Page 32 - 2019_11 Resto del Mondo-web
P. 32

A. Frisch and Y. Ofran
Figure 1. Screening of newly diagnosed cases of B-cell other acute lymphoblastic leukemia. *FISH-break-apart. **Targeted sequencing for mutations in JAK, IL7R, FLT3, SH2B3, RAS and PTPN11. ALL: acute lymphoblastic leukemia; LDA: low density microarray; FISH: fluorescence in situ hybridization; Ph-like: Philadelphia chro- mosome like.
low/moderate-intensity regimens, such as mini-Hyper- CVAD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) or other similar protocols.42-44
Until recently, the majority of Ph-like ALL patients were identified late during the course of treatment, usually after the completion of induction. Yet, with the implementa- tion of CRFL2 immunophenotyping tests and routine application of wide-spectrum, rapid FISH panels and LDA, it is reasonable that a patient could be diagnosed with a Ph-like aberration early during induction. Clinical trials, such as the COG AALL1521, examining the benefit of adding ruxolitinib to standard induction, are currently recruiting patients. However, should the identification of an EPOR or JAK translocation entail alteration of the selected induction regimen for patients treated outside clinical trials? Ph-like ALL patients tend to remain MRD- positive after induction13,14 and are therefore planned for intensification of consolidation therapy by most pediatric protocols.45-47 Pediatric-oriented intensification regimens are extremely toxic and difficult to administer to high-risk adult patients. The presence of the EPOR translocation is an established adverse prognostic feature,5,23 but due to its rarity, randomized studies to assess a potential benefit of different induction or intensification regimens will proba- bly never be conducted. In the absence of such clinical tri- als, intensified induction seems reasonable.
Among 148 recently reported adults with ALL, the achievement of MRD negativity did not translate into a better outcome in the 49 patients who were diagnosed
with a Ph-like disease.13 These patients were treated with Hyper-CVAD or augmented BFM (Berlin-Frankfurt- Munich) protocols with no specific intensification or mod- ification for their high-risk ALL. In a pediatric series of 488 patients, those from the very high-risk group remained at a high risk of relapse even if MRD negativity was achieved.48 A new comprehensive study from the United Kingdom has suggested that the cutoff level for clinically relevant MRD is different for various genetic subtypes of ALL.49 Thus, it is reasonable to consider all Ph-like ALL patients as high risk, regardless of their MRD status. Some data from 344 pediatric patients suggest that therapy intensification for Ph-like MRD-positive patients can lead to MRD eradication and improve outcome.28 However, confirmation from additional, large studies is required to feel confident about adopting chemotherapy intensifica- tion as a suitable therapeutic approach to be used as induction in Ph-like ALL patients. Notably, a randomized trial testing the value of enhancing therapy for MRD-pos- itive patients, regardless of their genetic background, showed only a moderate improvement in event-free sur- vival. However, even such benefit cannot be readily extrapolated to genetically very high-risk groups.50
As to practical suggestions for the patient in question, although not specifically tested in the context of Ph-like ALL, addition of rituximab if leukemic cells are CD20+ and the use of L-asparaginase or PEG-asparaginase, known to be active in high-risk ALL, may be recommended. At the same time, the risk of asparaginase-related complications at his age needs to be considered.51-53
Blinatumomab, a bispecific antibody targeting CD19
2138
haematologica | 2019; 104(11)


































































































   30   31   32   33   34