A Restrospective Study of Secondary Malignancies in Myelofibrosis Patients Receiving Ruxolitinib Therapy
Myelofibrosis (MF) is a chronic, rare, and often fatal type of blood cancer characterized by a progressive replacement of bone marrow with fibrous scar tissue. This type of myeloproliferative neoplasm (MPN) leads to progressive spleen enlargement, systemic symptoms such as fatigue and gout, and a predisposition for acute leukemia. The incidence of MF in the United States is about 17,000 people. Secondary primary malignancies (SPMs) represent a major cause of morbidity and mortality in MF patients, which have a significantly higher risk. Additionally, MPNs are also associated with a risk for lymphoproliferative disorders. Ruxolitinib (RUX) is a selective JAK1/JAK2 inhibitor approved for the treatment of splenomegaly and its symptoms in MF patients. RUX therapy provides spleen reduction as well as symptom relief in the majority of cases, with a potential for survival prolongation. However, RUX use has been associated with increased risk of non-melanoma skin cancers (NMSCs). A recent study of 647 MPN patients with SPMs showed that the concurrent use anti metabolite chemotherapeutic hydroxycarbamide (HU) and RUX increased the risk of NMSCs. Another study also described a 16-fold increase in the risk of aggressive lymphomas in patients during RUX treatment. These previous study results have raised the concern of possible negative outcomes of RUX treatment. In response, this study set out to provide clarity and guidance for providers considering RUX treatment by analyzing the present collection of real world data.
The study goals were to: (1) describe SPMs in terms of their incidence, type and timing; (2) identify risk factors associated with SPM development; and (3) provide survival information and evaluate RUX treatments in patients.
This study was retrospective in design, conducted from June 2011 until January 2020. Data were extracted from electronic sources that included patients with chronic-phase MF treated with RUX in 20 European hematology centers. All patients were followed continuously until death or the study end date.
Treatment options and toxicities have been previously published for RUX, showing causation for myelosuppression, progressive multifocal leukoencephalopathy, thrombocytopenia, and infections such as Herpes zoster. As a result of this published data, several major thrombotic events were of interest in this study, including ischemic stroke, transient ischemic attack, acute myocardial infarction, unstable angina pectoris, peripheral arterial thrombosis, retinal artery or vein occlusion, deep venous thrombosis and pulmonary embolism.
In addition to electronic data sourcing, a survey was conducted in order to obtain comprehensive information regarding all malignancies which occurred prior to, or after, RUX therapy initiation. Data were collected including the following details: site, histology, stage, date of diagnosis, treatment (surgery, chemotherapy and/or radiotherapy) and outcome. Cancers were diagnosed and classified according to the International Classification of diseases. Acute leukemias present in patients receiving RUX were excluded from the study as they represent the natural progression of MF.
Specific data on previous therapies for MF were collected and included the following: utilization, duration and number of cytoreductive therapies (hydroxycarbamide, busulfan, pipobroman, melphalan, interferons).
The study was approved by the individual Ethic committees of each participating center.
Descriptive statistics were utilized to describe characteristics of the study cohort, SPM features, and the outcomes. The Wilcoxon–Mann–Whitney rank-sum test was used to compare quantitative variables between patient groups. The association between categorical variables was measured by the chi-squared test. The cumulative incidence of SPMs was calculated using the Fine and Gray model considering “death without SPM” as a competitive event. Uni- and multivariate analyses were also conducted using Fine and Gray proportional hazard regression for competing risks, giving the incidences of: (1) SPMs overall; (2) NMSCs only; and (3) SPMs excluding NMSCs.
