The Paediatric LMB Protocol Has High Curative Potential in Adults with Burkitt Lymphoma and High Proliferation DLBCL.
Authors: Cuthill Kirsty , Moonim Mufaddal , Neat Michael , Fields Paul , Carr Robert 
Published: October 2019

Abstract
Abstract 3702
Poster Board III-638

Background
The optimum treatment for adults with aggressive, high proliferation rate B-cell NHL remains uncertain. A proportion are classified as Burkitt Lymphoma (BL), based on typical morphology, immunophenotype and the presence of a MYC rearrangement (MYC+); the remainder as diffuse large B-cell lymphoma (DLBCL) or intermediate BL/DLBCL. Recent gene-expression studies report up to 30% of cases classified as DLBCL by morphology have the genetic signature of BL. BL is most commonly treated in the UK using CODOX-M/IVAC. Non-Burkitt, high-proliferation DLBCL is most commonly treated with R-CHOP. A recent UK study of CODOX-M/IVAC for B-NHL with >95% proliferation achieved 2yr EFS for BL 64% (34/53), DLBCL 54% (31/57). A recent large international collaborative trial using the risk-adapted LMB protocol for both BL and DLBCL in children and adolescents to age 21 achieved 4yr EFS of 80% for patients with B-ALL or CNS disease, and >85% for all others. The EFS for BL and DLBCL were identical. In recent years we have adopted the LMB strategy for treating younger adults diagnosed as BL, Burkitt-like lymphoma or mature B-ALL. We report the outcome of 22 adults treated in a single institution.

Methods
Case histology was reviewed and re-classified as BL if characteristic morphology, phenotype (CD20+ CD10+ Bcl-6+ Bcl-2–) and, where tissue available, presence of rearranged MYC by FISH. DLBCL cases had high proliferation (≥95%) but did not fulfill criteria for BL. Intermediate BL/DLBCL included DLBCL with MYC+. There were no BCL2+/ MYC+ “double hit” lymphomas. B-ALLs had a purely marrow presentation with vacuolated blasts and mature B phenotype. All patients had staging CT and PET, and CNS MRI where brain/spinal involvement suspected. Treatment was based on the LMB 86/89 protocol with 3 levels of intensity as published (Patte C et al. Blood 2001 97:3370). All received low-dose vincristine, cyclophosphamide, prednisolone induction 7 days prior to 2, 5 or 8 intensive chemotherapy blocks as dictated by stage, marrow and/or CNS involvement. The interval between the start of the first 2 intensive blocks was kept strictly to 21 days. HIV positive cases were treated concomitantly with HAART.

Results
Twenty two consecutive cases have been treated, 11 BL, 6 DLBCL, 2 intermediate BL/DLBCL, 3 B-ALL. Eleven cases were HIV positive, 2 others followed renal transplant. Median age 37 years (range 15-49) plus 1 older patient of 62 yrs. Lymphoma case IPI scores I (n=6), II (4), III (4), IV (5). Pre-treatment PET scanning increased clinical stage in 10 cases and escalated planned treatment from schedule A to B in 3 cases. One patient received LMB schedule A (resected stage I), 7 schedule C for B-ALL (3) BL with marrow blasts >70% (1) or CNS disease (3), all others (14) received schedule B. High dose methotrexate (MTX) dose was only reduced in the two renal transplant patients to limit toxicity to the transplanted kidney, as guided by MTX levels. Neutropenia was mostly short-lived and G-CSF used infrequently to prevent treatment delay. One third of patients experienced significant sepsis. Two HIV patients experienced complications of CMV reactivation. All HIV and renal transplant patients experienced significant post-MTX mucositis, severe in 5. In non-immunosuppressed patients mucositis was mild. All patients had >50% response to the 3 drug induction. All 22 patients achieved CR defined by PET ± CT. There were no treatment related deaths. Three relapsed from CR within 3 months of completing chemotherapy: 1 had B-ALL without MYC+, the other 2 were HIV+, MYC+ BL. All 3 died from disease progression during salvage therapy. The 62 yr old died of HIV in CR 2yrs post Rx. The remaining 18 patients are alive and in CR at median 40 (8-177) months from diagnosis (Relapse rate 14%; PFS 82%).

Conclusions
The risk-adapted LMB protocol is safe, with manageable toxicity in adults <50 years. Outcomes in this series compare favourably with CODOX-M/IVAC. As in children, our experience suggests the LMB protocol may be equally effective for BL and high proliferation DLBCL in adults, thus circumventing the need for diagnostic separation of two diseases whose differentiation based on histology alone is problematic. These data suggest the LMB protocol warrants testing by randomised trial in younger adults with high proliferation DLBCL and BL.

Disclosures:
No relevant conflicts of interest to declare.