Efficacy and Safety of Bortezomib Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Vs R-CHOP in Japanese Patients (Pts) with Newly Diagnosed Mantle Cell Lymphoma (MCL) Not Considered for Transplantation Enrolled in the International, Randomized, Phase 3 LYM-3002 Study (NCT00722137)

Background:

LYM-3002 was a global study evaluating the efficacy and safety of frontline VR-CAP vs R-CHOP in newly diagnosed MCL pts who were not considered for hematopoietic stem cell transplantation. 487 pts (243 VR-CAP, 244 R-CHOP) were enrolled in 28 countries in the EU, North/South America, and Rest of World. VR-CAP was associated with significantly longer progression-free survival (PFS) by independent radiology review committee (IRC) vs R-CHOP (median 24.7 vs 14.4 mos; hazard ratio [HR] 0.63 [0.50, 0.79]; p<0.001). Secondary efficacy endpoints including complete response (CR)/unconfirmed CR (CR/CRu) rates by IRC (odds ratio [OR] 1.69), time to progression by IRC (HR 0.58), time to next therapy (TTNT; HR 0.50), treatment-free interval (TFI; HR 0.50), overall survival (OS; HR 0.80), and 4-yr OS rates (64.4% vs 53.9%) were also consistently improved with VR-CAP vs R-CHOP, with additional but expected and manageable toxicity (Cavalli et al. ASCO 2014, Abs 8500; Robak et al. EHA 2014, Abs S1345). VR-CAP has not previously been evaluated in Japanese pts with newly diagnosed B-cell lymphoma. This sub-analysis of LYM-3002 evaluated the efficacy and safety of VR-CAP vs R-CHOP in the cohort of Japanese MCL pts enrolled in the study. While the traditional drug development process in Japan requires a small separate phase 1/2 study in Japanese patients to confirm international study results, here a pre-planned Japanese subgroup was included in the larger phase 3 study.

Methods:

Adults with measurable stage II–IV MCL and ECOG PS 0–2 were randomized 1:1 (stratified by International Prognostic Index [IPI] score and disease stage) to 6–8 × 21-d cycles of rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², all IV d 1, and prednisone 100 mg/m² PO d 1–5, plus bortezomib 1.3 mg/m² IV d 1, 4, 8, 11 (VR-CAP) or vincristine 1.4 mg/m² (max 2 mg) IV d 1 (R-CHOP). Response was assessed by IRC and by investigator (INV) per International Lymphoma Workshop Response Criteria. Time-to-event outcomes were estimated by Kaplan-Meier methodology. The Cochran-Mantel-Haenszel Chi-squared test was used for response rate comparisons. Adverse events (AEs) were graded per NCI-CTCAE v3.0.

Results:

18 Asian pts with centrally confirmed MCL (7 VR-CAP, 11 R-CHOP) were enrolled in Japan. For VR-CAP vs R-CHOP, pts’ median age was 70 (64–74) and 70 (66–82) yrs; 6 vs 11 pts were aged >65 yrs. 4 vs 8 pts were male, 4/2/1 vs 8/3/0 pts had ECOG PS 0/1/2, 0/2/5 vs 1/1/9 pts had stage II/III/IV disease at diagnosis, and 0/3/3/1 vs 1/3/6/1 pts had IPI score low (0–1)/low–intermediate (2)/high–intermediate (3)/high (4–5). All pts completed ≥6 cycles, except for 1 pt on VR-CAP who discontinued after 2 cycles (grade 2 hypertension). After a median follow-up of ~33 mos, median PFS by IRC with VR-CAP vs R-CHOP was not reached (NR) vs 19.5 mos (1/7 vs 7/11 progression/death events; HR 0.39 [0.04, 3.52]; p=0.384; Figure) and by INV was NR vs 16.2 mos (2/7 vs 9/11 progression/death events; HR 0.46 [0.09, 2.45]; p=0.351). In 17 response-evaluable pts (7 VR-CAP vs 10 R-CHOP), rates of CR/CRu by IRC (bone marrow and LDH-verified) were 71% vs 50% (OR 3.0 [0.15, 59.89]; p=0.495) with median duration of CR/CRu NR vs 16.6 mos, and overall response rates (ORR; CR+CRu+partial response [PR]) were 100% in both arms. Median TFI was NR vs 19.1 mos (HR 0.71 [0.13, 3.89]; p=0.688) and median TTNT was NR vs 24.3 mos (HR 0.71 [0.13, 3.89]; p=0.688), respectively. After only 1 death (R-CHOP arm), median OS for VR-CAP and R-CHOP were not estimable (NE). 3-yr OS rates were 100.0% (NE, NE) vs 80.0% (20.4%, 96.9%). All pts experienced at least one grade ≥3 AE, most commonly neutropenia (100% VR-CAP vs 100% R-CHOP), thrombocytopenia (71% vs 0), febrile neutropenia (43% vs 45%), lymphopenia (43% vs 27%), leukopenia (29% vs 27%), and anemia (0 vs 27%). No grade ≥3 bleeding AEs were reported and grade ≥3 infection AEs occurred in only 1 pt on VR-CAP (herpes zoster infection). Peripheral neuropathy rates were 71% vs 45% (grade ≥3: 14% vs 9%). 1 R-CHOP pt experienced serious AEs (bile duct stone, femur fracture). There were no on-treatment deaths.

Conclusions:

Results from this cohort of Japanese pts enrolled in LYM-3002, showing improved efficacy in favor of VR-CAP with additional but manageable toxicity, appear consistent with the findings in the overall study population. VR-CAP could be considered as an alternative frontline treatment option for newly diagnosed, transplantation-ineligible MCL pts in Japan.

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