Page 18 - Haematologica May 2020

Editorials
Figure 1. Comparison of two cytogenetic risk classifications for Philadelphia chromosome-negative acute lymphoblastic leukemia. The modified Medical Research Council – Eastern Cooperative Oncology Group (MRC-ECOG) score at diagnosis versus the Center for International Blood and Marrow Transplant Research (CIBMTR) risk score for post-transplant Philadelphia chromosome-negative acute lymphoblastic leukemia. Differences between the risk scores are shown in red.
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are derived from the largest cohort of Ph- patients treated with SCT to date and show clear distinctions in leukemia- free survival (LFS) using just three risk groups.
Several aspects of the article by Lazaryan et al.11 are of interest. Post-transplant risk scores differ from those for patients treated with conventional therapy. This may be a consequence of graft-versus-tumor susceptibility. It is interesting to see that translocations, except for t(8;14) and t(1;19), are noticeably absent from the CIBMTR risk score compared to the modified MRC-ECOG risk score (Figure 1). While t(1;19)(q23;p13), t(4;11)(q21;q23), t(5;14)(q35;q32) and t(17;19)(q22;p13) were identified as risk factors at diagnosis/before SCT, they were not consid- ered to be adverse post-SCT. It is feasible that the abnor- mal proteins produced by translocations may directly or indirectly affect malignant cell immunogenicity and enhance the graft-versus-tumor effect.
The translocations t(8;14) and t(11;19) still remain in the high-risk category. A possible reason might be the associ- ation of t(8;14) with the involvement of the myc gene on chromosome 8 and of t(11;19) with the MLL gene, under- lying the prevalence of tumor-specific rather than immunogenic factors.
Multiple mechanisms have been proposed to be respon- sible for the high relapse rate in diseases with monosomy 7 and complex karyotype, including loss of tumor sup- pressor genes, haplo-insufficiency or loss of IKZF1. These alterations may be less susceptible to graft-versus-tumor reactions. The results are similar to those previously seen
in acute myeloid leukemia, in which t(11;19),16-18 mono- somy 7, deletion 7q19,20 and complex karyotype are also risk factors and play an important role in outcome. Similar mechanisms might therefore influence relapse rates after SCT in both acute myeloid leukemia and ALL.
A further consequence of the results of the analysis by Lazaryan et al. is the evident need to reduce the relapse rate in high-risk (but also in normal-risk) patients. This may be possible by evaluating minimal residual disease before and after SCT. The important role of minimal resid- ual disease in predicting outcome at an individual level has recently been published.21 Optimizing SCT outcome by tailoring immunosuppression in the early phase, in response to post-transplant monitoring of disease-specific minimal residual disease or chimerism would be an appro- priate approach. The relapse risk in Ph- ALL may be reduced by new drugs, such as blinatumomab, inotuzum- ab ozogamycin or tisagenlecleucel. In this context, the results presented by Lazaryan et al. should provide a stim- ulus for prospective clinical studies.
Furthermore, those translocations associated with implied susceptibility to graft-versus-tumor reactions may provide a lead for the identification of immunogenic tumor-specific antigens, while all translocations are poten- tial targets for small molecules able to neutralize disease- specific products, such as driver kinases or activation path- ways. In patients with deletions or monosomy such efforts might be difficult.
Finally, scores might be influenced by the different treat-
haematologica | 2020; 105(5)