Pediatric Hodgkin Lymphoma in Low- and Middle-Income Countries (LMICs). A Narrative Review 

Maria Luisa Moleti1, Anna Maria Testi1, Salma Al-Hadad2, Mazin Faisal Al-Jadiry2 and Robin Foà1.

1 Department of Translational and Precision Medicine, Sapienza, University of Rome, Rome, Italy.
2 College of Medicine-University of Baghdad, Children Welfare Teaching Hospital-Medical City, Baghdad, Iraq.
.

Correspondence to: Anna Maria Testi, MD. Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome. Via Benevento 6, 00161 Rome, Italy. Phone: +39-3394723402. Fax: +39-06-44241984. Email: testi@bce.uniroma1.it ORCID: 0000-0002-1354-3659.

Published: November 01, 2024
Received: September 17, 2024
Accepted: October 08, 2024
Mediterr J Hematol Infect Dis 2024, 16(1): e2024078 DOI 10.4084/MJHID.2024.078

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pediatric Hodgkin lymphoma (HL) is a curable disease for more than 90% of children and adolescents in high-income countries. However, similar results cannot be achieved, particularly for advanced disease, in low- and middle-income countries (LMICs), where challenging socio-economic realities and the consequent scarcity of local resources heavily impact the treatment and patients’ outcome. Information regarding the management and outcome of pediatric HL in LMICs is still limited. In this narrative review, we summarize the results reported in the literature so far and discuss the critical key points that have emerged from this overview.

Introduction

In high-income countries (HICs), more than 90% of children and adolescents with Hodgkin lymphoma (HL) can be cured with combined chemo-radiotherapy adapted to the pediatric age.[1,2] During the last decade, multicenter pediatric studies aimed at modulating treatment according to well-defined risk groups and, in particular, at evaluating the reduction/omission of radiotherapy according to the early metabolic positron emission tomography (PET) response (ERA).[3-7] In low- and middle-income countries (LMICs), treatment strategies must find a balance between curative goals, toxicities, and local resources. The socio-economic, political, and cultural situation present in many LMICs leads to multiple problems that significantly impact pediatric HL treatment and outcomes. These issues include delays in referring patients to hospitals, the presence of comorbidities and malnutrition, high rates of abandonment, and a variety of other challenges that affect different countries to varying degrees. Owing to the lack of adequate supportive therapy, the more intensive schemes, successfully employed in HICs, are usually unsafe in the above setting. Radiotherapy is not always available, and HL treatment must often rely only on chemotherapy. Moreover, an accurate staging work-up at presentation and definition of response to treatment cannot be carried out in the absence of effective diagnostic/follow-up tools such as PET. It should also be recalled that information regarding the epidemiology and outcome of pediatric HL in LMICs is still limited, due to the lack of proper country registries and the paucity of updated reports and follow-up data also due to the increasing standards required for scientific papers and a preference for prospective multicenter studies that limit the publication of real-life reports from LMICs.
For this narrative review, we utilized PubMed to search articles about pediatric HL management in LMICs. The search was narrowed to articles between 1990 and 2023, excluding sub-Saharan Africa, which has been the subject of a recent exhaustive report,[8] and far-East LMICs, for which data in the English literature are insufficient. A total of 33 articles were included. We summarized the results reported so far in these papers and discussed the lessons that have been derived from these different real-life experiences.

Epidemiology

The epidemiology of pediatric HL varies greatly among geographic areas with different socio-economic levels. In HICs, HL is the sixth most frequent childhood neoplasm, accounting for 5-6% of childhood cancers.[9] Data regarding the real incidence of pediatric HL in other parts of the world concern only some geographic areas and are often not updated. In developing countries, HL is more frequent, being the fourth most common neoplasm in childhood.[10] In Latin America, the incidence of childhood HL is particularly high, 1-1.5 per 100,000 children.[10]
In HICs, HL presents two peaks of age distribution in young adults (20-34 years) and older people (55-74 years).[11] In LMICs, the first peak occurs at a younger age in both children and adolescents, with 20% to 30% of childhood HL cases occurring before the age of 5, compared to about 5% in HICs.[12] Such patterns of occurrence are similar to those of Epstein-Barr virus (EBV) and other infections, suggesting an etiologic role of environmental exposure. In HICs, the incidence of EBV tumor cell positivity for HL ranges from 15% to 25% in adolescents and young adults.[13-15] It is significantly higher - between 70% and 100% - in LMICs where primary EBV infection occurs within a few months to years after birth. EBV-associated HL is more frequent in children below the age of 10, in males, and in the mixed cellularity (MC) subtype.[16,17] In India, EBV has been found in 78% of HL cases at all ages and in up to 98% of childhood HL.[18,19]
MC is the most common subtype of pediatric HL in LMICs (46-60%), and its association with EBV infection is well documented.
In LMICs, there is a male predominance in pediatric HL, particularly under the age of 10, with an M: F ratio between 2.5:1 and 5:1. The M:F ratio reaches 10.5:1 in Indian cases.[20,21] The reasons for this gender distribution are not fully understood. Increased male susceptibility to infection, as well as social-cultural factors leading to reduced attention to female children, have been suggested.[22]

