Intensified CHOP (ICHOP) +/− Rituximab in Primary Mediastinal Diffuse Large B Cell Lymphoma (PMBCL): The Role of Doxorubicin/Cyclophosphamide Dose-Intensity
Authors: Mazza Rita , Demarco Monica , Spina Michele , Magagnoli Massimo , Castagna Luca , Siracusano Licia , Giordano Laura , Tirelli Umberto , Santoro Armando , Balzarotti Monica 
Published: October 2019

Abstract
Background PMBCL is a clinical/biological distinct entity, sharing some characteristics with both classical DLBCL and Hodgkin’s lymphoma. MACOP B is considered the treatment of choice.
Methods Starting from 1997, we treated PMBCL with an ICHOP regimen including cyclophosphamide 1750 mg/mq with MESNA uroprotection, doxorubicin 75 mg/mq, vincristine 1.4 mg/mq with 2 mg cap, and prednisone 100 mg d 1–5 of each 14-day courses, GCSF from day 7 to day 12. Rituximab (R) 375mg/mq/course was added to ICHOP (R-ICHOP) from 2002. Treatment plan included five courses of ICHOP±R. Cases with unfavourable prognosis according to age-adjusted International Prognostic Index (aaIPI2–3) were submitted to high dose chemotherapy (HDT) and peripheral stem cell rescue. Radiotherapy on involved sites was then delivered to all patients if at least partial remission (PR) was reached. Clinical response was evaluated through CT +/− Gallium scan (14 pts) up to 2002, and thorough CT + PET scan (16 pts) thereafter, according to Cheson criteria.
Results: up to 2006, 30 pts were treated, with the following characteristics: M/F 10/20, median age 34 years (range 22–53), Ann Arbor stage I: 4, II –IIE:19, III: 1, IV: 6; bulky disease: 29; B symptoms: 14; aa IPI 0–1: 24, 2–3: 6; RICHOP/ICHOP 21/9. After ICHOP±R 15 patients achieved complete (CR) or unconfirmed complete remission (CRU), 14 PR, 1 stable disease. At the end of the whole program 29/30 pts reached CR and one progressed. Seven pts received HDT, six following ICHOP±R and one after II line chemotherapy for refractory disease. After a median observation time of 60 months 1 patient progressed and 1 patient relapsed, respectively. Both died of lymphoma.
One patient with stage IIE IPI 0 relapsed 18 months after completion of ICHOP and RT and died after further 5 treatment lines including alloBMT. The other patient with stage II EB IPI 1, progressed shortly after R-ICHOP and RT and died five months later. Five-yr failure free survival and overall survival are 93.2 and 92.8, respectively. ICHOP±R was well tolerated, with neither toxic death or life-threatening toxicity. No patient interrupted the planned treatment because of toxicity. Hospitalization was required in seven cases due to febrile neutropenia (6), hemorrhagic cystitis (3 cases), and pneumonia (1). Five episodes of grade III–IV mucositis were observed in 4 patients. Of 147 delivered cycles, 25 were delayed (13 pts).
Conclusion: in PMBCL, the results obtained with the ICHOP protocol are better than standard CHOP and comparable to MACOP-B, emphasizing the role of doxorubicin and cyclophosphamide dose-intensity. In this limited series, the impact of adding rituximab is not clear.
R-ICHOP ICHOP Tot. Patients (N°) 21 9 30 * IPI 0; ^ IPI 1 IPI 0–1 16 8 24 IPI 2–3 5 1 6 Response to CT (N°) Complete Remission 10 5 15 Partial Remission 11 3 14 Induction Failure 0 1* 1* Response CT +RT+/− HDT (N°) Complete Remission 20 9 29 Partial Remission 0 0 0 Induction Failure 1 0 1 Relapse (N°) 0 1^ 1^ 5-yr FFP 95.2 88.9 93.2 5-yr OS 95.2 88.9 92.8 Median follow up (range) 52 months 104 months 60 months