Chronic Myeloproliferative Disorders • Research Paper Pegylated interferon for the treatment of high risk
essential thrombocythemia: results of a phase II study

Background and Objectives. Patients with high-risk essential thrombocythemia require cytoreductive therapy in order to normalize the elevated platelet counts. We evaluated the efficacy and toxicity of pegylated interferon in high-risk essential thrombocythemia Design and Methods. Thirty-six patients with high-risk essential thrombocythemia (median age 54 years; range, 24-72 years) were studied. The dose of pegylated inter- feron was initially 50 mg per week and could be escalated up to 150 mg per week.
Results. During the first three months platelet counts decreased significantly from amedian baseline count of 895¥109/L (range: 383-1779) to a median count of 485¥109/L (range: 211-1283; p£0.001). A complete response was defined as platelet counts < 450¥109/L. The complete response rate was 39%, 47%, 58% and 67% at 3, 6, 9 and 12 months of treatment, respectively. There were 25%, 11%, 8% and 0% poorresponders, defined as patients with platelet counts > 600¥109/L, at 3, 6, 9 and 12 months of treatment, respectively. After a median time of 23 months (range 3–39months) 23 of 36 patients (64%) are still receiving pegylated interferon. In ten patients(28%) treatment was stopped due to grade 1 to 2 toxicity, classified according to theWHO standard toxicity scale. One patient, who responded partially to pegylated inter-feron (platelet count 542¥109/L), had a cerebral stroke after 23 months of treatment. Interpretations and Conclusions. In high-risk essential thrombocythemia sustainedtreatment with pegylated interferon is effective and safe in reducing platelet countswith a toxicity comparable to that of conventional interferon.
Key words: pegylated interferon, treatment, essential thrombocythemia, ET.
From the Department of MedicineIII, University of Ulm, Germany(CL, SS, MG, HB); Department ofMedicine III, Klinikum Mannheim,Fakultät für Klinische Medizin Essential thrombocythemia is a Phi- the best studied drug and has been proven to reduce complications related to essen- als;8,9 however, this drug has a potential to Mannheim der UniversitätHeidelberg, Mannheim, Germany (EL); Institue of Pathology, University physicians are still reluctant to treat young tions.2 However, in about one third of all patients the disease is benign and there are urea. However, there is no clear proof that hydroxyurea alone is increasing the risk of Center of Clinical Research,University Hospital Freiburg, Therefore, the identification of patients at genic drug, conventional interferon-a, has risk is important. According to retrospec- University of Vienna, Vienna,Austria (HG). tive studies, high-risk patients are charac- terized by an age > 60 years, a very high years.14-16 The major disadvantage of inter- bolic event.4-7 The need for cytoreductive therapy in these high-risk patients is wide- file of interferon-a through addition of a Robert-Koch-Strasse 8, D-89081Ulm, Federal Republic of Germany. ly accepted.3-9 Treatment options include polyethyleneglycol (pegylation) has result- cytoreductive drugs, such as hydroxyurea, ed in slower absorption and a lower elim- ination rate, thus enabling weekly admin- sistration, potentially improving compli- haematologica/the hematology journal | 2005; 90(10) | 1333 | ance.17 The aim of this phase II study was to evaluatethe safety, toxicity and efficacy of pegylated interfer- Table 1. Baseline characteristics of the 36 high-risk patients withessential thrombocythemia at enrollment into the study.
on in a group of 36 patients with high-risk essentialthrombocythemia.
Design and Methods
Patients’ characteristics and study design
Between December 2001 and September 2003 a total of 36 patients with high-risk essential thrombo- cythemia were enrolled into this study by 16 German and Austrian centers. A total of 48 patients had beeneligible for the trial, but 12 patients refused to give their consent and were thus excluded from the protocol.
Patients were eligible if they were older 18 years, had adiagnosis of essential thrombocythemia meeting the WHO criteria for this disease and fulfilled at least one of the following criteria for high-risk essential throm-bocythemia: a platelet count > 1500¥109/L, age > 60 years, or previous complications related to essential thrombocythemia (thromboembolic or major hemor-rhagic events). Microvascular disturbances were notregarded as an inclusion criterion for high-risk essentialthrombocythemia. With the exception of conventional ously described.21,22 Data is presented as a ratio between interferon-a cytoreductive pretreatment was permit- PRV-1 and the housekeeping gene GAPDH (PRV- ted. A previous history of psychiatric disorders (in par- 1/GAPDH ratio). PRV-1 positivity was defined as a ticular previous depression) or severe cardiac, liver or PRV-1/GAPDH ratio of < 1.15 and PRV-1 negativity renal dysfunction were regarded as exclusion criteria.
defined as a PRV-1/GAPDH ratio of > 1.19. Out of the The study was approved by the local ethic committees 26 patients, 18 were negative and 8 were positive for of the participating centers and written informed con- PRV-1. Follow-up data are available for six patients: one sent was obtained from each patient enrolled into this patient became PRV-1 negative after 11 months and is still negative after 24 months of therapy with pegylat- The baseline characteristics at enrollment are shown ed interferon, the other five patients with follow-up in Table 1. Treatment was indicated for at least one of data were already negative at entry into the study. the following reasons: age > 60 years in 14 patients Follow-up evaluations were performed on a weekly (39%), a platelet count > 1500¥109/L in 13 patients basis during the first three months and subsequently (36%) or previous complications related to essential every third month. The follow-up evaluations consist- thrombocythemia in 18 patients (50%). Ten patients ed of medical history, physical examination, full blood (28%) had already received some treatment: eight had count, serum biochemical assays including liver and been treated with hydroxyurea and two with anagre- lide. The median time between diagnosis and entryinto the study was 6.6 months (range: 0.3–93 months).
Treatment plan and study endpoints
Pegylated interferon a-2b (Peg-IFNa2b, PegIntron) Pretreatment evaluation and follow-up
was supplied by Essex Pharma, Germany in vials con- Pretreatment evaluation included a complete medical taining 50 mg, 100 mg and 150 mg lyophilized powder, history and physical examination, abdominal ultra- along with sterile water for injection. Pegylated inter- sound, assessment of cardiovascular risk factors (ciga- feron was administered subcutaneously once weekly rette smoking, hypertension, diabetes mellitus, and at a starting dose of 50 mg. In those patients who did hyperlipidemia), full blood count, electrolytes, liver and not achieve a platelet count below 500¥109/L after 8-12 renal functions, baseline coagulation tests, bone mar- weeks, the dosages were increased by 25 mg per week row cytology and histology and qualitative polymerase up to 150 mg per week. Dose reduction by 25 mg per chain reaction analysis to rule out the bcr-abl rearrange- week was recommended in the case of adverse effects ment. All 36 patients were bcr-abl negative. At study related to pegylated interferon and in patients with a entry, PRV-1 positivity or negativity was determined in stable platelet count below <450¥109/L for at least four a quantitative RT-PCR analysis in 26 patients as previ- weeks. Concomitant therapy with acetaminophen | 1334 | haematologica/the hematology journal | 2005; 90(10) (500-1000 mg) was recommended approximately 30minutes before administration of the pegylated inter- feron to reduce flu-like symptoms. The use of low dose aspirin (100 mg/day) was optional and at the dis- cretion of the attending physician. No other cytoreduc- tive therapy was permitted while the patient was in le
te 1000

We defined the following events as end-points regarding the treatment with pegylated interferon: (i)major thromboembolic events. (ii) major bleeding, defined as a decrease in hemoglobin of more than 2 g/dL, life-threatening bleeding or cerebral bleeding; (iii) microvascular disturbances; (iv) transformation into baseline
myelofibrosis or blast crisis; (v) intolerable side effects Months on therapy with pegylated interferon
or patient’s refusal to continue the treatment.
Figure 1. Box plot of the platelet counts at baseline and after 3,6, 9, 12, 18 and 21 months of therapy with pegylated interferon.
Response and toxicity criteria
Each box represents the median and interquartile range of values, A complete hematologic response was defined as a with the ends of the vertical lines indicating the minimum andmaximum data values.
sustained reduction of platelet counts below 450¥109/Lfor at least one month. A partial hematologic responsewas defined as the reduction of platelets counts tobetween 450 and 600¥109/L. A poor hematologicresponse or no response was defined as a sustained Efficacy of treatment with pegylated interferon
platelet count > 600¥109/L in spite of therapy.
During the first three months of treatment platelet Treatment-related toxicity was graded according to the counts decreased significantly from a median base- WHO standard toxicity scale on a scale of 0 to 4.
line count of 895¥109/L (range: 383-1779) to a medi-an count of 485¥109/L (range: 211-1283; p<0.001).
Statistical analyses
Figure 1 represents the course of the platelet counts The SAS system was used for the statistical analyses.
as box plots at baseline and after 3, 6, 9, 12, 18 and 21 All response data of patients who received at least one months of treatment with pegylated interferon. The dose of pegylated interferon were calculated according complete response rate (platelet counts <450¥109/L) to an intention-to-treat analysis. Values were compared was 39% (14 of 36 patients), 47% (17 of 36 patients), using the two-sided Wilcoxon test for parallel groups.
58% (21 of 36 patients) and 67% (24 of 36 patients) All significance levels are two-sided. A box plot analy- at 3, 6, 9 and 12 months of treatment, respectively.
sis was used for the course of the platelet counts at The overall response rate (complete and partial baseline and after 3, 6, 9, 12, 18 and 21 months of ther- response, i.e. platelet counts <600¥109/L) was 72% apy. The box itself represents the middle 50% of the (26 of 36 patients), 72% (26 of 36 patients), 69% (25 data. The upper edge of the box indicates the 75th per- of 36 patients) and 75% (27 of 36 patients) at 3, 6, 9 centile of the data set, and the lower edge indicates the and 12 months of therapy, respectively. The rate of 25th percentile. The line in the box indicates the median poor responders (platelet counts > 600¥109/L) was value of the data. The ends of the vertical lines indicate 25% (9 of 36 patients), 11% (4 of 36 patients), 8% (3 the minimum and maximum data values.
of 36 patients) and 0% (0 of 36 patients) at 3, 6, 9 and12 months of treatment, respectively. Figure 2 showsthe efficacy of pegylated interferon treatment for all 36 patients with essential thrombocythemia at 3, 6,9, 12, 18 and 21 months. Patients and dosage level of pegylated interferon
In this phase II study 36 patients with high-risk Discontinuation and side effects of pegylated
essential thrombocythemia were treated with pegy- interferon therapy during follow-up
lated interferon (PegIntron). The initial dosage level After a median time of 23 months (range 3–39 of pegylated interferon used was 50 mg per week.
months) with a total observation time of 763 months, During follow up the median dose was 50 mg per 23 of 36 patients (64%) are still receiving pegylated week (range 12.5-150 µg). After 12 months 81% of all interferon. During the first six months of therapy treated patients were on a dose £50 mg per week and with pegylated interferon 28 of 36 patients (78%) after 21 months 88% of all treated patients were on reported flu-like symptoms including fever, fatigue, headache and myalgia. After 12 months of treatment haematologica/the hematology journal | 2005; 90(10) | 1335 | Discontinuation of pegylated interferon
NC (platelet count > 600¥109/L)
PR (platelet count 450-600¥109/L)
CR (platelet count < 450¥109/L)
Figure 2. Efficacy of pegylated interferon treatment for all 36 patients with essential thrombocythemia at 3, 6, 9, 12, 18 and21 months. CR: complete remission; PR: partial remission; NC: no change or poor response. The black bars indicate patients who discontinued therapy with pegylated interferon at the Months on therapy with pegylated interferon
the frequency of flu-like symptoms among patients ered sufficiently with pegylated interferon and an still on therapy decreased to 36%. Other reported alternative cytoreductive therapy was initiated. The side effects included mild depression in up to 15% of median duration of treatment until its cessation was treated patients as well as mild hair loss in up to 18% of treated patients. Furthermore, skin changes, main-ly consisting of increased dryness, were reported by Thrombotic complications during follow-up
37% of the patients treated over time. All reported After 23.0 months on therapy with pegylated inter- side effects decreased in intensity over time. None of feron a 45-year old patient suffered from a cerebral the reported adverse events exceeded a grade 2 toxic- stroke and was subsequently taken out of the study.
ity according to the WHO standard toxicity scale.
