Patient information from Dr. Hans Carl Hasselbalch

On the nature of the disease – MPNs are a hematological cancer with the potential to transform to myelofibrosis and acute leukemia – and .

On the  rationale and goal for treatment. IFN-alpha2 has been known for three decades in the treatment of MPNs and accordingly it is no longer experimental but routine  therapy for patients with MPNs at several centres. The mechanisms of action of the drug are partially unknown but important mechanisms involve enhancement of  various immune cells and accordingly enhancement of “Tumor Immune Surveillance.”

ET and PV patients: These diseases are hematological malignancies which untreated may evolve during years with a steady increase in symptomatic disease burden. There is a risk of thrombosis and bleeding and ultimately a possibility of transformation into myelofibrosis and/or acute leukemia

The goal of treatment with IFN-alpha2 is to normalize elevated blood counts which likely occurs within the first 6-12 months in concert with a decrease in the need for phlebotomies in the PV-patient . By doing so, significant risk factors for thrombosis (elevated leukocyte and platelets counts) and bleeding ( highly elevated platelet counts ) will likely be reduced since it has been shown in several studies that normalization of elevated blood counts during IFN-alpha2 are associated with a decrease in thrombotic and bleeding events .

For the JAK2V617F-positive patient:  IFN-alpha2 likely reduces “the JAK2 –level” within the first year but in many patients the JAK2-levels significantly decrease in the second ( or third year) of treatment only. After about 5-7 years of treatment (in some after 3 years) the JAK2 levels may have reached low levels ( below 1 %) in those patients starting with “high JAK2 level disease” ( > 50 %) At this point I may discontinue treatment and observe with regular monitoring ( thrice yearly) of blood counts , including the JAK2V617-allele burden. Several patients today are followed off therapy with normal peripheral blood counts , “low-burden JAK2 “ ( < 1-5 % mutated alleles) and are feeling very well without any complaints from their MPN-disease.

The significance of achieving normal blood counts and “low-burden JAK” in terms of survival and later development of myelofibrosis and acute leukemia  is unknown ( no randomized studies due to the rarity of the diseases ). However, considering the biology of all other cancers and in the context that we have reduced the “tumor burden” to a minimum – only detectable by very sensitive methodology ( qPCR JAK2V617F ), The risk of transformation to myelofibrosis and acute leukemia is far less with minimal tumor burden remaining to elicit such transformations.

Information to the patient on toxicities relating to IFN-alpha2 treatment, how to manage them and how to administer IFN-alpha , dosage and schedule  for monitoring of treatment

Treatment with IFN-alpha2 may be associated with side effects, which – on low-dose IFN-alpha2- are but modest and transient in the large majority of patientsm including flu-like symptoms after the first 3-5 injections. Many patients have read about IFN-alpha2, some being reluctant to start treatment referring to data on drop-out rates of 30-50 % . Many of these figures are based upon previous studies using IFN-alpha2 thrice weekly and in much larger doses accounting for the high rates of side effect and reported toxicity  in several previous studies .  I treat with pegylated IFN-alpha2 , requiring administration once weekly and probably after 1-2 years every 10 day or every second week .

I use either inj. Pegasys ( pegylated IFN-alpha2a , Roche), given in a dosage of 45- 90 ug subcutaneously (sc.) per week  or inj. PegIntron ( pegylated IFN-alpha2b, Merck) in a dosage of 30-50 ug sc. About half an hour before the first injection- administered in the evening before bed-time, your advised to take 1 Tbl. Paracetamol 1 g. During the first 3-5 injections the patient is advised to take 1 Tbl. Paracetamol 1 g x 3 (4) daily on days 1 -5 in order to dampen flu-like symptoms which usually vanish thereafter.

Other side effects include fatigue ( which may persist in a subset of patients for several months ) , depression ( a history of depression is a relative contraindication) , thyroid dysfunction  abnormal  liver function tests (most often transient  not a contraindication for continuing IFN-alpha2 and usually normalize after dose reduction or short discontinuation of IFN-alpha2 ) , and very rarely hair thinning, pulmonary or renal impairment. Sexual dysfunction may be seen . Contact me immediately if you experience any discomfort with the treatment other than transient flu-like symptoms .

