Novel Therapies for Myelofibrosis

Purpose of Review

The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.

Recent Findings

Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents.

Summary

Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.

     

Ruxolitinib Rechallenge Can Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis: A Case Series

Introduction

Myelofibrosis (MF) is one of the classic myeloproliferative neoplasms and can occur de novo or following transformation from polycythemia vera (PPV MF) or essential thrombocythemia (PET MF). It can be associated with constitutional symptoms and splenomegaly, both of which can negatively impact quality of life. The only curative option for MF is allogeneic stem cell transplantation. Studies have shown that JAK2 inhibitors such as ruxolitinib are effective in reducing both splenomegaly and symptom burden. Although there is no approved treatment for patients who progress on ruxolitinib, anecdotal evidence suggests patients may respond to a re-challenge of ruxolitinib after drug cessation.

Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis

Myelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors—ruxolitinib, fedratinib, pacritinib, momelotinib—or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia.Subject terms: Molecularly targeted therapy, Targeted therapies     

Ruxolitinib for Myelofibrosis–An Update of Its Clinical Effects

Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In 2 randomized phase III studies, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib significantly improved splenomegaly and disease-related symptoms compared with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib therapy was associated with dose-dependent anemia and thrombocytopenia, these adverse events rarely led to treatment discontinuation. This update of the clinical effects of ruxolitinib in patients with MF was based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations suggest that improvement of splenomegaly and symptoms is durable. Patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. In COMFORT-I, platelet counts stabilized with dose adjustments, and hemoglobin levels gradually recovered to slightly below baseline after the first 8 to 12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to that found in the placebo group. The 2-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.     

Classical Philadelphia-negative myeloproliferative neoplasms: focus on mutations and JAK2 inhibitors

Classical Philadelphia- negative myeloproliferative neoplasms (MPNs) encompass three main myeloid malignancies: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Phenotype-driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes are mutually exclusive and occur with a variable frequency. Driver mutations influence disease phenotype and prognosis. PV patients with JAK2 exon 14 mutation do not differ in number of thrombotic events, risk of leukemic and fibrotic transformation, and overall survival to those with JAK2 exon 12 mutation. Type 2-like CALR-mutated ET patients have lower risk of thrombosis if compared with those carrying JAK2 or type 1-like CALR mutation. For ET, overall survival is comparable between patients with JAK2 and either type 1-like and type 2-like CALR mutations. For MF, better OS is demonstrated for patients harboring a type 1-like CALR mutation than those with type 2-like CALR or JAK2. The discovery of driver mutations in MPNs has prompted the development of molecularly targeted therapy. Among JAK2 inhibitors, ruxolitinib (RUX) has been approved for (1) treatment of intermediate-2 and high-risk MF and (2) PV patients who are resistant to or intolerant to hydroxyurea. RUX reduces spleen size and alleviates disease symptoms in a proportion of MF patients. RUX in MF leads to prolonged survival and reduces risk of death. RUX controls hematocrit, reduces spleen size and alleviates symptoms in PV. Adverse events of RUX are moderate, however, its long-term use may be associated with opportunistic infections. Trials with other JAK2 inhibitors are ongoing.     

Definition and management of ruxolitinib treatment failure in myelofibrosis

Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2–3 years. In the current perspective, we examine the incidence and causes of ruxolitinib ‘treatment failure'' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.     

Management of Myelofibrosis-Related Cytopenias

Purpose of Review

Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies.

Recent Findings

The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias.

Summary

Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future.

     

Predicting success in regulatory approval from Phase I results

Purpose

Drug development in oncology is resource intensive and has a high failure rate. In this exploratory analysis, we aimed to identify the characteristics and outcomes of published Phase I studies associated with future Food and Drug Administration (FDA) approval.

Methods

Phase I studies of approved and non-approved anticancer agents between 2000 and 2013 were retrospectively examined. Fisher’s exact and chi-squared tests were used to compare the potential predictive measures.

Results

Phase I studies of 88 anticancer agents (54 approved and 34 non-approved by the FDA), treating a total of 4,423 subjects, were examined. The median number of patients in Phase I trials of approved and non-approved agents was 44.5 and 32, respectively. A total of 423 subjects (86 reporting studies) had a complete responses, and 342 subjects (80 reporting studies) had a partial responses (PR). A higher number of PR (P < 0.001), PR rate (P = 0.003) and longer PR duration (P = 0.001) were predictive of regulatory success.

Conclusions

These preliminary findings indicate that objective responses in Phase I trials may have predictive value for later regulatory approval.     

Evaluating the serial use of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement: performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial

BACKGROUND:

Symptomatic burden from constitutional symptoms, anemia, and splenomegaly‐related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF‐specific instrument for capturing the burden of MF‐associated disease‐related symptoms, the Myelofibrosis Symptom Assessment Form.

METHODS:

The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF.

RESULTS:

The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6‐minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6‐minute walk test).

CONCLUSIONS:

The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents. Cancer 2011;. © 2011 American Cancer Society.     

The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication

Myelofibrosis (MF) is a BCR-ABL1⁻ myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need.     

