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J-C. Ianotto et al. AB
Figure 2. Survival according to treatment status. Kaplan-Meier estimated (A) overall and (B) leukemia-free survival differentiating patients who were still being treat- ed with pegylated-interferon from patients who had stopped interferon because of intolerance or resistance.
(33.3%) were given ruxolitinib, seven (15.6%) underwent allogeneic stem cell transplantation (ASCT) and 23 patients (51.1%) were treated with different drugs or received no further medicine (Figure 3). The median sur- vival after cessation of pegylated interferon-α2a was 17 months (range, 3-62). The median survival of patients who received ruxolitinib was 22 months compared to 14 months for those who did not (P=0.12) or 10 months for patients who underwent ASCT (P=0.003).
Nineteen patients (30.6%) received an erythropoietin- stimulating agent during interferon therapy; we did not observe that these patients, compared to those not given such agents, had increased resistance to pegylated interfer- on-α2a, greater occurrence of acute myeloid leukemia or a difference in overall or leukemia-free survival.
Evolution of the allele burden of driver mutations
The median mutant allele burdens at the time of starting pegylated interferon-α2a treatment, studied in 31 JAK2- mutated and eight CALR-mutated patients were 66.8% (range, 8.9-98.3) and 41.2% (range, 32-46.1), respectively.
The JAK2V617F allele burden was quantified serially in 27/31 patients. In this group, the median allele burden prior to pegylated interferon-α2a treatment was 57.3%; the burden remained stable during the first year and then decreased to 47.1% at 24 months and 29% at 36 months. We observed a decrease of mutant allele burden with a more than 10% reduction in 17/27 patients (63%), more than 20% in 15/27 patients (55.6%), and more than 50% in 10/27 patients (37%). Four patients (15%) achieved a reduction of more than 95%, including two patients who had complete molecular responses (below the detection threshold of 0.1% in our assay). Among the other patients, 7/27 (26%) had a stable allele burden (±10%) and three patients had a more than 10% increase in allele bur- den (Figure 4). We did not observe any difference of out- come (death or acute myeloid leukemia evolution) between patients whose JAK2V617F allele burden did or did not decrease.
Sequential quantification of mutant CALR allele burden was available in only four patients. The median value remained essentially stable, altering from 42.4% to 46.8%. Only one patient experienced a reduction of mutant CALR allele burden, which decreased by 33%.
Figure 3. Patients’ treatment. ASCT: allogeneic stem cell transplantation; disc: discontinuation (of Peg-Ifn); dur: duration; FU: follow-up; m: months; n: number; Peg-Ifn: pegylated-interferon.
Impact of non-driver mutations
Of the 49 patients analyzed with targeted next-genera- tion sequencing, 28 (57.1%) carried at least one additional mutation different from the driver mutation. Overall 44 mutations were identified (1.6 per patient) in 16 different genes (Figure 5). Of these mutations, 47% affected epige- netic regulators, 21% signaling and 16% splicing or other categories (Figure 5). The most frequent mutations involved ASXL1 and TET2 genes (7 cases each). The num- ber of patients harboring non-driver mutations was simi- lar between JAK2-mutated (21/34, 61.8%) and CALR- mutated (6/12, 50%) patients (P=0.51). Additional muta- tions were found in 68% (23/34) of patients who discon- tinued pegylated interferon-α2a treatment (9/15, 60% for intolerance and 14/19, 74% for resistance) compared to only 33% (5/15) of patients who remained on pegylated interferon-α2a treatment (P=0.02).
Patients with at least one non-driver mutation had shorter overall survival than those with only driver muta- tions (6.1 years versus not reached, P=0.06) (Figure 6A). The same was true for leukemia-free survival (not reached in both groups, P=0.026) (Figure 6B). In detail, leukemia- free survival was significantly different between patients
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haematologica | 2018; 103(3)