Leukemia & Lymphoma, 2015; Early Online: 1–2 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.988153
Commentary
Hedgehog inhibition as monotherapy in myelofibrosis: is there any role? Aparna Kalyan & Brady L. Stein
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
Division of Hematology-Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center and Northwestern Medicine Developmental Therapeutics Institute of Northwestern University, Chicago, IL, USA
cilium and interacts with Suppressor of Fused (SUFU), an inhibitor of Hh signaling, promoting the downstream activation and nuclear translocation of glioma-associated oncogene homolog 1 (GLI-1) and GLI-2 [1,11–13]. In the absence of Hh ligand, PTCH catalytically inhibits the activity of SMO, and hence no downstream signaling occurs. Aberrant signaling and oncogenic properties of the Hh pathway were first recognized in Gorlin syndrome, which is associated with an increased risk of developing rhabdomyosarcoma, medulloblastoma and basal cell carcinoma [1,13]. Subsequently, Hh signaling has been implicated in breast cancer, skin cancer, lymphoma, prostate cancer and brain cancer [11]. There has been increasing focus on the contribution of the Hh signaling pathway to disease pathogenesis in hematological malignancies, perhaps in the maintenance and expansion of leukemic stem cells (reviewed in [12]). In murine models of chronic myeloid leukemia (CML), it was shown that SMO deletion reduced the number of leukemic stem cells as well as prolonged the latency period of leukemia; complementary results were shown with pharmacological inhibition [12]. When SMO inhibitors were used either alone or in combination with tyrosine kinase inhibitors in CML cell lines, it was shown to decrease the incidence of leukemic blast transformation and prolong survival [12] in cell lines. Preclinical data in BCR–ABL negative MPNs, including MF, are limited, but a recent study reported a 20–100-fold increase in expression of Hh target genes, including Gli1 and Ptch1, by quantitative polymerase chain reaction (PCR) in granulocytes isolated from patients with MPN as compared to controls [14]. Sasaki et al. [10] expand on the clinical strategy of Hh inhibition in MF in this issue of Leukemia and Lymphoma. In this phase II study, 14 patients with MF received IPI-926 given continuously at a dose of 160 mg daily. The primary endpoint in this study was overall response rate, defined as clinical improvement, partial remission or complete remission as per the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). The secondary
Myelofibrosis (MF) is a BCR–ABL negative myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic stem cells and a pronounced symptom burden, attributed to cytopenias, extramedullary hematopoiesis leading to splenomegaly and constitutional and/or systemic symptoms including cachexia, night sweats, fevers, weight loss, pruritus and fatigue [1–3]. Dysregulation of Janus kinase (JAK)–signal transducer activator of transcription (STAT) is universal [4], in part driven by the presence of the JAK2V617F mutation identified in 60% of cases of MF [1–3]. Other JAK–STAT deregulating mutations in patients with JAK2V617F negative MF include calreticulin (CALR) and MPL mutations. Because JAK–STAT dysregulation is a prominent feature in MF, JAK inhibition is a rational therapy, and ruxolitinib was the first JAK inhibitor approved by the Food and Drug Administration (FDA) in patients with intermediate- and high-risk MF. Ruxolitinib has been shown to reduce splenomegaly and relieve MF-associated symptoms, and is associated with a modest survival benefit in comparison to placebo [5], best therapy [6] and historical controls [7]. Other JAK inhibitors in advanced development include pacritinib [8], which appears to lack myelosuppressive properties, and momelotinib [9], which may relieve anemia. However, JAK inhibitors do not lead to complete remission, resistance can occur and response can be lost promptly after discontinuation. Accordingly, and because of heterogeneous contributors to disease pathogenesis, novel treatment approaches are required. In this issue of Leukemia and Lymphoma, Sasaki et al. [10] present results with the hedgehog (Hh) inhibitor, IPI-926, in patients with MF. The Hh signaling pathway regulates self-renewal and terminal differentiation in embryonic development [11] but is usually “turned off” in adults until required for tissue repair. The signaling cascade begins with binding of the Hh ligand to patched 1 protein (PTCH), a transmembrane protein, causing internalization and degradation, and the release of Smoothened (SMO), a seven-transmembrane-span protein, by PTCH1 [1,11–13]. SMO is then activated in the primary
Correspondence: Brady L. Stein, 645 N. Michigan Avenue, Suite 1020, Chicago, IL 60611, USA. Tel: 312-695-6832. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