Splanchnic Vein Thrombosis in the Myeloproliferative Neoplasms

Purpose of Review

To review the epidemiology, diagnostic challenges, pathogenesis, and treatment strategies for patients with myeloproliferative neoplasm-associated splanchnic vein thrombosis.

Recent Findings

The epidemiology of myeloproliferative neoplasm-associated splanchnic vein thrombosis (MPN-SVT) has been well characterized. While typical MPN-associated thrombosis affects older patients and involves the arterial circulation, MPN-SVT mostly impacts younger women. An association with JAK2 V617F is well-known; recent studies have demonstrated only a weak association with CALR mutations. JAK inhibition may represent a novel treatment strategy, complementing anticoagulation, and management of portal hypertension.

Summary

While the epidemiology has been well characterized, more work is needed to identify novel contributors to disease pathogenesis, beyond the JAK2 V617F mutation itself, and endothelial compromise. Testing for MPN mutations in the setting of non-cirrhotic SVT is commonplace; JAK2 V617F is the most likely to be identified. Testing for CALR or MPL mutations requires clinical judgement, though not unreasonable. The mainstay of therapy is indefinite anticoagulation; the role of direct oral anticoagulants is unclear. JAK inhibition may play a role in addressing associated splenomegaly and portal hypertension.

     

Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis

Purpose of Review

The purpose of this review is to help doctors in the management of patients with post-polycythemia (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF) facing diagnostic criteria, prognostication, and treatment possibilities.

Recent Findings

Diagnostic criteria of primary myelofibrosis (PMF) have been recently updated from the WHO classification. A clear-cut distinction between pre-fibrotic and overt PMF has been done. Concerning PPV and PET MF, the criteria come from 2008. Prognostication of PMF has been well established on clinical criteria, but recent molecular acquisitions will improve the strategy. For PPV and PET MF, the new MYSEC-PM is helpful for prediction of survival. JAK2-inhibitors and stem cell transplant are the two critical therapeutic approaches in myelofibrosis.

Summary

Differences between PMF and SMF substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools and to use such categorization to evaluate available treatment modalities.

     

Patterns of Care for Older Patients With Myelofibrosis: A Population-based Study

BackgroundCurrent treatments for myelofibrosis (MF) are largely palliative, with the JAK inhibitor ruxolitinib being the breakthrough approved for higher-risk patients by the United States Food and Drug Administration in November 2011. There are limited data on the “real-world” clinical experiences among patients with MF who are treated in the JAK inhibitor era.Patients and MethodsWe evaluated patterns of care for older patients with MF before and after ruxolitinib approval, using the Surveillance, Epidemiology, and End Results-Medicare database. Treatment patterns were assessed using Medicare part B and D claims.ResultsThis study included 528 patients diagnosed during 2007 to 2015, with a median age at diagnosis of 76 years. Among 298 patients diagnosed in the ruxolitinib era (2012-2015), 113 (37.9%) were ruxolitinib users. Similar numbers of users started ruxolitinib at 5, 10, 15, or 20 milligrams twice a day (BID). Among 31 patients starting at 5 milligrams BID or less, 48.4% were unable to escalate the dose, and < 11 users could increase the dose to the maximum 25 mg BID. Approximately one-half of ruxolitinib users took hydroxyurea and/or prednisone simultaneously with ruxolitinib. The median time on ruxolitinib was 11.9 months (interquartile range, 4.2-21.7 months).ConclusionIt would be important to optimize the use of ruxolitinib and develop new drugs that may be administered together with or after ruxolitinib to accomplish better outcomes in older patients with MF.     

Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials

Purpose

Sorafenib (Nexavar^®) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. Sorafenib has demonstrated preclinical and clinical activity against several tumor types, as a monotherapy and in combination with other anti-cancer agents.

Methods

This review summarizes the safety, pharmacokinetics, and anti-tumor activity of sorafenib combined with other targeted agents or cytotoxics from a series of Phase I/II trials in approximately 600 patients with advanced solid tumors.

Results

Sorafenib in combination with other agents was generally well tolerated, and most adverse events were mild to moderate in severity. Frequent drug-related toxicities were dermatologic, gastrointestinal, or constitutional. Most trials supported sorafenib 400 mg bid as the recommended dose for combination. Sorafenib generally had little effect on the pharmacokinetics of coadministered agents and vice versa. Preliminary anti-tumor activity was observed; overall disease control rates (partial response plus stable disease) ranged from 33 to 92%. Particularly promising activity was observed in patients with melanoma, hepatocellular carcinoma, and non-small-cell lung cancer receiving sorafenib plus paclitaxel/carboplatin, doxorubicin, and gefitinib, respectively.

Conclusions

Sorafenib demonstrated a good safety profile and encouraging anti-tumor effects when coadministered with other agents in patients with advanced solid tumors.     

Homoharringtonine is an effective therapy for patients with polycythemia vera or essential thrombocythemia who have failed or were intolerant to hydroxycarbamide or interferon-α therapy

Background

At present, the treatment of polycythemia vera (PV) and essential thrombocythemia (ET) is still largely supportive and symptomatic. Homoharringtonine (HHT), a valid drug for treating chronic myelogenous leukemia, has shown some effect on leukemic stem cells. The aim of this study was to observe the effect of HHT on patients with high-risk PV and ET.

