Efficiency of interferon therapy in patients with essential thrombocythemia or polycythemia vera

2016 ◽  
Vol 88 (12) ◽  
pp. 69-77
Author(s):  
M A Sokolova ◽  
A G Turkina ◽  
A L Melikian ◽  
A B Sudarikov ◽  
S A Treglazova ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mutant Gene ◽  
Jak2v617f Mutation ◽  
Relative Reduction ◽  
Molecular Response ◽  
Morphological Pattern ◽  
Recombinant Interferon ◽  
Long Term Treatment

Aim. To evaluate the efficiency of interferon (IFN) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Subjects and methods. A total of 61 patients (41 with ET and 20 with PV) were examined. Prior to study enrolment, 44 (72%) patients with ET or PV received one or other therapy (aspirin was not taken into account). The mean Jak2V617F mutant allele at baseline was 23% (6—54%) in the patients with ET and 40% (11—88%) in those with PV. The median time from diagnosis to enrollment was 49 months. Results. The paper presents the clinical and molecular findings of long-term INF-α therapy in patients with ET or PV. The median follow-up was 52 months. Recombinant IFN-α2 showed its ability to induce complete hematologic remission (ET (76%), PV (70%)) and a complete molecular response. 22 (69%) out of 32 patients were noted to have a smaller number of cells with the Jak2V617F mutation. In the patients with PV and in those with ET, the relative reduction in the proportion of cells with the Jak2V617F mutant gene averaged 85% and 56% of the baseline values, respectively. There was a reduction in the proportion of cells expressing the Jak2V617F mutation in both the ET (from 12 to 2.2%; p=0.001) and PV (from 32.7% to 3.2%) groups (р=0.001). Ten (31%) patients achieved a deep molecular remission (≤2% Jak2V617F allele); among them, 5 patients were not found to have Jak2V617F mutation. The obtained molecular response remained in 7 of the 10 patients untreated for 11 to 86 months. The long-term treatment with IFN-α led to normalization of the morphological pattern of bone marrow in 5 of the 7 PV or ET patients. Conclusion. Significant molecular remissions achieved by therapy with recombinant interferon-α2 confirm the appropriateness of this treatment option in in the majority of patients with ET or PV.