The following variables were separately tested at the initiaion of RUX therapy and for association with subsequent SPM:
- male gender
- age ≥ 65 years
- type of MF [primary (PMF) versus secondary (SMF)]
- dynamic international prognostic scoring system (DIPSS) risk for PMF (intermediate-1 versus interme diate-2/high)
- myelofibrosis secondary to polycythaemia vera and essential thrombocythaemia prognostic model (MYSEC PM) for post-polycythaemia vera/post-essential thrombocythaemia myelofibrosis PPV/PET-MF (low/intermediate-1 versus intermediate-2/high)
- thrombocytosis (platelet> 400 x 109/l)
- leukocytosis (white blood cell count (WBC) > 11.9 x 109/l)
- smoking habits
- neoplasms and/or major thrombosis diagnosed before ruxolitinib therapy
- use of HU only
- HU exposure ≥ 5 years
- use of alkylating agents
- need for sequential cytoreductive therapy
- use of interferons (IFN)
- use of low-dose (≤100 mg/day) aspirin
- RUX therapy ≥ 5 years
The univariate analyses were represented via a forest plot. In order to validate the use a parsimonious model for a limited number of events, only variables with a P value ≤ 0.05 in univariate analysis were then considered for multivariate analysis.
To avoid the issue of multicollinearity, and to remove highly correlated predictors from the model, collinearity amongst variables was determined by the Pearson correlation test. Variables associated with other factors in univariate analysis were also excluded from multivariate analysis.
A Cox regression model was employed to determine the impact of SPM diagnosis on RUX discontinuation relative to survival of the patient. Given that SPM is a time-dependent covariate, these results were calculated with survival curves obtained with the Simon–Makuch technique to consider any change in a patient’s covariate status in time.
Three years from ruxolitinib initiation was used as the landmark time point for the survival curves.
700 MF patients treated with RUX were included in this retrospective analysis.
The median follow-up from MF diagnosis was 5.4 years (range, 0.3–36.4), and the median RUX exposure was 2.1 years (range, 0.1–8.5). Thrombocytosis > 400 x 109/l at RUX start was present in 188 (26.9%) patients, and in 152 (82.9%) cases it was persistent from the time of diagnosis.
AT RUX initiation, 67 cohorts (9.6%) had a previous neoplasia. Pre-existing cancers were specifically noted to be: prostate (19.4%), NMSC (16.4%), breast (14.9%), gastrointestinal (10.4%), renal (9%), bladder (4.5%), osteosarcoma/melanoma/lung/uterus/ thyroid (3% each), neuroendocrine (1.4%) or hematological cancers (six cases, 9%).
The median time from neoplasm pre-RUX to RUX start was 5.7 years with a range of 0.1 to 35.6.
Before RUX start, a major thrombosis was observed in 65 (9.3%) patients.
445 patients who required cytoreductive therapy before ruxolitinib. 428 of these patients received HU for a median time of 4.2 years.
The median follow-up from RUX start to last contact was 2.9 years (range 0.1–8.4).
SPM from RUX start
Eighty out of the 700 cohort patients (11.4%) developed 87 SPMs, after a median time of 5.2 years (range 0.3–32.2) from MF diagnosis and 2.8 years from RUX start (range 0.1–7.3).
The cumulative incidence of SPMs was 2.6%, 4.9% and 18.8% at one, two and five years respectively.
The SPMs were NMSCs in 44 (50.6%) of the 87 cases (15 cases of basal cell carcinoma were recorded in 14 patients and 29 squamous cell skin cancers were registered in 24 patients). The other 42 (52.5%) patients had 43 neoplasms involving the urological area (14 cases, 32.6%), lungs (11 cases, 25.5%), the gastrointestinal tract (6 cases, 14.0%), melanoma (3 cases, 7.0%) and other areas (9 cases, 20.9%).
No lymphoproliferative neoplasms were encountered.
Risk factors for SPM
Using univariate analysis, male sex (P < 0.001) and platelets > 400 x 109/l at RUX start (P = 0.001) were associated with an increased incidence of SPMs and both maintained statistical significance in the multivariate analysis (HR: 2.37, 95%CI: 1.22–4.60, P = 0.01 and HR: 1.98, 95%CI: 1.10–4.60, P = 0.02, respectively).
Five-year cumulative incidence of SPMs was 25.5% in male versus 10.2% of female patients and 31.4% in patients with thrombocytosis versus 13.7% of patients with a lower platelet count, respectively.
Compared to female subjects, more males were smokers (P < 0.001), had primary MF (P = 0.018) and received HU therapy (P = 0.048) or other cytoreductive therapy before RUX start (P = 0.008).
The incidence of SPMs was not influenced by RUX starting dose.
Risk factors for NMSC, and for SPMs excluding NMSC
Subsequently, we performed a sub-analysis on NMSCs excluding other neoplasms and for SPMs excluding skin cancers.
Risk factors for NMSC alone were male sex (P = 0.02), age ≥ 65 (P = 0.03), secondary MF (P = 0.02), HU (P = 0.01) and RUX (P = 0.003) time-exposure ≥ 5 years in univariate analysis.
In multivariate analysis, male sex, prolonged HU and RUX exposures maintained statistical significance (HR: 3.14, 95%CI: 1. 24–7.92, P = 0.02; HR: 3.20, 95% CI: 1.17–8.75, P = 0.02; and HR: 2.93, 95%CI: 1.39–6.17, P = 0.005 respectively).
HU and RUX exposure were not found as a risk factors for other subtypes of cancer.
Ruxolitinib management after SPM
Twelve patients received an SPM diagnosis after a median time of 0.9 years (range, 0.1–4.4) after RUX discontinuation due to other causes.
Among the 75 cases in which SPMs developed while on RUX therapy, 23 (30.7%) patients abruptly discontinued RUX, four (5.3%) patients reduced RUX dosage because of the occurrence of anemia or thrombocytopenia during concomitant SPM treatment and 48 (64.0%) continued RUX with dose unchanged.
Overall, the diagnosis of a SPM was shown to be significantly associated with a four-fold increase of RUX discontinuation (HR: 4.0, 95%CI: 2.8–5.7, P < 0.001). Conversely, SPM treatment was not adjusted in any patients because of MF and/or RUX treatment.
Outcomes after SPM
A total of 2,287 person-years were accumulated, and 281 deaths occurred, with a mortality rate of 12.3 per 100 patient-years (95% CI: 10.9–13.8). SPMs represented the fourth most common cause of death (21 cases, 7.5%), after MF progression (26.3%), evolution into acute leukaemia (20.6%) and infections (14.9%).
NMSC were diagnosed in the early phase in 81% of cases, being the final cause of death of three out of 38 patients (7.9%).
SPM occurrence did influence MF overall outcome.
As evaluated by Cox regression for time-dependent variables, patients developing SPMs had an increased risk of death (HR 3.2, 95%CI: 2.3–4.5, P < 0.001).
Notably, the negative prognostic significance of a second cancer diagnosis was maintained also for NMSC only; NMSC diagnosis was associated with an almost twofold increased risk for death compared to patients with no SPM (HR: 1.89, 95%CI 1.14–3.14, P = 0.01).
As demonstration by this and other studies, secondary cancers in patients with existing neoplasia is of clinical concern. In contrast with conventional chemotherapy, the tyrosine kinase inhibitors are generally not associated with a significantly increased incidence of SPMs. However, RUX inhibits hyper-activated signal pathways that are not specific to cancer cells. This unfortunate non-specificity results in the inhibition of JAK1 which exerts immunomodulatory properties, likely compromising anti-cancer immune surveillance, and so predisposing patients to SPMs, particularly NSMCs.
In this study, SPMs occurred in around 10% of 700 MF patients treated with RUX, their incidence increased over time, correlated with higher RUX discontinuation, and represented the fourth cause of death. The proportion of patients who died because of secondary cancers (7.5%) was slightly higher than the data reported in other studies prior to RUX availability.
Among SPMs, NMSCs were the most frequent and were significantly associated with long-term exposure (≥5 years) to HU and RUX. This result is congruent with previous reports and suggests periodic skin screening is a reasonable precaution for patients who start RUX after a prolonged period of HU therapy. The dermal toxicity of HU, particularly in MPN patients, is known from previous research. For example, HU-exposed patients have been shown to have a two-fold higher risk of NMSC.
The association between RUX and NMSC has also been cited in several studies for MF patients as well as in patients with polycythemia vera.
Male sex was confirmed as a negative prognostic factor for all SPMs. Gender-based discrepancies have been observed in terms of incidence, response to therapies and prognosis in several cancers, possibly due to deferentially activated genetic/molecular patterns, immune system function, expression of sex hormones and drug metabolism. Males are indeed at higher risk than females for the vast majority of neoplasia, including but not limited to NMSC, urinary, lung and gastrointestinal tumors. The noted significant sex discrepancies highlighted the importance of considering both genders independently. Future data on RUX therapy in patients stratified by sex will help contribute to the development of personalized strategies for optimal therapy management.
This study is the first to note that male sex is associated with the development of secondary cancers in patients with MF, and with RUX therapy. Additionally, the diagnosis of NMSC did not cause RUX discontinuation in most cases, suggesting that treating hematologists felt that the risk of NMSC progression was lower than the risk of losing the clinical benefit of RUX therapy. Continuing RUX therapies resulted in very low toxicity in this study. Only four patients required dose reductions due to anemia and/or thrombocytopenia.
Besides gender, thrombocytosis and previous arterial thrombosis were correlated with higher risk of SPM, particularly after excluding NMSC. These associations are well known in general medicine.
Inflammation is a commonality of both arterial thrombosis and thrombocytosis. Interestingly, both factors were present for years in most patients prior to the start of the RUX. In fact, the median time between arterial thrombosis and RUX start was five years, and thrombocytosis was present from MPN diagnosis in most cases. Therefore, the underlying inflammatory process causing thrombocytosis and arterial events has persisted over time, creating the substrate favorable to the accumulation of genetic damages, from which second cancers may result. One could therefore suggest that the abnormal inflammatory activation (a hallmark of MF) could not only promote MF progression, but also lead to thrombosis and other cancers. As a result of these findings, it would be prudent to screen MF patients with RUX exposure and arterial thrombosis history for secondary cancers. This is, in fact, recommended by the International Society on Thrombosis and Haemostasis for patients presenting with unprovoked venous thromboembolism. Our observations may have other practical implications, suggesting careful skin screening for the diagnosis of early NMSC in all MF patients during RUX therapy, and particularly in those patients who have received prolonged exposure to HU.
In this study, researchers also found that SPMs reflected an overall greater risk for RUX discontinuation and a four-time decrease of life expectancy compared to unaffected MF patients. The high mortality associated with the second cancer is probably related not only to the biological aggressiveness of the concomitant neoplasia, but also to the decreased hematological surveillance and to the discontinuation of RUX therapy, which is known to be associated with severely reduced survival.
Based on these results, the previous history of a malignancy, or a diagnosis of SPM, should not generally preclude or reduce the use of RUX, which usage risk should be evaluated specifically for each patient.
This study lacked a control arm, and cannot determine to what extent RUX may increase the incidence of NMSC. However, it was observed that RUX exposure ≥ 5 years had a positive association with NMSC. Whether this is due to continued exposure risk with therapy in time, or to a real carcinogenic effect of RUX after prolonged administration, remains a question to be answered by long-term and prospective studies. In this study, the median exposure time to RUX was relatively short (2.9 years) and it cannot be excluded that the incidence of SPM (and NMSC) may increase if the observation period is extended.
We acknowledge that due to the retrospective nature of this study, issues regarding under/overreporting and misclassification of events may arise. Nonetheless, observational studies can provide to deeper insights on disease management and treatment complications by observing large patient populations over an extended period of time. We included a large cohort of RUX-treated MF patients who were observed in a long-term setting until death or data cut-off, and we collected detailed information regarding neoplasia sites, treatments and outcomes, all of which are difficult to derive from prospective studies.
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