|Year : 2012 | Volume
| Issue : 3 | Page : 260-265
Janus Activated Kinase inhibition in Myelofibrosis
Division of Medicine, SMS Medical College Hospital, Jaipur, India
|Date of Web Publication||12-Dec-2012|
Division of Medicine, SMS Medical College Hospital, Jaipur
Source of Support: None, Conflict of Interest: None
Janus Activated Kinase (JAK) 2 plays an important role in the pathogenesis of myelofibrosis (MF). Ruxolitinib (INCB018424, Jakafi) is a potent dual JAK1 and JAK2 inhibitor. In November 2011, it became approved by the US FDA for the treatment of intermediate or high-risk MF. This review shall outline the role of Ruxolitinib in the current management of MF and its potential future.
Keywords: Jak2, QoL, ruxolitinib, splenic size, symptom control
|How to cite this article:|
Malhotra H. Janus Activated Kinase inhibition in Myelofibrosis. Indian J Cancer 2012;49:260-5
| » Introduction|| |
In 1951 an elegant paper by William Dameshek described myeloproliferative syndromes.  Myelofibrosis (MF) belongs to the group of myeloproliferative neoplasm (MPN). It is characterized by general symptoms that are often very severe (weight loss, fatigue, weakness, pruritus as well as pain in the abdomen and bones), cachexia, splemonegaly (that is often massive and the cause of impaired quality of life) and abnormal blood counts (anemia, thrombocytopenia/cytosis, and leukopeina/cytosis). This is usually accompanied by significant elevation of proinflammatory cytokines, platelet derived growth factor (PDGF), transforming growth factor beta (TGF b) and basic fibroblast growth factor (bFGF) being implicated. ,
The consequence is a shortened overall survival that can be as little as 2 years.  In fact, of all the bcr-abl negative MPNs, the worse prognosis is seen in MF.  Based on the International Prognostic Scoring System, the medial survival of patients with MF is 135 months for low risk group, 95 months for intermediate risk-1, 48 months for intermediate risk-2 and only 27 months for high risk group. 
In 1976, Adamson et al, first proposed the clonal nature of myeloproliferative hematopoietic stem cells due to a single glucose-6-phosphate dehydrogenase isoform present in erythrocytes, granulocytes and platelets obtained from patients with Polycythemia Vera.  This findings were later confirmed in 1990's by PCR analysis and extended to patients with essential thrombocythemia and polycythemia vera.  The connection between Polycythemia vera, essential thrombocythemia and Primary myelofibrosis was later substantiated in recent years with the discovery of recurrent somatic point mutation in the pseudokinase (JH2) domain of the JAK2 gene, an abnormality shared by large proportion of patients with myeloproliferative neoplasia.
For several decades the only therapies available were splenectomy, splenic irradiation and hematopoietic stem cell transplantation [Table 1]. The potentially curative hematopoietic stem cell transplantation was applicable to only a small fraction of patients. And the other "standard" therapy available before the Ruxolitinib era only provided short term benefit at the cost of significant morbidity/ mortality, without any evidence of real alternation in the natural course of the disease. 
Janus Activated Kinase 2 (JAK2) is a tyrosine kinase involved in normal haematopoiesis [Figure 1]. Hence it is logical to expect its hyperactivation to have a role in myeloproliferation. Also Jak0 1 mediates the effect of proinflammatory cytokines like IL6 and IL23. These in turn are responsible for release of several other cytokines, chemokines and adhesion molecules that propagate the inflammatory cytokine cascade.
|Figure 1: The JAK2V617F mutation involves a G to T alteration in the pseudokinase domain of JAK. This results in a valine-to-phenyl alanine substitution at codon 617 that disrupt its auto-inhibitory activity and leads to constitutive kinase activity that leads to cytokine-independent growth in hematopoietic cells|
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Several groups have shown that direct activation point mutation in the JAK2 gene is seen in about half the patients with MF [Table 2]. 
