Diagnosed Diffuse Large B-Cell Research Articles

Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas.

8003 Background: Dose-adjusted (DA) EPOCH-R is a frontline treatment for aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression in lymphomas and is antagonized by BH3 mimetic venetoclax (ven). We conducted a phase I study combining ven with DA-EPOCH-R in aggressive B-cell lymphomas. Methods: This phase 1 study used Bayesian optimal interval design with dose expansion. Eligible patients (pts) were 18 years with newly diagnosed diffuse large B-cell (DLBCL), primary mediastinal, and high grade B-cell lymphoma (HGBCL) with double hit (DHL) or not otherwise specified (NOS). Ven was dosed at 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3) daily for 10 days with 6 cycles of DA-EPOCH-R. A subsequent cohort received ven 600 mg daily for 5 days (DL2B). Toxicities were graded by CTCAE v4.0 and response assessed by Lugano criteria. Dose limiting toxicity (DLT) period was cycle 1 and primarily included grade (gr) ≥3 neutropenia on cycle 2 day 1, gr ≥4 febrile neutropenia/thrombocytopenia, and gr ≥3 nausea, vomiting, diarrhea despite supportive care. Results: 30 pts enrolled with median age 64 (24-79), and 50% female. Ann Arbor stage was III-IV in 23. IPI was high risk in > 50%. Diagnosis was DHL (15), DLBCL NOS (13), and HGBCL NOS (2). 18 had MYC and 14 had BCL2 rearrangements. Bcl-2 was expressed ≥50% by IHC in 21/26 with data. There were no DLTs in DL1 (3 pts) or DL2 (9 pts). 1/6 had DLT in DL3 (gr 4 thrombocytopenia). Ven dose reductions occurred in subsequent cycles in 4 (2 in DL2; 2 in DL3). Of 18 in DL1-3, EPOCH was escalated above level 1 in 1 and de-escalated below level 1 in 7. Because of delays and ven dose reductions in DL2-3 due in part to cytopenias, infections and GI toxicities, we accrued DL2B. In DL2B, 0/12 pts had DLTs or ven dose reductions. EPOCH was escalated above level 1 in 4 and de-escalated below level 1 in 3. 1 died of sepsis during cycle 3. Most common gr 3-4 toxicities across all dose levels were cytopenias; febrile neutropenia occurred in 57%. Most common non-hematologic toxicities of all grades were hypocalcemia, nausea, diarrhea, hypokalemia and fatigue. ORR (N = 30) ITT was 97% with 27 (90%) complete and 2 (7%) partial responses; 1 was not evaluable. Follow up is ongoing. Of 15 DHL, ORR and CRR were 93% and 80%. Conclusions: We identified ven 600 mg for 5 days per cycle as RP2D with DA-EPOCH-R. DL2B was well tolerated and required no ven dose reductions. Further efficacy and safety is being evaluated in Alliance 51701, DA-EPOCH-R/R-CHOP in DH/double expressor lymphomas, using the dosing regimen defined by this study. Clinical trial information: NCT03036904 .

A Phase I/II Trial of Lenalidomide and RCHOP (R2CHOP) in Patients with Newly Diagnosed Diffuse Large B -Cell (DLBCL) and Follicular Grade 3 Lymphoma.

Abstract 1669Poster Board I-695 BackgroundThe addition of rituximab to chemotherapy significantly improved the results of therapy in aggressive non-Hodgkin's B cell lymphoma (NHL). However, significant number of the patients relapse following initial therapy. Lenalidomide was shown to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol 26:4952-7, 2008) however the safety in combination with standard first line immunochemotherapy is unknown. We initiated a phase I/II trial of R2-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone rituximab and lenalidomide) to establish the safety and efficacy of this therapy in the treatment of patients with newly diagnosed aggressive B cell NHL. Herein, we report the results of phase I portion of this study. MethodsA phase I study was designed to define the maximum tolerated dose (MTD) of lenalidomide administered on days 1-10 with R-CHOP chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1-5 of 21 day cycle) utilizing 3+3 dose escalation design. Lenalidomide dose escalation levels were 15 mg, 20 mg and 25 mg. All patients received 6 mg pegfilgrastim injection on day 2. Dose limiting toxicity (DLT) was defined as any grade 3 or more non-hematological toxicity or a hematological toxicity requiring a delay of the next cycle of chemotherapy due to cytopenia. The latter criterion was to ensure maintenance of the dose intensity and schedule of RCHOP; a potentially curative therapy in this setting. Eligible patients were adults newly diagnosed with CD20 positive diffuse large cell or follicular grade III B cell lymphoma, ECOG PS 0-2 and good organ function. There was no upper age restriction to participate in this study. ResultsTwelve patients were enrolled in phase I of this study. The median age was 69 years (range, 49-82) and 58% (7/12) of patients were males. Ten patients (83%) had DLBCL and two (17%) patients had follicular grade 3B lymphoma. International prognostic index was intermediate, high- intermediate and high in 6, 4 and 2 patients respectively. Patients distribution by lenalidomide dose was: 3 patients received 15 mg/day, 3 received 20 mg/day and 6 received 25 mg/day on days 1-10. Non-hematological toxicities included: grade 3 toxicity - neuropathy in one patient (8.3%), grade 2 toxicities were: infection in 17% (2/12) patients (skin in one patient, otitis media, and urinary tract infection in one patient); nausea 8% (1/12), rash 8% (1/12) and alopecia 41% (5/12). The most common toxicity to R2-CHOP was myelosuppresion. Grade 3 and 4 neutropenia occurred in 17% (2/12) and 41% (5/12) of patients, respectively. The neutropenia was of short duration, and no patients developed neutropenic complications. Grade 3 thrombocytopenia was seen in 8% (1/12). Most importantly, there were no delays in chemotherapy due to cytopenias. No DLT was seen. The 25 mg/day days 1-10 dose of lenalidomide was taken forward to an ongoing phase 2 trial. ConclusionLenalidomide at a dose of 25 mg/day for days 1- 10 combined with R-CHOP chemotherapy is well tolerated. The addition of lenalidomide did not affect hematological recovery and did not result in treatment delays. This dose and schedule is now being evaluated in the phase II part of the trial. DisclosuresZent:Genentech, Bayer, Genzyme, Novartis: Research Funding. Witzig:Novartis: Research Funding.