Safety and efficacy of a dose-dense short-term therapy in patients with MYC-translocated aggressive lymphoma

Abstract

Patients with aggressive B-cell lymphoma and MYC rearrangement at fluorescence in situ hybridization exhibit poor outcome after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In the last decade, 68 patients with Burkitt lymphoma ([BL] n = 46) or high-grade B-cell lymphoma ([HGBCL] single, double, or triple hit; n = 22) were treated with a dose-dense, short-term therapy termed "CARMEN regimen" at 5 Italian centers. Forty-six (68%) patients were HIV+. CARMEN included a 36-day induction with sequential, single weekly doses of cyclophosphamide, vincristine, rituximab, methotrexate, etoposide, and doxorubicin plus intrathecal chemotherapy, followed by high-dose-cytarabine-based consolidation. Patients who did not achieve complete remission (CR) after induction received BEAM (carmustina, etoposide, cytarabine, melfalan)-conditioned autologous stem cell transplantation (ASCT) after consolidation. Sixty-one (90%) patients completed induction, and 59 (87%) completed consolidation. Seventeen patients received ASCT. Grade 4 hematological toxicity was common but did not cause treatment discontinuation; grade 4 nonhematological toxicity was recorded in 11 (16%) patients, with grade 4 infections in 6 (9%). Six (9%) patients died of toxicity (sepsis in 4, COVID-19, acute respiratory distress syndrome). CR rate after the whole treatment was 73% (95% confidence interval [CI], 55% to 91%) for patients with HGBCL and 78% (95% CI, 66% to 90%) for patients with BL. At a median follow-up of 65 (interquartile range, 40-109) months, 48 patients remain event free, with a 5-year progression-free survival of 63% (95% CI, 58% to 68%) for HGBCL and 72% (95% CI, 71% to 73%) for BL, with a 5-year overall survival (OS) of 63% (95% CI, 58% to 68%) and 76% (95% CI, 75% to 77%), respectively. HIV seropositivity did not have a detrimental effect on outcome. This retrospective study shows that CARMEN is a safe and active regimen both in HIV-negative and -positive patients with MYC-rearranged lymphomas. Encouraging survival figures, attained with a single dose of doxorubicin and cyclophosphamide, deserve further investigation in HGBCL and other aggressive lymphomas.

Graphical abstract

Figure 1

Treatment schedule. Drugs, doses, and plan of induction and consolidation phases. Intrathecal chemotherapy was delivered weekly in patients with meningeal disease. Methotrexate dose on day 21 was 5 g/m² in HIV-positive patients. Graphic represents consolidation phase for HIV⁻ patients. Consolidation phase for HIV⁺ patients is reported in Table 1.

Figure 2

Consolidated Standards of Reporting Trials diagram. See Table 2 for “intensification” as salvage therapy. AML, acute myeloid leukemia; BSC, best supportive care; CRs, complete responders; HD-MTX, high-dose methotrexate; MATRix, methotrexate, cytarabine, thiotepa, and rituximab; PD, progressive disease; PR, partial responders; RICE, rituximab, ifosfamide, cyclophosphamide, and etoposide; RT, radiation therapy.

Figure 3

PFS and OS survival curves. PFS curves are represented in the left graphics and OS curves in right ones. PFS (A) and OS (B) curves of the whole series and of analyzed subgroups according to lymphoma entity (C-D) and to HIV sieropositivity (E-F). (G) PFS curves of the subgroup of patients with double-/triple-hit lymphoma; PFS and OS curves were superimposable in patients with double-/triple-hit lymphoma. OS (H) curves of patients according to the response to the induction (P = .02).