2 A. Kalyan & B. L. Stein endpoints included severity and incidence of toxicities, and change in bone marrow fibrosis, circulating inflammatory cytokines and symptoms as per the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), a validated patient-reported outcome tool. Of the 14 patients evaluated, eight had primary MF (five high risk, three intermediate-2 risk) and the remaining six had secondary MF. The median duration of treatment was 5.1 months and all patients discontinued therapy by 7.5 months (nine due to lack of efficacy, two after development of acute leukemia and one due to disease progression). Reduction in splenomegaly was modest, and symptoms as per MPN-SAF did not consistently improve. The most common adverse effects included elevated transaminases (11/14 patients), nausea (8/14 patients) and elevated bilirubin in four patients. Four patients (10 evaluated) had minimal to modest decreases in bone marrow fibrosis density scores after 3 months. The remaining patients had increases in the fibrosis density scores. Exploratory studies evaluating markers of Hh signaling were assessed by means of of GLI-1 mRNA and protein levels along with JAK2V617F allelic burden measurement. While some changes in this were observed, none were considered significant by the authors. Taking all results together, the authors concluded that there was no clinical benefit when using IPI-926 alone for the treatment of MF. At present, the clinical utility of Hh inhibitors needs further exploration in MF. First, although Sasaki et al. review contributions to other fibrotic diseases, and there are preclinical data in CML, whether aberrant Hh signaling strongly contributes to the pathogenesis of MF is not yet known. Second, although a lack of efficacy was noted with IPI-926, perhaps in part due to incomplete target inhibition, other Hh inhibitors may fare better (Table I). As an example, in a series of patients with hematological malignancies, including six with MF, five obtained stable disease and one had a clinical improvement in splenomegaly when treated with PF-04449913 [15]. As the authors state, the therapeutic potential of Hh inhibition may be maximized when combined with a JAK inhibitor, based on preclinical studies showing synergy between LDE225 (sonidegib) and ruxolitinib [14]. In this study by Bhagwat Table I. Oral hedgehog inhibitors in clinical trials at present. Name LDE225 LEQ506* GDC-0449* BMS-833923* IPI926 PF-04449913* GANT61
Action SMO antagonist (phase I/II study in combination with ruxolitinib) SMO antagonist SMO antagonist SMO antagonist SMO antagonist (results from phase II reported here) SMO antagonist Direct GLI inhibitor (currently in preclinical phase)
*Clinical trials currently under way in patients without MF.
SMO, Smoothened; GLI, glioma-associated oncogene; MF, myelofibrosis.
et al., combination therapy resulted in improvements in leukocytosis, thrombocytosis, bone marrow fibrosis and the mutant allele burden [14]. Further, according to Sasaki et al. [10], IPI-926 did not appear to be myelosuppressive, adding to its potential as a partner to JAK inhibitor therapy. In keeping with most hematological malignancies, given heterogeneous contributions to MF disease pathogenesis, further improvement in patient outcomes will come through development of rational combination therapies, rather than monotherapy, and thankfully, a number of clinical trials evaluating novel combinations have been conceptualized or opened for enrollment [2]. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Tibes R, Mesa RA. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies. J Hematol Oncol 2014;7:18. [2] Stein BL, Swords R, Hochhaus A, et al. Novel myelofibrosis treatment strategies: potential partners for combination therapies. Leukemia 2014;28:2139–2147. [3] Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, riskstratification, and management. Am J Hematol 2014;89:915–925. [4] Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood 2014;123:e123–e133. [5] Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799–807. [6] Cervantes F, Vannucchi AM, Kiladjian J-J, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122:4047–4053. [7] Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood 2014;123:1833–1835. [8] Dean JP, Cernohous P, Komrokji RS, et al. Pacritinib, a dual JAK2/ FLT3 inhibitor: an integrated efficacy and safety analysis of phase II trial data in patients with primary and secondary myelofibrosis (MF) and platelet counts 100,000/ml. Blood 2013;122(Suppl. 1): Abstract 395. [9] Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, Hogan WJ, Litzow MR, Leontovich A, Kowalski M, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27(6):1322–7. [10] Sasaki K, Gotlib J, Mesa RA, et al. Phase II evaluation of IPI-926, an oral hedgehog inhibitor, in patients with myelofibrosis. Leuk Lymphoma 2015;56:XXX–XXX. [11] Lin TL, Matsui W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. Oncotargets Ther 2012; 5:47–58. [12] Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood 2012;119:2196–2204. [13] Ng JMY, Curran T. The Hedgehog’s tale: developing strategies for targeting cancer. Nat Rev Cancer 2011;11:493–501. [14] Bhagwat N, Keller MD, Rampal RK, et al. Improved efficacy of combination of JAK2 and hedgehog inhibitors in myelofibrosis. Blood 2013;122(Suppl. 1): Abstract 666. [15] Jamieson C, Cortes JE, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood 2011;118(Suppl. 1): Abstract 424.
