Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Christina Peters et al
J Clin Oncol. 2020 Dec 17;JCO2002529. doi: 10.1200/JCO.20.02529. Online ahead of print.
In January 2012, experts in the treatment of childhood leukemia and stem cell transplantation met in front of the Forum Romanum in Rome. High-risk patients have an excellent survival with allogeneic stem cell transplantation (HSCT) from matched related or unrelated donors. But despite its efficacy, TBI is a detrimental intervention with long-term sequelae, especially in young children. To further improve not only outcome but also quality of life in children with acute lymphoblastic leukaemia (ALL) was the birth certificate of the FORUM trial (For Omitting Radiation Under Majority Age (FORUM).
The manuscript published in JCO (Dec 2020) describes the outcome of 417 patients who were randomly assigned to either TBI/etoposide or a chemotherapy-based conditioning consisting of fludarabine, thiotepa combined with either busulfan or treosulfan.
Surprisingly, an interim analysis showed that patients randomized to TBI had significantly higher survival and lower relapse rates than those randomized to the chemo-conditioning. Even more surprising, acute toxicity and treatment-related mortality were worse after chemo-conditioning. These early but highly significant findings were confirmed after extensive analysis and randomization was terminated early.
Finally, TBI in combination with etoposide results in excellent overall and event-free survival with the lowest ever reported treatment-related mortality in children and adolescents with ALL. This landmark study represents the first cooperative group trial of TBI versus chemo-conditioning for children and adolescents with high-risk ALL receiving HSCT. Pediatricians involved in stem cell transplantation should recognize these findings. Furthermore hemato-oncologists treating adults with ALL now have evidence that TBI remains an essential curative approach compared to purely chemotherapy based conditioning regimens.
The impact of cytogenetic risk on the outcomes of allogeneic hematopoietic cell transplantation in patients with relapsed/refractory acute myeloid leukemia: On behalf of the acute leukemia working party (ALWP) of the European group for blood and marrow transplantation (EBMT)
Monica Poiani et al
Am J Hematol. 2021 Jan;96(1):40-50. doi: 10.1002/ajh.26000. Epub 2020 Oct 8.
Karyotypic analysis for risk stratification at diagnosis of acute myeloid leukemia (AML) is a highly predictive tool for treatment response and overall survival in adults and children.
Obviously similar outcomes in relation to karyotypes could play a role in pre-transplant patients. On the other hand, an intensified stem cell targeted treatment regimen (conditioning) together with a graft-versus-leukemia (GvL) based ‘immunotherapy’ could annihilate conventional stratification marker.
This question was raised by Poiani et al, who did a retrospective EBMT registry-based analysis in 2089 patients with either refractory (n = 972) or relapsed AML (n = 1117) transplanted between 2000-2017. Overall, 154 patients had a favorable risk, 1283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Included were adult patients (≥ 18) with >5% of residual morphologic blasts at time of allo-HCT. The outcome of this trial was not surprising and reflected the original risk stratification at diagnosis. Important with regard to the non-relapse mortality of 21% though is the observation that the intensity of the conditioning regimen did not influence transplant outcomes. A comparative analysis including patients in morphological remission, or even better with a proper minimal residual disease (MRD) status prior to transplant with an identical risk stratification could have helped to assess the predictive value of disease activity and the relevance to attempt pre-transplant remission. This might be of importance with the emergence of AML specific CART and other targeted treatment approaches that currently being evaluated. (see also Nagler A et al, BMT 2021)
Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial
R Pettengell et al
Bone Marrow Transplant. 2021 Jan 15. doi: 10.1038/s41409-020-01182-w. Online ahead of print.
The EBMT LYM1 trial is coming of age and rarely very late follow-ups of rare prospective randomized trials are presented reflecting a settled and sustained outcome.
The prospective randomized EBMT LYM1 trial, originally also by Ruth Pettengell et al assessed patients with relapsed follicular lymphoma (FL) who achieved either complete or very good partial remission with salvage chemotherapy who then were randomly assigned using a factorial design to rituximab purging (RP) or observation before HDC-ASCT and to maintenance with rituximab (RM) (once every 2 months for four infusions) or observation. 280 patients were enrolled. 10-year PFS from date of random assignment for the whole group was 44% (95% CI 38–50). It was shown that RM independent of RP continues to significantly improve PFS. The 10-year PFS post ASCT was 58% (95% CI 49–68%) for RM (NP+RM or RP+ RM) patients and 36% (95% CI 27–47%) for NM (NP + NM or RP + NM) patients [p = 0.002; HR 0.548 (95% CI 0.38–0.80)]. Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. But pre-transplantation rituximab in vivo purging, even in rituximab-naive patients, persistently failed to improve PFS or OS.