Abstract
Introduction
The diagnosis of adult hematologic malignancies primarily originating in the bone marrow (BM) requires comprehensive evaluation. In many cases, a definitive diagnosis necessitates referring patients from peripheral healthcare centers to tertiary hospitals. This study aimed to analyze incidence patterns and age-specific trends of such malignancies over a decade at one national tertiary hospital in Indonesia.
Methods
A retrospective cross-sectional study was conducted using bone marrow aspiration (BMA) results from patients suspected of having primary BM hematologic malignancies. Procedures were performed in the Division of Hematology and Medical Oncology, Department of Internal Medicine, and analyses were conducted in the Department of Clinical Pathology at Sardjito Hospital between 2012 and 2022. Sex and age data were collected to calculate crude incidence rates (CIR), age-specific incidence rates (ASR), and age-standardized incidence rates (ASIR).
Result
A total of 3,144 cases were analyzed and the results showed that the incidence of myeloid lineage malignancies was higher than lymphoid, predominantly in males. ASR showed that Myeloproliferative Neoplasms (MPN) and Myelodysplastic Syndromes (MDS) increased with age. Acute Myeloid Leukemia (AML) remained stable in younger age groups but increased significantly in older adults. Acute Lymphoblastic Leukemia (ALL) was more common in younger individuals, particularly in the 20–24 age group. Meanwhile, the incidences of Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) increased with age. A linear regression analysis of incidence trends over the years showed no statistically significant trend.
Conclusion
This study provides essential epidemiological evidence on hematological malignancies of primary BM origin in Indonesia, showing the predominance of myeloid lineage malignancies and distinct age-related patterns. These findings may support age-targeted awareness, early detection strategies, and coordinated national efforts to address the growing burden of hematologic malignancies in adults.
Plain Language Summary
The diagnosis of adult hematologic malignancies primarily originating in the bone marrow (BM) requires comprehensive evaluation. In many cases, a definitive diagnosis necessitates referring patients from peripheral healthcare centers to tertiary hospitals. This study aimed to analyze incidence patterns and age-specific trends of the malignancies over a decade at one national tertiary hospital in Indonesia. A retrospective cross-sectional study was conducted using bone marrow aspiration (BMA) results from patients suspected of having primary BM hematologic malignancies. Procedures were performed in the Division of Hematology and Medical Oncology, Department of Internal Medicine, and analyses were conducted in the Department of Clinical Pathology at Sardjito Hospital between 2012 and 2022. Sex and age data were collected to calculate crude incidence rates (CIR), age-specific incidence rates (ASR), and age-standardized incidence rates (ASIR). As a result, a total of 3,144 cases were analyzed and the results showed that the incidence of myeloid lineage malignancies was higher than lymphoid, predominantly in males. ASR showed that Myeloproliferative Neoplasms (MPN) and Myelodysplastic Syndromes (MDS) increased with age. Acute Myeloid Leukemia (AML) remained stable in younger age groups but increased significantly in older adults. Acute Lymphoblastic Leukemia (ALL) was more common in younger individuals, particularly in the 20–24 age group. Meanwhile, the incidences of Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) increased with age. In conclusion, this study filled a major gap in the literature on primary bone marrow hematologic malignancies by providing essential epidemiological data on disease burden. Myeloid malignancies predominated and demonstrated distinct age-related incidence patterns.
Introduction
Hematologic malignancies of primary bone marrow origin comprise a heterogenous group of disorders that arise primarily from two main cell lineages, namely myeloid and lymphoid precursor cells. 1 Myeloid lineage malignancies include Myeloproliferative Neoplasms (MPN), Myelodysplastic Syndromes (MDS), overlapping MDS/MPN syndromes, and Acute Myeloid Leukemia (AML). Meanwhile, lymphoid lineage includes Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Multiple Myeloma (MM), along with other miscellaneous/less common subtypes.2,3 Each of these malignancies present distinct epidemiological patterns in terms of gender and age, leading to disease-specific clinical challenges.
Each disease, with distinct clinical features and symptom profiles, requires a comprehensive diagnostic method. This process typically commences with medical history taking, physical examination, and laboratory testing. Diagnosis then proceeds with gold-standard diagnostic procedures, including bone marrow aspiration (BMA) to obtain material for cytomorphology, immunohistochemistry, cytogenetic analysis, fusion gene detection, and other molecular and genetic assessments.
