IV High-Dose Methotrexate With IT Liposomal Cytarabine and R-CHOP Effective for Patients With Risk of CNS Relapse, Including DLBCL With Primary Testis Localization

The administration of intravenous (IV) high-dose methotrexate (MTX) in combination with intrathecal (IT) liposomal cytarabine and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days is an effective treatment among patient populations with very high risks of central nervous system (CNS) relapse, specifically primary testicular diffuse large B-cell lymphoma (PTL), according to phase 2 results from the IELSG30 trial.

“DLBCL with primary testis localization is a rare entity, accounting for <2% of all non-Hodgkin lymphoma, however, it represents the most frequent testicular neoplasm in older patients,” explained Annarita Conconi, MD, Division of Hematology, Ospedale degli Infermi, Biella, Italy, and colleagues, adding, “It is recognized as a unique condition characterized in historical series by high long-term risk of contralateral testis and central nervous system (CNS) relapse, despite most patients having a low CNS International Prognostic Index score.”

 This multicenter, phase 2 prospective study examined the progression-free survival (PFS) of 6 cycles of the standard 21-day R-CHOP (CHOP21) regimen; 4 doses of IT liposomal cytarabine; 2 cycles of IV HD-MTX; and prophylactic radiotherapy (RT) to the contralateral testis. From October 2009 to July 2017, 54 consecutive patients were enrolled; all patients had diagnostic orchiectomy. It was noted that 32 patients had stage 1 disease and 22 patients had stage 2 disease. All but 3 patients had a baseline PET/CT, and the diffuse large B-cell lymphoma (DLBCL) histology was confirmed by an expert pathologist review in all patients.

The treatment consisted of R-CHOP21, which included rituximab (375 mg/m² per day IV) on day 0 or day 1, cyclophosphamide (750 mg/m² per day IV) on day 1, doxorubicin (50 mg/m² day IV) on day 1, vincristine (1.4 mg/m² per day IV, maximum 2 mg) on day 1, and prednisone (40 mg/m² per day, orally) on day 1 to 5. These treatment cycles were repeated every 21 days, and all patients were restaged after 3 cycles of R-CHOP21. Patients with stage 1 and 2 disease received a total of 6 cycles of R-CHOP21. Furthermore, all patients were planned to receive CNS prophylaxis with 4 doses of IT liposomal cytarabine (50 mg) given on day 0 of cycles 2, 3, 4, and 5 of R-CHOP21 and 2 cycles of IV HD-MTX (1.5 g/m²) given at the end of the chemoimmunotherapy program.

Trial results demonstrated of the 54 patients, 51 (94%) completed R-CHOP21 as planned, as this treatment was well tolerated with no unexpected adverse events. Additionally, at a median follow-up of 6 years, there was no CNS relapse. Investigators noted that 7 patients progressed, and 8 died, with 5-year PFS and overall survival (OS) rates of 91% (95% confidence interval [CI], 79 to 96) and 92% (95% CI, 81 to 97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Furthermore, intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, which were mainly at extranodal sites, represented the most relevant pattern of failure.

The safety profile measured that adverse events induced by IT prophylaxis were mild and occurred at low frequency (only 1 patient discontinued treatment after 3 doses because of systemic toxicity related to R-CHOP21). It was noted that IV HD-MTX was feasible, with only 3 patients discontinuing treatment after the first dose because of adverse events (intracranial hemorrhage, acute kidney failure, and grade 3 mucositis, in 1 patient each.)

 Conconi and colleagues concluded, “The IELSG30 prospective trial demonstrates that the administration of IV HD-MTX in combination with IT liposomal cytarabine and the R-CHOP21 program is feasible and effective in a patient population with very high risk of CNS relapse and advanced age at diagnosis in many cases.”

“Late relapses, mainly involving extranodal sites, still represent a clinical challenge in the management of PTL. Hopefully, a better knowledge of the molecular pathogenesis of the disease will help refine the optimal therapeutical strategy,” they added.

Source:

Conconi A, Chiappella A, Ferreri A, et al. IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma. Blood Adv (2024) 8 (6): 1541–1549. doi: 10.1182/bloodadvances.2023011251