Progressive or Relapsed Burkitt Lymphoma or Leukemia in Children and Adolescents after BFM-type First-line Therapy

Abstract

Children with refractory or relapsed Burkitt lymphoma have a poor chance to survive. We describe characteristics, outcome, re-induction and transplantation-approaches and evaluate risk factors among children with progression of a Burkitt lymphoma/leukemia included in NHL-BFM studies between 1986 and 2016. Treatment recommendation was re-induction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5{plus minus}3%. Survival significantly improved from 11{plus minus}3% before to 27{plus minus}5% after 2000 (p<.001) allowing for risk factor analyses among the latter 75 patients, of whom 28 had disease progressive during initial therapy. Survival of 14 patients with relapse after initial therapy for low risk disease (R1/R2) was 50{plus minus}13% compared to 21{plus minus}5% for 61 patients progressing after R3/R4-therapy (p<.02). 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during re-induction, 15 of 16 not reaching a complete remission before transplantation, 9 of 10 treated with rituximab front-line and all 13 patients not receiving rituximab during re-induction died. 46 patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining Rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67{plus minus}12% compared to 18{plus minus}5% for all other regimen and transplantations (p=.003). Patients with relapsed Burkitt lymphoma/leukemia have a poor chance to survive after current effective front-line therapies. Progression during initial or re-induction chemotherapy and initial high-risk disease are risk-factors in relapse. Time-condensed continuous-infusion re-induction followed by stem cell transplantation forms the basis for testing new drugs.

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations

“…The conditioning regimen for autologous HSCT was based on busulfan (25 patients, 10 alive), BEAM [ 3 ] (21, 11 alive), TBI (7, 3 alive) or individualized regimens (11, 5 alive). For allogeneic HSCT, the most frequently used conditioning regimens were TBI-based (36 patients, 15 alive), Burkitt-specific combination of rituximab, fludarabine, thiotepa, carboplatin, mitoxantrone, paclitaxel [ 20 ] (20, 14 alive), busulfan (13, 5 alive), treosulfan (6, 1 alive) or individualized regimens (12, 5 alive).…”

“…Current risk-adapted first-line protocols for NHL result in event-free survival rates of more than 80% or even 90% [ 1 ]. In contrast, survival for patients who suffer relapse is poor ( Table S7 ) [ 6 , 9 , 19 , 20 ]. Therefore, there is a clear medical need for improving outcomes [ 35 ].…”

“…NHL relapse rates vary according to histological subtype from approximately 25% for anaplastic large cell lymphoma [ 4 ], 10–15% for lymphoblastic lymphoma (LBL) [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ] and 4–10% for B-NHL [ 3 , 8 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Data on relapse rates usually cover cases of refractory disease, disease progression and relapse after CR1 (r/r NHL).…”

“…The second trial evaluates ibrutinib in combination with chemo-immunotherapy (NCT02703272) [ 33 ]. Part one was recently published with 21 patients showing that ibrutinib can be combined with RICE [ 32 ] (rituximab plus ICE) or RVICI [ 20 ] (rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone). In both trials, the type and details of HSCT were not part of the clinical assessment.…”

Ibrutinib plus CIT for R/R mature B-NHL in children (SPARKLE trial): initial safety, pharmacokinetics, and efficacy

“…Pediatric patients with relapsed/refractory (R/R) mature Bcell non-Hodgkin lymphoma (B-NHL) have a 2-year overall survival rate with chemoimmunotherapy (CIT) of 15-33% [1,2]. Rituximab plus ifosfamide, carboplatin, and etoposide (RICE) is widely used in R/R children with NHL [3] and rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) has been used in Europe [4,5].…”