Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Pascal Turlure ◽  
Nathalie Cambier ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Residual Disease ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
First Year ◽  
Molecular Response ◽  
Sequential Samples ◽  
Low Toxicity ◽  
Pegylated Interferon Alfa

Abstract Interferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

Pegylated Interferon-Alfa-2a Induces Complete Hematologic and Molecular Responses with Low Toxicity in Essential Thrombocythemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1743-1743 ◽  
Author(s):  
Mohamed A. Yassin ◽  
Nader Al-Dewik ◽  
Hanadi Rafii El-Ayoubi
Keyword(s):  
Research Funding ◽  
Pegylated Interferon ◽  
First Year ◽  
Molecular Response ◽  
Research Fund ◽  
Jak2 Mutation ◽  
Hematologic Response ◽  
History Of ◽  
Low Toxicity

Abstract Abstract 1743 Essential thrombocythemia (ET) is a myeloproliferative Neoplasm (MPNs) marked by a risk of thrombotic and hemorrhagic complications, and by a long-term risk of evolution to myelofibrosis (MF), myelodys-plastic syndrome (MDS), and acute leukemia (AL). In addition to its role in pathophysiology and diagnosis, the constitutively active JAK2V617F mutation may be a prognostic marker because the percentage of circulating mutated alleles (%V617F) appears to be significantly higher in patients who develop vascular complications. Interferon alfa2a (pegasis) is a nonleukemogenic drug that can induce cytogenetic remissions or reversion from monoclonal to polyclonal patterns of hematopoiesis in some cases, this is the first study addressing the effects of pegasis in ET. Methods. Inclusion criteria were: Patients with ET diagnosed as per WHO classification 2008, age 18 to 45 years, and either no previous treatment or Hydroxyurea or anagralide for less than 1 years. ET diagnosis workup included ferritin, exclusion of secondary causes like infections and not meeting WHO criteria for PV, MDS and CML Pretreatment evaluation also included patient history, physical examination, complete blood count (CBC) and serum chemistries (UE), including liver and renal function studies, thyroid function tests (TFT), and molecular study for JAK2V617F mutation. Exclusion criteria included (significant hepatic and renal dysfunction, history of psychiatric disorder, in particular depression, autoimmune hepatitis, severe cardiac dysfunction, known hypersensitivity to IFN. The primary end point was hematologic response to pegasis at 12 months. Complete hematologic response (CR) as per ELN guidelines' and Molecular response (MR) was defined as “complete” when JAK2V617F became undetectable with the technique used (ie, %V617F < 1%), “partial” when > 50% decrease of baseline %V617F was obtained, and “minor” when %V617F decrease was between 20% and 49%. Follow-up evaluations included adverse event (AE) assessment monthly for 3 months, then every third month until the 12th month with CBC, UE weekly during the first month and monthly thereafter. TFT, CBC, JAK2 mutation studies were taken every 6 months. After inclusion, HU was stopped 2 weeks before Pegasis initiation. Pegasis was started subcutaneously at 50 microgram weekly for 4 weeks then 135 microgramg/wk from week 5. Baseline characteristics of the patients are. Median age was 31.5 years (19–44) years), and 16 patients were males 24 were femals Five patients had a history of major thrombotic events. Treatment before inclusion included HU in 15 patients, and no treatment in the remaining 25 patients, all recently diagnosed. JAK2 mutation was found in all patients All the patients responded to Pegasis at the 12-month evaluation including 35 hematologic CRs (94.6%), and 5 PRs (5.4%). Cumulative incidences of hematologic CRs and PRs showing that 100% of responses were achieved within 12 months. No patient experienced signs or symptoms of thrombosis or hemorrhage during the whole study period. Median relative decrease of %V617F during the first year was 50% (33%-60%). %V617F decreased in all patients, After the first year, %V617F continued to decrease without evidence for a plateau, the proportion of mutant JAK2 being always similar or lower in the last sample compared with the previous one and none of the responding patient experienced an increase of %V617F during follow-up. Median %V617F was, 58% at 12 months, (P<.001). Complete or partial MR was observed in all patients. Hematologic response was achieved in all of the patients within 2 months and were sustained beyond the first year. Most common toxicities during the first month included musculoskeletal pain in 6 patients, skin toxicity in 4, and GI symptoms in 2, none of the toxicity exceeds WHO Grade 2. Conclusion. Pegylated Interferon alfa2a is effective and promising treatment for ET Reducing the vascular risk and preventing evolution to MF, MDS, and AL.with low toxicity profiles and good Hematological and Molecular response, Percentage of V617F appears to be a good tool to monitor minimal residual disease and to evaluate treatment efficacy however further studies are needed to confirm these results. Disclosures: Yassin: Qatar National Research Fund: Patents & Royalties, Research Funding. Off Label Use: use of pegelated interferon alfa 2a in treatment of patients with ET. Al-Dewik:Qatar National Research Fund: Patents & Royalties, Research Funding. Rafii El-Ayoubi:Qatar National Research Fund: Patents & Royalties, Research Funding.

