Zanubrutinib/Rituximab Induction Before Short-Course R-DHAOx Draws Responses in Mantle Cell Lymphoma

Qingqing Cai, MD

Frontline zanubrutinib (Brukinsa) plus rituximab (Rituxan) induction followed by short-course rituximab plus dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAOx) demonstrated antitumor activity in patients with mantle cell lymphoma (MCL), according to data from the phase 2 CHESS trial (NCT04624958) presented at the 2024 ASCO Annual Meeting.¹

Findings showed that at the January 2024 data cutoff, evaluable patients who underwent a post-treatment PET evaluation (n = 37) experienced a best complete response (CR) rate following zanubrutinib/rituximab induction of 91.9%. Among those complete responders, 94.1% obtained a CR after 2 to 4 cycles of zanubrutinib plus rituximab. The bone marrow minimal residual disease (MRD)–negative CR rate was 92.0% (n = 23 of 25).

Additionally, 1 patient experienced disease progression among the 27 patients who finished chemotherapy and were evaluable for response.

At a median follow-up of 11.6 months, the 1-year progression-free survival (PFS) rate was 90.1%, and the 1-year overall survival rate was 96.7%.

“Zanubrutinib [plus] rituximab followed by short-course chemotherapy yielded promising antitumor efficacy as frontline treatment of MCL,” lead study investigator Qingqing Cai, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues, wrote in a poster presentation. “This strategy might reduce the toxicity of cytarabine-based chemotherapy without weakening the therapeutic efficacy.”

Combining BTK inhibitors and rituximab has shown favorable efficacy as first-line therapy for patients with MCL. In November 2019, zanubrutinib received accelerated approval from the FDA for the treatment of adult patients with MCL who received at least 1 prior line of therapy.²

In the multicenter CHESS trial, investigators evaluated the efficacy and safety of zanubrutinib plus rituximab induction therapy, followed by short-course cytarabine-based chemotherapy and zanubrutinib maintenance in the frontline of treatment of patients with MCL.

Notably, previous data from CHESS reported at the 2022 ASH Annual Meeting demonstrated that at a median follow-up of 11.6 months (range, 1.93-20.03), patients treated with this regimen (n = 17) CR rate of 88.2%.³

CHESS enrolled patients 18 to 75 years of age with histologically confirmed CD20-positive MCL who were symptomatic from their disease and in need of treatment. Patients needed to have at least 1 of the following specific clinical features: blastoid or pleomorphic variants; bulky masses exceeding 7 cm or at least 2 tumors each 5 cm or greater in diameter; TP53, c-MYC, or NOTCH mutations; a spleen size of 20 cm of greater; lymphoma-related B symptoms; a MCL International Prognostic Index (MIPI) score greater than 3; or organ function threatened by lymphoma.⁴

Additionally, eligible patients must not have received prior anti-lymphoma treatment; have at least 1 evaluable lesion; have Ann Arbor stage II to IV disease, and an ECOG performance status of 0, 1, or 2. Inclusion was contingent upon a life expectancy greater than 3 months and adequate organ function.

Exclusion criteria included patients with central nervous system involvement; hemophagocytic syndrome; active bleeding or bleeding requiring anticoagulation; requirement for treatment with strong CYP3A inhibitors; uncontrolled active infections; history of HIV or AIDS; active hepatitis B or C; and pregnancy.

Previously untreated patients were enrolled onto the clinical trial to receive induction therapy consisting of 160 mg of zanubrutinib twice per day plus 375 mg/m2 on day 1 of each 28-day cycle. Induction continued until patients achieved a CR or for a maximum of 12 cycles. R-DHAOx was then given for 4 cycles, which consisted of 375mg/m2 of rituximab on day 1, 20 mg of dexamethasone on days 1 to 4, 2000 mg/m2 of cytarabine (or 1000mg/m2 for patients over 65 years of age) on days 2 and 3, and 130 mg/m2 of oxaliplatin on day 1. Patients who achieved CR following R-DHAOx received maintenance zanubrutinib at 160 mg twice per day for up to 1 year.^1,4

The primary end point of CHESS was CR following induction therapy. Additionally, MRD was evaluated in both bone marrow and peripheral blood conducted by flow cytometry.

Of the 42 patients included in the study, the median age was 57 years (interquartile range, 51-64) and a majority of patients were male (83.3%). Simplified MIPI risk scores included low (57.1%), intermediate (35.7%), and high (7.1%). Additionally, 81.0% of patients had classic cytomorphology was defined as classic, and 19.0% had blastoid, small cell, and pleomorphic cytomorphology.

“This trial has finished enrollment, and the final analysis will be published,” Cai reported.

References

1. Cai Q, Xia Y, Huang H, et al. Frontline treatment with zanubrutinib plus rituximab (ZR) followed by short course R-DHAOx in patients with mantle cell lymphoma (MCL): results of the phase II CHESS clinical trial. J Clin Oncol. 2024;42(suppl 16):7062. doi:10.1200/JCO.2024.42.16_suppl.7062
2. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. FDA. November 14, 2019. Accessed June 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-therapy-treat-patients-relapsed-and-refractory-mantle-cell-lymphoma-supported-clinical
3. Cai Q, Xia Y, Liu P, et al. Frontline treatment with zanubrutinib plus rituximab (ZR) followed by short course R-Dhaox shows potent efficacy in patients with mantle cell lymphoma (MCL) - preliminary results of phase II CHESS clinical trial. Blood. 2022;140(suppl 1):9356–9357. doi:10.1182/blood-2022-166237
4. Zanubrutinib and rituximab followed by R-DHAOx then maintenance with zanubrutinib for newly diagnosed MCL. ClinicalTrials.gov. Updated May 9, 2022. Accessed January 4, 2023. https://clinicaltrials.gov/ct2/show/NCT04624958