JAK2V617F mutation occurs in exon 14 at 9p24 and replaces G by A such that the amino acid phenylalanine replaces valine at position 617. Thus, with the identification of the key pathogenic role played by alterations in the JAK - STAT pathway, the steps in the contribution of cytokine signalling involving the JAK 1 and JAK 2 in the pathogenesis of myelofibrosis has been established in detail. ,,
|Table 2: Incidence of various driver mutations in myeloproliferative disorders (other than CML)|
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Indirect activation (without JAK2 mutation) acts on STAT transcription pathway or the JAK intracellular signal transduction and also has implications in the pathogenesis. Thus autonomous activation of the JAK2 kinase domain with subsequently persisting phosphorylation of STAT and MAPK proteins occurs in patients with and without JAK2V617F mutations [Figure 2]. 
This knowledge has been explored to identify new molecules and treatment strategies - that have revolutionized how we approach the management of myelofibrosis. 
Ruxolitinib (INCB018424, Jakafi)
Ruxolitinib (INCB018424, Jakafi) is a potent dual JAK1 and JAK2 inhibitor. It acts by competitive inhibition of the ATP binding kinase domain site. This action is against both the wild and the mutated forms of JAK2. Its benefit has been studied in intermediate and high-risk myelofibrosis in a Phase 1, 2 and 3 clinical trials (INCB18424-251, COMFORT-I and COMFORT-II). ,, It may also have a role in other diseases such as polycythemia vera rubra, lymphomas, pancreatic cancer and plaque psoriasis. For primary myelofibrosis, oral JAK2 inhibitors have been developed with the dual objective of reduction in splenic size and meaningful improvement in symptoms. 
The randomized, double-blind, placebo-controlled trial, Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I (COMFORT-I), included patients with intermediate-2 or high-risk myelofibrosis. Patients in the study arm were given ruxolitinib twice a day (15 mg if platelet count was between 100 and 200 x 10 9 /L and 20 mg if platelet count exceeded 200 x 10 9 /L ). In the 309 patients studied, results showed significant reductions in splenomegaly (primary endpoint being > 35% reduction in splenic volume as measured by MRI or CT Scan) accompanied by improvements in disease related symptoms. At 24 weeks, 41.9 % of patients in the study arm met the primary end point as compared to 0.7% in the placebo arm (P < 0.0001; [Figure 3]). Improvement in constitutional symptoms was also seen in a similar percentage (45.9% in study arm compared to 0.7% in placebo arm). Survival at 52 weeks (median) showed a reduction in death with hazard ratio of 0.499. This was achieved with tolerable side effects. Grade 3 or 4 anemia was seen in 45% of study arm and 19.2% of placebo arm. Thrombocytopenia was also higher in the study arm (12.9% versus 1.3% in placebo arm). On the other hand the commonest non haematological toxicity was diarrhoea, and it was similar in both the arms, being seen in 23.2% of study patients and 21.2% of control patients).  The superior probability of survival in the ruxolotinib arm (P = 0.04) is shown in [Figure 4].
|Figure 3: Percentage of patients with > 35% splenic volume reduction (primary end point)|
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|Figure 4: Kaplan - Meier curve showing probability of survival in COMFORT-I study (from Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Richard S. Levy, Vikas Gupta, John F. DiPersio et al: A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Engl J Med 2012;366:799-807)|
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The subsequent COMFORT-II trial also confirmed these findings.  This was also a randomized phase III study. In this instance, ruxolitinib was compared to the best available therapy (BAT) in nine European countries. The patients were intermediate-2 or high risk MF and the primary endpoint was splenic volume reduction, as in COMFORT-I. A total of 219 patients were studied. Reduction in splenic volume by more than 35% was seen in 28.5% of study arm patients as compared to 0% in the control arm patients (P< 0.00001; [Figure 3]).
