Original Article Real-­world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea 1 Alberto Alvarez-­Larrán, MD ; Marta Garrote, MD1; Francisca Ferrer-­Marín, MD2; Manuel Pérez-­Encinas, MD3; M. Isabel Mata-­Vazquez, MD ; Beatriz Bellosillo, MD5; Eduardo Arellano-­Rodrigo, MD 4 1 ; Montse Gómez, MD6; 7 8 Regina García, MD ; Valentín García-­Gutiérrez, MD ; Mercedes Gasior, MD ; Beatriz Cuevas, MD10; Anna Angona, MD11; 9 María Teresa Gómez-­Casares, MD ; Clara M. Martínez, MD13; Elena Magro, MD14; Rosa Ayala, MD15; 12 Rafael del Orbe-­Barreto, MD16; Raúl Pérez-­López, MD17; Maria Laura Fox, MD18; José-­María Raya, MD19; Lucía Guerrero, MD20; Carmen García-­Hernández, MD21; Gonzalo Caballero, MD22; Ilda Murillo, MD23; Blanca Xicoy, MD24; M. José Ramírez, MD25; Gonzalo Carreño-­Tarragona, MD15; Juan Carlos Hernández-­Boluda, MD6; and Arturo Pereira, MD1; for the MPN Spanish Group (Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas) BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-­progression is unknown. METHODS: A retrospective, real-­world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombo- sis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To mini- mize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this per- sisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-­ 1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-­up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. Cancer 2022;128:2441-2448. © 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. LAY SUMMARY: • Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. • We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). • Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-­modifying effect could not be demonstrated for ruxolitinib in this patient population. KEYWORDS: hemorrhage, myelofibrosis, myeloproliferative neoplasms, polycythemia vera, ruxolitinib, therapy, thrombosis. Corresponding Author: Alberto Alvarez-­Larrán, MD, Hematology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain (aalvar@clinic.cat). 1 Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 2 Hospital Morales Messeguer, Universidad Católica San Antonio de Murcia, Murcia, Centro de Investigación Biomédica en Red de Enfermedades Raras, Murcia, Spain; 3 Hospital Clínico Universitario, Santiago de Compostela, Spain; 4 Hospital Costa del Sol, Marbella, Spain; 5 Hospital del Mar, Barcelona, Spain; 6 Hospital Clínico, Valencia, Spain; 7 Hospital Virgen de la Victoria, Málaga, Spain; 8 Hospital Ramón y Cajal, Instituto Ramón y Cajal de investigación sanitaria, Madrid, Spain; 9 Hospital La Paz, Madrid, Spain; 10 Hospital Universitario de Burgos, Burgos, Spain; 11 Hospital Josep Trueta, Institut Català d’Oncologia, Girona, Spain; 12 Hospital Doctor Negrín, Las Palmas de Gran Canaria, Spain; 13 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 14 Hospital Príncipe de Asturias, Alcalá de Henares, Spain; 15 Hospital Universitario 12 de Octubre, Madrid, Spain; 16 Hospital Universitario de Cruces, Barakaldo, Spain; 17 Hospital Virgen de la Arrixaca, Murcia, Spain; 18 Hospital Vall d’Hebron, Barcelona, Spain; 19 Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain; 20 Hospital Río Carrión, Palencia, Spain; 21 Hospital General, Alicante, Spain; 22 Hospital Miguel Servet, Zaragoza, Spain; 23 Hospital San Jorge, Huesca, Spain; 24 Hospital Germans Trias i Pujol, Institut Català d’Oncologia, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain; 25 Hospital General, Jerez de la Frontera, Spain We are indebted to all members of the Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas participating in the Spanish Registry of Polycythemia Vera. We also thank MFAR staff (Narcís Borrell and Eduard Cabré) for their technical assistance. Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.34195, Received: October 29, 2021; Revised: January 21, 2022; Accepted: February 14, 2022, Published online April 13, 2022 in Wiley Online Library ­(wileyonlinelibrary.com) Cancer   July 1, 2022 2441 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article INTRODUCTION more than 1 year after R/I development were excluded Polycythemia vera (PV) is a chronic myeloproliferative from the study. The indication of ruxolitinib was decided neoplasm characterized by an increased risk of thrombosis by local physicians according to the clinical guidelines and bleeding and, in the long term, progression to my- and prevailing recommendations at that time. elofibrosis and acute myeloid leukemia.1,2 Hydroxyurea The diagnosis of PV was established according to (HU) is the most widely used drug and achieves clinical the World Health Organization criteria.14 Informed con- and hematological control in most patients.3,4 However, sent was obtained for scientific use of patients’ clinicohe- approximately 20% to 30% of patients develop resistance/ matological data. The study was approved by the Hospital intolerance to HU, which translates into inadequate con- del Mar institutional review board. trol of the disease and an increased risk of thrombosis.4-­8 Furthermore, mutations in TP53 or in chromatin/splicing Outcomes genes are frequently found in PV patients with resistance The main outcomes of the study were survival, major to HU, and they confer an increased risk of transforma- thrombosis (total, arterial, and venous [including super- tion to acute leukemia and myelofibrosis.9 ficial thrombophlebitis]), hemorrhage (total, major, and Ruxolitinib is a JAK1/JAK2 inhibitor approved for minor), disease progression to acute myeloid leukemia, the treatment of patients with PV who have developed myelofibrosis, and the occurrence of a second primary resistance/intolerance (R/I) to HU. In these patients, the cancer. Relevant symptomatology and hematological val- RESPONSE and RESPONSE-­ 2 studies have demon- ues at the time of R/I to HU and later were retrospectively strated the superiority of ruxolitinib over the best available reviewed. For details, see the Supporting Methods. therapy (BAT) in terms of hematocrit control, symptom re- lief, and spleen size reduction.10,11 However, most patients Statistical Methods assigned to BAT in these clinical trials were crossed over to Rates of thrombosis, bleeding, myelofibrosis, acute mye- ruxolitinib prematurely, and this precluded any compari- loid leukemia, and second cancers were calculated with the son of the incidence of vascular events, disease transforma- incidence rate method. The time at risk ranged from the tion, or survival between the 2 treatment options.11,12 date of R/I to the last follow-­up or death. Outcomes were The objective of the current study was to analyze the compared according to treatment (BAT vs ruxolitinib). main clinical outcomes for 377 patients with R/I to HU Periods on anticoagulants and on antiplatelet agents from the Spanish Registry of Polycythemia Vera who were were evaluated as time-­varying covariates. Multivariable subsequently treated with ruxolitinib or BAT. analyses of factors influencing the incidence rates were performed by Poisson regression. A propensity score (PS) was calculated from the binary logistic regression of initial MATERIALS AND METHODS clinical features predicting ruxolitinib therapy, and it was Study Design forced into the Poisson models to control for confounding. The Spanish Registry of Polycythemia Vera was started in Overall survival and time to event curves were drawn by July 2011 and is periodically updated. It is sponsored by the Kaplan-­Meier method (see the Supporting Methods). the Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas. By April 2021, a total of 2245 pa- tients from 60 Spanish hospitals had been included in the RESULTS registry, and 1784 of them had been treated with HU. Patient Characteristics Patients were eligible for inclusion in the current study The main clinical and hematological characteristics at the if they had developed R/I to HU. R/I was assessed ac- time of R/I to HU are shown in Table 1. The median cording to the modified European LeukemiaNet criteria age of the overall series was 73 years (interquartile range, as described by Barosi et al.13 63-­75 years). Patients