JAK2V617F Complete Molecular Remission in Long-Term Follow-up of Patients with Polycythemia Vera and Essential Thrombocythemia Treated with Ruxolitinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3185-3185
Author(s):  
Lisa Pieri ◽  
Alessandro Pancrazzi ◽  
Annalisa Pacilli ◽  
Claudia Rabuzzi ◽  
Giada Rotunno ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Jak2v617f Mutation ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
Molecular Remission ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by the presence of JAK2V617F mutation in >95% and 60% of patients (pts), respectively. This mutation usually affects one allele in ET while most PV pts are homozygous due to mitotic recombination. Acquisition of the JAK2V617F mutation is strongly associated with the germline 46/1 predisposition haplotype. Ruxolitinib is a JAK1/JAK2 inhibitor recently approved for myelofibrosis (MF) and under investigation in PV and ET pts intolerant or resistant to hydroxyurea. We enrolled 24 pts, 11 with PV and 13 with ET, in the phase II INCB18424-256 trial that overall included 34 PV and 39 ET pts. 21/24 pts were still on treatment at 5 years (yr), of which 19 JAK2V617F mutated. Results of the PV cohort have been reported recently (Verstovsek et al. Cancer, 2014): with a median follow up of 35 months (mo), the JAK2V617F allele burden decreased by a mean of 8%, 14%, and 22%, respectively, after 12, 24 and 36 mo. The proportion of pts who achieved a reduction ≥50 % at any time during the 1st yr, 2nd yr, and 3rd yr were 5.9%, 14.7%, and 23.5%, respectively, but no patients achieved a complete remission. In our series of pts we evaluated the JAK2V617F allele burden by two RTQ-PCR methods, according to Lippert (sensitivity, 0.8%) and to Larsen (sensitivity, 0.08%) method. We also analysed by next generation sequencing (NGS; Ion Torrent platform) a series of MPN-associated mutations including TET2, ASXL1, IDH1/2, LNK, CBL, SRSF2, EZH2 and MPL at baseline and at 5 yr of treatment in ruxolitinib treated pts who achieved a >25% JAK2V617F allele burden reduction at 5 yr (n=13/19). JAK2V617F allele burden decreased by a mean of 7%, 11%, and 19% at 12, 24 and 36 mo, and decreased further by a mean of 28% after 60 mo. Three (1 PV, 2 ET) of 19 pts (16%) achieved a 50% or greater allele burden reduction after 2 yr; no additional pts achieved this degree of allele burden reduction even in prolonged follow up. These 3 pts further improved their molecular response to a complete molecular response (CMR) after 5 yr of treatment. Their mean JAK2V617F allele burden was 46.6% at baseline, 28.3%, 16.3%, 8.7% and 0% after 1 yr, 2 yr, 3 yr and 5 yr, respectively. The JAK2 CMR was confirmed in at least one independent sample at 3 mo after first discovery. At this last timepoint, the PV pt was in complete haematological remission according to ELN criteria, the 2 ET pts were in partial remission due to platelet count still >400x109/L: 422x109/L and 812x109/L, respectively. BM histopathology in the 2 ET pts at 5 yr, while they were in CMR, showed still evidence of megakaryocyte hyperplasia. In the PV pt, histopathology at 5 yr is pending; evaluation at 3 yr, a time when she was in complete hematologic remission and JAK allele burden had decreased from 69 to 8%, showed normalization of cellularity, megakaryocyte and myeloid lineage compared to baseline but still slight erythroid hyperplasia. All 3 pts had normal karyotype at baseline that remained unchanged thereafter. CMR for JAK2V617F was confirmed by NGS. The 2 ET pts achieving CMR did not show any additional mutations, while the PV pts presented a TET2 Y867H mutation with an allele burden of 48.9% and 52%, respectively at baseline and 5 yr. No recurrent mutations in genes other than JAK2 were found in all other examined cases at baseline or at 5 yr. In 3 informative pts, we also analysed the proportion of JAK2V617F homozygous, heterozygous and wild type clones by the method of Hasan et al (Leukemia 2013) based on allelic discrimination of 46/1 haplotype and JAK2. We found that JAK2V617F/V617F clones were reduced by a mean of 95.5%, JAK2V617F/WT showed an uneven trend with a mean reduction of 45.54% while JAK2WT/WT conversely increased (mean 61.43%) at 5 yr, suggesting that in a subset a patients who present significant reduction of VF allele burden ruxolitinib may preferentially target the homozygous clones. Until now, complete molecular remission in PV pts has been described only in patients treated with interferon. Our data suggest that a subset of pts who present a rapid and sustained reduction of the JAK2V617F allele burden under ruxolitinib may eventually reach a condition of CMR with prolonged treatment. However, similar to findings with interferon, mutations establishing clonality, such as in TET2, may still persist in patients who eventually show the disappearance of JAK2V617F mutated subclones. Disclosures Verstovsek: Incyte: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS) Therapy Renders High Clinical and Molecular Response Rates in Patients with Essential Thrombocythemia (ET) and Polycythemia VERA (PV)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 658-658 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge Cortes ◽  
Marie Ann Richie ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Clinical Activity ◽  
Molecular Response ◽  
Significant Activity ◽  
Recombinant Interferon ◽  
Starting Dose ◽  
Grade 3 ◽  
Initial Starting

