Abstract
Background:
Ruxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials.
Methods:
We performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients.
Results:
140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between “MPN-focused” and “non-MPN-focused” physicians in certain areas.
Conclusion:
Physician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of “MPN-focused” and “non-MPN-focused” physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management.
Keywords: Ruxolitinib, Myelofibrosis, Management decisions, Physician survey
1. Background
Ruxolitinib is established treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) on the basis of its superiority to placebo or other treatments available to symptomatic MF patients as demonstrated in the COMFORTI and II randomized clinical trials [1,2].
Long-term follow up of the COMFORT studies has demonstrated that a large number of patients stop taking ruxolitinib. In COMFORT I, at a median follow up of 149 weeks, 77 of the 155 patients (49.7%) originally randomized to ruxolitinib and 57 (51.4%) of the 111 patients who had crossed over from placebo to ruxolitinib were still receiving ruxolitinib therapy In patients originally randomized to ruxolitinib, estimated discontinuation rates were 21% at year 1, 35% at year 2, and 51% at year 3. Reasons for discontinuation included disease progression (23.1%), adverse events (19.2%) and death (19.2%) [3]. In the recent final 5 year analysis of the COMFORT II study, 39 patients (26.7%) in the ruxolitinib arm and 11 of the 45 patients (24.4%) who crossed over from the best available therapy (BAT) arm to receive ruxolitinib completed 5 years of on-study treatment. Ruxolitinib discontinuation occurred because of adverse events (24.0%) and disease progression (21.9%) [4]. Registry [5] and observational studies [6,7] that have been conducted reveal a similar pattern of attrition with 10–29% of patients discontinuing ruxolitinib within one year and up to 50% of patients requiring dose reductions, particularly because of thrombocytopenia or anemia.
These data highlight the fact that the need for decision making regarding continued ruxolitinib administration is common and ongoing in the management of MF patients. Dose adjustments are frequently necessary to ameliorate side effects of the drug, particularly bone marrow suppression but this may lead to under-dosing and concomitant loss of clinical effect. Little is known about the way in which physicians employ current literature and clinical guidelines in the treatment of MF patients on ruxolitinib in routine practice. Therefore we performed this study to assess the way in which practicing hematologists currently manage ruxolitinib administration and dosing and how they employ other treatment options in a variety of common clinical scenarios encountered in the management of MF patients.
2. Methods
An online survey of physicians’ decisions regarding ruxolitinib treatment of MF patients in various clinical situations was conducted using SurveyMonkey©. The survey was distributed by email to practicing clinical hematologists in Europe, Israel, the United Kingdom and the United States. Responses were anonymous and were analyzed overall and by physician self-identification as having MPNs as a primary clinical interest or not. Physicians self-identifying as having MPN as a primary clinical interest are referred to as “MPN-focused” and those not having MPN as a primary clnical interest are termed “non-MPN focused” for the purposes of this study. Differences between “MPN-focused” and “non-MPN-focused” physicians were analyzed using the student’s T test and P < 0.05 was regarded as statistically significant. Data was also collected regarding country of practice, number of years in practice, number of MPN patients seen per week, use of structured versus non-structured symptom assessment tools and access to clinical trials.
3. Results
140 physicians responded to the survey. The characteristics of the respondents and features of their MPN-related practice are described in Table 1.
Table 1.
Characteristics of the responding physicians relating to their treatment of MPNs.
| MPNasprimary clinical interestN (%) | Yes 94 (67.2) |
No 46 (32.8) |
|||
| MPN patients seen per week N (%) | < 10 58 (41.4) |
10–20 44 (31.5) |
> 20 38 (27.1) |
||
| Years in practice N (%) | < 10 32 (22.8) |
10–20 54 (38.6) |
> 20 54 (38.6) |
||
| Location of practice N (%) | Europe 69 |
Israel 32 |
United Kingdom 18 |
United States 18 |
Other 5 |
| Method of symptom scoring used routinely N (%) | MPN TSS 47 (33.6) |
Non-MPN structured form 1 (0.7) |
General symptoms elicited* 27 (19.3) |
MPN symptoms elicited* 65 (46.4) |
|
| Clinical trial available to physician N (%) | Yes 107 (76.4) |
No 33 (23.6) |
No structured form used.
