Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma

Preetesh Jain, MD, DM, PhD; Shuangtao Zhao, PhD; Hun Ju Lee, MD; Holly A. Hill, MPH; Chi Young Ok, MD; Rashmi Kanagal-Shamanna, MD; Fredrick B. Hagemeister, MD; Nathan Fowler, MD; Luis Fayad, MD; Yixin Yao, PhD; Yang Liu, PhD; Omar B. Moghrabi, BS; Lucy Navsaria, MBBS; Lei Feng, MS; Graciela M. Nogueras Gonzalez, MPH; Guofan Xu, MD; Selvi Thirumurthi, MD; David Santos, MD; Cezar Iliescu, MD; Guilin Tang, MD, PhD; L. Jeffrey Medeiros, MD; Francisco Vega, MD, PhD; Michelle Avellaneda, BS; Maria Badillo, BS; Christopher R. Flowers, MD; Linghua Wang, PhD; Michael L. Wang, MD

Disclosures

J Clin Oncol. 2022;40(2):202-212. 

In This Article

Discussion

Treatment of previously untreated older patients with MCL is challenging because of generally coexisting comorbidities and age-related complications. Traditionally, older patients with MCL are treated with chemoimmunotherapy. In general, adverse effects from chemoimmunotherapies can limit the quality of life in older patients. The adverse impact of conventional chemoimmunotherapies[2,6–9] on patient's performance status, worsening of comorbidities, risk of severe infections, second cancers, and the need for hospitalization are the major factors to consider in treating older patients with MCL. Therefore, development of safe and efficacious therapies for older patients with MCL is a major unmet need. The advent of orally administered and well-tolerated nonchemotherapeutic targeted agents, such as ibrutinib, was significant for older patients with MCL. After the approval of BTK inhibitors in relapsed MCL,[10–14] it was natural to investigate ibrutinib with rituximab combination in the frontline setting. Therefore, we designed this completely chemotherapy-free approach with IR combination for previously untreated older patients with MCL.

There has been a continuous natural evolution of frontline therapies for the elderly patients with MCL. In the Data Supplement, we have summarized the results from previous studies in elderly patients with MCL after other standard therapies. Chemoimmunotherapy, such as rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone–based studies, induced an ORR (CR) of 86% (34%) in the MCL elderly study,[6] and bortezomib–rituximab, cyclophosphamide, doxorubicin, and prednisone,[7] 92% (53%), whereas the other commonly practiced bendamustine-rituximab–based studies induced an ORR (CR) of 93% (40%) in the StiL study.[21] Other bendamustine-rituximab–based studies with rituximab, bendamustine, and cytarabine induced an ORR (CR) of 91% (91%),[8] and in the rituximab, bendamustine, bortezomib and dexamethasone[22] study, 84% (75%). Of note, the rituximab, bendamustine, and cytarabine therapy[8] was also myelosuppressive (50%) in older patients with MCL. With chemoimmunotherapies, the grade 3–4 myelosuppression was observed in 40%-50% of patients and with a longer follow-up, about 10% of patients developed second cancers. Furthermore, lenalidomide with rituximab[23] combination was investigated in the frontline setting (excluding blastoid/pleomorphic histology) in a phase II multicenter study (n = 38; 24 patients age > 60 years), but 16% of patients developed second cancers and 42% developed grade 3 neutropenia, similar to myelosuppression observed with chemoimmunotherapies. The combination of lenalidomide with bendamustine rituximab[24] was also investigated in elderly patients with MCL and was associated with 38% grade 3 neutropenia, 42% severe infections, and 16% risk of second primary cancers.

It is in such a historical context that we designed the current trial. Our study excluded patients with Ki-67% > 50% and/or blastoid/pleomorphic histology because we were not confident that this combination would be effective in patients with high-risk MCL. Our data demonstrated a lower rate of grade 3–4 myelosuppression and a lower risk of hospitalization for infections (< 10%) than previously published chemoimmunotherapy results.[6–8] These were the major advantages of IR combination in elderly patients with MCL, compared with other treatment modalities with chemoimmunotherapy or lenalidomide-rituximab.