Abstract Patients with high-risk essential thrombocythemia (ET) and polycythemia vera (PV) are typically managed with cytoreductive agents such as recombinant interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in ET and PV, this agent is frequently hindered by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, resulting in decreased renal excretion and increased serum half-life that allows for weekly administration. On this basis, we are conducting a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 76 patients have been enrolled and treated thus far (36 ET, 40 PV). Median age is 53 years (range, 18–77), time from diagnosis to PEG-IFN-α-2a 49 months (range, 0–355), WBC count 8.7×109/L (range, 3.7–27.8), hemoglobin 13.5 g/dL (range, 8.9–18.8), and platelet count 554×109/L (range, 140–1641). Prior therapies (median 1; range 0–6) included HU (n=44), AG (n=29), IFN-α (n=11: 5 oral and 6 sc), imatinib (n=7), and dasatinib (n=1). PEG-IFN-α-2a was the initial therapy in 13 patients that refused therapy with HU. The JAK2 V617F mutation was detected in 20 (56%) of 36 ET and in 37 (92.5%) of 40 PV patients. Nine (12%) patients had abnormal cytogenetics. Initial starting dose of PEG-IFN-α-2a was 450 mcg/week, but that was modified to the current starting dose of 90 mcg/week. Dose modifications are allowed according to response or toxicity. Patients are currently receiving 450 mcg (n=1), 270 mcg (n=3), 180 mcg (n=14), 135 mcg (n=8), 90 mcg (n=27), and 45 mcg (n=7). After a median follow-up of 23 months (range, 2–38), 63 (85%) of 74 assessable patients have responded. The median time to response was 4 weeks (range, 0.5–26). Complete response (CR) was achieved by 60 (81%) patients (for ET: platelets <440×109/L, off HU and AG, in the absence of thromboembolic events; for PV: Hb <15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly) whereas 3 (4%) patients (1 PV, 2 ET) had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). Of 5 assessable patients with abnormal karyotype at the start of the study, 2 reverted to diploid cytogenetics. The mutant JAK2 V617F to total JAK2 ratio was determined by quantitative pyrosequencing assay in all 76 patients prior to PEG-IFN-α-2a and was repeated at least once during therapy in 41 JAK2 V617F-positive patients. Overall, 23 (56%) had >10% reduction in JAK2 V617F expression, including 14 (34%) who had a >50% reduction. In 5 (11%) of the latter the mutant allele became undetectable. PEG-IFN-α-2a was well tolerated in most patients. Thirty-nine episodes of grade 3–4 toxicity were reported: neutropenia (n=15), elevated transaminases (n=5), infection (n=4), fatigue (n=3), pain (n=3), cardiac (n=2), and anemia, thrombocytopenia, depression, shortness of breath, pruritus, thrombosis, and dizziness in 1 case each. Sixteen (21%) patients were taken off study after a median of 8 months (range, 2–26) on PEG-IFN-α-2a but only 7 (9%) of them due to due to therapy-related toxicities: grade 3 neutropenia, anorexia, depression, ischemic retinopathy, dyspnea, confusion, and pruritic rash. In conclusion, PEG-IFN-α-2a therapy results in remarkable clinical activity with an acceptable toxicity profile in advanced, previously treated, patients with ET or PV. Clinical responses are frequently accompanied by significant reduction of JAK2 V617F allele burden, which becomes undetectable in a proportion of them, suggesting selective targeting of the malignant clone.

scholarly journals Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3623-3623
Author(s):  
Lierni Fernández-Ibarrondo ◽  
Joan Gibert ◽  
Concepción Fernández-Rodríguez ◽  
Laura Camacho ◽  
Anna Angona ◽  
...  
Keyword(s):  
Dna Repair ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Evolutionary Dynamics ◽  
Driver Mutations ◽  
Molecular Response ◽  
Increased Risk ◽  
Cytoreductive Treatment ◽  
Allelic Burden

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p&lt;0.001), and displayed higher leukocyte count (p&lt;0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

Long-term use of anagrelide in young patients with essential thrombocythemia

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 863-866 ◽  
Author(s):  
Elizabeth C. Storen ◽  
Ayalew Tefferi
Keyword(s):  
Side Effects ◽  
Essential Thrombocythemia ◽  
Young Patients ◽  
Drug Efficacy ◽  
Initial Response ◽  
Drug Dosage ◽  
Similar Proportion ◽  
Term Therapy ◽  
Long Term Treatment

Abstract Anagrelide is a novel platelet-lowering agent that has recently been approved for use in essential thrombocythemia (ET) and related disorders. Short-term drug efficacy and toxicity data have previously been presented. The purpose of this study was to obtain additional information regarding long-term anagrelide use. This is a retrospective series of 35 young patients (17 to 48 years) with ET who received anagrelide treatment before 1992. Initial drug dosage ranged between 1 and 10 mg/d, and the median maintenance dosage was 2.5 mg/d. The overall initial response rate of 94% included 74% complete remissions and 20% partial remissions. Of the 33 responding patients, 27 (82%) remained on anagrelide therapy for a median of 10.8 years (range, 7 to 15.5). Of these, 66% maintained a complete and 34% a partial remission over the study period. In general, the reporting of somatic side effects decreased over time, and anemia was the only new side effect that emerged after long-term therapy. Eight patients (24%) experienced a more than 3 g/dL decrease in hemoglobin level. Despite active therapy, 20% of the patients experienced a total of 10 thrombotic episodes, and a similar proportion experienced major hemorrhagic events. All thrombohemorrhagic complications occurred at a platelet count of more than 400 × 109/L. It is concluded that long-term treatment of ET with anagrelide is associated with decreased reporting of initial side effects and the development of mild-to-moderate anemia. Complete normalization of platelet counts may be needed to minimize residual thrombohemorrhagic risk during therapy.

