A Phase II Study of Oral Interferon-Alpha (IFN-a) for Patients with Essential Thrombocythemia or Polycythemia Vera.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4880-4880
Author(s):  
Alfonso Quintas-Cardama ◽  
Francis Giles ◽  
Jorge Cortes ◽  
Hagop Kantarjian ◽  
Srdan Verstovsek
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Mucosal Route ◽  
Previously Treated ◽  
To Receive

Abstract Recombinant human IFN-α has been the mainstay of therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders for many years. However, the response rates of IFN-α therapy have been frequently challenged by high dropout rates due to side effects and inconvenient subcutaneous dosing schedules. Accordingly, we design a phase II study to evaluate the efficacy and safety of natural human IFN-α administered by the oral mucosal route in patients (pts) with essential thrombocythemia (ET) or polycythemia vera (PV). Pts were eligible if they had failed (inability to normalize platelet count in ET, or to reduce the frequency of phlebotomy or splenomegaly by 50% in PV, after 6 months of therapy with hydroxyurea (HU) and anagrelide (AG)), were intolerant to HU and AG, or refused to receive standard cytoreductive therapy. HU or AG therapy had to be stopped at least 3 weeks prior to start of oral IFN-α. Prior exposure to IFN-α was not allowed. Oral IFN-α was administered at 150 IU three times daily as a lozenge. A total of 14 pts (8 PV, 6 ET) have been treated. Median age was 57 (range, 32 to 79), time from diagnosis to oral IFN-α therapy 2 months (range, 0 to 32), Hb 14.2 gm/dL (range, 11.2 to 15.4), WBC 9.75 ×109/L, (range, 5.6 to 17.3), platelets 812 ×109/L (range, 360 to 1389). Five patients were previously treated with HU, four with AG, and 3 with imatinib mesylate. Six pts with PV had received phlebotomies and 2 presented with marked splenomegaly. The JAK2 V617F mutation was detected in 10 of 11 evaluated pts and 2 of 14 pts (14%) had abnormal cytogenetics. All 14 pts are evaluable for response and toxicity. No responses have been observed among any of the 14 pts treated. Ten (71%) pts discontinued oral IFN-α therapy due to lack of response (n=9) or disease progression (n=1, elevation of platelets), and 4 are currently on therapy. Duration of therapy varied: 2.5 months = 2 pts, 3 months = 6 pts, 4 months = 4 pts, 6 months = 2 pts. Therapy with oral IFN-α was very well tolerated: grade 1 headache was noted in 2 pts, and grade 1 paresthesia in 1 pt. We conclude that oral IFN-α is very well tolerated but has no activity in the treatment of pts with ET or PV at the dose and schedule employed in this study.

Phase II Study of CEP701, an Orally Available JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3543-3543 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ayalew Tefferi ◽  
Steven Kornblau ◽  
Deborah Thomas ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study ◽  
Subcutaneous Administration ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Common Mutation ◽  
Tyrosine Kinase 2

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative disorders (MPDs) associated with activating mutations of Janus tyrosine kinase 2 (JAK2) gene. The most common mutation, JAK2 V617F, has been reported in ∼97% of patients with PV, ∼50% with ET, and ∼50% with PMF. The resultant JAK2 protein is continuously autophosporylated and therefore always active. It is believed that this mutated tyrosine kinase contributes to the existence and progression of MPDs. CEP701 is an orally available potent low nanomolar inhibitor of wild type and mutated JAK2 tyrosine kinase in enzymatic and cellular assays. Significant inhibition (growth stasis) was observed following CEP-701 subcutaneous administration to V617F-mutated JAK2-dependent HEL.92 xenografts grown in immunocompromised mice. These results indicate that CEP-701 is an attractive candidate for clinical evaluation in patients with MPD carrying a mutated, constitutively activated JAK2. CEP701 is also a potent inhibitor of FLT3 and is being evaluated as FLT3 inhibitor in Phase II/III studies in patients with acute myeloid leukemia, at the starting dose of 80mg PO BID. We designed a Phase II study of CEP701, at the dose of 80 mg PO BID, in patients with PMF and post PV/ET MF, who harbor JAK2 V617F mutation. Eleven patients have been treated so far, seven males, median age 56 years (range, 38–69), median 3 prior therapies (range 0–6); 7 with abnormal cytogenetics; 8 with enlarged spleen (2 had splenectomy); 4 with enlarged liver; 5 transfusion dependent. Five patients have been followed for at least 1 month and have had stable disease. Response will be evaluated using International Working Group for MF Consensus Response Criteria. JAK2 V617F allele burden is being measured monthly. Except for Grade 2 nausea in one patient, no toxicities have been noted so far. Updated results will be presented at the meeting.