Commentary
Hedgehog inhibition as monotherapy in myelofibrosis: is there any role? Aparna Kalyan & Brady L. Stein
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
Division of Hematology-Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center and Northwestern Medicine Developmental Therapeutics Institute of Northwestern University, Chicago, IL, USA
cilium and interacts with Suppressor of Fused (SUFU), an inhibitor of Hh signaling, promoting the downstream activation and nuclear translocation of glioma-associated oncogene homolog 1 (GLI-1) and GLI-2 [1,11–13]. In the absence of Hh ligand, PTCH catalytically inhibits the activity of SMO, and hence no downstream signaling occurs. Aberrant signaling and oncogenic properties of the Hh pathway were first recognized in Gorlin syndrome, which is associated with an increased risk of developing rhabdomyosarcoma, medulloblastoma and basal cell carcinoma [1,13]. Subsequently, Hh signaling has been implicated in breast cancer, skin cancer, lymphoma, prostate cancer and brain cancer [11]. There has been increasing focus on the contribution of the Hh signaling pathway to disease pathogenesis in hematological malignancies, perhaps in the maintenance and expansion of leukemic stem cells (reviewed in [12]). In murine models of chronic myeloid leukemia (CML), it was shown that SMO deletion reduced the number of leukemic stem cells as well as prolonged the latency period of leukemia; complementary results were shown with pharmacological inhibition [12]. When SMO inhibitors were used either alone or in combination with tyrosine kinase inhibitors in CML cell lines, it was shown to decrease the incidence of leukemic blast transformation and prolong survival [12] in cell lines. Preclinical data in BCR–ABL negative MPNs, including MF, are limited, but a recent study reported a 20–100-fold increase in expression of Hh target genes, including Gli1 and Ptch1, by quantitative polymerase chain reaction (PCR) in granulocytes isolated from patients with MPN as compared to controls [14]. Sasaki et al. [10] expand on the clinical strategy of Hh inhibition in MF in this issue of Leukemia and Lymphoma. In this phase II study, 14 patients with MF received IPI-926 given continuously at a dose of 160 mg daily. The primary endpoint in this study was overall response rate, defined as clinical improvement, partial remission or complete remission as per the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). The secondary
Myelofibrosis (MF) is a BCR–ABL negative myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic stem cells and a pronounced symptom burden, attributed to cytopenias, extramedullary hematopoiesis leading to splenomegaly and constitutional and/or systemic symptoms including cachexia, night sweats, fevers, weight loss, pruritus and fatigue [1–3]. Dysregulation of Janus kinase (JAK)–signal transducer activator of transcription (STAT) is universal [4], in part driven by the presence of the JAK2V617F mutation identified in 60% of cases of MF [1–3]. Other JAK–STAT deregulating mutations in patients with JAK2V617F negative MF include calreticulin (CALR) and MPL mutations. Because JAK–STAT dysregulation is a prominent feature in MF, JAK inhibition is a rational therapy, and ruxolitinib was the first JAK inhibitor approved by the Food and Drug Administration (FDA) in patients with intermediate- and high-risk MF. Ruxolitinib has been shown to reduce splenomegaly and relieve MF-associated symptoms, and is associated with a modest survival benefit in comparison to placebo [5], best therapy [6] and historical controls [7]. Other JAK inhibitors in advanced development include pacritinib [8], which appears to lack myelosuppressive properties, and momelotinib [9], which may relieve anemia. However, JAK inhibitors do not lead to complete remission, resistance can occur and response can be lost promptly after discontinuation. Accordingly, and because of heterogeneous contributors to disease pathogenesis, novel treatment approaches are required. In this issue of Leukemia and Lymphoma, Sasaki et al. [10] present results with the hedgehog (Hh) inhibitor, IPI-926, in patients with MF. The Hh signaling pathway regulates self-renewal and terminal differentiation in embryonic development [11] but is usually “turned off” in adults until required for tissue repair. The signaling cascade begins with binding of the Hh ligand to patched 1 protein (PTCH), a transmembrane protein, causing internalization and degradation, and the release of Smoothened (SMO), a seven-transmembrane-span protein, by PTCH1 [1,11–13]. SMO is then activated in the primary
Correspondence: Brady L. Stein, 645 N. Michigan Avenue, Suite 1020, Chicago, IL 60611, USA. Tel: 312-695-6832. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
