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S. Chiaretti et al.
Figure 2. Minimal residual disease clearance. Patients were stratified according to fusion protein (A) and molecular status at the end of induction (B). CMR: complete molecular response; d= day.
Relapse and cumulative incidence of relapse
Seventeen relapses occurred at a median time of 7 months from the end of induction (range, 3-40.1), of which two were extramedullary (one CNS and one psoas muscle): 13 patients relapsed during consolidation and four patients relapsed after allo-SCT.
At a median follow up of 57.4 months, the cumulative incidence of hematologic relapse (CIR) was 29.8% (95% Confidence Interval [CI]: 18.4-42.1) (Figure 3). The CIR, stratified according to the molecular response at day +85, was 10% in CMR patients as opposed to 35.6% in non- CMR patients; this difference did not reach statistical signif- icance, probably due to the small number of relapses.
Toxicity and deaths
Overall, 188 adverse events (AE) (grade >2) were record- ed in 41 patients (Online Supplementary Table S1), the most frequent were hematologic (124 of 177, 66%), gastrointesti- nal (12 of 188, 6%) and infectious (12 of 188, 6%). As expected, hematologic toxicity was mainly recorded during induction and was most likely sustained by the disease itself. The most frequent AE reported with dasatinib was one registered case of pleural effusion and one registered case of peripheral edema, while no cases of pulmonary hypertension were recorded.
Eighteen severe adverse events (SAE) were recorded in ten patients (Table 2), and six SAE were due to treatment:
infections and gastrointestinal disorders were the most fre- quent (27% and 22%, respectively).
While no deaths occurred during the induction phase, 24 deaths were recorded in the post-induction phase: 12 for dis- ease progression, 11 in CHR for toxicity and one for both. Causes of death in CHR patients were represented by sepsis in four patients, multi-organ failure (kidney and lung) in two patients and transplant-related mortality in five patients (one for graft versus host disease, two for viral pneumonitis, two for an encephalitis and two for hemolytic anemia).
BCR-ABL1 mutations and copy number evolution analysis BCR-ABL1 mutational screening was performed in cases with biological material available at either MRD increase or overt hematologic relapse. A total of 13 cases were screened (ten with a hematologic relapse and three with MRD increase) and the following BCR-ABL1 mutations were detected in ten cases: five cases of T315I, three cases of V299L (one of which with concomitant F317I and F317L mutations), one case of E281K and one case of G254E. No difference in the incidence of BCR-ABL1 mutations was found between p190+ and p210+ patients. Notably, in the three cases with a MRD increase a mutation was detected (E281K, T315I and V299L), but it did not translate into a subsequent hematologic relapse. A total of nine mutated cases were retrospectively evaluated on the diagnostic
material and no mutations were detected.
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haematologica | 2021; 106(7)