94(67%) physicians considered MPNs to be their primary area of clinical interest (referred to as “MPN-focused”) compared to 46(33%) who did not (referred to as “non-MPN-focused”). 58 (41%) physicians saw fewer than 10 MPN patients per week, 44(32%) saw 10–20 and 38 (27%) saw more than 20 MPN patients per week. MPN as a primary clinical interest correlated with seeing more than 20 MPN patients per week. 31 (23%) physicians had been in practice for fewer than 10 years, 54 (39%) for 10–20 years and 53 (38%) for more than 20 years. There was no correlation with years in practice and MPN as a primary interest or with the number of MPN patients seen weekly. Concerning symptoms, 46 (34%) physicians used the MPN10 symptom scoring system, 1 (0.7%) used another structured form to elicit patient symptoms while 65 (46%) elicited MPN specific symptoms from patients and 27 (19.3%) elicited only general symptoms from MPN patients. There was a correlation between MPN as a primary clinical interest and use of the MPN10 score.
106 (76%) physicians were able to enroll patients on clinical trials while 34 (34%) were not. Those with a primary interest in MPNs were more likely to have access to clinical trials.69 (49%) physicians practiced in Europe, 32 (22%) in Israel, 18 (13%) each in the United Kingdom and the United States and 5 (3%) in other countries.
The survey questions and the responses received from the entire cohort of physicians are shown in Appendix 1 in Supplementary material. The “MPN-focused” versus “non-MPN-focused” physician responses are shown in Appendix 2 in Supplementary material.
Ten clinical vignettes were constructed to determine physicians’ practices regarding ruxolitinib treatment in MF patients with anemia (cases 1 and 3), thrombocytopenia (cases 2, 4 and 5), patient frailty (case 6), infection (case 9) and treatment failure (cases 7, 8 and 10).
4. Anemia
When ruxolitinib20 mg twice daily resulted in the development of significant anemia early in the course of therapy, 40% of physicians elected to continue treatment at the same dose and provide transfusion support only if the anemia is symptomatic, 26% chose to continue with the same dose and support with erythropoietin and 21% reduced the dose to 10 mg twice daily. There were no differences between “MPN-focused” and “non-MPN-focused” physicians.
When anemia preceded ruxolitinib initiation, 30% of physicians began treatment with 20 mg twice daily while 47% began at 10 mg twice daily and 15% at 5 mg twice daily. In this setting more “non-MPN-focused” physicians began treatment with ruxolitinb 10 mg twice daily (52.2%) than did “MPN-focused” physicians (44%), P < 0.05.
5. Thrombocytopenia
In a patient developing worsening thrombocytopenia on ruxolitinib that was dose-adjusted aprioiri for baseline mild thrombocytopenia, 27% of physicians maintained the starting dose of 15 mg twice daily while 44.5% reduced to 10 mg and 28% to 5 mg twice daily.
When a patient with moderate thrombocytopenia (80 000/μL) is treated initially, 12% of physicians would use full dose ruxolitinib 20 mg twice daily and monitor platelet counts closely, while 45% would start with 10 mg and 40% with 5 mg twice daily, and titrate the dose upwards if the platelet count did not drop further. In this setting, “MPN-focused” physicians were more likely to be more moderate in their dose-reduction of ruxolitinib and chose to start treatment with 10 mg rather than 5 mg twice daily than “non-MPN-focused” physicians who tended to prefer the lower dose (P < 0.05).
