Abstract
Introduction
BCR-ABL1 negative classical Myeloproliferative neoplasms (MPNs), a group of clonal proliferation of hematological precursors, encompass three distinct clinical subsets, namely, polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). 1 PMF is a rare disease with an annual incidence rate of 0.47 per 100,000 population as reported by a meta-analysis of 12 studies which were highly heterogenous. 1 MF, characterized by myeloid cell hyperproliferation, marrow fibrosis, and constitutional symptoms, can arise de novo (primary MF) or occur in those with antecedent PV or ET (secondary MF).2,3
Sarawak, the largest state in Malaysia, has a very diverse population where close to 3 million people from 26 ethnic groups living on the Borneo Island, with the Dayaks accounting for 40%, Chinese and Malay a quarter each, and the remaining by the other minority groups.4,5 Global epidemiological studies on MPNs remain scarce. To the extent of our knowledge, only one study reported the epidemiology and clinical characteristics of MPNs in Malaysia. 6 There is currently no published data reporting the demographics and outcome of myelofibrosis (MF) patients in Sarawak, Malaysia. We hope this study would show the real-world data of myelofibrosis in our stateto gage the clinical performance of our management model and allow forward planning.
Materials and methods
This non-interventional, retrospective study was conducted in four fully funded government hospitals in Sarawak, namely, Sarawak General Hospital, which is a tertiary referral hospital; Sibu Hospital, Bintulu Hospital, and Miri Hospital which are secondary referral hospitals. All primary and secondary MF patients who met the World Health Organization 2016 diagnostic criteria, aged 18 years old or older at the time of diagnosis, and diagnosed between January 2001 and 31 December 2021, were included. Patients with incomplete diagnostic criteria of MF or diagnosed with other MPNs subtypes were excluded. Due to the descriptive nature of the study, no formal justification was provided to estimate the minimum number of sample size required. All eligible patients fulfilling the inclusion and exclusion criteria were included.
The primary objective was to determine the disease evolution of myelofibrosis patients by reporting the annual incidence of MF cases in Sarawak. The secondary objectives were to: (1) determine the prevalence of MF cases over the general population; (2) study the demographics and clinical characteristics; (3) to describe the treatment pattern and outcomes of MF patients; and (4) to determine the overall survival (OS) by risk category.
Secondary data retrieved from medical records were collected in English using a standardized case report form, quality checked, and reviewed. Demographic data collected included age at diagnosis, gender, and ethnicity. Clinical data pertaining to MF comprised the type of MF, performance status, medical comorbidities, constitutional symptoms, spleen size, MPN symptoms, transfusion history, hematological parameters, marrow fibrosis grading, mutation type, karyotype, types of treatment, and outcome. A data-derived Dynamic International Prognostic Scoring System (DIPSS) plus risk categorization 7 was determined for all patients at the time of diagnosis.
Statistical analyses
Categorical variables (nominal or ordinal) were reported as frequency and percentage; continuous variables were presented as median and range. Chi-square test was used for comparing categorical variables, and Mann–Whitney U test and Analysis of Variances were used to compare the continuous variables. OS is the time from date of MF diagnosis to death due to any cause. Patients still alive at data collection were censored on the date of last follow-up. OS was analyzed by Kaplan–Meier methods and log-rank test was used to test for survival difference between groups. Univariate and multivariate Cox regression were fitted for OS to generate hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were conducted using RStudio of version 1.1.456 Posit (Public Benefit Corporation, Boston, MA, USA) and p-value < 0.05 was considered statistically significant.
Results
A total of 63 patients (male 31; male-to-female ratio 1:1.03) with MF were identified—47 (74.6%) primary MF and 16 (25.4%) secondary MF. Eleven had antecedent PV, whereas five transformed from ET.
The incidence of myelofibrosis from 2001 to 2021 in Sarawak is shown in Table 1. The combined annual incidence rate was 0.182 per 100,000 population. The period prevalence per 100,000 population over the entire study duration was 2.502.
Incidence of myelofibrosis in Sarawak, Malaysia from 2001 to 2021.
No new cases for the years 2001–2004, 2006–2008, and in 2010.
Data on Sarawak population per year was derived from Department of Statistics Malaysia. [cited June 2022]. Available from: https://www.dosm.gov.my/v1/index.php?r=column/cone&menu_id=clJnWTlTbWFHdmUwbmtSTE1EQStFZz09#.