in the ruxolitinib group had been A total of 431 patients (24%) developed R/I to HU exposed to HU for a longer time before R/I, with 54% of and were stratified into 2 groups according to the treat- them exposed for more than 3 years in contrast to 43% in ment received subsequently. Patients never exposed to the BAT group (P = .04). ruxolitinib (n = 272) were assigned to the BAT group, Table 2 summarizes the distributions of the pa- and those who received ruxolitinib within the first year tients according to the different criteria of R/I, symptom- after R/I to HU made up the ruxolitinib group (n = 105). atic burden, and hematological values at the time of R/I Fifty-­ four additional patients who started ruxolitinib to HU. Progressive splenomegaly was more frequent in 2442 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Ruxolitinib versus BAT in PV/Alvarez-­Larrán et al TABLE 1. Main Clinical Characteristics of TABLE 2. Type of Resistance/Intolerance 377 Patients With Resistance/Intolerance to to Hydroxyurea, Symptomatic Burden, and Hydroxyurea According to the Subsequent Hematological Values in 377 Patients With Treatment Polycythemia Vera According to the Subsequent Treatment Ruxolitinib BAT (n = 105) (n = 272) P Ruxolitinib BAT (n = 105) (n = 272) P Age, median (IQR), y 71 (63-­75) 74 (66-­80) .0006 Male sex, No. (%) 55 (53) 132 (49) .45 Type of resistance/intoler- Time from diagnosis, median 6.3 (2.5-­10.1) 2.8 (0.6-­6.6) .001 ance, No. (%)a (IQR), y Need for phlebotomies 16 (15) 49 (18) .5 Cardiovascular risk factors, Progressive splenomegaly 9 (9) 5 (2) .002 No. (%) Myeloproliferation 12 (11) 24 (9) .4 Smoking 15 (14) 42 (15) .8 Cytopenia 4 (4) 39 (14) .004 Diabetes 21 (15) 42 (20) .3 Extrahematological 66 (63) 199 (73) .05 Hypertension 55 (52) 163 (60) .2 toxicityb Hypercholesterolemia 32 (30) 66 (24) .2 Symptomatic burden, No. (%) Atrial fibrillation 5 (5) 15 (5.5) .8 Constitutional symptomsc 30 (31) 17 (10) <.0001 Prior thrombosis, No. (%) Microvascular symptomsd 18 (18) 8 (5) .001 Arterial 18 (17) 59 (22) .3 Prurituse 47 (47) 26 (16) <.0001 Venous 12 (11) 25 (9) .5 Symptomatic 7 (7) 5 (3) .2 Prior bleeding, No. (%) 14 (13) 28 (10) .4 splenomegalyf Hematological values, median Abbreviations: BAT, best available therapy; IQR, interquartile range. (IQR) Hemoglobin, g/L 141 (126-­153) 141 (121-­155) .97 Leukocyte count, ×109/L 8.7 (5.9-­13) 7.2 (5.1-­11.2) .01 ruxolitinib-­treated patients, whereas cytopenia and extrahe- Platelet count, ×109/L 371 (252-­601) 328 (194-­499) .02 matological toxicity were more frequent in the BAT cohort. Abbreviations: BAT, best available therapy; IQR, interquartile range. a Resistance/intolerance to hydroxyurea was defined according to the modi- Therapy fied European LeukemiaNet criteria. b Extrahematological toxicity included the following: leg ulcers (n = 112), other BAT consisted of HU (in 60% of the patients), interferon mucocutaneous toxicity (n = 106), hydroxyurea-­related fever (n = 16), gastro- (4%), anagrelide (9%), busulfan (15%), melphalan (2%), intestinal toxicity (n = 23), and other (n = 17). c Available in 261 cases. radioactive phosphorus (1%), other treatments (2%), d Available in 253 cases. and no medication (8%). By logistic regression, the use e Available in 257 cases. f of ruxolitinib was significantly associated with age (odds Available in 263 cases. ratio [OR], 0.96; 95% confidence interval [CI], 0.94-­ 0.98; P = .002), longer disease duration (OR, 1.10; 95% Table 1). As for hematological values, ruxolitinib resulted CI, 1.05-­1.15; P < .0001), and less cytopenia (OR, 0.23; in significantly better hemoglobin values and hemato- 95% CI, 0.08-­0.71; P = .01). The predicted probabil- crit control than BAT (Supporting Table 1). Supporting ity of starting on ruxolitinib for each of the 377 patients, Table 2 summarizes the cumulative incidence of the main conditional on the aforementioned clinical features, events defining the natural history of PV. ranged from 0.035 to 0.838, and it was used as a PS in Survival subsequent analyses. The median duration