Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study

PURPOSE Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. METHODS This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). RESULTS Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. CONCLUSION The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.


INTRODUCTION
Hematologic malignancies (HMs) originate from uncontrolled growth of hematopoietic and lymphoid tissues. These biologically and clinically heterogeneous disorders account for 6.5% of all cancers around the world, including approximately 9.0% in the United States and Europe. 1,2 Less is known about HM epidemiology in Latin America (Central and South America). The region has witnessed a considerable increase in the amount of hematology and oncology research; however, most of the contributions were observed in just a few countries (Brazil, Argentina, Mexico, Peru, Chile, and Uruguay). 3 In the multinational CONCORD program, which estimates survival from cancer in 1.9 million adults from 101 population-based cancer registries in 31 countries on 5 continents, only 2 of the participating countries were located in Latin America. 4 Moreover, according to the WHO, only 8% of Latin American populations are covered by cancer registries. 5 Real-world data on HMs in Latin America are needed to inform decisions about patient care and health policy. The past 15 years have brought paradigm shifts in diagnosis, staging, and treatment of HMs around the world, but progress in Latin America and the suitability (and potential effects) of new therapies for its residents are largely unknown. [6][7][8][9][10][11][12][13] The primary aim of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns in individuals with diagnoses of multiple myeloma (MM), chronic lymphocytic leukemia (CLL), or non-Hodgkin lymphoma (NHL) managed at oncology (tertiary care) hospitals in Latin American countries.

METHODS
In this multicenter, observational study, the medical records of Latin American patients with CLL, MM, or NHL were retrospectively reviewed (ClinicalTrials.gov identifier: NCT02559583). Adults with HMs were studied at 30 oncology specialty hospitals in 7 countries: Argentina (4 private, 1 public setting), Brazil (1 private, 8 public settings), Chile (1 public setting), Colombia (5 private settings), Mexico (1 private, 5 public settings), Panama (1 private, 2 public settings), and Guatemala (1 public setting). The hospitals were selected based on their experience in providing clinical treatment to patients with CLL, MM, or NHL; geographical representation; the type of practice; interest in participating in the study; and fulfillment of the study requirements. All study sites were eligible to include all 3 types of cancer.
Patient population inclusion criteria were incident or prevalent CLL, MM, or NHL diagnosed between January 1, 2006, and December 31, 2015; age ≥ 18 years at the time of first observed diagnosis of these HMs (whether incident or prevalent); ≥ 1 year of patient data after first observed diagnosis (except in the event of patient death within 1 year of being diagnosed); and ability and willingness to provide informed consent (except if a waiver of informed consent was obtained). There were no exclusion criteria.
The study was conducted under the Guidelines for Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology, the Declaration of Helsinki and its amendments, and any applicable national guidelines. Each study was approved by its local ethics committee and followed local country requirements (Brazil, approval by central ethics committee; Colombia, notification to Instituto Nacional de Vigilancia de Medicamentos y Alimentos; Argentina, approval by Direccion Nacional de Protección de Datos Personales; Mexico, approval by Secretaria de Salud/COFEPRIS, Comisión Nacional de Investigación Cientificas; and Guatemala, notification to Ministerio de Salud Publica).
Each study site selected and prepared medical records for chart abstractors to review, and the principal investigator provided clarification in cases of doubt. The study employed chart abstractors with previous experience in performing medical record reviews, and the chart abstractors were centrally trained by Janssen Cilag personnel on the electronic data capture system, study protocol, and how to complete the electronic case report forms (CRFs). The data fields, such as laboratory results, diagnosis specification, and other clinical criteria in the CRFs, had predefined ranges in clickable fields as opposed to free-text fields. This was designed to ensure that the abstractor looked only for the required information in the medical chart and selected the field that contained the specific range in the CRF where the data fit. Each trained chart abstractor signed a training form to document training module completed and date of training. All training materials and records were available for review, and future chart abstractors were required to undergo the same training.under Source document verification visits CONTEXT Key Objective Despite improved assessment and management of multiple myeloma, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) around the world, there is a paucity of high-quality, real-world data on these diseases in Latin America. The aim of the HOLA study is to investigate patient and treatment characteristics to understand the unmet needs in cancer care in Latin America. Knowledge Generated More than 5,000 patients were included from 7 Latin American countries, with the median age at diagnosis being slightly different from other regions' reports (range, 57 years in patients with NHL to 67 years in patients with CLL). Most patients had comorbid conditions, and there was considerable regional heterogeneity in characteristics related to both patients and their management. Relevance Findings from this study can fill an important gap for physicians, patients, and health authorities in Latin America for the management of hematologic malignancies and can be used to understand the disease landscape in this region for further improvement of patient care.
were performed at selected sites, which represented 60% of all study sites.