Indonesia has implemented a Universal Health Coverage (UHC) system through Jaminan Kesehatan Nasional (JKN) administered by Badan Penyelenggara Jaminan Sosial (BPJS) Kesehatan, aimed at providing equitable access to comprehensive healthcare for the entire population. This scheme incorporates a tiered referral system requiring patients to initially obtain care at first-level primary health facilities. Referral then proceeds systematically to secondary and tertiary facilities for advanced diagnostic and therapeutic services, optimizing resource use and continuity of care. 4 Due to the complexity and resource requirements of the diagnostic modalities for hematologic malignancies originating primarily in bone marrow, patients are often referred to tertiary facilities capable of fulfilling the necessary diagnostic standards. Despite the rising burden of hematologic malignancies globally, population-based data on primary bone marrow malignancies in Indonesia and Southeast Asia remain limited. 5 National cancer statistics are largely hospital-based, with limited diagnostic detail and infrequent reporting of subtype-specific, age-standardized incidence rates. By using eleven years of BMA data from a national tertiary referral center (Sardjito Hospital) and linking these cases to provincial population statistics, this study addresses this gap by providing crude, age-specific, and age-standardized incidence estimates for primary bone marrow malignancies, an area where previous studies have shown heterogeneous trends across populations.6-10
Materials and Methods
Study Design Area, and Period
This retrospective cross-sectional study was conducted at Sardjito Hospital, a national tertiary referral hospital in Indonesia, located in Yogyakarta Special Region (YSR) Province in the southern part of Central Java on Java Island, the most populous island in the country. It is a province with approximately 3.6–3.7 million inhabitants, compared with about 150 million on Java Island and roughly 270 million in Indonesia. The hospital’s adult hematology service received patients suspected of hematological malignancies through referrals from other hospitals. Most referrals originated in the province and surrounding areas, including southern part of Central Java, eastern part of West Java and western part of East Java provinces, with occasional referrals from provinces outside Java Island. The data collection period spanned from January 2012 to December 2022, during which the hospital served as the only national tertiary referral center for hematological malignancies in these areas. Therefore, our findings are likely to reflect the regional epidemiology rather than a narrow institutional subset.
Study Population and Data Collection Procedures
The study population included adult patients aged ≥18 years with suspected primary bone marrow-origin hematological malignancies. Diagnosis was established through BMA, followed by cytomorphological examination using Wright-Giemsa staining to evaluate marrow cellularity, blast percentage, lineage differentiation and maturation, myeloid-to-erythroid ratio, and dysplastic features. Cytochemical staining with periodic acid–Schiff (PAS) and Sudan Black B (SBB) was added to further support lineage characterization. Ancillary diagnostic modalities such as flow cytometry, immunohistochemistry, cytogenetic, or molecular testing were not routinely performed and were not included in this analysis. Diagnoses were therefore based on bone marrow cytomorphology and cytochemical staining and were subsequently assigned to the closest corresponding 2008 World Health Organization (WHO) diagnostic category. 11 Data were collected from all consecutive adult patients who were subjected to BMA procedure in the Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing/Sardjito Hospital, Yogyakarta, Indonesia. No a priori sample size calculation was performed; all eligible cases during the study period were included. Data from 2019-2022 were obtained from the electronic medical record system. Earlier data from 2012–2018 were extracted from hard-copy medical records, as these preceded the implementation of the electronic medical record system at the hospital.