Methods

Patients with high-risk PV (n = 17) or ET (n = 18) who had failed or were intolerant to hydroxycarbamide or interferon-α therapy received HHT at a dose of 1.5 mg/m² daily by continuous infusion for 7 days every month. Hematological responses were evaluated at the 6th month after HHT therapy.

Results

After six courses of HHT therapy, the hematological response rates were 64.7 % (11/17) in PV and 72.2 % (13/18) in ET. In PV, the single sign remission rates of constitutional symptoms, symptomatic splenomegaly, pruritus and bone pain were 70.0 % (7/10), 77.8 % (7/9), 50 % (1/2) and 100 % (3/3), respectively. The remission rates of constitutional symptoms and symptomatic splenomegaly in ET were 66.7 % (6/9) and 71.4 % (5/7), respectively. The rates of grade 1 granulocytopenia and thrombocytopenia were 1.8 and 0.9 %, respectively. No grade 2 or over events, or pancytopenia were observed.

Conclusions

Low-dose HHT alone has considerable short-term efficacy for high-risk PV/ET and may used as a second-line drug for PV/ET treatment in patients who have failed or were intolerant to hydroxycarbamide or interferon-α therapy.     

Lenalidomide in solid tumors

Background

Lenalidomide is a thalidomide analogue with immunomodulatory and anti-angiogenic properties that include altering cytokine production, activating T cells, and augmenting natural killer cell function. Lenalidomide is approved by the U.S. Food and Drug Administration (FDA) for single-agent treatment of myelodysplastic syndromes associated with a 5q deletion and as a combination therapy with dexamethasone for the treatment of multiple myeloma.

Methods

All prospective phase I–III clinical trials and preclinical data published until October 2011 and relevant literature were reviewed.

Results

In phase I and/or II studies of single-agent lenalidomide in patients with advanced cancer, responses were reported in patients with prostate, thyroid, hepatocellular, pancreatic, and renal cancer and melanoma. The most common toxicities were hematologic, and in the first clinical trials, thrombotic events were noted. When anticoagulation prophylaxis and exclusion of patients with a history of thrombosis were implemented, thrombotic complications became uncommon.

Conclusion

Monitoring of blood counts and for evidence of thromboembolic events is essential for patients treated with lenalidomide. Ongoing trials of lenalidomide combination therapy offer a treatment option for patients with advanced cancer and will better define the role of lenalidomide in solid tumors.     

Verbesserte Behandlungschancen durch molekulares Targeting in der Radioonkologie

Context

Intensity-modulated and biologically guided high precision radiotherapy determine today’s modern radio-oncology. Relatively unexploited, however, is the administration of targeted molecular drugs for radiosensitization of malignant solid tumors.

Objective

The current status of these novel treatment strategies given simultaneously to radiotherapy will be discussed with respect to preclinical and clinical data.

Material and methods

Research and analysis of the literature and clinical trials.

Results

Through better understanding of tumor biology, potential target molecules for pharmacological inhibitors and antibodies were identified of which a selected number have been evaluated in preclinical and clinical studies. Locoregional tumor control and overall survival were increased, for example after radiotherapy by antibody-mediated inhibition of the epidermal growth factor receptor (EGFR) in radiotherapy patients suffering from head and neck cancer. Selected antibodies are, in contrast to pharmacological inhibitors, approved for certain tumor entities in combination with radiotherapy or radiochemotherapy.     

SOHO State of the Art Updates and Next Questions: Identifying and Treating “Progression” in Myelofibrosis

Over the last decade, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has become widely established as the cornerstone of pharmacologic therapy for most patients with myelofibrosis (MF), providing dramatic and durable benefits in terms of splenomegaly and symptoms, and prolonging survival. Ruxolitinib does not address all aspects of the disease, however; notably cytopenias, and its ability to modify the underlying biology of the disease remains in question. Furthermore, patients eventually lose response to ruxolitinib. Multiple groups have reported the median overall survival of MF patients after ruxolitinib discontinuation to be 13 to 14 months. While consensus criteria only recognize splenic and blast progression as “progressive disease” in patients with MF, disease progression can occur in a variety of ways. Besides increasing splenomegaly and progression to accelerated phase/leukemic transformation, patients may develop worsening disease-related symptoms, cytopenias, progressive leukocytosis, extramedullary hematopoiesis, etc. As in the frontline setting, treatment needs to be tailored to the clinical needs of the patient. Current treatment options for patients with MF who fail ruxolitinib remain unsatisfactory, and this continues to represent an area of major unmet medical need. The regulatory approval of fedratinib has introduced an important option in the postruxolitinib setting. Fortunately, a plethora of novel agents, both new JAK inhibitors and drugs from other classes, eg, bromodomain and extraterminal (BET), murine double minute 2 (MDM2) and telomerase inhibitors, activin receptor ligand traps, BH3-mimetics and more, are poised to greatly expand the therapeutic armamentarium for patients with MF if successful in pivotal trials.