plenty of room for improvement when it comes to helping patients with CLL,” he continued.

COVID-19 is a relatively new disease, so an encyclopedic level of evidence is lacking and clinicians are learning as they go, said Munoz. “Is COVID-19 more lethal in patients with cancer than in patients without cancer?” asked Munoz. “The answer is ‘yes.’” He noted the evidence of the many COVID-19 and cancer registries that have been initiated since the pandemic began.² Risk factors for mortality include age, being male, smoking history, number of comorbidities, and poor performance status. Compounding these challenges are oncologic features that may predict for worse outcomes, including tumor stage, disease trajectory, and lung cancer.

Although traditional vaccine development can take 15 years or more, the timeline for the vaccine against SARS-CoV and MERSCoV, the viruses responsible for the development of COVID-19, were accelerated, said Munoz. He noted that the lengthy discovery phase in traditional vaccine development was skipped, with phase 1/2 studies initiated, followed by the initiation of phase 3 trials after interim analysis of the early phase trials, with several trials running in parallel.

Munoz noted that evidence for COVID-19 and blood cancers had an encouraging start with a study (NCT04665115) evaluating the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) that is indicated for indolent B-cell malignancies and chronic graft-vs-host disease by Treon et al.³ The investigators followed 6 patients receiving ibrutinib for Waldenström macroglobulinemia who were diagnosed with COVID-19. Five patients received the recommended treatment dose, but 1 patient received a reduced dose because of arthralgias. The patients who received the recommended dose did not experience dyspnea and did not require hospitalization.

A larger international study⁴ across 43 international centers described the experience of investigators treating patients with CLL using BTK inhibitors who had symptomatic COVID-19. In the study, the investigators reported that the use of BTK inhibitors did not affect survival, with a case fatality rate of 34% vs 35%.

Turning to the issue of the effect of anticancer treatment on the response to vaccines, Munoz emphasized that unvaccinated patients develop more antibodies after vaccination compared with vaccinated patients. The risk for developing blood clots, which carries a 16.5% risk with COVID-19, is higher, compared with the use of oral contraceptives (0.05% to 0.12%), smoking (0.18%), or the use of the vaccine (0.0004%). All these were points leading Munoz to emphasize the importance of getting a COVID-19 vaccine for patients with CLL. “Please do not wait. Please get vaccinated as soon as possible,” Munoz said. Further, Munoz encouraged mask-wearing as well as obtaining a booster dose for patients with CLL.

Current CLL guidelines suggest ibrutinib, acalabrutinib (Calquence), and venetoclax (Venclexta) plus rituximab (Rituxan) in patients older than 65 years or patients younger than 65 with significant comorbidities. Patients younger than 65 without significant comorbidities are candidates for ibrutinib, acalabrutinib, and venetoclax plus rituximab, according to National Comprehensive Cancer Network guidelines.⁵ “I look for excuses not to prescribe chemotherapy,” Munoz said.

Looking to the future, Munoz was encouraged by the research evaluating reversible BTK inhibitors that are designed to overcome resistance mutations. Newer agents target C481 mutation. These agents change ibrutinib to a reversible inhibitor with decreasing binding efficiency and increased BTK enzymatic activity. Another potential treatment focuses on mutations in PLCγ2 and the R665, L845, and S707 hot spots, which promote the gain of function in the setting of B-cell receptors.

In cellular therapies, preliminary data suggest that lisocabtagene maraleucel (Breyanzi) in combination with ibrutinib has manageable safety, including a low incidence of grade 3 cytokine release syndrome and grade 3 or greater neurologic events.⁶ “Overall, the future is bright for patients with CLL,” Munoz concluded.

_REFERENCES:

_{1. Munoz J. Effective practices for treating patients with CLL during the COVID-19 era and beyond. Presented at: Association of Community Cancer Centers 38th National Oncology Conference; November 8-10, 2021. Accessed November 15, 2021.}

_{2. Lee AJX, Purshouse K. COVID-19 and cancer registries: learning from the fi rst peak of the SARS-CoV-2 pandemic. Br J Cancer. 2021;124(11):1777-1784. doi:10.1038/s41416-021-01324-x}

_{3. Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912-1915. doi:10.1182/blood.2020006288}

_{4. Mato AR, Roeker LE, Lamanna N, et al. Outcomes of COVID-19 in patients with CLL: a multicenter international experience. Blood. 2020;136(10):1134-1143. doi:10.1182/blood.2020006965}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Acute lymphocystic leukemia, version 2.2021. Accessed November 14, 2021. https:// bit.ly/3ne4HIn 6. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2021;blood.2021011895. doi:10.1182/ blood.2021011895}