Abstract
Background: Mantle cell lymphoma (MCL) is an unfavorable sub-type of B-cell non-Hodgkin lymphoma (NHL) characterized by brief progression-free survival (PFS) and median overall survival (OS) of only 3–4 y. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a great need for novel treatment strategies for this lymphoma entity.
Method: We conducted a phase-2 study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO;14;925, 1996). Eligible patients had a confirmed diagnosis of MCL using WHO criteria, age 18–75 y, ECOG PS ≤2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures including colonoscopy. Prior to initiating thalidomide, subjects were enrolled into S.T.E.P.S.® program. Therapy consisted of R-MACLO (rituximab 375 mg/m2 IV on d 1, Adriamycin, 45 mg/m2 IV on d 1, cyclophosphamide, 800 mg/m2 IV on d 1 and 200 mg/m2/d on d 2–5, vincristine, 1.5 mg/m2 on d 1 and d 8 capped to 2mg, methotrexate, 1.2 g/m2 IV on d 10 IV over 1 h followed by 5.52 g/m2 over 23 h followed by leucovorin 36 h later. G-CSF was begun on d 13. When ANC was >1.5x10e9/L R-IVAM was begun including rituximab, 375 mg/m2 IV d 1, cytarabine, 2.0 g/m2 IV every 12 h on d 1 and 2, ifosfamide, 1.5 g/m2 d 1–5 with mesna and etoposide, 60 mg/m2 d 1–5. Therapy was repeated 14 d after hospital discharge. After recovery from cycle-2 subjects were re-staged and responses assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide, 200 mg/d until lymphoma-recurrence or toxicity.
Results: 18 subjects enrolled; 17 are evaluable. Median age was 59 y (range, 44–73y), all had ≥stage-3 MCL with bone marrow involvement in 15 and gastrointestinal involvement in 9. Distribution according to IPI: 0–1 factor, 2; 2 factors, 7; 3 factors, 6; and ≥4 factors, 3. 16 subjects had diffuse variant and 2, blastic variant. 14 subjects completed the 4 cycles of therapy; the therapy was stopped after 2 and 3 cycles, respectively, in the remaining two patients. 1 subject died of septicemia on d 8 of first cycle. All subjects completing ≥1 cycle achieved CR. No subject relapsed and 15 are alive with a median follow-up of 18 mo (range, 4–40 mo). One patient died at 38m from non-small cell lung cancer diagnosed 19m post MCL diagnosis. Common severe toxicities were grade-3–4 neutropenia, thrombocytopenia and anemia in 48%, 21% and 24% of R-MACLO cycles and in 81%, 84% and 40% of R-IVAM cycles. There were 10 bacteremias in 65 cycles 9 of which were after R-IVAM therapy. 5 episodes of reversible grade-1–2 renal toxicity occurred after methotrexate. 5 subjects receiving thalidomide had dose-reductions because of neutropenia.
Conclusions The R-MACLO-IVAM-T therapy results in a high overall response rate with 100% CR and no relapses at median follow-up of 18 months. The contribution of each element of the regimen to this outcome requires study. Further clinical trials are suggested.
Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma