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Polycythaemia vera and precision medicine: a prescription for the 21st century
Comment
Polycythaemia vera is the most common myeloproliferative neoplasm and the ultimate phenotypic consequence of the Janus kinase 2 (JAK2) Val617Phe mutation. First described in the 19th century, we now understand the molecular pathogenesis of polycythaemia vera, its natural history, and the basis for its many complications. Remarkably, however, still no consensus exists about its clinical management. Erythrocytosis is the hallmark of polycythaemia vera and the cause of the most common serious complication associated with the disease: major vessel thrombosis. Thrombosis prevention is the cornerstone of polycythaemia vera therapy and the use of phlebotomy to achieve a sex-specific normal haematocrit concentration is the most effective means to accomplish this.1 However, phlebotomy has been widely shunned in favour of chemotherapy, even though in large-scale clinical trials, alkyating agents, ³²P, or hydroxyurea therapy did not prevent thrombosis or prolong survival relative to phlebotomy alone in polycythaemia vera but did increase leukaemic transformation.2,3 These results notwithstanding, chemotherapy is still recommended for so-called high-risk patients with polycythaemia vera, defined as those aged older than 60 years or with a history of thrombosis,4 even though thrombosis in polycythaemia vera is provoked by hyperviscosity, disease complications do not differ in patients aged younger than or older than 60 years,5 and no evidence suggests that major vessel thrombosis is a consequence of either leukocytosis or thrombocytosis. Furthermore, not all patients with polycythaemia vera will develop extramedullary haematopoiesis or myelofibrosis.6 The discovery of the JAK2 Val617Phe mutation ushered in a new framework for the treatment of myeloproliferative neoplasms. Targeted therapy of committed haematopoietic progenitor cells expressing activated JAK2 fosters the proliferation of these cells and the production of inflammatory cytokines. Targeted therapy is now a standard of care for high-risk patients with primary or secondary myelofibrosis, in whom a JAK1 or JAK2 inhibitor (ruxolitinib) controlled blood counts, reduced inflammatory cytokine production and extramedullary haematopoiesis, and improved survival.7
Ruxolitinib has now been assessed in two clinical trials in polycythaemia vera without myelofibrosis. In The Lancet Oncology,8 Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomised, open-label, phase 3b trial of ruxolitinib in patients with polycythaemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial—like the previous RESPONSE trial,9 in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythaemia vera with splenomegaly—a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high risk patients, and were phlebotomy-dependent. Unsurprisingly, for the primary endpoint of patients achieving haematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs 14 [19%] of 75 in the best available therapy group; odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001), and also for the key secondary endpoint for patients achieving complete haematological remission (23% vs 5%). Additionally, symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”. However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythaemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythaemia vera to achieve European LeukemiaNet criteria for complete haematological remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.10 Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or haematological remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely
www.thelancet.com/oncology Published online December 1, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30591-5
Jim West/Science Photo Library
Polycythaemia vera and precision medicine: a prescription for the 21st century
Lancet Oncol 2016 Published Online December 1, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30591-5 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30558-7
1
Comment
that insurers would support the use of ruxolitinib in polycythaemia vera for haematocrit control without proof of greater efficacy than phlebotomy therapy. Third, no study of ruxolitinib in polycythaemia vera has capitalised on the observation, based on both clinical and gene-expression data, that patients with polycythaemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression.6 Thus, it should not be presumed that all patients with polycytaemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythaemia vera is an haematopoietic stemcell disorder and, so far, ruxolitinib does not seem to affect haematopoietic stem cell behaviour. At present, pegylated interferon is the only drug that targets haematopoietic stem cells and produces haematological and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression—a setting most appropriate for precision medicine.