Although the goal of treatment is normalization of elevated blood counts in some cases the leukocyte or platelet counts will transiently turn subnormal but this does not usually matter . Blood counts will be monitored on a regular basis with blood samples ( Hb-concentration, white blood cell count count , platelet count, liver and renal function tests ) every second week the first 2 months and thereafter every month or every second or third month when blood cell counts  have normalized (“complete hematological remission”) .

Before and about half yearly after starting treatment I will also monitor thyroid function (plasma TSH). In the JAK2V617F-positive patients I will assess the “JAK2-level” every 3 or 4 months . I will tell my patients that achieving normal peripheral blood counts do not necessarily imply a concomitant decline in the JAK2V617F-allele burden, which may show a definite decline later in the second or third year of treatment. After 3 and 5 years I will perform a bone marrow biopsy to assess the impact of IFN-alpha2 upon the bone marrow, including potential regression of fibrosis.

Information to the patient on PegIntron and Pegasys in low-dose in regard to toxicities , and combination therapy with hydroxyurea

We have the option to shift from PegIntron to Pegasys and vice versa depending upon the individual tolerance to the drug given. In addition, the dosage will be tapered to the lowest dose – possible administered every second week – which secures normal blood counts . Accordingly, if  side effects are experienced, we have the possibility to lower the dose more rapidly – and, in addition, to combine IFN-alpha2 with hydroxyurea (HU) or anagrelide ( the latter agent being used in those patients having elevated platelets only  ) .

Information on hydroxyurea , efficacy and safety, toxicities with particular focus on skin toxicity, skin cancer and the concern on leukemogenicity after long-term exposure

HU administered orally has been used during the last 30 years in patients with MPNs. It effectively normalizes elevated blood cell counts in the large majority of patients and it is the single agent which in larger randomized studies has shown to reduce the increased risk of thrombosis and bleeding in MPNs. However, despite normalizing elevated leukocyte and platelet counts HU does not  fundamentally influence disease progression at the molecular level.

Treatment with HU has not proven to  induce sustained normalization of blood cell counts or sustained lowering of the JAK2V617F allele burden which is being recorded in a substantial and increasing number of patients with ET and PV during long-term treatment with IFN-alpha2. Furthermore, there is concern that long-term exposure to HU ( > 10 years) may elicit a pre-stage ( myelodysplastic syndrome)  to acute myelogenous leukemia (AML) or overt AML. Therefore, HU is not used in younger patients in several centers , eg. in UK . In other countries – eg. Denmark – IFN-alpha2 is also offered to elderly patients ( also those above 60 years ), since the elderly in general tolerate IFN-alpha2 very well when used in the dosages mentioned above.

In determining the choice between IFN-alpha2, hydroxyurea and anagrelide ( the latter agent for patients with elevated platelet counts only) significant side effects and toxicities of hydroxyurea , including the risk of significant skin toxicity (eg eczema, leg ulcers and skin cancer ) , stomatitis, diarrhea, fatigue, and rarely monosymptomatic fever or pulmonary dysfunction need to considered.

Information to the myelofibrosis patient in regard to IFN-treatment

For patients with hypercellular myelofibrosis , here’s why I  recommend IFN-alpha2 . You are in an early stage of myelofibrosis and IFN has been shown to  resolve bone marrow fibrosis and normalize the blood cell count while reducing spleen size and alleviating hypermetabolic  and pressure symptoms from the enlarged spleen. The treatment has to be given for several months ((6-12 months) before substantial improvement is recorded . For the patient with huge splenomegaly (below umbilical level) and/or  pronounced hypermetabolic symptoms (weight loss, night sweats, fatigue, low-grade fever) I do not recommend IFN but instead a JAK2-inhibitor.

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– H.C.Hasselbalch

© MPN Quarterly Journal, 2013. This work is licensed under a Creative Commons Attribution-NonCommercial No-Derivs 3.0 Unported License.