Data collection for the study commenced on March 1st, 2023, and was completed on August 31st, 2023. The process began following the approval of ethical clearance (EC) on February 27th, 2023, and was finished before the EC expired. The EC was granted by the Institutional Review Board (IRB) of the Medical and Health Research Ethics Committee (MHREC) of the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, with the approval number of KE/FK/0315/EC/2023, ensuring that all research was conducted in accordance with relevant guidelines and regulations. The study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2024. The requirement for informed consent was waived due to the retrospective nature of the study using anonymized secondary data, as all patient details had been de-identified. Cases were classified into established disease categories according to lineage. Myeloid lineage included MPN, MDS, MDS/MPN, and AML. Lymphoid lineage comprised ALL, CLL, MM, and other mature lymphoid malignancies including rare subtypes such as hairy cell leukemia and prolymphocytic leukemia, grouped as other miscellaneous. All diagnoses were confirmed by board-certified clinical pathologists from the Department of Clinical Pathology and Laboratory Medicine in accordance with institutional protocols and World Health Organization (WHO) classification criteria.11,12
Data Analysis
In this study, data were analyzed descriptively using IBM SPSS Statistics 25. Means and percentages were adopted to describe the incidence, frequency, and proportion of variables for each type of hematologic malignancy. In addition to diagnosis, gender and age were included to analyze crude incidence rate (CIR), age-specific incidence rate (ASR), and age-standardized incidence rate (ASIR). CIR was derived by dividing the total malignancy cases by the average population of YSR province over the past decade from Statistics Indonesia/Badan Pusat Statistik(BPS Indonesia). 13 ASR was computed by dividing the new cases in each age cohort by the corresponding at-risk population in YSR province. To facilitate comparative analyses among populations with differing age demographics, ASIR was calculated using WHO standard population, which entailed adjusting the age-specific rates according to this standard. 14 The reporting of this study conforms to the STROBE guidelines. 15
Results
Sociodemographic Characteristics of the Study
The flow diagram illustrating the selection process of cases included in this study is shown in Figure 1A. Initially, 5,407 BMA records from adult patients performed between January 2012 and December 2022 were collected. Of these, 1,364 duplicate records were excluded, leaving 4,043 cases. A further 571 cases were excluded due to inadequate BMA material (n = 424) or incomplete reports (n = 147), resulting in 3,472 cases. Subsequently, 328 additional cases were excluded because of inconclusive diagnoses (n = 173), aplastic anemia (n = 86), autoimmune hemolytic anemia (AIHA) (n = 11), immune thrombocytopenia (ITP) (n = 27), normal marrow findings (n = 10), thalassemia (n = 3), lymphoma (n = 13), or first diagnosis before 18 years of age (n = 5). The final study cohort consisted of 3,144 adult cases. One hundred thirty-five cases from the 2012 cohort with missing age data were retained because they had been recorded in the adult hematology service database. The yearly distribution of cases during the study period is presented in Figure 1B. (A) Flow Diagram of case selection for adult primary bone marrow hematological malignancies included in the study (2012–2022). (B) Number of cases of primary bone marrow malignancies (2012 – 2022)
Baseline Characteristics of Study Population
MPN: Myeloproliferative Neoplasms; MDS: Myelodysplastic Syndromes; AML: Acute Myeloid Leukemia; ALL: Acute Lymphoblastic Leukemia; CLL: Chronic Lymphocytic Leukemia; MM: Multiple Myeloma.
Myeloid lineage malignancy was found in 72.68% (2,285/3,144) cases, while lymphoid lineage was only 27.32% (859/3,144). In myeloid lineage, MPN constituted 36.54% (835/2,285), MDS 31.60% (722/2,285), MDS/MPN 1.44% (33/2,285), and AML 30.42% (695/2,285). In lymphoid lineage, ALL was most prevalent in 33.18% (285/859), CLL in 16.53% (142/859), MM in 48.54% (417/859), and other miscellaneous in 1.75% (15/859).
Male-To-Female Ratio and Crude Incidence Rate by Type of Malignancy
Male-To-Female Ratio and Crude Incidence Rate by Type of Malignancy
Age-specific Incidence Rate of Hematologic Malignancies of Primary Bone Marrow Origin
Figure 2 shows ASR for various myeloid lineage hematological malignancies expressed per 100,000 people consecutively. ASR for MPN, MDS, AML, ALL, CLL, and MM exhibited variability across age ranges, reflecting the incidence of these diseases in the population. MPN started at an incidence rate of 0.32 in the 15-19 age group and increased to a peak of 5.75 in the 60-64 age group before declining to 3.00 in those aged >75. MDS showed a similar pattern, commencing at 0.50 in the 15-19 age group, peaking at 5.42 in the 65-69 age group, and then slightly decreasing to 3.65 in the oldest age group. AML incidence rate in adults showed a consistent increase with age, from 0.57 in the 15-19 age group to its highest at 4.63 in the range of 65-69, declining to 2.70 in the ≥75 age group. Furthermore, MDS/MPN incidence rates were considerably lower than the other categories, with the highest rate being 0.37 in the ≥75 age group. This pattern suggested a higher risk of myeloid disorders with advancing age, where the most significant increase was observed in the sixth and seventh decades of life. Age-specific incidence rate of myeloid-lineage primary bone marrow malignancies
Figure 3 shows ASR for various lymphoid lineage malignancies. ALL incidence rates were relatively higher in the younger age group (15-20 years), with a rate of 1.25. There was a relatively low ASR in adult age groups, with slight variations that did not show a clear trend with age. CLL showed an incidence rate of zero in the youngest age group and showed an increase after the 35-39 age group, with the incidence rate climbing significantly after the age of 60. In this case, the incidence rate peaked at 1.69 in the 60-64 age group, but slightly decreased in the oldest age group. MM incidence was absent in the youngest age groups, commenced at age 40, and reached a peak of 3.944 among patients aged 60 to 64 years. The miscellaneous category followed a varied pattern, with the highest incidence rate of 0.68 among individuals aged 70 to 74 years. In general, incidence rates of lymphoid malignancies increased with age, and the highest was observed in middle to older adulthood. Peak incidence occurred in the early second decade for ALL (ages 15–20) and in the seventh decade for CLL and MM (ages 65–69). Other lymphoid malignancies showed no distinct age-specific peak but showed the highest incidence in the eighth decade (ages 70–74), although at comparatively lower rates. Age-specific incidence rate of lymphoid-lineage primary bone marrow malignancies
Age-Standardized Incidence Rate of Hematologic Malignancies of Primary Bone Marrow Origin
Age-Standardized Incidence Rates by Subtype and Gender
Discussion
This study provides a comprehensive analysis of the incidence and distribution of hematological malignancies of primary bone marrow origin at a national tertiary referral hospital in Indonesia. Although the data originate from a single institution, they effectively encompass nearly all primary bone marrow hematologic malignancy diagnoses among YSR residents and are representative of the region’s broader epidemiological situation. The dataset represents an important institutional cohort contributing to national hematologic cancer epidemiology.