2 A. Kalyan & B. L. Stein endpoints included severity and incidence of toxicities, and change in bone marrow fibrosis, circulating inflammatory cytokines and symptoms as per the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), a validated patient-reported outcome tool. Of the 14 patients evaluated, eight had primary MF (five high risk, three intermediate-2 risk) and the remaining six had secondary MF. The median duration of treatment was 5.1 months and all patients discontinued therapy by 7.5 months (nine due to lack of efficacy, two after development of acute leukemia and one due to disease progression). Reduction in splenomegaly was modest, and symptoms as per MPN-SAF did not consistently improve. The most common adverse effects included elevated transaminases (11/14 patients), nausea (8/14 patients) and elevated bilirubin in four patients. Four patients (10 evaluated) had minimal to modest decreases in bone marrow fibrosis density scores after 3 months. The remaining patients had increases in the fibrosis density scores. Exploratory studies evaluating markers of Hh signaling were assessed by means of of GLI-1 mRNA and protein levels along with JAK2V617F allelic burden measurement. While some changes in this were observed, none were considered significant by the authors. Taking all results together, the authors concluded that there was no clinical benefit when using IPI-926 alone for the treatment of MF. At present, the clinical utility of Hh inhibitors needs further exploration in MF. First, although Sasaki et al. review contributions to other fibrotic diseases, and there are preclinical data in CML, whether aberrant Hh signaling strongly contributes to the pathogenesis of MF is not yet known. Second, although a lack of efficacy was noted with IPI-926, perhaps in part due to incomplete target inhibition, other Hh inhibitors may fare better (Table I). As an example, in a series of patients with hematological malignancies, including six with MF, five obtained stable disease and one had a clinical improvement in splenomegaly when treated with PF-04449913 [15]. As the authors state, the therapeutic potential of Hh inhibition may be maximized when combined with a JAK inhibitor, based on preclinical studies showing synergy between LDE225 (sonidegib) and ruxolitinib [14]. In this study by Bhagwat Table I. Oral hedgehog inhibitors in clinical trials at present. Name LDE225 LEQ506* GDC-0449* BMS-833923* IPI926 PF-04449913* GANT61
Action SMO antagonist (phase I/II study in combination with ruxolitinib) SMO antagonist SMO antagonist SMO antagonist SMO antagonist (results from phase II reported here) SMO antagonist Direct GLI inhibitor (currently in preclinical phase)
*Clinical trials currently under way in patients without MF.
SMO, Smoothened; GLI, glioma-associated oncogene; MF, myelofibrosis.
et al., combination therapy resulted in improvements in leukocytosis, thrombocytosis, bone marrow fibrosis and the mutant allele burden [14]. Further, according to Sasaki et al. [10], IPI-926 did not appear to be myelosuppressive, adding to its potential as a partner to JAK inhibitor therapy. In keeping with most hematological malignancies, given heterogeneous contributions to MF disease pathogenesis, further improvement in patient outcomes will come through development of rational combination therapies, rather than monotherapy, and thankfully, a number of clinical trials evaluating novel combinations have been conceptualized or opened for enrollment [2]. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Tibes R, Mesa RA. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies. J Hematol Oncol 2014;7:18. [2] Stein BL, Swords R, Hochhaus A, et al. Novel myelofibrosis treatment strategies: potential partners for combination therapies. Leukemia 2014;28:2139–2147. [3] Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, riskstratification, and management. Am J Hematol 2014;89:915–925. [4] Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood 2014;123:e123–e133. [5] Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799–807. [6] Cervantes F, Vannucchi AM, Kiladjian J-J, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122:4047–4053. [7] Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood 2014;123:1833–1835. [8] Dean JP, Cernohous P, Komrokji RS, et al. Pacritinib, a dual JAK2/ FLT3 inhibitor: an integrated efficacy and safety analysis of phase II trial data in patients with primary and secondary myelofibrosis (MF) and platelet counts 100,000/ml. Blood 2013;122(Suppl. 1): Abstract 395. [9] Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, Hogan WJ, Litzow MR, Leontovich A, Kowalski M, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27(6):1322–7. [10] Sasaki K, Gotlib J, Mesa RA, et al. Phase II evaluation of IPI-926, an oral hedgehog inhibitor, in patients with myelofibrosis. Leuk Lymphoma 2015;56:XXX–XXX. [11] Lin TL, Matsui W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. Oncotargets Ther 2012; 5:47–58. [12] Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood 2012;119:2196–2204. [13] Ng JMY, Curran T. The Hedgehog’s tale: developing strategies for targeting cancer. Nat Rev Cancer 2011;11:493–501. [14] Bhagwat N, Keller MD, Rampal RK, et al. Improved efficacy of combination of JAK2 and hedgehog inhibitors in myelofibrosis. Blood 2013;122(Suppl. 1): Abstract 666. [15] Jamieson C, Cortes JE, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood 2011;118(Suppl. 1): Abstract 424.
