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Editorials
during consolidation had a low positive or negative end- Ib MRD, emphasizing the importance of early identifica- tion of ABL-class fusions and prompt TKI addition to achieve deep MRD response and, potentially, better out- comes. Despite the heterogeneity of ABL-class fusions, Cario et al. demonstrated that most ABL-class rearrange- ments could be detected by techniques such as fluores- cence in situ hybridization (FISH) or polymerase chain reaction (PCR), which are standard techniques in clinical laboratories. Much effort in recent years has focused on screening for the kinase-activated signature that defines Ph-like ALL; however, ultimately, the clinically relevant goal is the prompt detection of the underlying therapeu- tically targetable genomic lesions. The Children’s Oncology Group (COG) is now expanding their FISH panel to include ABL1, ABL2 and PDGFRB/CSF1R dual- colored break-apart probes to screen for ABL-class gene rearrangements in order to introduce TKI by mid-induc- tion. This strategy could perhaps overcome the high rates of induction failure and eradicate MRD levels early in the course of therapy for the majority of ABL-class patients, as early TKI introduction has done for Ph+ ALL.14,15 Prospective evaluation of the early addition of TKI to therapy of patients with ABL-class lesions is required; this can only be achieved by harnessing international collabo- rations to effectively design precision medicine trials for such rare disease entities as exemplified by the Ph+ ALL experience (clinicaltrials.gov identifers: NCT0146016 and NCT03007147).
The article by Cario et al. also raises two fundamental questions which underlie the role of HSCT and the opti- mal chemotherapy backbone for ABL-class fusion posi- tive B-ALL. HSCT appears to be an effective modality for disease control as fewer relapses occurred among ABL- class patients in the no-TKI group who underwent HSCT in CR1 (13.2% vs. 43.8%, P=0.06). A single-center study previously reported comparable outcomes between chil- dren with Ph-like ALL and non-Ph-like ALL (5-year EFS 90.0% vs. 88.4%, P=0.41, respectively), using MRD- directed therapy intensification for relevant patients.16 Consequently, a significant higher proportion of Ph-like ALL patients underwent HSCT in CR1 due to end-induc- tion MRD levels ≥1%.16 Nevertheless, HSCT is associated with unacceptably high TRM rates, which account for a considerable proportion of events in this AIEOP-BFM ret- rospective cohort. Given that ABL-class fusion positive B-ALL biologically and clinically phenocopies Ph+ ALL, one can speculate that early and continuous TKI adminis- tration in combination with chemotherapy may avoid HSCT in CR1 for a subset of ABL-class patients, allowing it to be reserved for patients at the highest risk of relapse.
With regards to the optimal chemotherapy backbone for pediatric ABL-class patients, three regimens are cur- rently being investigated in clinical trials: 1) the Total Therapy-based chemotherapy backbone from St. Jude Children’s Research Hospital (clinicaltrials.gov identifer: NCT03117751); 2) the multinational European EsPhALL regimen as utilized in EsPhALL2010 (clinicaltrials.gov iden- tifer: NCT00287105) and AALL1122 (clinicaltrials.gov iden- tifer: NCT01460160); and 3) the COG AALL1131 modi- fied augmented BFM backbone (clinicaltrials.gov identifer: NCT02883049). The latter two regimens are being com-
pared in a randomized fashion in the phase III interna- tional trial for Ph+ ALL in a non-inferior design (COG AALL1631; clinicaltrials.gov identifer: NCT03007147), which investigators plan to amend to also include ABL- class fusion patients. While awaiting the AALL1631 results to determine the optimal chemotherapy backbone for ABL-class patients, Cario et al. alluded to the high TRM rates when treating with the EsPhALL-inspired reg- imen, contributing to the poor outcomes of ABL-class patients. Similar findings have been observed in a recent publication from the AIEOP-BFM consortia; older adoles- cents aged 15-17 years also experienced significantly higher treatment-related deaths compared to their younger counterparts when treated on the AEIOP-BFM ALL 2000 chemotherapy backbone (without TKI), partic- ularly in the HR arm that is the chemotherapy backbone to the EsPhALL regimen.17 Given that the prevalence of Ph-like ALL rises with increasing age, toxicity remains a primary concern when adding TKI to the EsPhALL post- induction chemotherapy backbone for ABL-class patients. While therapy intensification has been an effec- tive strategy to better outcomes in the past, in the mod- ern era, we might have reached a plateau where further intensification is more likely to result in excessive toxici- ties rather than improve survival. Fortunately, the land- scape of relapsed/refractory ALL therapy has witnessed major paradigm shifts with the emergence of immunotherapy. The bispecific CD3/CD19 T-cell engager, blinatumomab, or the anti-CD22 antibody drug conjugate, inotuzumab ozogamicin, in monotherapy or in combination with TKI, have been used in Ph+/Ph-like ALL with promising early results.18-20 Therefore, incorpo- ration of immunotherapy blocks intercalated within con- ventional chemotherapy backbone may represent an effi- cacious strategy to intensify therapy and reduce overlap- ping toxicities for ABL-class Ph-like ALL.
Cario et al. have provided an important dataset to fulfill the clinical portrait of the rare subset of ABL-class fusion positive B-ALL. The genomic landscape of Ph-like ALL and its associated poor prognosis have now been recog- nized for over a decade; thus, the time has come to act! The prospect of targeted therapy, immunotherapy and targeted use of CR1 HSCT, combined with lessons learned from previous Ph+ ALL studies and international collaborations to conduct well-designed precision medi- cine trials, can establish pathways to increase cures for this high-risk ALL subset. One may dream that by improving outcomes of Ph-like ALL, we will be able to cure all ALL!
References
1. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663-1669.
2. Rheingold SR, Ji L, Xu X, et al. Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): A Children’s Oncology Group (COG) study. J Clin Oncol. 2019;37(15_suppl): 1008-1008.
3. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125-134.
haematologica | 2020; 105(6)