scholarly journals A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis

Leukemia ◽  
2008 ◽  
Vol 22 (5) ◽  
pp. 965-970 ◽  
Author(s):  
A Quintás-Cardama ◽  
W Tong ◽  
H Kantarjian ◽  
D Thomas ◽  
F Ravandi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study

Phase II Study of Sunitinib in Patients With Primary or Post–Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

2010 ◽  
Vol 10 (4) ◽  
pp. 281-284 ◽  
Author(s):  
Effrosyni Apostolidou ◽  
Hagop Kantarjian ◽  
Deborah Thomas ◽  
Ian Burger ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Essential Thrombocythemia ◽  
Phase Ii Study

Multicenter phase II study of cetuximab and irinotecan as third line chemotherapy in patients (pts) with metastatic colorectal cancer (MCRC) previously treated with both irinotecan and oxaliplatin regimens

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13551-13551 ◽  
Author(s):  
C. Grande ◽  
J. R. Mel ◽  
M. Salgado ◽  
M. Reboredo ◽  
S. Candamio ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Tumour Progression ◽  
Multicenter Phase ◽  
Igg1 Monoclonal Antibody ◽  
Previously Treated ◽  
Third Line ◽  
Metastatic Sites ◽  
Ecog Ps ◽  
To Receive

13551 Background: Pts with chemotherapy-resistant MCRC have a really poor prognosis with few therapeutic options. Cetuximab (Erbitux®) is an IgG1 monoclonal antibody targeting the EGFR, shown to be effective in pts with EGFR-expressing MCRC refractory to prior irinotecan-based chemotherapy (Cunningham NEJM 2004). Methods: The goal of this multicenter phase II study is to investigate the safety and efficacy of cetuximab in combination with irinotecan as third line treatment in 40 pts with heavily pre-treated MCRC. From Jan to Dec 2005, 40 pts with EGFR-expressing MCRC, refractory to irinotecan, pre-treated with both irinotecan and oxaliplatin with fluorouracil or capecitabine combinations, and PS 0–2, were included to receive cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus irinotecan (180 mg/m2 every 2 weeks) until tumour progression or unacceptable toxicity. Pts were analysed weekly for toxicity and every 12 weeks for response. Recruitment is completed. Currently, 38 pts are evaluable for toxicity (2 pts recently recruited) and 23 pts for response (16 pts on treatment for <12 weeks and 1 pt withdrew at week 6 due to lung thromboembolism not related to study treatment). Results: M/F 24/14, median age 63 years (range: 33–78), colon/rectum 23/15, ECOG PS=0/1/2 9/23/6, Metastatic sites 1/2/>2 16/19/3 (Liver 43%, lung 23%, nodes 17%, pelvic 5%, others 12%). A total of 418 weekly infusions were administered (mean: 11; range: 3–37). Preliminary efficacy data is as follows: 3 PR, 3 SD, 17 PD with an overall response rate of 13% (95% CI: 3–34%) and disease control rate of 26% (95% CI: 10–48%). Major toxicities (G 1–2/G 3–4) were: Acne-like skin rash 58/11%, Anemia 32/3%, Neutropenia 16/13%, Nausea-vomiting 32/0%, Diarrhoea 32/11%. Median time to progression was 3.5 months (Range: 1–10+) and median overall survival was 7.3 months (Range: 1.5–12+). Conclusions: These preliminary results suggest that cetuximab and irinotecan combination, is a reasonably effective treatment for pts with highly pre-treated MCRC with an acceptable toxicity profile No significant financial relationships to disclose.

