PURPOSE To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408 ) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy. PATIENTS AND METHODS Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy. RESULTS One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again. CONCLUSION Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.

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.

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies NPM-ALK/ 10 4 copies of ABL1 identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of NPM-ALK was 61±12% compared to 21±5% for the remaining 73 patients ( P =0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies NPM-ALK /10 4 copies ABL1 for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.