The median age for overall study population was 59.0 years old (33.0–93.0). Majority had high-risk (34/63 (54.0%)) and intermediate-2 risk disease (19/63 (30.2%)). JAK2V617F mutation was identified in 52 patients (82.5%), followed by CALR mutation in 6 (9.5%) and negative for both mutations in 5 (7.9%). Forty-five (71.2%) patients had baseline symptom assessment using MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) with fatigue being reported in 77.8% (35/45), followed by early satiety (44.4% (20/45)), and weight loss (40.0% (18/45)). The severity of each symptom was not captured in the medical records. Demographic and clinical characteristics of these individuals, categorized using DIPSS+ risk groups, were shown in Table 2.
Demographic and clinical characteristics of patients with myelofibrosis categorized using DIPSS+ risk groups.
DIPSS+: Dynamic International Prognostic Scoring System Plus; MF: Myelofibrosis; MPN: Myeloproliferative Neoplasms.
While there were no absolute patterns to show a clear relationship between various biomarkers and duration of treatment or risk categories, better improvements were generally observed in low to intermediate-1 DIPSS+ risk groups for MPN assessment score and spleen size (Table 3). Comparing the hemoglobin trend over different DIPSS+ risk groups at baseline, patients with low and intermediate risks had higher hemoglobin level than high-risk group (p < 0.001).
Summary of change in certain biomarkers of patients with myelofibrosis stratified by DIPSS+ risk groups.
Statistics presented are the mean (standard deviation).
DIPSS+: Dynamic International Prognostic Scoring System Plus; MPN: Myeloproliferative Neoplasms.
Sankey plot of treatment pattern switching from first to second line for MF patients was shown in Figure 1. Hydroxyurea was used as first-line therapy in two-thirds of our patients—41/63 (65.1%), followed by interferon (8/63 (12.7%)), and ruxolitinib (4/63 (6.3%)). Out of 46 patients who received second-line therapy, 18 (39.1%) were switched to ruxolitinib and 9 (19.6%) interferon. Ruxolitinib was used as third-line therapy in five patients. Only one patient each underwent splenectomy and allogeneic hematopoietic stem cell transplant (HSCT), respectively, and both patients had high-risk disease.
Sankey plot of treatment pattern switching from first- to second-line therapy for myelofibrosis patients.
Hydroxyurea intolerance was reported in 4/41 (9.8%), and hydroxyurea resistance in 9/41 (22.0%). Four out of eight patients on first-line interferon were unable to tolerate due to its associated side effects, including flu-like syndrome, myalgia, and fatigue. Almost all patients tolerated ruxolitinib well, except one had both grade II upper respiratory tract and herpes zoster infections which were suspected to be drug related. The patient recovered well from these adverse events.
The median survival for overall patients was 6.8 years (Figure 2). Among low, intermediate-1 and intermediate-2 risk patients, the median 5-year survival had not been reached, whereas the median survival among high-risk patients was 4.88 years (p = 0.0054, log-rank test; Figure 3). At the time of data analysis, 24 (38.1%) had died, with the majority dying due to infection (11/24 (45.8%)) and disease progression or leukemic transformation (10/24 (41.7%)). Two succumbed to Coronavirus disease (COVID-19) and one to an unknown cause.
Kaplan–Meier plot of overall survival for myelofibrosis patients.
Kaplan–Meier plot of overall survival for myelofibrosis patients by categorized DIPSS+ risk groups.
The use of ruxolitinib in myelofibrosis patients showed a better overall 5-year survival compared to no ruxolitinib arm, but the difference was not statistically significant (p = 0.34, log-rank test; Figure 4).
Kaplan-Meier plot of overall 5-year survival for myelofibrosis patients by initiation status of ruxolitinib in any course.
In the overall cohort, after adjusting for confounders, performance status and DIPSS+ risk category at time of MF diagnosis were identified as independent risk factors for mortality. Patients who had good performance status had lower hazard of death than patients who had poor performance status (HR (95% CI): 0.06 (0.013–0.239), p < 0.001). Patients with intermediate risk disease had better OS compared to those in high-risk category (HR (95% CI): 0.24 (0.082–0.695), p = 0.009).