of ruxolitinib treatment was 2 years (range, 0.1-­8 years), with 27, 24, After a median follow-­up of 3.8 years (interquartile range, 25, and 29 patients receiving ruxolitinib for less than 1, 2.0-­7.0 years), a total of 92 patients (24%) had died. 1 to 2, 2 to 3, and >3 years, respectively. Permanent dis- Causes of death are shown in Supporting Table 3. Figure 1 continuation of ruxolitinib was recorded in 17 patients shows the expected survival after R/I to HU according to (16%) because of an inadequate response (n = 4), he- the treatment group. Death occurred in 10 and 82 pa- matological toxicity (n = 1), extrahematological toxicity tients in the ruxolitinib and BAT cohorts, respectively. (n = 6), severe infections (n = 2), and a second primary The incidence rate of death was 4.2 per 100 patient-­years cancer (n = 4). in the ruxolitinib group and 6.4 per 100 patient-­years in the BAT group. The PS-­adjusted incidence rate ratio Symptoms and Hematological Response (IRR) of death associated with the use of ruxolitinib was The proportion of patients with pruritus and microvas- 0.8 (95% CI, 0.4-­1.5; P = .4). cular and constitutional symptoms decreased over time In a subgroup analysis, there was no difference in among patients receiving ruxolitinib, whereas it remained mortality between the ruxolitinib and BAT groups when stable among those treated with BAT (Supporting the analysis was restricted to patients with either resistance Cancer   July 1, 2022 2443 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article 1.0 0.8 Probability 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 Years At risk: BAT 272 243 221 186 157 129 104 73 60 Ruxolitinib 105 83 54 29 14 9 5 3 1 BAT Ruxolitinib FIGURE 1. Survival after resistance/intolerance to hydroxyurea according to therapy in 377 patients with polycythemia vera. The red line corresponds to ruxolitinib (n = 105). The blue line corresponds to BAT (n = 272). The hazard ratio was 0.8 (95% confidence interval, 0.4-­1.7; P = .6). The Cox regression included the type of therapy and the propensity score for ruxolitinib. BAT indicates best available therapy. 1.0 0.8 0.6 Probability 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 Years At risk: BAT 272 239 212 174 143 114 92 66 54 Ruxolitinib 105 82 53 26 11 6 3 2 1 BAT Ruxolitinib FIGURE 2. Time to myelofibrosis after resistance/intolerance to hydroxyurea according to therapy in 377 patients with polycythemia vera. The red line corresponds to ruxolitinib (n = 105). The blue line corresponds to BAT (n = 272). The hazard ratio was 0.8 (95% confidence interval, 0.4-­2.3; P = .9). The Cox regression included the type of therapy and the propensity score for ruxolitinib. BAT indicates best available therapy. 2444 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Ruxolitinib versus BAT in PV/Alvarez-­Larrán et al TABLE 3. Incidence of Thrombosis and Major Bleeding in 377 Patients With Polycythemia Vera Who Were Treated With Ruxolitinib or BAT After Developing Resistance/Intolerance to Hydroxyurea Ruxolitinib (251 Person-­y) BAT (1272 Person-­y) No. of Events Incidence Ratea No. of Events Incidence Ratea P b Arterial thrombosis 1 0.4 29 2.3 .03 Venous thrombosisc 2 0.8 14 1.1 .7 Major bleedingd 2 0.8 11 0.9 .9 Abbreviations: BAT, best available therapy; CI, confidence interval; IRR, incidence rate ratio. a Events per 100 person-­years. b IRR, 0.18; 95% CI, 0.02-­1.3; P = .09 (adjusted by propensity score). c IRR, 1.1; 95% CI, 0.3-­3.9; P = .9 (adjusted by propensity score). d IRR, 0.9; 95% CI, 0.2-­4.9; P = .9 (adjusted by propensity score). (IRR, 0.55, 95% CI.16-­1.80; P = .32) or intolerance to when all tumors were considered or after noncutaneous HU (IRR, 0.88; 95% CI, 0.40-­1.89; P = .71). carcinoma and nonmelanoma skin cancer were disaggre- gated (Table 4). Male sex was associated with a higher rate Disease Progression of second neoplasia (P < .0001), especially for cutaneous Eleven cases progressed to acute myeloid leukemia (n = 9) basal cell carcinoma (P = .002) and cutaneous squamous or myelodysplastic syndrome (n = 2), and all were in cell carcinoma (P = .005). The duration of HU exposure the BAT cohort (Supporting Table 4). The time to acute before R/I was associated with a trend for a higher rate of transformation is shown in Supporting Figure 1. The in- cutaneous basal cell carcinoma (P = .06). cidence rate of acute transformation in the BAT cohort was 0.86 events per 100 person-­years (P = .1 for the com- DISCUSSION parison with the ruxolitinib group). The outcomes of PV patients after R/I to HU who were Thirty-­ four patients progressed to myelofibrosis: treated with ruxolitinib or BAT were described in the 6 in the ruxolitinib group and 28 in the BAT cohort RESPONSE and RESPONSE-­ 2 trials, which showed (Fig. 2). The incidence rate of myelofibrosis was 2.5 and the superiority of ruxolitinib over BAT in achieving he- 2.3 events per 100 person-­years in the ruxolitinib and matocrit control and improving symptoms and quality of BAT cohort, respectively (IRR, 0.98; 95% CI, 0.4-­2.3; life.10-­12 However, other relevant clinical outcomes could P = .9 [adjusted for PS]). not be explored because of early crossover, which resulted Thrombosis and Bleeding in short follow-­up in the BAT arms of the RESPONSE A total of 46 thrombotic events (30 arterial and 16 ve- trials.10-­12 In the current retrospective study, the out- nous) were registered in 1523 person-­years of follow-­up. comes of 272 patients on BAT followed for a total of The incidence rates of arterial and venous thrombosis 1272 person-­ years were compared with those of 105 according to the treatment group are shown in Table 3. patients receiving ruxolitinib for R/I to HU. The treat- Patients receiving ruxolitinib had a significantly lower ment modalities in the BAT group, ruxolitinib expo- rate of arterial thrombosis after adjustment for the time sure, and reasons for discontinuation were similar to the on anticoagulation and antiplatelet drugs. This lower rate ones reported in the RESPONSE trials and 2 real-­world remained a statistically nonsignificant trend after adjust- studies.11,12,15,16 ment for PS (IRR, 0.18; 95% CI, 0.02-­1.30; P = .09). We observed only 1 arterial thrombotic event in the There were no significant differences between the 2 study ruxolitinib group; this resulted in a rate of 0.4 events per groups in rates of venous thrombosis and major bleeding 100 patient-­years, which was 5 times below the incidence after adjustment for being or not being on anticoagulants observed in patients treated with BAT. In contrast, the or antiplatelet agents at the time of the event (Table 3). incidence of venous thrombosis was quite similar in the 2 treatment groups. Notably, the rates of total thrombosis Second Primary Cancer in our study (1.2 and 3.4 per 100 patient-­years in the Table 4 summarizes the incidence rates for all second pri- ruxolitinib and BAT groups, respectively) were compa- mary cancers and specifically for nonmelanoma skin can- rable to the figures reported in the 5-­year update of the cer and noncutaneous cancer. Ruxolitinib exposure was RESPONSE trial and in a recent meta-­analysis of patients not associated with a higher rate of second cancers either with PV treated with HU.12,17 Cancer   July 1, 2022 2445 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article TABLE 4. Incidence of Second Cancers in 377 Patients With Polycythemia Vera Who Were Treated With Ruxolitinib or BAT After Developing Resistance/Intolerance to Hydroxyurea Ruxolitinib (251 Person-­y) BAT (1272 Person-­y) No. of Events Incidence Ratea No. of Events Incidence Ratea P b Total cancer 6 2.4 34 2.7 .8 Noncutaneous cancerc 3 1.2 12 0.9 .7 Cutaneous carcinoma Basal celld 1 0.4 8 0.6 .7 Squamous celle 2 0.8 9 0.7 .8 Abbreviations: BAT, best available therapy; CI, confidence interval; IRR, incidence rate ratio. All IRRs were adjusted by propensity score. a Events per 100 person-­years. b IRR, 1.1; 95% CI, 0.5-­2.8; P = .8. c IRR, 1.72; 95% CI, 0.46-­6.4; P = .4. d IRR, 0.8; 95% CI, 0.1-­5.9; P = .8. e IRR, 1.3; 95% CI, 0.25-­6.6; P = .7. Two meta-­analyses have reported a lower incidence A post hoc analysis of the RESPONSE trial has shown of thrombosis in patients with PV treated with ruxoli- that ruxolitinib reduces the JAK2V617F allele burden in par- tinib in comparison with controls.18,19 Samuelson et al,18 allel with a reduction of the spleen size.28 This finding has in a study including patients with myelofibrosis from the led to speculation about a potentially beneficial effect of the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor drug in decreasing the risk of disease progression to myelo- Treatment Trial (COMFORT) and patients with PV from fibrosis, which is particularly increased in patients with R/I the RESPONSE trials, observed a significant reduction to HU.4,7 However, our data showed similar rates of pro- of thrombotic events in the ruxolitinib-­treated patients gression to myelofibrosis in patients treated with ruxolitinib (risk ratio, 0.46; 95% CI, 0.23-­0.88). This lower risk was and patients treated with BAT. Nevertheless, the absence of driven by a larger reduction in the rate of arterial events cases progressing to acute myeloid leukemia in the ruxoli- (risk ratio, 0.42; 95% CI, 0.14-­1.01) versus venous events tinib group was striking, and this finding could be partially (risk ratio, 0.46; 95% CI, 0.14-­1.48). Masciulli et al,19 explained by a lower frequency of cytopenia as a criterion for in a meta-­analysis of 663 patients from the RESPONSE, R/I to HU.7,29 In addition, we were unable to demonstrate a RESPONSE-­2, A RandoMised study of best Available survival benefit in patients treated with ruxolitinib after ad- therapy versus JAK Inhibition in patients with high risk justment for the propensity to be started on this drug instead Polycythaemia Vera or Essential Thrombocythaemia of BAT. Although there was some trend for better survival who are resistant or intolerant to HydroxyCarbamide with ruxolitinib when the analysis was restricted to the resis- (MAJIC), and RELIEF clinical trials, observed a nonsig- tance group, it should be noted that patients who received nificantly lower number of thrombotic events with rux- ruxolitinib were significantly younger and had less frequent olitinib in comparison with controls (IRR, 0.56; 95% CI, cytopenia than their counterparts in the BAT group. 0.28-­1.11; P = .09). There is a biological basis to support There is growing concern about a potential car- these clinical observations. Indeed, ruxolitinib inhibits cinogenetic effect of ruxolitinib, which could be es- both platelet function20 and hyperplasia of the arterial in- pecially relevant in patients with PV because of their timal layer21; levels of inflammatory cytokines are higher prolonged survival with potentially longer drug ex- in myeloproliferative neoplasms than the general popula- posures in comparison with patients with myelofi- tion,22-­24 and they decrease after exposure to ruxolitinib, brosis. Notably, both the RESPONSE and MPN-­K at least in patients with myelofibrosis.25 Finally, there is (Secondary Cancers in Myeloproliferative Neoplasms) a correlation between the serum levels of C-­reactive pro- studies have reported an increased risk of nonmelanoma tein, the risk of thrombosis, and the JAK2V617F allele skin cancer in patients treated with ruxolitinib.12,30 The burden in PV and essential thrombocythemia.26,27 Taken RESPONSE trial showed a higher incidence of non- together, our results and the aforementioned clinical and melanoma skin cancer in patients on ruxolitinib (5.1% biological observations allow us to speculate on a possible and 2.7% for ruxolitinib and BAT, respectively), with role for the anti-­inflammatory effects of ruxolitinib in de- the incidence being markedly higher in patients with creasing the risk of arterial thrombosis, a hypothesis that a history of nonmelanoma skin cancer. In contrast, would be worth investigating in future studies. the incidence of nonmelanoma skin cancer was clearly 2446 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Ruxolitinib versus BAT in PV/Alvarez-­Larrán et al lower in our study (1.2% and 