Hematologic Malignancies in Latin America
Journal of Global Oncology with a median follow-up of 2.2 years (range, , 0.1-12.1 years). One third of the patients with MM (506; 33.3%) died during the observation period (range, 18.4% in Panama/Guatemala to 54.4% in Brazil; Table 1). The median age at diagnosis was 61 years (range, 23-91 years). The most frequent age categories were 60 to , 70 years (31.1%) and 50 to , 60 years (28.3%). There was a slight predominance of males (50.7%) over females (49.3%), and the sex balance varied across regions ( Table 2).
MM was highly comorbid with a range of chronic and other conditions, with approximately 53% of patients with one or two comorbidities and approximately 15% with more than two comorbidities. Hypertension was reported most frequently in 36.5% of patients (range, 28.2% in Argentina to 49.2% in Brazil). Other frequent comorbidities were diabetes and heart disease in 12.6% and 11.5% of patients, respectively. Potential manifestations of target organ damage included a history of bone disorders in 7.2% of patients and renal disease in 11.1% (Table 2).

DISCUSSION
To our knowledge, the HOLA registry-unprecedented in size and scope-provides high-quality, real-world data from . 5,000 patients with HMs observed for 8 years in Latin America. Despite considerable heterogeneity across the 7 participating countries, certain common themes are of potential concern to health care providers and policymakers. First, large proportions of patients with HMs had comorbidities, which can limit therapeutic options. Second, considerable numbers of patients also had high-grade and other aggressive forms of disease (eg, DLBCL), and approximately 26% of patients died during the observation period.
Our study identified potential regional access-to-care issues. Between 28% and 50% of patients with MM received thalidomide-based chemotherapy in Argentina, Brazil, Mexico, and Chile, and 36% of those in Colombia received bortezomib. Furthermore, there was wide variation between countries in the proportion of patients with MM who had undergone transplantation. In Argentina, 20-fold more patients underwent ASCT than in Chile. The treatment regimens in Latin American were different compared with those of other countries in the world. For example, the majority of transplantation recipients with MM were administered thalidomide-based (30.4%) or bortezomib-based (25.2%) treatment in the studied regions, while lenalidomide, bortezomib, and dexamethasone chemotherapy is the most commonly used frontline treatment of transplantation-eligible patients with MM in the United States. Differences in treatment regimens were probably due to the restricted access and lack of approved novel agents in these studied regions.
With regard to comorbidities, these included hypertension (range across HMs, 29.0%-46.1%), diabetes (12.6%-15.1%), and heart disease (8.0%-15.7%). In one study, patients with MM who received treatment with thalidomide experienced a 23% increase in grade 3-4 adverse events, including, most frequently, cardiovascular disease followed by other hematologic conditions, thromboembolic events, infection, and neuropathy. 14 A Latin American observational study found the median age of patients with MM to be 67.4 years, and 70.7% Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; NE, not estimated; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; RCVP, rituximab, cyclophosphamide, vincristine, and prednisone; SD, standard deviation.  .   15 An analysis of medical records for 9,120 patients at a hematologic clinic in Puebla, Mexico, over 20 years identified 855 individuals with HMs, including 66 (7.7%) with MM; median age was 66 years, and 51% survived through 540 days. The authors contended that a range of immunoproliferative disorders are less frequent in the indigenous Mexican population (mestizos) compared with whites, including CLL (5 times less frequent) and monoclonal gammopathy of undetermined significance (4 times less frequent). 16 In The combination of the HOLA cohort size (N = 5,140) and broad scope of follow-up data (8 years) are study strengths. Given the liberal eligibility criteria and observational nature of the study, the findings should be generalizable to most Latin American practitioners' treatment populations and settings. Chart abstractors were centrally trained and had considerable expertise in using clearly prespecified disease definitions. On the other hand, the cohort represented a convenience population, which potentially reduces the generalizability of the findings. Because of potential medical surveillance bias, the prevailing tertiary care nature of the treatment milieus may have resulted in overestimations of the percentage of patients with HMs, comorbidities, and treatment patterns compared with lessspecialized clinics. Given that Latin American cancer care delivery systems are largely skewed toward urban settings, individuals who reside in rural locales may have been underrepresented. Rural workers may experience greater vocational exposure to insecticides and other lymphomagens. 20 The International Classification of Diseases for Oncology codes used to identify patients with MM, CLL, and NHL were developed for reimbursement, not for case ascertainment purposes. Numbers of centers, and hence overall denominators in calculations, were somewhat small, especially in Chile and Panama/Guatemala.
In conclusion, the HOLA study generated an unprecedented level of high-quality, real-world evidence on the disease and treatment characteristics of patients with HMs. Considerable regional variations in HM management were observed, and the findings can likely be ascribed to heterogeneity in both patient characteristics and treatment patterns. Results from this study can be used to understand the disease landscape in Latin America. Future research is needed to explicitly associate observed trends with treatment outcomes.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript.     .   Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; NE, not estimated; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; RCVP, rituximab, cyclophosphamide, vincristine, and prednisone; SD, standard deviation.