A cerebral stroke had been the initial presenting Table 2 shows the reasons for discontinuation of symptom of his essential thrombocythemia and the pegylated interferon in the 13 patients who ceased to reason why he had entered the study. At the time of take the drug. In ten patients (28%) therapy was the second event the dose of pegylated interferon stopped at the patients´ request due to grade 1 or 2 being administered was 100 mg per week and his drug related adverse effects: flu-like symptoms with platelet count was 542¥109/L. This complication sustained fatigue (n=6), depression (n=1), prolonged accounted for the total complication rate of 1.7% per diarrhea (n=1) and alopecia in female patients (n=2).
patient-year. No further thrombocythemia-related One patient was lost to follow-up after 2.6 months. In complications were observed in other patients during another patient the platelet count could not be low- the total observation period of our study.
Table 2. Reasons for therapy discontinuation in 13 out of 36 patients treated with pegylated interferon. Side effects are classified accord-ing to the WHO standard toxicity scale. of therapy with pegylated interferon *not related to pegylated interferon. | 1336 | haematologica/the hematology journal | 2005; 90(10) patient under therapy with pegylated inter- feron. This patient was PRV-1 positive at time (months)
after 11 months of therapy with pegylated previously described.21,22 Data are presentedas a ratio between PRV-1 and the house-keeping gene GAPDH (PRV-1/GAPDH ratio).
PRV-1 positivity is defined as a PRV-1/GAPDH ratio of < 1.15 and PRV-1 negativ- 11.01.2005
> 1.19. The other five patients with PRV-1follow-up data were already negative at 17.02.2004
entry into the study and remained negativeduring follow-up (data not shown in this fig- PRV-1 expression at study entry and during follow up
period of 23 months (range 3-39 months) ten of 36 At study entry, PRV-1 positivity or negativity was patients (28%) stopped therapy with pegylated inter- determined in quantitative reverse transcription feron due to grade 1 or 2 drug-related side effects. The polymerase chain reaction analysis in 26 patients. Of observed side effects and the drop-out rate due to these 26 patients, 18 were negative and 8 were posi- adverse events are comparable to those reported for tive for PRV-1. Follow-up data are available for six patients: one patient became PRV-1 negative after 11 This trial demonstrates that pegylated interferon is months and is still negative after 24 months of thera- an effective platelet-lowering drug in patients with py with pegylated interferon (Figure 3). The other high-risk essential thrombocythemia. Pegylated inter- five patients with follow-up data were already nega- feron exerted its platelet-lowering efficacy not only in newly diagnosed patients with a high initial plateletcount but also in patients who had been pretreatedwith hydroxyurea or anagrelide. After three months of Discussion
therapy with pegylated interferon, the proportion ofpatients with a reduction of platelet count <600¥109/L In this phase II trial 36 patients with high-risk essen- was 72% (26 of 36 patients). However, after three tial thrombocythemia were treated with pegylated months nine of 36 patients (25%) still had a platelet interferon (PegIntron) to evaluate the safety, toxicity count >600¥109/L in spite of therapy with pegylated and efficacy of this drug. Conventional, recombinant interferon. The hematologic response improved over interferon-a is an effective treatment in essential time and after 12 months 75% of our patients (27 of 36 thrombocythemia and a complete hematologic remis- patients) achieved a platelet count <600¥109/L (24 sion is obtained in about 54% of patients.5 However, patients with a platelet count <450¥109/L). At this time about 15% of all essential thrombocythemia patients there was no patient on treatment with pegylated are primarily resistant to interferon-a and frequent interferon who had a platelet count > 600¥109/L. The side effects limit therapy with this drug.5,14 In a meta- complete hematologic response rate for pegylated analysis of 273 patients with essential thrombo- interferon was at least as good as that reported for con- cythemia, interferon-a was terminated in 25% of all ventional interferon-a, ranging from 54% to 70%.5,16,17 patients and in up to 66% of patients in individual tri- One patient suffered from a cerebral stroke while on als.14 Utilization of new interferon-a formulations such pegylated interferon. This event rate of 1.7% per as pegylated interferon may help to overcome some of patient-year is comparable to the complication rate in hydroxyurea-treated high-risk essential thrombo- The administration of pegylated interferon was safe.
