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E-mail: YISHAI OFRAN - y_ofran@rambam.health.gov.il doi:10.3324/haematol.2020.278077
Novel therapies are revolutionizing the treatment strategies for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ten years ago, the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) ALL Working Party pioneered a chemotherapy- free induction regimen using the dasatinib-steroid combina- tion,1 which brought about complete hematological remis- sion (CHR) in all 53 evaluable patients2 and complete molec- ular response (CMR) in ten of them (18.8%).
In this issue, final results of a subsequent LAL1509- GIMEMA prospective single-arm trial are reported.3 The treatment protocol included 1-month induction with the aforementioned combination, followed by dasatinib exten- sion until day 85. The post-remission regimen was assigned based on the minimal residual disease (MRD) status. Of the 60 enrolled patients (median age 41.9 years [range, 18-60]), those who achieved CMR were subject to dasatinib mainte- nance with no further intensification. The majority of patients (47 of 60; 78%) achieved CHR, while testing MRD- positive post-induction. These patients were assigned to allo- geneic stem cell transplantation (allo-SCT) with or without consolidation chemotherapy. Patients ineligible for trans- plantation were consolidated with chemotherapy only. No induction deaths were reported and the CHR rate by day 85 was 97%, with CMR achieved in 11 of 60 (18.3%) patients. At a median follow-up of almost 5 years, overall survival (OS) and disease-free survival (DFS) were 56.3% and 47.2%, respectively.
Are these impressive data sufficient to set the stage for a new standard of care in Ph+ALL? One of the critical achieve- ments of these two studies, that should be taken into consid- eration, is the absence of induction deaths among the 113
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patients treated. To that end, future Ph+ALL treatment pro- tocols should be designed with the aim to maintain such a minimal induction-related mortality rate. However, this attractive low-intensity induction regimen may be unsuit- able for higher-risk Ph+ALL patients. In the LAL1509- GIMEMA protocol, the post-induction MRD status has been the sole factor used to stratify patients for intensive consoli- dation followed by allo-SCT versus dasatinib maintenance only. Yet, the clinical significance of MRD results depends on a variety of patient- and treatment-related parameters.
Based on data from previous ALL studies, the Food and Drug Admisnsitration has accepted an MRD level of less than 0.01% as a surrogate efficacy endpoint for new drugs in ALL.4 Surprisingly and disappointingly, in the current trial, four of 11 (36%) patients who achieved CMR with the dasa- tinib-steroid induction eventually relapsed. Three of these relapses were diagnosed early at a molecular level and there- fore never fulfilled the former criteria of relapse. This must raise a red flag and a message regarding the complexity of MRD clinical interpretation should be played out loud. MRD negativity is not synonymous to cure but it is rather its bio- marker. No matter how sensitive the available tests are, there is still room for residual disease presence at a level below the threshold of detection. Thus, ultimate degrees of disease eradication for patients who achieve MRD negativity follow- ing intensive and less intensive induction may be different. A negative MRD result following intensive induction reflects an even deeper response than the sensitivity cutoff of the test used. This should not be extrapolated to the outcome predic- tion following less intensive protocols when the actual level of response below the MRD negativity cutoff may be lower (Figure 1). Not only the specific induction protocol but also
EDITORIALS
A chemotherapy-free regimen for Philadelphia chromosome-positive acute lymphoblastic leukemia: are we there yet?
Yishai Ofran1,2
1Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, and 2The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
Figure 1. Response after intensive and non-intensive induction in a population of Philadelphia chromosome-positive acute lymphoblastic leukemia patients. (A) Distribution of response levels after intensive induction. (B) Distribution of response levels after non-intensive induction. The distribution of the actual depth of response across patients who achieved minimal residual disease negativity following intensive and non-intensive induction differs and so does the risk of relapse.
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