Toxicities have ranged from myelosuppression to significant diarrhea. Grade 3 or 4 thrombocytopenia was 7.5% in the study arm and 4.1% in the control arm. Similarly Grade 3 or 4 anemia was 11% in study arm and 4.1% in control arm. Diarrhoea grade 3 or 4 was seen only in 1% of cases.
Based on these results, Ruxolitinib was approved by the US FDA for the treatment of intermediate or high-risk myelofibrosis in November 2011 
JAK2 V617F allelic burden
In the COMFORT-I study, within the JAK2 V617F-positive subgroup, study arm patients had a decrease in allele burden when baseline was compared to that at weeks 24 and 48 (−10.9% and −21.5%, respectively). This was in contrast to the increase in allele burden among the placebo arm (3.5% and 6.3%, respectively).  COMFORT-II study also analyzed changes in JAK2 V617F allele burden (%V617F) as an exploratory endpoint for molecular response to ruxolitinib - with confirmation of consistent benefit in the study arm as compared to BAT [Table 3]. 
Interestingly the response to ruxolitinib (mean % reduction in splenic volume as well as response rate at 48 weeks) was seen irrespective of the V617F allelic burden at baseline [Table 4].
|Table 3: Comparison of V617F reduction in Ruxolitinib and BAT arms in COMFORT-II study|
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|Table 4: Response to ruxolitinib is seen irrespective of baseline V617F allele burden|
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Quality of Life (QoL)
In MF, patients usually have a symptom burden that significantly impacts their QoL. This is at least as comparable to that seen in patients with AML as well as other malignancies. (COMFORT-II study). Some of the symptoms correlate with splenomegaly (night sweats and insomnia) whereas other constitutional features exist irrespective of splenic size (fatigue, dyspnea and pain).
The good news is that ruxolitinib consistently results in reduction in symptoms. In fact more than 40% of patients in the study arm had > 50% reduction in total symptom score as compared to less than 10% in the placebo arm in COMFORT-I [Figure 5]. In fact, as compared to baseline, all the studied symptoms show improvement in the study arm while they deteriorate in the placebo arm [Figure 6].
|Figure 5: Comparison of total symptom reduction in Ruxolitinib arm to Placebo arm (from Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Richard S. Levy, Vikas Gupta, John F. DiPersio et al: A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Engl J Med 2012;366:799-807)|
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|Figure 6: Comparison of change in baseline symptoms between the study arm and the placebo arm in COMFORT-I (adapted from Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Richard S. Levy, Vikas Gupta, John F. DiPersio et al: A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Engl J Med 2012;366:799-807.|
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The JAK-STAT pathway is important in MF pathogenesis. Its manipulation influences downstream mediators of JAK signalling in MPNs. The leader in this class of agents is Ruxolitinib, currently the only one to gain FDA-approval.  This new agent has changed the treatment approach for MF leading to significant clinical benefit for patients.
Studies have also been commenced with ruxolitinib in patients with MF using a sustained release formulation, alternate dosing schedules, and those with baseline platelet counts less than 100 x 10 9 /L.
Ruxolitinib studies for other indications include patients with relapsed/ refractory solid tumors (prostate cancer and pancreatic cancer) as well as other haematological malignancies (multiple myeloma and lymphoma). Data from treatment of psoriasis and rheumatoid arthritis also show promise.
JAK2 inhibitors probably have no effect on the malignant stem cell pool of uncommitted hematopoietic progenitors of myeloproliferative malignancies. Therefore it may not correct pathologic bone marrow abnormalities or lead to cytogenetic/molecular remissions. Current data does not support any role in modification of the natural progression of disease or overall survival. To cure such patients, JAK2 inhibitors will probably have to be combined with other drugs. 
Additional agents with other mechanisms of action are also targeting JAK2, including histone deacetylase inhibitors and mTOR inhibitors. Knowledge of how useful will they really be await the outcome of several clinical trials. ,
| » References|| |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]