Pegylated Interferon-alfa-2a (PEG-IFN-α-2A; PEGASYS™) for Essential Thrombocythemia (ET) and Polycythemia Vera (PV): An Update of an Ongoing Phase II Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge Cortes ◽  
Marie Ann Richie ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Human Interferon ◽  
Clinical Activity ◽  
Significant Activity ◽  
Starting Dose ◽  
Grade 3 ◽  
Initial Starting

Abstract Therapy for patients with high-risk Philadelphia chromosome-negative myeloproliferative disorders (MPDs) involves the use of cytoreductive agents such as recombinant human interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in MPDs, therapy with 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, which results in decreased renal excretion and increased serum half-life that allows for weekly administration with acceptable toxicity. Based on the superior pharmacokinetic profile of PEG-IFN-α-2a relative to conventional IFN-α, we designed a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 50 patients have been enrolled and treated thus far (22 ET, 28 PV). Median age is 53 years (range, 23–77) and time from diagnosis to PEG-IFN-α-2a 64 months (range, 1–348). Prior therapies (median 2; range 0–6) included HU (n=33), AN (n=22), phlebotomy (n=27), IFN-α (n=8: 5 oral and 3 sc), other (n=10). PEG-IFN-α-2a was the initial therapy in 4 patients. The JAK2 V617F mutation was detected in 11 (50%) of 22 ET and in 26 (93%) of 28 PV patients. Six (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), 360 mcg (n=1), 270 mcg (n=5), 180 mcg (n=11), 135 mcg (n=8), 90 mcg (n=9), and 45 mcg (n=5). After a median follow-up of 11 months (range, 2–28), 47 (94%) patients have responded. Complete response (CR) was achieved by 46 (92%) patients (for ET: platelets <440x109/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 1 (2%) patient with PV had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). The mutant JAK2 V617F to total JAK2 ratio was determined by PCR (n=37) and by a quantitative pyrosequencing assay (n=30) prior to PEG-IFN-α-2a. JAK2 V617F mutational analysis was subsequently performed after 6 and 12 months into PEG-IFN-α-2a therapy in 20 and 10 patients, respectively. Nine (30%) of the 30 patients assessable for JAK2 V617V quantitation had >10% reduction in JAK2 V617F expression, including 2 (7%) in whom the mutant allele became undetectable. In addition, 4 (13%) patients had a 5%–10% reduction. JAK2 V617F quantitation has not been repeated yet in 9 patients. PEG-IFN-α-2a was well tolerated in most patients. Twenty-two episodes of grade 3–4 toxicity were reported, including neutropenia (n=11), elevated transaminases (n=4), and anemia, thrombocytopenia, depression, fatigue, infection, cardiac, and pain in 1 case each. Ten patients were taken off study, including 6 (12%) due to therapy-related toxicities: grade 3 neutropenia (n=1), fatigue (n=1), depression (n=1), ischemic retinopathy (n=1), dyspnea (n=1),and diarrhea (n=1). In summary, therapy with PEG-IFN-α-2a results in remarkable clinical activity and acceptable toxicity profile in patients with ET or PV. Significant reduction of JAK2 V617F allele burden occurred in a proportion of responders, suggesting selective targeting of the malignant clone.

Phase II Study of Dasatinib (SPRYCEL™) in Philadelphia Chromosome-Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3551-3551 ◽  
Author(s):  
Srdan Verstovsek ◽  
Tefferi Ayalew ◽  
Cortes Jorge ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myeloid Leukemia ◽  
Phase Ii Study ◽  
Systemic Mastocytosis ◽  
Hematologic Malignancy ◽  
Hypereosinophilic Syndrome ◽  
Philadelphia Chromosome ◽  
Kit Mutation ◽  
Previously Treated ◽  
Grade 3