In a patient treated with ruxolitinib20 mg twice daily and aspirin in whom moderate thrombocytopenia (55 000/μL) and clinically significant but non-major hemorrhage (epistaxis requiring intervention) developed, nearly all physicians would reduce the dose of ruxolitinib but to varying degrees: 27% of physicians to 15 mg, 34% to 10 mg and 31% to 5 mg twice daily. Only 5% would stop the medication. Regarding concomitant aspirin use, 54% would stop this drug but 46% would continue. In this instance too, “MPN-focused” physicians were more tolerant of worsening thrombocytopenia and mild bleeding than were “non-MPN-focused” physicians and continued ruxolitinib 20 mg twice daily or reduced to 10 mg rather than 5 mg twice daily than did “non-MPN-focused” physicians (P < 0.05).
6. Frailty
When treating an older MF patient with profound weight loss and poor performance status, 34% of physicians would begin ruxolitinib at 20 mg twice daily while 58% would choose a lower dose: 38%–10 mg and 20%–5 mg twice daily. 7% of physicians would consider such a patient ineligible for ruxolitinib. There were no differences between “MPN-focused” and “non-MPN-focused” physicians.
7. Infection
When dermatomal zoster developed in a patient on ruxolitinib all physicians prescribed a course of valacyclovir. 69% of physicians elected to continue treatment uninterrupted while 31% discontinued the ruxolitinib until resolution of the infection. None considered this complication an indication for permanent ruxolitinib discontinuation. There were no differences between “MPN-focused” and “non-MPN-focused” physicians.
Zoster prophylaxis was routinely administered by 16% of physicians at the time of ruxolitinib initiation, but not by the remaining 84%. Zoster prophylaxis after previous infection was more likely to be used by “MPN-focused” than “non-MPN-focused” physicians (P < 0.05).
8. Treatment failure
When a patient previously failing hydroxyurea and now on ruxolitinib 10 mg twice daily because of headache associated with 20 mg twice daily has no clinical response, 69% of physicians opted for enrollment on a clinical trial. 30% would increase the dose to 20 mg twice daily despite severe headaches, 20% would add interferon to the current ruxolinib at the current dose, 20% would perform splenic irradiation, 19% would replace ruxolitinib with interferon and 10% would perform splenectomy.
Failure of spleen response to ruxolitinib 20 mg twice daily resulted in 40% of physicians choosing enrolment on a clinical trial, 23% increasing the dose to 25 mg twice daily, 12% stopping ruxolitinib and starting an alternate drug such as hydroxyurea, 11% adding hydroxyurea to ruxolitinib and 3% recommending splenectomy.
In the case of a patient losing a spleen response but maintaining a symptom response to ruxolitinib 25 mg twice a day, 56% of physicians continued treatment, 25% added hydroxyurea or interferon, 11% recommended a “drug holiday” while few physicians recommended: hydroxyurea or interferon instead of ruxolitinib, splenectomy or splenic irradiation.
“MPN-focused” physicians were more likely to enroll patients failing ruxolitinib treatment on a clinical trial than were “non-MPN-focused” physicians (P < 0.05).
9. Discussion
Ruxolitinib is the first agent licensed specifically for the treatment of MPN-associated MF. Two large randomized clinical trials demonstrated its superiority compared to best available therapy or placebo for symptom control and amelioration of splenomegaly [1,2]. However, many patients stop taking the drug because of intolerance or lack of efficacy. Long term follow up of the COMFORT studies and observational studies conducted in the setting of routine clinical practice demonstrate an attrition rate of up to 50% [3–7]. These data have called into question the true value of ruxolitinib as a drug that offers persistent symptomatic improvement in MF patients. In fact a recent Cochrane review concluded that ruxolitinib fails to meet the standard for long-term symptom and spleen control [8]. This together with differing recommendations for ruxolitinib treatment published by different professional organizations [9–11] and licensing bodies [12] prompted a recent effort by a panel of hematologists with acknowledged expertise in MPNs from the European Leukemia Network and the Italian Society of Hematology (ELN-SIE) to provide guidance regarding which MF patients should receive ruxolitinib [13]. Using the GRADE system with its evidence-based derivation they concluded that ruxolitinib is strongly recommended for improving symptomatic or severe (palpable > 15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. They also highly recommended ruxolitinib for improving systemic symptoms in patients with an MPN10 score > 44, refractory severe itching, unintended weight loss or unexplained fever.