0.9% for ruxolitinib and and consulting fees from Novartis and Incyte, and meeting support from Novartis. Manuel Pérez-­Encinas participated on an advisory board and BAT, respectively). Several factors, including a longer received speaker fees from Novartis. Regina García participated on ad- disease duration in the RESPONSE series in compar- visory boards for and received payments for lectures and expert testi- mony and support for attending meetings from Novartis, Jansen, and ison with our patients (8 vs 6 years), a higher propor- AbbVie.Valentín García-­Gutiérrez received speaker honorarium and sup- tion of patients with a history of nonmelanoma skin port for attending meetings from Novartis and Incyte, and participated cancer (11% in RESPONSE vs 3% in our study), and on advisory boards for Novartis and Incyte. Clara M. Martínez received payments or honoraria from Novartis. Maria Laura Fox received consult- longer ruxolitinib exposure in RESPONSE (428 vs ing fees from Sierra Oncology and Novartis, payment for lectures from 251 person-­years), may account for this discrepancy. Novartis, and support for attending meetings from Novartis and Sanofi. Rosa Ayala received speaker honoraria from Astellas, Celgene, and Furthermore, ruxolitinib exposure was not associated Novartis and participated on advisory boards for Novartis and Incyte. with an increased risk of second malignancies in an- Ilda Murillo received support for attending meetings and/or travel from Novartis and Janssen. Rafael del Orbe-­Barreto received support for at- other real-­world study including 289 patients with PV, tending meetings and/or travel from Novartis. Gonzalo Caballero re- 95 of whom were treated with ruxolitinib.31 ceived support for attending meetings and/or travel from Novartis and Although the current study constitutes a good rep- Janssen and participated on a board for AstraZeneca. Marta Garrote received support for attending meetings from Roche and Transglobal. resentation of real practice in patients with R/I to HU, M. Isabel Mata-­Vazquez participated on advisory boards and received several limitations should be taken into account when speaker and consulting fees and support for attending meetings from Incyte and Novartis. Gonzalo Carreño-­Tarragona received payments or the results are interpreted. First, the patient cohorts were honoraria from Novartis, Incyte, Astellas, SEHH (Sociedad Española de not contemporaneous. Most patients in the BAT group Hematología y Hemoterapia), and AMHH (Asociación Madrileña de Hematología y Hemoterapia). Juan Carlos Hernández-­Boluda reported developed R/I to HU before the approval of ruxolitinib consulting fees from AOP Pharma, Celgene, and BMS; payments or and had, therefore, a longer follow-­up than patients who honoraria from Novartis; support for attending meetings and/or travel received ruxolitinib. We dealt with this potential source of from Incyte; and participation on boards for Celgene and BMS. The other authors made no disclosures. bias by considering only the first 8 years after R/I to HU. Second, the observational design of our study precluded us from establishing causal associations. Indeed, despite AUTHOR CONTRIBUTIONS Alberto Alvarez-­Larrán: Study design, data collection, statistical analy- adjustments for the PS to be in the ruxolitinib group, sis, analysis and interpretation of the results, and writing of the manu- unaccounted confounders or imperfect adjustments may script. Marta Garrote: Data collection, interpretation of the results, and writing of the manuscript. Francisca Ferrer-­Marín: Data collection, have influenced the results. Additionally, the ability to interpretation of the results, and approval of the final version. Manuel assess the impact of ruxolitinib on disease modification Pérez-­Encinas: Data collection, interpretation of the results, and ap- proval of the final version. M. Isabel Mata-­Vazquez: Data collection, may have been eroded by the relatively short follow-­up interpretation of the results, and approval of the final version. Beatriz (a median of 3.8 