cythemia patients (1.6% per patient-year) observed in With a median dosage of 50 mg pegylated interferon a prospective study after a median observation time of per week (range 12.5–150 mg) we observed no case in which a dose reduction was necessary due to impaired There is one small published pilot study concerning hematopoiesis. In the majority of patients 50 mg pegy- 11 patients with essential thrombocythemia who were lated interferon per week or less was sufficient to con- treated with pegylated interferon. All patients were in trol the platelet count. During the first six months most complete remission after 4 months.18 After a median of our patients suffered from mild to moderate flu-like observation time of 9 months (range 4-17 months) two symptoms. After one year these side effects disap- of 11 patients (18%) discontinued therapy because of peared in most patients. After a median observation side effects. One patient discontinued therapy at 4 haematologica/the hematology journal | 2005; 90(10) | 1337 | All authors contributed to the concept of the study, analysis and months because of persistent grade III fatigue and a interpretation of the data, and drafting and revising the article. All second patient at 5 months because of anxiety and approved the final version. In detail, CL was the secretary and co- depression. No events related to essential thrombo- ordinator of the trial; EL was in the steering committee of the trial and was one of its coordinators. HLP performed the PRV-1 assays; cythemia were observed during the observation peri- HB performed the statistical analyses; SS was the data manager od. The initial dose of pegylated interferon was higher of the trial; HG was in the steering committee of the trial and its co- than that used in our study (1.5 – 4.5 mg/kg per week).
ordinator in Austria; MG was the principal investigator of this trial. Responsible for all Tables and Figures: MG. The authors also Further trials with pegylated interferon in essential declare that they have no potential conflicts of interest. thrombocythemia are currently under way.19,20 This work was supported by the German Competence Net Preliminary data from these trials report similar “Acute and chronic Leukemias” (Project 25). We would like to thank Barbara Stade from essex pharma for organizing supply of response rates with pegylated interferon20 but a higher pegylated interferon. We are especially grateful to the following discontinuation rate due to side effects.19 Our data sug- centres for participating in this trial: Prof. Dr. Dreyling, Klinikum gest that pegylated interferon is at least equally effec- Großhadern Münschen, Dr. Fricke-Jjaya, Elisabeth-Kranken- haus, Recklinghausen, PD Dr. Matzdorff, Universität Giessen, tive as unmodified interferon in reducing interferon Dr. Wojatschek, Bad Friedrichshall, PD Dr. Kropff, Universität platelet counts. Due to an initial slow response to Münster, Dr. Goldmann, Lüneburg, Dr. Jakob, Medizinische pegylated interferon, a large proportion of patients Klinik II, Offenburg, Dr. Procaccianti, Karlsruhe, Dr. Kaesberger, Diakonissenkrankenhaus Stuttgart, Dr. Lengerke, Universiät require sustained treatment for several months in order Tübingen, Dr. Fuxius, Heidelberg, Prof. Dr. Kersting, Ev Stift St. to achieve a hematologic remission. For those patients who respond slowly in the first months of treatment Essex Pharma provided the pegylated interferon free of charge for this trial. Our department received an unrestricted educational with pegylated interferon, concomitant cytoreductive grant for the documentation work of this study. The data are owned therapy with hydroxyurea might help to achieve a by the main investigator and study participants and were evaluat- more effective platelet count reduction.
ed and analyzed by the principal investigator (MG). Manuscript received May 14, 2005. Accepted August 8, 2005 References
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Source: http://medizin1.uniklinik-freiburg.de/forschung/experimentelle-forschung/molecularhema/cvpahl/pulications/PDF19.pdf

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