Responses and Survival under Pegylated Interferon α 2 a Treatment for Patients with Post-MPN Acute Myeloid Leukemia and Acute Panmyelosis with Myelofibrosis

1Service d’Hématologie Clinique, Institut de Cancéro-Hématologie, Hôpital Morvan, CHRU Brest, France 2Laboratoire d’Hématologie, Hôpital de La Cavale Blanche, CHRU Brest, France 3Service des Maladies du Sang, CHU Angers, France 4Service d’Hématologie, CH Saint-Brieuc, France 5Laboratoire d’Hématologie, CHU Angers, France 6Laboratoire de Cytogénétique, Hôpital Morvan, CHRU Brest, France 7Laboratoire d’Anatomo-pathologie, Hôpital Morvan, CHRU Brest, France


Responses and Survival under Pegylated Interferon α2a Treatment for Patients with Post-MPN Acute Myeloid Leukemia and Acute Panmyelosis with Myelofibrosis
Leukemic transformations (LT) of a Philadelphia-negative myeloproliferative neoplasm (MPN) including polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF) are rare events and portend a dismal prognosis, with a median overall survival (OS) not exceeding a few months.Various strategies have been used to improve patient outcomes, including hypomethylating agents and intensive chemotherapy combined with allogeneic hematopoietic stem cell transplantation (ASCT), which seems to be the more efficient approach [1][2][3].Interferons have been used with success in acute myeloid leukemia (AML) during the induction, post-ASCT and maintenance phases.This treatment is less burdensome than classical chemotherapy because patients can administer the drug at home (no long hospitalization), sub-cutaneous injection can be used (less need for central venous catheter), there are few side effects (no concomitant therapy to reduce the symptoms), and patients do not need to undergo transfusion [4].
We report here our experience using Pegylated-Interferon (Peg-Ifn) α2a in four consecutive patients with high-grade myelofibrotic MPN-LT who were unfit for intensive chemotherapy and in whom we observed a high level of clinical and biological responses and impressive survival (    We have extensive experience in the use of Peg-Ifn in our two centers and have treated more than three hundred patients with this drug.In cases of AML, patients should be treated as recommended by the French cooperative groups with intensive chemotherapy or azacitidine (adjusted to the age).If this is not possible, due to co-morbidities or patient preference, our locals recommendations are to propose Peg-Ifn α2a to patients with both AML and myelofibrosis (with fibrotic grade ≥2), regardless of the patient's performance status (0 to 2).These attitudes have been validated by clinicians belonging to five hospitals.Patients gave their oral agreement to receive this treatment.
Case 1 is a 42-year-old female with pancytopenia and circulating blasts who was diagnosed with acute panmyelosis with myelofibrosis (APM) upon bone marrow biopsy (grade 3 fibrosis).Cytogenetic exams showed an unfavorable karyotype.Molecular testing showed no JAK2V617F, calreticulin or MPL mutations.After discussion with the patient, a strategy based on weekly injections of 135 µg of Peg-Ifn α2a was established.After 6 months of treatment with no adverse events reported, we obtained both hematological and cytogenetic complete remissions.The patient underwent a geno-identical ASCT and is still alive 26 months after diagnosis, with durable remission and without any symptoms of graft versus host disease (GVHd).

Results and Case reports
Case 2 is male who was diagnosed with ET in 1984 and is positive for a calreticulin type 2 mutation.He did not receive any treatment since his diagnosis.After 26 years, at 52 years of age, the patient presented with leukocytosis and circulating blasts.Bone marrow exams showed a grade 3 fibrosis with 80% blast infiltration and secondary AML with an unfavorable karyotype; the patient was then refused by clinicians for intensive chemotherapy.Peg-Ifn α2a was started at 135 µg weekly and then increased to 180 µg weekly because of a partial response (the patient experimented flu-like symptoms during the first month of increased dose).At 12 months, the patient achieved complete hematological and cytogenetical responses.An ASCT was then performed, and at d30, histological and cytogenetical complete remissions were obtained.The patient died three months after ASCT from aspergillosis.Leukemic transformations are highly adverse events that arise during the course of MPN and occur in 1-3%, 5-15%, and 10-20% in patients with ET, PV or PMF, respectively, after ten years.The prognosis is catastrophic, and ASCT is considered the only curative therapy available, though it is mostly given to younger patients, who can achieve complete remission [1][2][3].In contrast, for older patients who are not candidates for ASCT, hypomethylating agents have been evaluated.In a cohort of 54 patients, azacitidine showed an overall response rate (ORR) of 38% and a median overall survival (OS) of 8 months in post-MPN AML and 11 months in post-MPN myelodysplastic syndrome (MDS) [2].Six patients treated with decitabine obtained an ORR of 50%, with a median OS of 9.5 months in a phase 2 trial, whereas 14/34 (41%) patients were responders with a median OS of 11.8 and 10.5 months in post-MPN accelerated phase or AML, respectively [2,5].No specific information is available on the efficacy of azacitidine in patients with AML and high-grade myelofibrosis.However, azacitidine induces a small benefit for patients with myelofibrosis [6].