2
Jerry L Spivak Traylor 924, John Hopkins University School of Medicine, 720 Rutland Avenue, Balimore, MD 21205, USA [email protected] I declare no competing interests. 1
2
3
4
5
6 7 8
9
10
Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219–21. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304: 441–47. Najean Y, Rain J. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997; 90: 3370–77. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90: 162–73. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma 2013; 54: 1989–95. Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in polycythemia vera. N Engl J Med 2014; 371: 808–17. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 2016; published online Dec 1. http://dx.doi.org/10.1016/ S1470-2045(16)30558-7. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 426–35. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012; 119: 1363–69.
www.thelancet.com/oncology Published online December 1, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30591-5
Polycythaemia vera is the most common myeloproliferative neoplasm and the ultimate phenotypic consequence of the Janus kinase 2 (JAK2) Val617Phe mutation. First described in the 19th century, we now understand the molecular pathogenesis of polycythaemia vera, its natural history, and the basis for its many complications. Remarkably, however, still no consensus exists about its clinical management. Erythrocytosis is the hallmark of polycythaemia vera and the cause of the most common serious complication associated with the disease: major vessel thrombosis. Thrombosis prevention is the cornerstone of polycythaemia vera therapy and the use of phlebotomy to achieve a sex-specific normal haematocrit concentration is the most effective means to accomplish this.1 However, phlebotomy has been widely shunned in favour of chemotherapy, even though in large-scale clinical trials, alkyating agents, ³²P, or hydroxyurea therapy did not prevent thrombosis or prolong survival relative to phlebotomy alone in polycythaemia vera but did increase leukaemic transformation.2,3 These results notwithstanding, chemotherapy is still recommended for so-called high-risk patients with polycythaemia vera, defined as those aged older than 60 years or with a history of thrombosis,4 even though thrombosis in polycythaemia vera is provoked by hyperviscosity, disease complications do not differ in patients aged younger than or older than 60 years,5 and no evidence suggests that major vessel thrombosis is a consequence of either leukocytosis or thrombocytosis. Furthermore, not all patients with polycythaemia vera will develop extramedullary haematopoiesis or myelofibrosis.6 The discovery of the JAK2 Val617Phe mutation ushered in a new framework for the treatment of myeloproliferative neoplasms. Targeted therapy of committed haematopoietic progenitor cells expressing activated JAK2 fosters the proliferation of these cells and the production of inflammatory cytokines. Targeted therapy is now a standard of care for high-risk patients with primary or secondary myelofibrosis, in whom a JAK1 or JAK2 inhibitor (ruxolitinib) controlled blood counts, reduced inflammatory cytokine production and extramedullary haematopoiesis, and improved survival.7
Ruxolitinib has now been assessed in two clinical trials in polycythaemia vera without myelofibrosis. In The Lancet Oncology,8 Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomised, open-label, phase 3b trial of ruxolitinib in patients with polycythaemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial—like the previous RESPONSE trial,9 in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythaemia vera with splenomegaly—a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high risk patients, and were phlebotomy-dependent. Unsurprisingly, for the primary endpoint of patients achieving haematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs 14 [19%] of 75 in the best available therapy group; odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001), and also for the key secondary endpoint for patients achieving complete haematological remission (23% vs 5%). Additionally, symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”. However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythaemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythaemia vera to achieve European LeukemiaNet criteria for complete haematological remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.10 Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or haematological remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely
www.thelancet.com/oncology Published online December 1, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30591-5
Jim West/Science Photo Library
Polycythaemia vera and precision medicine: a prescription for the 21st century
Lancet Oncol 2016 Published Online December 1, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30591-5 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(16)30558-7
1
Comment
that insurers would support the use of ruxolitinib in polycythaemia vera for haematocrit control without proof of greater efficacy than phlebotomy therapy. Third, no study of ruxolitinib in polycythaemia vera has capitalised on the observation, based on both clinical and gene-expression data, that patients with polycythaemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression.6 Thus, it should not be presumed that all patients with polycytaemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythaemia vera is an haematopoietic stemcell disorder and, so far, ruxolitinib does not seem to affect haematopoietic stem cell behaviour. At present, pegylated interferon is the only drug that targets haematopoietic stem cells and produces haematological and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression—a setting most appropriate for precision medicine.
2
Jerry L Spivak Traylor 924, John Hopkins University School of Medicine, 720 Rutland Avenue, Balimore, MD 21205, USA [email protected] I declare no competing interests. 1
2
3
4
5
6 7 8
9
10
Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219–21. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304: 441–47. Najean Y, Rain J. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997; 90: 3370–77. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90: 162–73. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma 2013; 54: 1989–95. Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in polycythemia vera. N Engl J Med 2014; 371: 808–17. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 2016; published online Dec 1. http://dx.doi.org/10.1016/ S1470-2045(16)30558-7. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 426–35. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012; 119: 1363–69.
www.thelancet.com/oncology Published online December 1, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30591-5