Molecular Long-Term Surveillance of CML Patients on Imatinib Therapy. Follow-Up of German Patients Treated within the IRIS Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1003-1003
Author(s):  
Martin C. Mueller ◽  
P. Paschka ◽  
T. Lahaye ◽  
Ch. Lorentz ◽  
N. Gattermann ◽  
...  
Keyword(s):  
Median Time ◽  
Nested Pcr ◽  
Residual Disease ◽  
Response To Therapy ◽  
Imatinib Therapy ◽  
Interferon Α ◽  
Tyrosine Kinase Domain ◽  
Molecular Response

Abstract High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (&lt;10 transcripts/2μl cDNA) or neg RQ-PCR, nested PCR was performed. Total ABL transcripts were quantified as internal controls. A single series of BCR-ABL plasmid dilutions served as standard for both BCR-ABL and ABL transcripts. In pts on 1st-line imatinib therapy median ratios BCR-ABL/ABL gradually decreased: 4.8% at mo 3, 0.88% at mo 6, 0.22% at mo 12, 0.17% at mo 18, 0.058% at mo 24, 0.066% at mo 30, and 0.023% at mo 36. After crossover to imatinib results were not significantly different: 15.5% at mo 3, 1.6% at mo 6, 0.28% at mo 12, 0.068% at mo 18, 0.045% at mo 24, and 0.041% at mo 30. After a median follow-up of 40 mo (1–47) 31/69 pts (45%) on 1st-line imatinib were still RQ-PCR pos, 20 pts (29%) were RQ-PCR neg and nested PCR pos, and in 4 pts (5.8%) BCR-ABL became undetectable by RQ- and nested PCR. After a median time of 25 mo (3–43) on 2nd-line imatinib therapy 19/41 pts (46%) were RQ-PCR pos, 9 pts (22%) were RQ-PCR neg and nested PCR pos, and in 5 pts (12%) BCR-ABL was undetectable by RQ- and nested PCR. Considering adequate RNA quality BCR-ABL became repeatedly undetectable in 4 pts after 18–33 mo of 1st-line imatinib therapy and in 5 pts 9–33 mo after crossover from IFN to imatinib. In one patient, BCR-ABL remained undetectable after a treatment free interval of 4 weeks. After achieving CCR, 5 pts (7.2%) on 1st-line and 2 pts (4.9%) on 2nd-line imatinib therapy experienced cytogenetic relapse after a median time of 10 mo (4–21). In none of these pts mutations of the tyrosine kinase domain of BCR-ABL were detected. BCR-ABL/ABL ratios after 12 mo of imatinib therapy were significantly lower in pts in continuous CCR vs pts with subsequent relapse (0.18 vs 0.60%, respectively, p=0.04). None of the relapsing patients had achieved a ratio BCR-ABL/ABL &lt;0.12% after 12 mo, which represents a 3-log reduction from baseline. During total follow-up ratios BCR-ABL/ABL &lt;0.12% have been achieved in 51 pts (74%) on 1st-line and in 21 pts (51%) on 2nd-line imatinib therapy. We conclude that (i) treatment with imatinib in newly diagnosed CML pts is associated with a rapid and steady decrease of BCR-ABL transcript levels, (ii) a short trial of IFN does not jeopardize molecular response to subsequent imatinib therapy, (iii) an increasing minority of pts achieve complete molecular remission, and (iv) ratios of BCR-ABL/ABL &lt;0.12% after 12 mo of therapy predict for long-term response.

High Degree of Hematological Response After Pegylated Interferon Alpha-2a Therapy In Myeloproliferative Neoplasms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5055-5055
Author(s):  
Jan Samuelsson ◽  
Gerd Larfars ◽  
Eva Ottosson ◽  
Mats Merup
Keyword(s):  
Side Effects ◽  
Median Time ◽  
Response Rate ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
Molecular Response ◽  
Hematological Response ◽  
Ifn Therapy

Abstract Abstract 5055 Objective: To retrospectively assess hematological response rates, and other clinical and molecular variables, in MPN patients treated with pegylated interferon α-2a (Pegasys®, Roche Ltd). Responses were graded according to criteria published by the European Leukemia Net for PV and ET (Barosi G et al Blood 2009;113:4829), with the exception that mesurement of spleen size using ultrasound was not routinely performed, and the European Myelofibrosis Network for PMF (Barosi G et al Blood 2005;106:2849), respectively. Patient characteristics: The 23 patient cohort consisted of 13 PV, 5 ET, 3 PMF and 2 post-ET/PV MF pts. Thirteen pts were JAK2V617F+, 6 were JAK2V617F wt, and in 4 pts JAK2 status is unknown. Median age was 50 years (range 26–69), 13 were female and 10 male. Median time from MPN diagnosis to start of pegylated interferon α-2a (Peg-IFN) therapy was 67 months (range 0–204). Six pts had a previous thrombotic event (TIA=2, portal vein thrombosis=2, DVT lower extremity=2), and 2 pts had a previous major hemorrhage (gynecological=1, gastrointestinal=1). Eleven pts had previously received therapy with anagrelide (n=8), hydroxyurea (n=4), interferon α-2b (n=1), busulfan (n=1) or P32 (n=1), while 12 pts had not received bone marrow suppressive therapy. All PV and ET pts were on aspirin. Phlebotomies were performed in PV with the aim of keeping the hematocrit < 0.45. Peg-IFN was given at a dose of 90 μg/week in 16 pts, 135μg/week in 6, and 180μg/week in 1. Results: The overall hematological response rate (CR+PR) was 18/21 (86 %), 14 pts achieving CR and 4 PR. Two pts are too early to evaluate at the time of astract submission. One PV and 1 PMF patient were non-responders. Resonse rates were similar in PV vs ET, female vs male pts, and previously treated vs previously untreated pts. Median time of follow-up on Peg-IFN therapy is 16 months (3+ - 49+). Thirteen pts are still on therapy, 9 in CR, 2 in PR, and 2 too early to evaluate. These 13 pts have very limited or no side effects. Therapy has also been stopped according to plan after long hematological CR with molecular response in 2 pts. Therapy has been discontinued in 8 pts, in five (22 %) due to side effects (depression n=3, joint pain n=3, hair loss n=2, pruritus n=1), non-response in 2 pts, and PMF progression in 1. Serial JAK2V617F measurements are available at time of abstract submission in 4 pts, 1 achieved molecular CR, 2 PR whereas 1 patient treated for 5 months had no molecular response. Three of 4 mildly anemic MF pts normalized their hemoglobin (HgB 113 → 137, 106 → 123, and 110 → 125 respectively). In one PMF patent a clear reduction of marrow fibrosis was noted, whereas it progressed in another. No thromboembolic or bleeding complications were observed during PEG-IFN therapy. Longer follow-up, as well as additional molecular and morphological studies will be presented. Conclusions: Pegylated interferon α-2a induced a higher hematological response rate with improved tolerability, compared to our previous experience with Peg-IFN α-2b (Samuelsson et al Cancer 2006;106:2397), although the current number of patients is limited. However, the two previous publications that describes Peg-IFN α-2a therapy in larger MPN patients cohorts have observed results similar to ours (Kiladjian JJ et al Blood. 2008;112:3065, Quintás-Cardama A et al J Clin Oncol. 2009;27:5418). Molecular responses noted in a subset of patients further highlights the effect of Peg-IFN α-2a on the malignant clone in MPN:s. Peg-IFN α-2a is a valuable therapeutic alternative in patients who tolerate initial side effects, and will soon be compared to hydroxyurea in a randomized trial in high-risk PV and ET pts performed by the MPD research consortium. Disclosures: Samuelsson: Roche Sweden: Advisory board on use of recombinant erytropoetin. Off Label Use: Alpha-interferon does not have a label for use in myeloproliferative neoplasms. Merup:Roche Sweden: Received honoraria for lectures on rituximab use in lymphoma.

scholarly journals Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera

2009 ◽  
Vol 27 (32) ◽  
pp. 5418-5424 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Taghi Manshouri ◽  
Rajyalakshmi Luthra ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Response Rate ◽  
Pegylated Interferon ◽  
Interferon Alfa ◽  
Clinical Activity ◽  
Molecular Response ◽  
Prior Therapy ◽  
Poor Tolerance ◽  
Pegylated Interferon Alfa

Purpose We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-α-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Patients and Methods Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-α-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-α-2a at 450 μg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 μg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. Results The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2V617F mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2V617F) in 6% and 14%, respectively. The JAK2V617F mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-α-2a at 90 μg weekly was excellent. Conclusion PEG-IFN-α-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-α-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

90Yttrium-Ibritumomab-Tiuxetan as First-Line Treatment for Follicular Lymphoma: 30 Months of Follow-Up Data From an International Multicenter Phase II Clinical Trial

2013 ◽  
Vol 31 (3) ◽  
pp. 308-313 ◽  
Author(s):  
Christian W. Scholz ◽  
Antonello Pinto ◽  
Werner Linkesch ◽  
Ola Lindén ◽  
Andreas Viardot ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Residual Disease ◽  
Standard Procedure ◽  
Complete Response ◽  
Molecular Response ◽  
First Line ◽  
Ibritumomab Tiuxetan ◽  
Multicenter Phase

Purpose We report on a multicenter phase II trial of 90yttrium-ibritumomab-tiuxetan (90YIT) as first-line stand-alone therapy for patients with follicular lymphoma (FL). Patients and Methods Fifty-nine patients with CD20+ FL grade 1 to 3a in stages II, III, or IV, age 50 years old or older requiring therapy were enrolled. They received 90YIT according to standard procedure. If complete response (CR) or unconfirmed complete response (CRu) without evidence for minimal residual disease (MRD) 6 months after application of 90YIT was achieved, patients were observed without further intervention. The same applied to patients with partial response (PR) or with stable disease (SD). Patients with CR but with persisting MRD were to receive a consolidation treatment with rituximab. Primary end point was the clinical and molecular response rate. Secondary end points were time to progression, safety, and tolerability. Results Six months after treatment with 90YIT, 56% of the patients showed a CR or CRu and 31% achieved a PR. After a median follow-up of 30.6 months, the progression-free survival (PFS) was 26 months. There was a trend for shorter PFS in patients with increased lactate dehydrogenase (LDH). Of the 26 patients who had CR 12 months after 90YIT, only three had relapsed. Median time to next treatment has not been reached. The most common toxicities were transient thrombocytopenia and leukocytopenia. Nonhematologic toxicities never exceeded grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE v2.0). Conclusion 90YIT is well tolerated and achieves high response rates. Patients with increased LDH tend to relapse earlier, and individuals in remission 1 year after 90YIT appear to have long- lasting responses.

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