Treatment Results and Malignant Complications in Patients on Long-Term Treatment with Tyrosine Kinase Inhibitors(TKIs) for Chronic Myeloid Leukemia(CML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3767-3767
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Takesi Okatani ◽  
Mitsuhiro Itagaki ◽  
Ryouta Imanaka ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Malignant Neoplasm ◽  
Incidence Rates ◽  
Term Treatment ◽  
Molecular Response ◽  
Malignant Diseases ◽  
Expected Number ◽  
Long Term Treatment

Abstract Abstract 3767 Background With the introduction of imatinib (IM) and subsequent TKIs such as nilotinib (NI) and dasatinib (DA), deaths due to progression of chronic myeloid leukemia (CML) have decreased dramatically. In such circumstances, the new occurrence of other malignant diseases in patients with CML on treatment with TKIs always causes distress. With the increase in long term surviving patients with CML, there is concern over whether these malignancies are related to treatment with TKIs or not. We investigated the improved prognosis in patients with CML on long-term treatment with TKIs and the occurrence of complicating malignancies. Methods We evaluated 173 patients (101 males, 72 females) in the chronic phase of CML, all of whom had CML diagnosed at our hospital between January 1990 and June 2011 and received treatment with TKIs for at least 1 year. The median age at the start of treatment with TKIs was 57 (19 – 92) years. Patients aged 60 years and older accounted for 72 (42%). The median follow-up period after the start of treatment with TKIs was 68 (12 – 128) months. Before the onset of CML, 11 patients had prior malignancies. Treatments for CML administered before use of TKIs were hydroxyurea (HU) alone 3, HU + interferon-α (IFN-α) 47, IFN-α alone 7, chemotherapy for AML + IFN-α 2 and chemotherapy for ML + IFN-α 1. TKIs were used as frontline therapy in 113.TKI treatment of all patients initially consisted of IM at the dose of 100 mg per 12 kg body weight. We switched the drug to NI when complete molecular response (CMR) was not achieved after long-term treatment with IM. In addition, a switch to DA was used to consolidate CMR. Treatments that contained TKIs consisted of IM alone in 42, IM → NI in 46, and IM →NI → DA in 85. Two patients with a complete cytogenetic response (CCR) underwent bone marrow transplantation. Results Among 173 patients, the best response to treatment in patients treated with TKIs was CMR in 72, a major molecular response (MMR) in 84, CCR in 15, and refractory CML in 2. Currently, 22 have maintained CMR for 6 to 111 months after discontinuation of TKIs, and 19 (11%; 17 males, 2 females) have developed new onset of a malignancy. In these 19, the median age at the onset of cancer was 70 (31 – 85) years. Patients aged 60 years and older accounted for 15 (79%). The median period from the start of TKIs to the onset of cancer was 38 (10 – 117) months. Affected organs were bladder 5; stomach 3; rectum 3; large intestine 2; lung 2; and esophagus, appendix, prostate, and pancreas each in 1. The TKIs given to the patients with malignant diseases were IM alone in 13, IM → NI in 4, and IM → NI → DA in 2. Prior treatments included HU + IFN-α in 8 and IFN-α alone in 1. The observed number of patients who were diagnosed as malignant neoplasm was compared with the expected number. The expected number was obtained through integration of age specific incidence rate of malignant neoplasm from the start age taking medicine to the age at which the diagnosis as malignancy was made or the follow up was finished for censoring. The age specific incidence rates were estimated by interpolating five year old specific incidence rates from of the 2007's survey that was conducted by Center for Cancer Control and Information Services, National Cancer Center, Japan. The observed number/expected number (O/E) ratio for the occurrence of all malignant diseases was 1.00 (19/18.97), and the O/E for gastrointestinal cancer was 1.118 (11/9.84). Therefore, no increase in the incidence of malignant diseases was observed in patients treated with TKIs. However, the O/E for bladder cancer was 4.525 (5/1.11) with a 95% confidence interval of 1.42 – 9.32 (P = 0.0002), which means that the incidence of bladder cancer in patients treated with TKIs was higher than that in the general Japanese population. So far 19 patients have died and the median age at death was 79 (59 – 94) years. In these patients, 8 deaths were related to cancer and the others were caused by diseases associated with old age that were unrelated to the worsening of CML. Conclusion The introduction of TKIs has undoubtedly improved the prognosis of patients with CML. Based on the results of this investigation, the apparent increase in malignant diseases observed during the long-term follow-up of patients treated with TKIs was generally considered to be attributable to the aging of patients. We should however further investigate whether the higher incidence of bladder cancer seen in patients treated with TKIs is incidental or not. Disclosures: No relevant conflicts of interest to declare.

