Efficacy and toxicity of a rituximab and methotrexate based regimen (GMALL B‐ALL/NHL 2002 protocol) in Burkitt's and primary mediastinal large B‐cell lymphoma

Abstract

There have been several attempts to improve treatment and outcome of patients with primary mediastinal B-cell lymphoma (PMBL) and Burkitt's lymphoma (BL). In recent years, chemotherapy dose intensification and the addition of rituximab have led to a remarkable progress and have developed into integral parts of treatment for both entities of lymphoma [1][2][3][4]. Here, we report our monocenter results of a highdose methotrexate based alternating regimen with rituximab (B-ALL/ NHL 2002 protocol) in 15 patients with PMBL and 28 patients with sporadic BL. Since the early 1980s, protocols of GMALL have been continuously adapted and in the meantime they have become reference treatment for BL and B-ALL in Germany. The latest changes comprised the additional use of rituximab, standardized G-CSF support, implementation of high-dose cytarabine, intrathecal triple therapy, and age-adjusted stratification. Furthermore, we additionally amended supportive care with palifermin as it reduced severity and prevalence of mucositis [5].Almost all patients responded to chemotherapy, leading to an overall response rate of 98% (PMBL 100%, 95% confidence interval (CI) 1.0-1.0; BL 96.4%, 95%CI 0.68-1.0). Complete remission (CR) was achieved in 83.8% (PMBL 80%, BL 85.7%), and the rate of partial remission (PR) was 14% (20% PMBL, BL 10.7%). On average, the individual best response to chemotherapy was achieved after 3.68 courses.After initial response, three patients (two BL, one PMBL) experienced a progression or relapse within 3, 5, and 10 months, respectively. Thus, 5-year progression-free survival (PFS) was 93.3% (95%CI 0.74-1.0) for patients with PMBL and 82.1% (95%CI 0.67-0.96) for BL. Five-year overall survival (OS) was 100% for PMBL and 94.1% (95%CI 0.83-1.0) for BL in the younger group, and 100% and 63.6% (95%CI 0.35-0.92), respectively, in patients >55 years (Fig. 1a,b). Regarding the BL group, two patients died from treatment-related sepsis, a 74-year-old woman discontinued therapy, and two progressed during salvage therapy.Postchemotherapy consolidation radiotherapy was performed in 66.7% in PMBL and in 10.7% in BL. A total of 93% of patients with PMBL and 100% of patients with BL received prophylactic intrathecal therapy.Overall response and survival rate of 100% of all patients in the PMBL subgroup was observed. Fietz et al. [6] already reported a CR rate of 73% and an OS of 80% at 8.6 years in a cohort of 15 patients with PMBL treated according a prior B-ALL protocol of the GMALL (without rituximab). Improved OS in our cohort may be explained by recent changes such as the additional use of rituximab or high-dose cytarabine. Additional use of rituximab had predominantly shown benefit in nonmethotrexate but not in methotrexate-containing regimens [3,4,[7][8][9]. Preliminary results of a current protocol by Hoelzer et al. [10] with 42 patients with PMBL showed an inferior CR rate of 69%, but a comparable 3-year OS of 90% in patients younger than 55 years and of 67% in the elderly group (>55 years). However, this difference c...

Clinical presentation, diagnosis and management of therapy‐related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly‐ADP‐ribose polymerase inhibitors: A single‐center experience

“…One patient with erythroblastic leukemia was refractory to various chemotherapy attempts and died for leukemia progression. The patient with ALL FAB‐L3 was treated with sequential high‐dose chemotherapy (GMALL B‐ALL/NHL 2002 Protocol) 21 obtaining CR. Eight months after, she is in CR of both her leukemia and EOC.…”

Primary Mediastinal Large B-cell Lymphoma

“…The first results on 44 patients treated (without rituximab but with consolidation radiotherapy) in a few German centers were published in 2002 and they showed ORR exceeding 90 %, PFS – 85 % and OS – 82 % [ 50 ]. In 2011 the results of the next cohort of 15 patients treated with rituximab confirmed the high efficacy of this regimen yielding 5-year PFS 93.3 %, and 5-year OS 100 % [ 51 •]. Our own experience in applying this intense chemotherapy regimen is also very encouraging.…”

“…Numbers in brackets refer to patient numbers in different chemotherapy groups (column 4) and to their outcome (OS, PFS) – columns 8, 9. All studies are retrospective, if not otherwise specified [Ref] Year (data collection) Setting Number of patients High IPI (%) CHTH RTH OS PFS [ 5 ] 2002 (1981-1999) Multicenter 426 (105/277/44) 21 CHOP(-like)//3rd-generation//HDT/SCT Yes in 84 % pts 10-y 65 % (44/71/ 77 %) 10-y 62 % (35/67/78 %) [ 42 ] 2004 (1982-1999) Multicenter 138 (43/95) 22 CHOP//MACOP-B( VACOP-B) Yes in 75.5 % pts in CR N/D 5-y EFS 39.5 %/75.7 % [ 8 ] 2005 (1980-1995) Single center 141(56/68/17) 28 CHOP(-like)//NHL-15//HDT/SCT Yes (only in 23 %) 10.9-y 66 % (51/84/78 %) 10.9-y 50 % (34/60/60 %) [ 6 ] 2006 (1980-2003) Population study 153 (63/47/18*) N/D (only aaiPI) CHOP(-like)//MACOP-B(VACOP-B)//R-CHOP Depending on recommendations 5-y 75 % (71/87/81 %) 5-y 69 % (N/D) [ 65 ] 2008 (1992-2006) Single center 68(42/26) 26 % CHOP/3rd generation Yes in 87 % 5-y 61 % (50/91 %) 5-y 52 % (33/83 %) [ 56 ] 2010 (N/D) Single center 54 N/D R-CHOP/ICE No 3-y 88 % 3-y 78 % [ 51 •] 2011 (2002-2010) Single center prospective 15 N/D GMALL B-ALL/NHL Yes in 67 % ...…”

Analysis of clinical characteristics and outcome of patients with previously untreated diffuse large B-cell lymphoma and renal involvement in the rituximab era

“…All patients received at least one cycle of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or a more aggressive regimen, the latter consisting of either R-CHOP with additional etoposide (R-CHOEP) or treatment according to the GMALL B-NHL/ALL 2002 protocol (six cycles of R-CHOEP-like substances plus cytarabine and high-dose methotrexate). [8] CNS-affecting therapy was administered to all patients with initial CNS involvement as well as those considered high risk for CNS relapse by our institutional tumor board and consisted of intrathecal methotrexate with or without additional intravenous high-dose methotrexate. Elevation of clinical biomarkers, that is, lactate dehydrogenase (LDH), creatinine, urea, soluble interleukin-2 (IL-2) receptor (sCD25), was defined as being above the upper limit of normal according to our institution's laboratories.…”