Patients and Methods
We showed here the efficacy of using Peg-Ifn α2a as the sole therapy in highly myelofibrotic post-MPN AML or APM.We obtained (i) complete cytogenetical response despite an unfavorable karyotype, (ii) reduction of the intensity of bone marrow fibrosis despite initial high-grade fibrosis and (iii) patient fitness for successful ASCT, and (iv) an increase in survival from 13 to 41 months compared with less than 3 months, as reported in the literature.We also tested low-dose drugs in three other patients with post-MPN AML who were more than 80 years old or had performance statuses of 3, but all of them died within three months of treatment initiation.
Case 3 is a 76-year-old male with a triple-negative untreated PMF (with grade 2 fibrosis) who experienced an 8-month rapid progression of constitutional symptoms that revealed an accelerated phase disease (19% of circulating blasts and unfavorable karyotype).The patient was too old to receive a classical chemotherapy regimen.He received Peg-Ifn α2a 135 µg/week, with improvement of his general condition and a partial regression of clinical symptoms and transfusion dependency at 6 months.The patient wanted to continue his treatment because of his good tolerance (only transient asthenia and skin reactions at the injection site) and because no alternative drug was available.After 41 months of therapy, he died from heart failure.
In our cases, Peg-Ifn permitted a long survival for patients with post-MPN AML, despite unfavorable karyotypes and high-grade myelofibrosis.At this time, when azacitidine and ruxolitinib are available and helpful in some cases but have not yet been tested in phase 2-3 trials, these four cases showed that Peg-Ifn α2a should also be considered as a potential active drug for these patients with an acceptable performance status.

Conclusion
The authors wanted to thank C. Riou for her precious help in English proof correction.

Acknowledgment
Case 4 is a 63-year-old male who was diagnosed with secondary AML with 47% medullar blasts and an intermediate karyotype 12 months after the diagnosis of a grade 3 fibrosis triple-negative untreated PMF.After the initial failure of a 3+7 regimen, he received a weekly dose of 135 µg of Peg-Ifn α2a with no reported side effects.Clinical improvement was observed, and a partial hematological response was obtained after six months.He died from pulmonary infection after 13 months of therapy.

Discussion
Furthermore, Ruxolitinib, known as a non-specific JAK1 and JAK2 inhibitor, was recently shown to induce complete remission and increase survival in some patients, mostly in combination with low-dose cytarabine or azacitidine [7,8].At the time of these cases, ruxolitinib has just begun to be prescribed and was available for patients with symptomatic myelofibrosis.
In contrast, direct blast toxicity has been reported as a consequence of the (i) reduced secretion of growth-promoting cytokines, (ii) stimulation of apoptosis, (iii) inhibition of cell proliferation and (iv) increased immunogenicity of the AML blast cells.The indirect antineoplastic effects are due to the stimulation of dendritic cells (DC), natural killer cells (NK) and T lymphocytes.The development of long-acting formulations of Peg-Ifn α2a and α2b have allowed both better tolerance and adherence to treatment, stable cytotoxic serum Ifn concentrations, and the ability to achieve adequate anti-leukemic control in some cases [2,9].Furthermore, two case reports showed an excellent response in patients with post-MPN AML after treatment with Peg-Ifn α2a as the sole therapy [10,11].

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Table 1 :
Characteristics of the four patients treated with Peg-Ifn α2a Journal of Hematology and Blood Disorders