Busulfan Induces Hematologic and Molecular Responses in Polycythemia Vera (PV) Refractory to Multiple Drugs

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5068-5068
Author(s):  
Emil Tom Kuriakose ◽  
Stefani Gjoni ◽  
Y. Lynn Wang ◽  
Amy Jones ◽  
Nicholas C.P. Cross ◽  
...  
Keyword(s):  
Response Time ◽  
Polycythemia Vera ◽  
Phase Iii ◽  
Molecular Response ◽  
Low Doses ◽  
Molecular Responses ◽  
Hematologic Response ◽  
Significant Difference ◽  
Multiple Drugs

Abstract Abstract 5068 Busulfan, a highly effective and established drug in polycythemia vera (PV), produces lasting clinical and hematologic responses. Its use as a first and second line therapy for PV recently diminished owing to largely unsubstantiated concerns of increased leukemogenicity. However, in a pivotal phase III trial of busulfan vs. P32 conducted by the EORTC in patients with PV, busulfan sustained long term clinical and hematologic responses as well as superior 10 year overall survival (70% vs. 55%). Toxicity was minimal and a low incidence of acute leukemia was reported (1% at 8 years). Accordingly, we treated 5 PV patients with busulfan, 4 of whom were refractory to multiple drugs including hydroxyurea (HU), pegylated interferon alfa-2a (pIFN), imatinib, dasatinib, and anagrelide. Clinical and hematologic response was graded according to PVSG criteria and molecular response according to ELN criteria. JAK2V617F allele burdens were determined by pyrosequencing, which quantifies mutant alleles more than 5%. If negative by pyrosequencing, we used an ARMS-PCR assay with a sensitivity of 0. 1%. Phlebotomy was performed to maintain the hematocrit (Hct) less than 45% for men and 42% for women. Treatment with busulfan was discontinued if patients experienced adverse side effects and/or had platelet counts less than 100, 000/mL while in clinical remission. All 5 patients had complete hematologic responses (CHR) within 3 months of starting busulfan (table 1). Molecular responses (MR) were: 1 complete (CMR) after 6 months, 1 partial (PMR) after 6 months, and 3 with no response (NMR) after 3, 7, and 60 months of treatment respectively. The 2 patients who had MR were homozygous for JAK2V617F, and the 3 who did not were heterozygous. Treatment was discontinued in the patient with CHR and CMR after 7 months due to thrombocytopenia; the patient has since maintained CHR and CMR for 3 years off treatment. The remaining 4 patients have maintained CHR on low doses of busulfan (table 1). No adverse events were observed over a median treatment duration of 15 months (range: 3–60 months). The significant difference in molecular response between patients with homozygous and heterozygous JAK2 mutations receiving similar doses of busulfan is noteworthy. This suggests a susceptibility of homozygous JAK2V617F clones to busulfan, but not to other drugs including HU, IFNa, and anagrelide. In summary, our 5 patients with multidrug refractory PV had rapid and sustained hematologic responses to busulfan at low doses, with favorable short and long term toxicity profiles. Two JAK2V617F homozygous patients had the best MR. Our findings indicate the effectiveness of a safe, relatively inexpensive drug in inducing clinical outcomes not significantly different from that of costly drugs, such as JAK2 inhibitors. In addition, the high rates of MR we observed in patients with homozygous JAK2 mutations warrant further study of busulfan with respect to this parameter. Table 1: Demographics and treatment results of 5 patients treated with busulfan for PV Patient Age (yr)-Sex (M/F) Prior treatments-duration (yr) Busulfan dose Adverse effects Duration of tx (months) Hematologic response/time to response (months) Molecular response/time to response (months) Pre-busulfan JAK2 allele burden 1 75-F HU-2 yr 4mg daily thrombocytopenia 7 CHR/3 CMR/6 100% 2 70-F HU+anagrelide-1yr Imatinib-2yr Dasatinib-3 yr IFNa-1 yr 2mg 3 times a week None 15 CHR/1 PMR/6 85% 3 84-F HU-2 yr Dasatinib- 3yr Imatinib-1yr 2mg 4 times a week None 18 CHR/3 None 27% 4 81-M HU-5 yr 2mg daily None 3 CHR/2 None 23% 5 81-F None 2mg 3 times a week None 60 CHR/3 None 45% Disclosures: No relevant conflicts of interest to declare.

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