Recurrence of clonal hematopoiesis after discontinuing pegylated recombinant interferon-alpha 2a in a patient with polycythemia vera.

Patients with polycythemia vera (PV) are most often treated with phlebotomy and low-dose aspirin therapy alone. Chemotherapeutic agents including hydroxyurea are frequently utilized in patients who are at a high risk of developing thromboses or have disease related systemic symptoms. Such treatment options are unsatisfactory due to the persistent susceptibility of patients to thrombosis and evolution to myelofibrosis and acute leukemia. Interferon- (IFN-) was first shown to be effective in controlling thrombocytosis in patients with essential thrombocythemia (ET) and PV and later shown to be capable of limiting the excess red cell production in patients with PV.1 Lengfelder et al.2 summarized the treatment results with IFN- therapy in 279 patients with PV. In addition to correction of thrombocytosis in approximately 90% of patients, a reduction of splenomegaly was observed in 77% of patients. Pruritus was controlled in 81% of patients, and the frequency of phlebotomy was reduced by 82%. Recombinant interferon- (rIFN-) inhibits erythroid progenitors and affects megakaryocyte function,3, 4 and thus may be a more rational treatment option for patients with PV. Since the initial studies of the use of rIFN- in treating patients with PV, many reports of its beneficial effects have been published.1, 2 PV is now treated with rIFN- with increasing frequency in order to avoid the complications associated with phlebotomy and/or chemotherapy, and to relieve pruritus and other constitutional symptoms. rIFN- therapy is, however, associated with the need for frequent subcutaneous injections and a relatively high rate of side effects leading to the discontinuation of therapy in 21% of patients with PV and in 25% of patients with ET.2 To overcome these barriers, pegylated forms of rIFN- (Peg-rIFN-) have recently been explored as treatment options for patients with PV.5, 6 Peg-rIFN- appears to be safe, non-leukemogenic and well tolerated, although adverse events including fever, thrombocytopenia and headache are not infrequent. A mutation in JAK2 (JAK2V617F) has recently been shown to play a role in the pathogenesis of PV and has been proposed as a mean of monitoring minimal residual disease.6, 7 In a phase 2 trial of Peg-rIFN- 2a in PV, Kiladjian et al.5 performed a prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%JAK2V617F) using real-time polymerase chain reaction (PCR). The %JAK2V617F was observed to be decreased in 24 of 27 treated patients. These results confirm the hypothesis that Peg-rIFN- preferentially targets the malignant clone in PV, and indicates that the %JAK2V617F may prove to be the first useful tool to monitor minimal residual disease in this disorder.5 In the present study, we report a female patient with PV treated with Peg-rIFN- 2a (Pegasys, Roche Laboratories, Nutley, NJ) at the dosage of 90 g weekly. The %JAK2V617F before treatment is shown in Figure 1a. Three weeks following the institution of the therapy, a reduction in blood counts and improvement in symptoms was observed (Figure 1a). The %JAK2V617F was also gradually decreased and became no longer detectable after 2 months (Figure 1a). Peg-rIFN- was discontinued due to the development of mild pancytopenia 3 months after the initiation of the treatment. The molecular complete remission as monitored by JAK2V617F was maintained for an additional 2 months. Simultaneously with the recurrence of the symptoms related to PV, a rapid increase of %JAK2V617F was observed 3 months after discontinuation of Peg-rIFN- (Figure 1a). Clonality assays have been used to determine the contribution of the malignant clone to the blood cell production and a variety of hematological malignancies.8 rIFN has been previously shown occasionally to be capable of converting clonal hematopoiesis to a polyclonal pattern, thought to be indicative of elimination of the malignant clone.8 During the period of time when the %JAK2V617F mutation was no longer detected, we performed an assessment of hematopoietic cell clonality using a transcriptional based assay system developed by Liu et al.8 We found that granulocytes were polyclonal at the time that the JAK2V617F was undetectable (Figure 1b). Furthermore, 4 months after discontinuation of Peg-rIFN-, a monoclonal pattern of the hematopoiesis was again documented, which corresponded with the increased percentage of JAK2V617F (Figure 1b). Although Peg-rIFN- is effective in decreasing the malignant clone, the discontinuation of this agent resulted in the reappearance of JAK2V617F and reestablishment of clonal hematopoiesis. These studies indicate that intermittent therapy with this agent might be suboptimal for eliminating the malignant clone in PV and that low-dose uninterrupted therapy with Peg-rIFN- might be required for these purposes. Further studies are clearly warranted to investigate the optimal dose and the schedule of Peg-rIFN- to eliminate the malignant clone in PV and to determine if such an approach alters the natural history of this disorder. This work was supported by grant 1P01CA108671 (to RH) from NCI and a grant (to MX) from the myeloproliferative disorder foundation.