Discussion
Majority of our study patients were of higher disease risks at diagnosis. This might be explained by late presentation and diagnosis, as well as low awareness of the disease among clinicians. This phenomenon is not only observed in myelofibrosis but is also consistent across all cancer types, like lung cancer, in our region. 8 The prevalence and incidence of MF in our study were derived using the number of patients visiting the corresponding hospitals in our state. Patient refusal to undergo bone marrow procedure is one of the hindrances to the diagnosis of MF. Our study only included those with available marrow findings. These may underestimate the actual values, resulting in lower prevalence and incidence rate as compared to those reported by other studies.1,9
The median age for our study population was slightly younger (59 years old) when compared to the data reported in the literature.10,11 In contrast, our results were in parallel with earlier studies published from Germany and Sweden, where the median ages reported were 57 and 55 years, respectively.12,13 No gender disparity was found in our cohort, in contrast to the other studies which reported male preponderance among MF patients.10,11 Despite the known high prevalence of disease-associated symptom burden in MF, symptoms particularly regarding the severity were poorly documented in our cohort, highlighting the importance of monitoring symptom burden using the MPN10 scoring tool in our routine clinical practice. Patients with MF frequently present with a variety of symptoms that negatively affect their quality of life (QoL). The measurement of the symptom burden is the cornerstone in the management of MF patients as well as in the evaluation of patients’ perception of how these symptoms interfere with their QoL and productivity. 14
Treatment recommendations for MF should be guided by patient risk stratification. However, our results show that hydroxyurea remains the most frequently used therapy in MF despite studies showing lower effectiveness than that of ruxolitinib.15,16 Only a minority of our cohort (four patients) were commenced on ruxolitinib as first-line treatment, emphasizing the fact that majority, including those having a significant symptom burden, were not accessible to therapies which may improve their disease control. This might be attributed to several limiting factors, including treatment cost and availability, healthcare policy, insurance coverage, and others. In addition, our cohort also highlights that ruxolitinib was mostly chosen as second-line therapy. Our treatment pattern is in accordance with the real-world practice in the United Kingdom. 17 It is also noteworthy to state that there are increasing clinical benefits for the early use of ruxolitinib which would be an ideal approach if resources permit. 18 Ruxolitinib has been shown to provide OS benefits in recent real-world evidence data. 19 It was also reported that earlier commencement of ruxolitinib in MF improves muscle mass. 20
Despite the fact that the majority of our cohort had high-risk disease (54.0%), only one patient underwent allogeneic HSCT. The plausible explanation for low levels of transplant referral includes various considerations for HSCT, such as patient age, insurance coverage, donor availability, financial constraint, and challenging logistic issue. Sarawak, located on the Borneo Island in the eastern part of Malaysia, has no accessibility to transplant facilities. Patients need to travel by air, across the South China Sea, to a transplant center in another state in Western part of the country. This highlights the need to set up a transplant unit in our state, despite the hurdles and challenges that may come along the way of embarking on this ambitious project.
Our study has several limitations. As a retrospective analysis of patient medical records, the data collected represent a convenience sample that may not be generalizable to all patients treated for MF. The data may be subject to recall bias, data incompleteness, or other unknown confounding variables. Underreporting and late reporting may have introduced bias. There is a rising incidence of the disease over time with stable rates from 2014 onward, suggesting a potential selection bias or improvement in diagnostic approach. It is possible that some patients had secondary MF. If MF was diagnosed late in disease progression, an antecedent PV or ET may have been missed. There were no data on MPL mutation and next generation sequencing resulting in incompleteness of the mutational and karyotypic analysis of our cohort. The sample size of this study was too small to generate enough power to show statistical significance, clinical relevance, and assess correlations, emphasizing the need of a nationwide registry to capture more data.
Conclusion
In conclusion, this registry is of paramount importance in terms of providing a real-world overview of MF patients in our state and highlighting key insight into the unmet clinical need. Prospective studies are warranted to further assess the disease spectrum, and comparative clinical outcomes between various treatments and novel molecular tools should be incorporated.
Footnotes
Acknowledgements
The authors would like to thank the Director General of Health Malaysia for the permission to publish this paper.
Author contribution
ASOT, TSL, QYW, XYT, CTK, KYN, EKJT, and LPC designed the study, analyzed the data, and participated in the interpretation of the data, as well as drafting and revising of the article. All authors read and approved the final article.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The SaMy study was supported by Novartis Corporation via Research Collaboration. The authors declare that they have no conflict of interests.
Ethical approval
Ethical approval and clearance for this study was obtained from the Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia with registered ID NMRR-20-2285-56865.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent
Informed consent was not sought for the present study because there are no human subjects in this article and informed consent is not applicable. This point has been included in the study protocol submitted to MREC for ethical approval. This is an observational study utilizing retrospective, anonymized data owned by respective institution. Hence, waiver number is not applicable.
Trial registration
This study was not registered in clincialtrials.gov, as it is not an Applicable Clinical Trial, and therefore registration in clinicaltrials.gov is not required based on food and drug adminstration regulations.
This study has been registered with the National Medical Research Register (NMRR) with NMRR ID NMRR-20-2285-56865, as per local Malaysia requirements. NMRR is under the purview of National Institutes of Health, Ministry of Health, Malaysia.