Myeloid lineage malignancies predominated over lymphoid malignancies, with distinct age- and sex-specific patterns. Collectively, these results provide valuable evidence to inform healthcare planning, policy development, and resource allocation.
The general ASIR of 6.86 is lower compared to developed countries but higher than other developing countries. High socio-demographic index (SDI) regions, such as Western Europe, 5 had an ASIR of 16.87 per 100,000 population for leukemia in 2019. In developing countries, the incidence of these malignancies tends to be lower but is influenced by various factors, such as socio-economic conditions, access to healthcare, and environment. 16 For example, in 2019, the primary bone marrow hematological malignancies incidence was found to be lower in regions, such as South Asia and Central Sub-Saharan Africa, with ASIR of 3.81 and 3.89 per 100,000 population, respectively. 5
Across the primary bone marrow hematological malignancies, myeloid lineage malignancies incidence overrides lymphoid malignancies.7,10 Approximately half of patients (47%) were 46 – 65 years old, suggesting a productive age. This result was consistent with the report of an 8-year study from India, that the peak was at the 51-60 years age group. 17 The male predominance observed in this study is also in concordance with global trends,2,6,7,10,17-20 ranging from 1.1 to 2.3. The exact reasons may vary depending on the specific type of malignancy. However, some studies suggest that genetic factors, hormonal differences, environmental exposure, and lifestyle factors play important roles.21-23
Compared with global data, the results of this study suggest distinct epidemiological patterns. CIR of MPN and MDS in the cohort appeared relatively higher and was comparable to a Spanish study reporting European ASIR of 5.14 per 100,000 for MPN, 4.71 for MDS, and 3.91 for AML. 24 However, the RARECARE project in Europe reported a higher crude incidence for AML (3.7 per 100,000) than for MPN (3.1 per 100,000). 25 A United Kingdom (UK) cohort also reported incidence rates of 5.4 per 100,000 for MPN, 3.7 for MDS, and 4.0 for AML, underscoring variability in the distribution of myeloid malignancies across populations. 26
In general, the incidence of MPN and MDS increased with age, consistent with the predominance in adults. The peak age range in the cohort (60–69 years) appeared younger than the reports in Western and Eastern populations, where the median age for MPN was 71.1 years in the UK and ≥75 years in Bahrain, and for MDS is 76.1 years and ≥75 years, respectively.10,26 This earlier age peak may suggest the presence of earlier genetic alterations or reflect the influence of population-specific factors, including genetic predisposition, epigenetic mechanisms, or occupational and environmental exposures relevant to Indonesian setting. However, this observation should be interpreted cautiously, given possible effects of referral bias, population age structure, and underdiagnosis in the elderly. AML showed a comparable peak age range (60–74 years).10,26 These patterns highlight the need to strengthen clinical awareness and early detection of myeloid malignancies in Indonesia, particularly among individuals entering late middle age.
Compared with Western countries, such as the UK (ASIR of 5.0), CLL appears less prevalent in the cohort and more comparable to rates reported in Eastern populations 10 (ASIR of 0.3). This difference may partly reflect underdiagnosis related to limited healthcare access and the lack of routine preventive medical check-ups in Indonesia, leading to fewer incidental detections and delayed diagnosis. Consequently, elderly with CLL may be underrepresented in hospital-based data, which could explain the younger peak age at diagnosis in the cohort (60–64 years) compared with developed countries, where CLL is most commonly diagnosed at ≥70 years.10,26 These results show the importance of strengthening primary care-based detection strategies, including opportunistic complete blood count screening and improved referral pathways, to facilitate earlier identification of indolent hematologic malignancies such as CLL.