years) and the longer disease duration Bellosillo: Data collection, interpretation of the results, and approval of in patients receiving ruxolitinib. Nevertheless, it should the final version. Eduardo Arellano-­Rodrigo: Data collection, interpre- tation of the results, and approval of the final version. Montse Gómez: be noted that most of the events that shape the natural Data collection, interpretation of the results, and approval of the final history of PV occur within the first years after R/I to HU. version. Regina García: Data collection, interpretation of the results, and approval of the final version. Valentín García-­Gutiérrez: Data col- In conclusion, the results of the current study sug- lection, interpretation of the results, and approval of the final version. gest that ruxolitinib may reduce the risk of arterial throm- Mercedes Gasior: Data collection, interpretation of the results, and ap- proval of the final version. Beatriz Cuevas: Data collection, interpre- bosis in patients with PV who have developed R/I to HU. tation of the results, and approval of the final version. Anna Angona: On the other hand, with the limitations derived from a Data collection, interpretation of the results, and approval of the final short follow-­up and a retrospective design, we have been version. María Teresa Gómez-­Casares: Data collection, interpretation of the results, and approval of the final version. Clara M. Martínez: Data unable to demonstrate a disease-­modifying effect of rux- collection, interpretation of the results, and approval of the final version. olitinib in this patient population. Elena Magro: Data collection, interpretation of the results, and approval of the final version. Rosa Ayala: Data collection, interpretation of the results, and approval of the final version. Rafael del Orbe-­Barreto: Data collection, interpretation of the results, and approval of the final version. FUNDING SUPPORT Raúl Pérez-­López: Data collection, interpretation of the results, and ap- This work was supported by the Instituto de Salud Carlos III through proval of the final version. Maria Laura Fox: Data collection, interpreta- a National Plan for Scientific and Technical Research and Innovation tion of the results, and approval of the final version. José-­María Raya: Innovación (PI18/01472, PI18/00205, and PI21/00231). The Spanish Data collection, interpretation of the results, and approval of the final Group of Myeloproliferative Neoplasms (GEMFIN) received a grant from version. Lucía Guerrero: Data collection, interpretation of the results, Novartis for developing the Spanish Registry of Polycythemia Vera and for and approval of the final version. Carmen García-­Hernández: Data col- conducting the current project. lection, interpretation of the results, and approval of the final version. Gonzalo Caballero: Data collection, interpretation of the results, and approval of the final version. Ilda Murillo: Data collection, interpre- CONFLICT OF INTEREST DISCLOSURES tation of the results, and approval of the final version. Blanca Xicoy: Alberto Alvarez-­Larrán participated on advisory boards and received Data collection, interpretation of the results, and approval of the final speaker and consulting fees from Novartis, AOP, and Celgene. Francisca version. M. José Ramírez: Data collection, interpretation of the results, Ferrer-­Marín received research support from Incyte and CTI, speaker and approval of the final version. Gonzalo Carreño-­Tarragona: Data Cancer   July 1, 2022 2447 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34195 by Readcube (Labtiva Inc.), Wiley Online Library on [26/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article collection, interpretation of the results, and approval of the final ver- 15. Coltoff A, Mesa R, Gotlib J, et al. Real-­world outcomes of ruxoli- sion. Juan Carlos Hernández-­Boluda: Data collection, interpretation tinib treatment for polycythemia vera. Clin Lymphoma Myeloma Leuk. of the results, and writing of the manuscript. 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