Of note, after a median follow-up of 45 months, 28 (56%) patients had discontinued IR therapy for various reasons, mainly because of intolerance in 21 of 28 patients. The median time to IR discontinuation was 32.6 months (Data Supplement). Although the rate of discontinuation because of disease progression (8%) was lower than some other therapies (40%-60%),[6,23] the rate of study discontinuation because of intolerance (42%) was higher in this study compared with previous studies with other therapies (10%-25%).[6,8,23] Furthermore, with a nearly similar median follow-up, the rate of study discontinuation because of intolerance was higher in our study compared with the IR combination in relapsed MCL[15] (56% v 18%, respectively). Possible reasons for these differences could be elderly patient population with comorbidities since 6 of 9 patients who discontinued IR combination in relapsed MCL were age ≥ 65 years.

Moreover, IR combination in relapsed MCL demonstrated that the incidence of atrial fibrillation was < 12%.[15,25] In this study, 17 patients developed atrial fibrillation. The numbers of baseline cardiovascular risk factors and baseline asymptomatic ECG abnormalities were higher in patients who developed atrial fibrillation compared with patients who did not develop atrial fibrillation, with median of 4 (range 1–8) vs median of 2 (range 1–4) and 13 of 17 (76%) versus 17 of 33 (51%) patients, respectively (described in the Data Supplement). These differences could potentially explain the increased incidence of atrial fibrillation observed in this study. At the time of initial enrollment in 2015 for this study, our screening process did not include a comprehensive cardiology evaluation in any patients before treatment with ibrutinib. Our results demonstrate that appropriate patient selection from cardiology standpoint before IR therapy is important. Recently, an echocardiogram-based baseline parameter such as left atrial volume index ≥ 40 mL/m2 has been reported[26] by cardiologists to identify patients who are prone to develop ibrutinib-associated atrial fibrillation.[27] To mitigate the risk of discontinuation because of intolerance, a frontline phase II study with acalabrutinib-rituximab in elderly patients with MCL is conducted at our center (NCT04765111).

With respect to survival outcomes, the median PFS and OS were not reached after almost a 4-year follow-up, but significantly higher risk of events was noted in patients with high-risk MIPI and those who did not attain CR. On comparing patients with a high (≥ 30%) and low (< 30%) Ki-67 index, the PFS and OS were not significantly different, but higher risk of progression event was noticeable in those patients with Ki-67 higher than 30%. Only three patients among the 18 evaluable patients had TP53 aberrations, where one patient progressed while other two discontinued therapy because of intolerance. The response rates in this limited number of patients with TP53 aberration were lower compared with patients without TP53 aberrations. These data further suggest that for elderly patients with high-risk[3] MCL, IR combination alone may not be sufficient and we will need to develop newer treatment modalities for these elderly patients with high-risk MCL. Furthermore, this is a single-arm study, which excluded high-risk (blastoid or Ki-67% > 50%) patients and may induce a selection bias, and therefore, the true efficacy of this regimen in MCL across various risk categories should be further evaluated in a randomized study and should be compared with standard treatments.

We further investigated for genomic predictors of response, using WES and bulk RNA sequencing, among the evaluable baseline tumor tissues. Our WES data demonstrate that partial responders to IR were enriched in KMT2D, FAT1, FAT4 (cell adhesion factor), ROS1, CARD11, NOTCH1, NSD2, and CCND1 mutations. These findings are consistent with other previous studies[28–32] showing disease resistance to BTK inhibitors with these mutations; however, STAB1 gene (lymphocyte homing and angiogenesis) deletions and ROS1 mutations were not previously reported in MCL. NCOR2 mutations were clustered in those with CR, and this could mediate the downregulation of targeted genes, which are unknown at this time in MCL.

Furthermore, the DEG data are interesting and demonstrate that BCR signaling pathway aberrations are predominant in patients with PR compared with those in CR. A cluster of differentially overexpressed genes—CCND1, BIRC3, BANK1, SETBP1, RRAS2, AXIN2, and IL2RA, were observed in patients who achieved a PR (n = 7) compared with patients who achieved CR (n = 9). Of note, BANK1 gene[33] expression is associated with sustained BCR signaling in lupus patients. These genomic data provide us a cleaner evidence to evaluate the baseline transcriptomic signature and understand the complexity of the BCR signaling pathway,[34] adapter proteins, and their relationship with the tumor microenvironment in MCL.

To conclude, IR combination is an effective, easily administered, and chemotherapy-free option in elderly patients with nonblastoid (and/or Ki-67 < 50%) MCL. New onset atrial fibrillation was observed in nine patients (18%). We recommend that pretreatment assessment of cardiovascular risk factors is beneficial before IR therapy. Long-term follow-up and randomized studies with standard treatments are needed to further evaluate the efficacy, safety, and pattern of relapse with IR combination.

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