Hematological Malignancies
Table 1: Drugs Being Tested in Myeloproliferative Neoplasms with Activity Against JAK2
Drug SB1518 INCB018424 Incyte SBio TG101348 Targen LBH589 RAD001 CEP-701
Company Indication Phase Class MF
PV-ET MF
MF Novartis MF Novartis MF Cepahalon MF PV-ET
III II II
II II II
II II
JAK1 and 2 inhibitor JAK2
inhibitor JAK2
inhibitor HDAC
inhibitor mTOR
inhibitor FLT3 and
Reference 32 33 34
35 36 37 38 JAK2 inhibitor 39
ET = essential cytothemia; FLT3 = fetal liver tyrosine kinase 3; HDAC = histone deacetylase; JAK = Janus-activated kinase; MF = myelofibrosis; mTOR = mammalian target of rapamycin; PV = polycythemia vera.
When considering overall weight loss in MPN, confounding variables of edema and spleen size must be taken into account as they may conceal ectomorphic body mass. Additionally, weight loss does not directly correlate with decreased adipose tissue, but rather may represent substantial muscle catabolism. As such, classification of a previously overweight patient into a ‘normal’ category may underestimate the true degree of muscle catabolism that has occurred.9
Data in terms of high-density lipoprotein-cholesterol (HDL-C) (>60mg/dl) in MPN patients appear to change over time, with some studies indicating increased HDL (>60mg/dl) at the time of diagnosis11
Despite adequate nutritional status, patients with MPN are more likely to be deficient in low-density lipoprotein cholesterol (LDL-C) (<100mg/dl) and total cholesterol (<150mg/dl) compared with age- matched controls.11
but decreased HDL with progressive disease.6,10,12 Hypocholesterolemia is exacerbated with untreated disease progression10 and is correlated with decreased weight.9
Given that the most frequent
variable associated with hypocholesterolemia is splenomegaly, the mechanism for decreased triglycerides may be similar in nature to the cytopenic effect seen with blood components, namely sequestration within the spleen with disease-induced hypercatabolism. Interestingly, there is no available evidence to suggest that the reduction in lipid profiles translates into cardioprotection. Rather, this effect is most likely a measure of disease-related cachexia, which correlates significantly with a poorer prognosis.11
The effect of hypocholesterolemia is more pronounced in MF compared with PV or ET.6
Impact of Therapy on Cachexia and Hypocholesterolemia in Myeloproliferative Neoplasms
Historically, treatment approaches in MPNs have remained focused on palliation of symptoms, primarily through surgical splenectomy and transfusions.12
Overall, few therapies are available to treat mild forms of disease, and there is much off-label use of therapeutics found clinically to be palliative. Currently, no commercially available agents appear to affect either the cachexia or hypocholesterolemia observed with MPNs, particularly MF.
62
Inadequate serum cholesterol has long been known to be a feature of MPNs.10
Splenomegaly can significantly affect quality of life and remains a major target for symptom reduction. The mainstay of treatment for mild to moderate enlargement should include agents with minimal toxicity profiles including oral myelosuppressive agents (hydroxyurea13 (melphalan14
), oral alkylators and busulfan15 lenalidomide,17 pomalidomide,18
), immunomodulatory drugs (thalidomide,16 and thalidomide with steroid19
cytoreductive agents (interferon alpha20 ), and ). Patients who develop severe
splenomegaly or extramedullary hematopoiesis should be considered for treatment with purine nucleoside analogs (2-chlorodeoxyadenosine21 hypomethylating agents (azacytidine22,23
) or and decitabine24 ). In refractory
cases, acute leukemia therapies including cytarabine or daunorubicin could be considered, but these therapies have had little clinical testing and should be considered only when clinical trials are not a viable option.7,25,26 To date, stem cell transplantation remains the only potentially curative therapy in the treatment of MPNs, but should be offered only to a limited population of MPN patients with aggressive forms of disease.26–28
JAK2 Inhibitors Have an Impact on Cachexia in Myelofibrosis The discovery of the JAK2 mutation in 2005 was a landmark development in the treatment of MPNs. This gene marker provided concrete evidence of the common link in PV, ET, and MF, and provided researchers with a new therapeutic target capable of directly inhibiting cellular proliferation. Continued research has yielded promising new therapeutics capable of inhibiting the JAK2 gene’s proliferative effects in vitro. Currently, 16 JAK2 inhibitors are under review in clinical trials, with the main agents in testing described in Table 1.26
Despite their potential, it can be said with certainty that these medications will require extensive investigations. Although mechanistically promising, testing with the prototypic compound furthest through development, INCB018424 (Incyte Corporation, Wilmington, DE), did not appear to attenuate the cytopenias or histologic changes common to MPNs.29
It did,
however, reduce the chronic inflammatory state associated with disease30 and improve qualitative symptoms.31
Early data suggest that administration
of INCB18424 in MF patients results in dose-dependent improvement in bodyweight gain after treatment (1.75kg increase in bodyweight versus 4kg increase in bodyweight with 25mg twice a day 90 days post- treatment).31
Increased bodyweight was observed in patients in both the highest and lowest quartiles, indicating a positive effect on weight regardless of the initial BMI (6.5kg weight gain in lowest BMI quartile versus 2kg weight gain in highest BMI quartile).31
INCB18424 treatment was also
associated with a significant increase in total cholesterol (100mg/dl baseline versus 125mg/dl at the final treatment cycle). Remarkably, serum levels of leptin, a neuropeptide associated with satiety, was elevated within 50 days of INCB treatment and was sustained above baseline throughout the course of treatment. High doses at 25mg twice per day resulted in a reduction in early satiety and cachexia in cases of splenomegaly.31
With the substantial number of JAK2 kinase inhibitors in development, more accurate methods to evaluate drug efficacy are required. The effectiveness of INCB18424 in reducing many symptoms associated with MPNs suggests that these medications hold the potential to evolve as standard treatment. It is very possible that many of the inhibitors of JAK2 (see Table 1) may have clinical activity not only against splenomegaly but also against the cachexia and hypocholesterolemia of disease.
US ONCOLOGY & HEMATOLOGY
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