Abstract Dasatinib is approved as a second line therapy (Rx) for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia, as it targets Bcr/Abl tyrosine kinase. Due to its activity against other kinases, like KIT and PDGFR, we conducted a Phase II study of dasatinib in patients with Ph-negative acute and chronic myeloid diseases. Sixty-eight patients were treated at the starting dose of 70mg PO BID (9 patients with SM received 140mg as a single dose daily); 4 weeks=1 cycle. All patients were assessed for response and toxicity (no Grade 4 toxicity was observed). The results by disease type are detailed. Systemic mastocytosis: 33 patients were treated (18 indolent, 9 aggressive, 6 with associated hematologic malignancy); median age 57 years (29–74); 14 were males, all PDGFRA−; # prior Rx 1 (0–4), 16 not previously treated; median # cycles 4 (1–20). Two achieved CR: one SM-MF (JAK2 V617F+, complex cytogenetics) and one SM-HES; both c-KIT mutation negative, low tryptase, anemic, failed erythropoietin, and had abnormal WBC differential. SM-MF patient progressed to AML after 8 months on Rx and died, and SM-HES is still in CR after 18+ months. Nine patients had improvement in symptoms related to SM, lasting from 3–18+ months. Nineteen Grade 3 toxicities were observed; dose was reduced to −1 level in 15, and to −2 level in 5 patients. Acute myeloid leukemia: 9 patients were treated; median age 70 years (51–91); 7 were males, 4 had abnormal cytogenetics; # prior Rx 2 (0–3); median # cycles 1 (1–18). CR was observed in an 80y old male with trisomy 8, previously treated with 3+7 chemotherapy with short CR. He relapsed on dasatinib Rx after 60 weeks. Eight patients had no response (4 stopped Rx within first month). Six Grade 3 toxicities were observed. Myelodysplastic syndrome/chronic myelomonocytic leukemia: 6 patients were treated (3+3); median age 68 years (51–75); 4 were males, 1 with abnormal cytogenetics; # prior Rx 1.5 (0–5); median # cycles 1 (1–2). No responses were observed (2 stopped Rx within first month); one Grade 3 toxicity was observed. Hypereosinophilic syndrome/chronic eosinophilic leukemia: 8 patients were treated (5+3); median age 58 years (23–75); 5 were males, 3 had abnormal cytogenetics, all PDGFRA-; # prior Rx 1.5 (0–3); median # cycles 3 (1–17). One female patient with HES achieved CR (previously Rx with gleevec without response). She relapsed after 58 weeks while off Rx due to toxicity. Other patients did not respond (1 stopped Rx within first month); 5 Grade 3 toxicities were observed. Polycythemia vera: one patient was treated; 50yr old female, with no prior Rx, had no response after 3 months of dasatinib Rx. Chronic idiopathic myelofibrosis: 11 patients were treated; median age 63 years (47–77); 10 were males, 2 had abnormal cytogenetics; # prior Rx 2 (0–7); median # cycles 6 (1–9). No responses were observed (1 stopped Rx within first month); 4 Grade 3 toxicities were observed. Conclusion: Dasatinib is active in systemic mastocytosis (overall response rate 33%). Updated clinical and molecular results will be presented.

scholarly journals Updates in the management of polycythemia vera and essential thrombocythemia

2019 ◽  
Vol 10 ◽  
pp. 204062071987005 ◽  
Author(s):  
Prithviraj Bose ◽  
Srdan Verstovsek
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Gene Mutations ◽  
Jak2 V617f ◽  
Additional Contribution ◽  
Thrombotic Risk ◽  
Targeted Next Generation Sequencing

Polycythemia vera (PV) and essential thrombocythemia (ET) are both classic, relatively indolent, chronic Philadelphia-chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs) characterized by elevated blood counts, thrombotic as well as hemorrhagic tendencies, a variety of symptoms, cumulative risks of progression to myelofibrosis and transformation to acute myeloid leukemia over time, and long survival. Molecularly, PV is more homogenous, being driven by JAK2 mutations in virtually all cases, while ET can be JAK2-, CALR-, or MPL-mutated, as well as ‘triple negative’. Recent targeted next-generation sequencing efforts have identified other, nondriver gene mutations, some with prognostic relevance. Prevention of thrombotic and hemorrhagic complications continues to be the major focus of management, although symptoms are increasingly being recognized as a relatively unmet need, particularly in ET. Thrombotic risk stratification in PV is still based on age and history of thrombosis, while in ET, the additional contribution of JAK2 V617F to thrombotic risk is now well established. The associations of leukocytosis with clotting risk (in both conditions) and mortality (in PV) have drawn increased attention with the availability of ruxolitinib as a second-line treatment in PV. Similarly, there is a renewed interest in interferons with the emergence of ropeginterferon alfa-2b as a potential new frontline treatment option in PV. Drug development is more difficult in ET, the most indolent of the classic Ph− MPNs, but ruxolitinib is being studied. Triggering apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (and synergism with interferon) is a new, promising therapeutic strategy.

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