The most prominent finding in this physician survey of practice patterns was the marked heterogeneity of approaches to commonly encountered issues in the area of ruxolitinib treatment for MF. Findings that were of particular interest included the relatively low use of an MPN-specific symptom scoring system among only one-third of the physicians (Table 1) and tolerance for moderate thrombocytopenia with dose adjustments being less than recommended among more than half of the physicians (Appendix 1, Cases 4 and 5 in the Supplementary material).
Practice variability was evident among both “MPN-focused” and “non-MPN-focused” physicians. We polled physicians’ practice patterns regarding initiating treatment in the face of thrombocytopenia or anemia and their approach to management when these commonly encountered hematologic toxicities occur or worsen on treatment. We evaluated physicians approach to ruxolitinib treatment in frail patients and also explored physicians’ approaches to primary resistance to ruxolitinib or loss of spleen or symptom response while on treatment. Finally we examined the rarer but clinically significant complication of viral reactivation evidenced by herpes zoster infection while on ruxolitinib. Our results show that regarding the common problems of anemia or thrombocytopenia encountered in MF patients on ruxolitinib, there was little consensus regarding dose adjustment. Interestingly, “MPN-focused” physicians tended to be more aggressive in their treatment with a greater tolerance for lower blood counts and were prepared to administer doses that were higher than those recommended by the manufacturer. In contrast, “non-MPN-focused” physicians tended to prescribe lower than recommended doses in certain cases of anemia. These patterns may suggest that greater experience with use of ruxolitinib may allow for variance from recommended practice, but the safety of such an approach is uncertain and should be formally documented before being considered a standard of care. In contrast it appears that there is an educational opportunity regarding maintaining higher doses of ruxolitinib in cases of anemia which could be explored among “non-MPN-focused” physicians.
Regarding frail patients including elderly patients (older than 80 years old) or patients with significant comorbidities, the ELN-SIE panel [13] recommended avoidance of this drug in such patients, until favorable evidence is available. Our results demonstrated that most physicians did recommended ruxolitinib treatment to this patient population, but mostly in reduced initial doses. Also in this scenario, “MPN-focused” physicians tended to prescribe higher doses of ruxolitnib.
Refractoriness to ruxolitinib treatment or loss of response was handled variably with treatment decisions ranging from drug treatment with hydroxyurea or interferon to splenic irradiation or splenectomy in a significant minority of physicians. Importantly, enrollment on a clinical trial was the most frequent option chosen, particularly by “MPN-focused” physicians. Here too we have identified areas in which practice may be improved: splenic irradiation and splenectomy are both procedures which should be probably performed very infrequently because of their lack of long term efficacy and because of the significant toxicity with which they are associated [14]. Furthermore, given the lack of effective treatment for highly symptomatic MF patients after failing ruxolitinib, novel agents are urgently needed and the ability to enroll patients on clinical trials should therefore be a priority for physicians [15].
Our study has a number of important limitations. First, the number of physicians responding to our poll was relatively small and may not be representative of hematologists treating MF patients. Furthermore, the limited sample size did not permit extensive statistical analysis. In addition, respondents to our survey emanated from relatively limited geographic locations and as such it cannot be regarded as being truly international. Finally, the responses that we obtained pertained to clinical vignettes and may not reflect decisions that these physicians make when actually treating patients.
Despite these concerns, this study to the best of our knowledge provides the first insight into physician opinions and attitudes regarding MF treatment decisions in the ruxolitinib era. The variable natural history and clinical presentation of this complex disease coupled with the introduction of a new drug has generated numerous treatment decisions not heretofore encountered. This reality creates both opportunities and challenges to optimize the care of MF patients.
Supplementary Material
Acknowledgement
The authors wish to acknowledge all their colleagues who contributed to this study by completing the online survey.
Footnotes
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.leukres.2017.08.002.
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