AUTHORS
Georgios N. Pongas, M.D., Dominic Earl Mitchell Jarrett, MD2, Jose Noy, MD3, Jennifer Chapman, MD4, Joseph Rosenblatt, MD5, Isildinha Reis, PhD6, Izidore S. S. Lossos, M.D.7
AFFILIATIONS
1 Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, Florida, United States
2 Department of Internal Medicine, Jackson Memorial Hospital, Miller School of Medicine, Miami, Florida, United States
3 Department of Internal Medicine, Jackson Memorial Hospital, Miller School of Medicine, Miami, Florida, United States
4 Division of Hematopathology, University of Miami, Miller School of Medicine, Miami, Florida, United States
5 Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, Florida, United States
6 Biostatistics and Bioinformatics Shared Resource, Sylvester Comprehensive Cancer Center, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, United States
7 Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, Florida, United States
ABSTRACT
Background: Mantle cell lymphoma is considered an incurable malignancy. We previously reported on the results of two studies assessing the R-MACLO-IVAM followed by thalidomide (Thal) (UM-MCL1-NCT00450801) and rituximab (R) (UM-MCL2-NCT00878254) maintenance. We now present the long-term follow-up results of these two studies along with a real-world (RW) experience with shortened R-MACLO-IVAM or R-IVAM followed by BTK inhibitor maintenance (BTKi-m).
Methods: The treatment and the eligibility criteria for the trials treated patients (pts) were previously reported (PMID:20038221; PMID:33735476). Pts were also treated off protocol (RW) with either R-MACLO-IVAM (2018-2021) or only R-IVAM (2021-2026) followed by BTKi-m. In RW-pts, restaging was performed with a PET CT after cycle 2 and pts achieving complete response (CR) started BTKi-m administered until disease progression or loss of tolerance. RW pts achieving partial response (PR) received additional cycles of chemotherapy (1 or 2) followed by BTKi-m. Of the 16 pts in the BTKi-m arm, 6 received R-MACLO-IVAM and 10 R-IVAM. Progression-free survival (PFS) was calculated from the day of chemotherapy initiation until date of progression or death. Overall survival (OS) was calculated from the day of chemotherapy initiation to the date of death. Lymphoma specific deaths were defined as deaths due to lymphoma or complications of the lymphoma directed therapy. Kaplan-Meier survival analysis, log-rank test, Cox regression followed by pairwise comparisons were used for statistical analyses.
Results: A total of 60 pts treated with R-MACLO-IVAM between 2004-2026 are included in this analysis (UM-MCL1 and 2, n=22 each and RW n=16). The median age was 58 yrs (39-73). Most pts were white (90%), male (76.6%), had ECOG≤1 (95%), stage IV disease (93.3%) and bone marrow involvement (85%). LDH was elevated in 35% and beta -2 microglobulin in 57.9% (n=57). Gastrointestinal system was involved in 64% of pts (n=50). Ki-67% was >30 in 50% out of n=50 pts. Most pts had intermediate/high MIPI (65%) and high-intermediate/high MIPIc (54%). Seven pts had blastoid histology (11.7%). The overall response rates (ORR), CR and PR rates were 100%, 100% and 0% for the UM-MCL1, 100%, 90% and 10% for the UM-MCL2 and 100%, 87.5% and 12.5% for the BTKi arm, respectively. The median PFS (mPFS) in the Thal and R arms were 7.83 (95%CI, 3.38-11.01) and 5.86 (2.78-18.41) years (yrs), respectively. The mPFS was not reached (NR) in the BTKi group during a median follow-up of 4.25 yrs. The median OS (mOS) in the Thal, R and BTKi arms were 18.41 (7.04-NR), 11.98 (5.54-NR) yrs and NR, respectively. In BTKi the 5-year PFS and OS were 70% (37.2-87.9%) and 83% (45.7-95.6%), respectively. There was no statistical difference between the three groups for PFS (P=0.77) and OS (P=0.97), and therefore the data was aggregated (n=60 total pts) to analyze overall response assessments, PFS, and OS.
Collectively the ORR, CR and PR rates were 100%, 93.2% and 6.7%. The overall mPFS for all pts was 7.7 yrs (95%CI, 4.12-10.15) and the overall mOS was 18.4 yrs (95%CI, 8.36-NR). The high-risk MIPI group had statistically significant shorter PFS compared with intermediate (HR=3.50 [95% CI 1.57-7.82], P=0.002) and low-risk (4.81 [2.06-11.27], <0.001), and also significantly shorter OS compared to the low-risk (3.49 [1.21-10.06] 0.021) and compared to intermediate-risk (2.61 [1.01-6.75] 0.049) pts. Pts with blastoid MCL (n=7) had a 5-year PFS and OS of 28.6% (95%CI, 8.9-92.2%) and 57.1% (30.1-100%), respectively.
Of the 60 pts, there were a total of 23 deaths, 15 (25%) of which were lymphoma related (including 2 deaths from complications related to allogenic transplant for AML and MDS). During a median follow up of 11.82 yrs (95%CI 9.02-15.81), the estimated cumulative incidence of lymphoma-related mortality at 7 and 10 years were 18.4% (95%CI 9.3-29.9%) and 27.7% (95%CI 15.9-40.8%), respectively and 18.3% of 60 pts were lymphoma free at 10 yrs with plateau on PFS curve.
Conclusions: Herein, we report long OS and lymphoma-specific survival in medically fit pts with mantle cell lymphoma treated with R-MACLO-IVAM chemotherapy. The incorporation of a BTK inhibitor as maintenance therapy for pts who achieve CR after induction has potential to reduce the number of required chemotherapy cycles and mitigate chemotherapy associated toxicity. While longer follow-up is needed, it is possible that some pts treated with this therapy may be cured.
DISCLOSURES
Georgios N. Pongas, M.D.: MEVOX, ltd - Current equity holder in private company; ADC Therapeutics - Consultancy (Includes expert testimony); BeOne Medicines - Consultancy (Includes expert testimony)