The age distribution of MM in this study differed from global trends, which typically show a peak incidence in individuals aged over 70 years. However, the cohort showed higher incidence rates between 55 and 74 years, followed by a marked decrease after 75 years of age.10,26 A relatively younger age at diagnosis was also reported in several Asia-Pacific populations, including Japan, South Korea, China, and other East and Southeast Asian countries, where the median age at diagnosis was generally in the early to mid-60s.27-29 These differences show a combination of factors, including variations in life expectancy, genetic susceptibility, environmental exposures, and disparities in healthcare access and diagnostic practices. In settings with lower life expectancy and limited routine health screening, MM in the elderly may be underdiagnosed or underrepresented, leading to an apparently younger age distribution at diagnosis.
The incidence rate of ALL in this study was significantly lower compared to global averages of 1.1 - 1.6 per 100,000 people,10,26,30 particularly because ALL predominates in the pediatric population. Furthermore, the age distribution of ALL patients in Indonesia shows a bimodal pattern, with peaks in both childhood and later adulthood, diverging from global trends where a single peak in childhood is more common8,10,27.
The implementation of UHC in Indonesia has strengthened diagnostic and treatment capacity at secondary-level facilities, including hematology services, enabling more cases to be managed locally and reducing tertiary referrals. 4 In addition, COVID-19-related service disruptions, reporting delays, and temporary underutilization of care may have contributed. The decrease in case numbers, as shown in Figure 1, suggests a collective shift in referral patterns and service utilization rather than a decreased burden of hematologic malignancies.
The predominance of cases in the 46–65 year age group highlights the importance of increasing awareness and preventive strategies among middle-aged populations. Importantly, the occurrence of hematological malignancies during the economically productive age period imposes substantial social and economic burdens, including productivity loss and increased healthcare expenditure, underscoring the need for policies that support early detection, workplace health programs, and timely access to care.
Although this study provides valuable insights, several limitations should be acknowledged. The data were derived from a single national tertiary referral hospital and may not fully represent the epidemiological distribution of hematological malignancies across Indonesia. As a major referral center, this institution receives a disproportionately complex case mix, which introduces referral bias, particularly an overrepresentation of advanced, complicated, or diagnostically challenging cases. Regions without established referral pathways to the center may also be underrepresented, thereby limiting the geographic generalizability of the results. In addition, no formal a priori sample size calculation was performed; however, the cohort size is considered adequate for the descriptive objectives of this study. Second, diagnosis was based solely on cytomorphological and cytochemical evaluation without incorporation of ancillary techniques such as flow cytometry, immunophenotyping, cytogenetic, or molecular analyses. This may have led to potential misclassification or limited diagnostic precision, particularly for entities that require immunophenotypic or genetic confirmation. The lack of these advanced modalities also precluded more detailed subclassification according to current WHO/ICC criteria. 12 Nevertheless, these approaches reflect real-world diagnostic practices in many resource-limited settings which are increasingly accessible in many Indonesian tertiary hospitals. As such, this method enhances data comparability across centers and provides a practical foundation for future multi-center collaboration, including the development of a national hematologic malignancy registry and the integration of more advanced diagnostic modalities.
Conclusion
This study provides essential epidemiological evidence on hematological malignancies of primary bone marrow origin in Indonesia, showing the predominance of myeloid lineage malignancies and distinct age-related patterns. These findings may support age-targeted awareness, early detection strategies, and coordinated national efforts to address the growing burden of hematologic malignancies in adults.
Footnotes
Ethical Considerations
This study was approved by the Medical and Health Research Ethics Committee (MHREC) of the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada (approval number: KE/FK/0315/EC/2023, dated February 27th, 2023). All study procedures were conducted in accordance with relevant guidelines and regulations. The requirement for informed consent was waived due to the retrospective nature of the study using anonymized secondary data.
Authors’ Contribution
MSH conceptualized the study, supervised the work, and contributed to manuscript writing. TR contributed to the methodology, particularly the interpretation of bone marrow puncture results. KM and BS performed the statistical analysis. IT, WH, RG, and SO collected the data. KWT critically reviewed the manuscript. All authors read and approved the final manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is funded by DAMAS 2023 from the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The data used in this study are not publicly available due to ethical and privacy restrictions, but are available from the corresponding author upon reasonable request.
