LAUSR

Sir, We read the paper by Julia Czech et al., “JAK2V617F but not CALR mutations confer increased molecular responses to interferonvia JAK1/STAT1 activation” [1], with great interest. This paper reports that JAK2V617Fmutated patients with myeloproliferative neoplasms (MPN) have a better molecular response to pegylated interferon-α (IFN) treatment than patients with mutated CALR. However, the authors noted similar hematological responses in groups of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Here, we report on an unusual polycythemia vera (PV) patient who harbored initially only a JAK2V617F mutation, but secondary also a CALR del52 and a MPLS505N mutations. The CALR del52 clone was resistant to IFN, which led to the absence of complete hematological (CHR) and complete molecular responses (CMR). In patients with MPN, IFN is a very effective treatment which results in clinical, hematological, molecular, and histopathological responses [2, 3]. A hematological response is most often observed in the first year of treatment, whereas the molecular response is usually seen in the second year of therapy [4, 5]. We report here a case of IFN-resistance in a patient harboring a very unusual association of JAK2, CALR, and MPL mutations. Indeed, CALR mutations are mainly observed in ET and PMF and very rarely in PV associated with mild thrombocytosis [6]. Moreover, in most MPN cases, JAK2 and CALR mutations are mutually exclusive [7, 8], despite infrequent double mutant cases corresponding to separate clones [9, 10]. A 60-year-old man initially presented with pulmonary embolism. A complete blood count revealed isolated increases in hemoglobin (230 g/L) and hematocrit (71%), and normal platelets (300 G/L), and leukocyte (10.5 G/L) counts. He was subsequently diagnosed with JAK2V617Fmutated PV with a 30% variant allele frequencies (VAF). Cytoreductive therapy with hydroxyurea (HU) was started and maintained for 4 years. CHR was obtained with 14 g HU/week and was associated with a decrease in the JAK2V617F VAF from 30 to 3% after 4 years. Due to a mild intolerance to HU and relatively young age, HU was progressively replaced by IFN that was initially administered in low doses and then increased to 135 μg per week. At the same time, HU was gradually reduced and finally stopped. Unfortunately, 2 months after HU was discontinued, the CHR was lost and both the platelet counts and hematocrit increased. IFN was then increased to 180 μg/week, but no CHR was obtained despite the higher doses. Moderate doses of HU (9 g/week) were therefore reintroduced for a period of 8 months. CHR and a good CMR were obtained since the JAK2V617F VAF in peripheral granulocytes remained stable at 3%. Another attempt was made to reduce HU, but Isabelle Plo, François Girodon: On behalf of the French Intergroup of MPNs (FIM)