Treatment

Therapeutic strategies and results in HICs. HL has been one of the most curable cancers since 1950, when the first successful protocols based on chemo and radiotherapy began to be used. In recent decades, the major focus, particularly in pediatric patients, has been to reduce the use of radiotherapy and chemotherapeutic agents such as anthracyclines and procarbazine, which are responsible for various severe long-term toxicities.[23] Nowadays, the survival rate of pediatric HL patients in HICs exceeds 90% with combined chemo-radiotherapy protocols adapted for younger patients.[1-3,5,6] In recent trials, staging, response assessment, and radiotherapy indications have been based on PET evaluations, and the number and intensity of cycles have been adjusted according to the risk group assignment. The 5-year event-free survival (EFS) ranges from 80% to 96% for children with low risk and from 79% to 90% for children with intermediate-high risk disease.[1,3-7,24-27] In the ongoing Children’s Oncology Group (COG) and the European Network Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, the intensity and duration of chemotherapy, as well as the indication, doses, and fields of radiotherapy, are modulated according to two criteria: the risk category (mainly determined by stage, bulky disease and B symptoms) and the early metabolic response to treatment. Promising immuno-chemotherapy approaches,[28,29] including monoclonal antibodies and checkpoint inhibitors such as brentuximab[30-32] and pembrolizumab,[33] are under evaluation for first-line treatment in pediatric patients, with the aim of further reducing chemotherapy-related toxicity.
Reported results in LMICs. There are very little data in the literature on the treatment and outcome of pediatric HL in LMICs prior to the second decade of the 2000s. These studies are generally retrospective and mainly based on single-center experiences. Heterogeneous treatment approaches, including radiotherapy or not, as well as different modalities of data analysis, often censoring abandonment, make these studies difficult to interpret and compare. More recently, prospective cooperative studies have been implemented in Latin America[34] and in the Indian subcontinent.[35-37]
Papers on pediatric HL from LMICs, present in the literature from the 1990s, are summarized in Tables 1-3. These studies include patients up to the age of 14-21. In most studies, the median age is low, around 7 years, with many children less than 5 (from 8.3% up to 37%, median 16%).
Table 1 Table 1. Childhood/adolescent Hodgkin lymphoma in low-middle income countries. Treatment results I: Chemotherapy alone or sporadic radiotherapy.

Table 2A Table 2A. Children/adolescents Hodgkin lymphoma in Low-middle income countries. Treatment results II: Combined chemoradiotherapy
Table 2B Table 2B. Children/adolescents Hodgkin lymphoma in Low-middle income countries. Treatment results II: Combined chemoradiotherapy
Table 2C Table 2C. Children/adolescents Hodgkin lymphoma in Low-middle income countries. Treatment results II: Combined chemoradiotherapy

Table 3 Table 3. Children/adolescents Hodgkin lymphoma in Low-middle income countries. Treatment results II: ERA based Combined chemoradiotherapy.
The M:F ratio is high (median 3.8:1), ranging from values similar to Western countries (1.6-1.7:1) in Egypt,[38,39] Iran,[40] and Argentina,[41] and up to 10.5:1 in India[20,21] where very high rates are reported in all studies.
All the studies, except two excluding nodular lymphocyte predominance HL,[61,62] include all HL histologic subtypes. An MC histology is reported in more than 40% of cases, with this histologic subtype being even more represented (up to 86%) in Indian patients.[42] Many patients present with advanced stage (stage III-IV), with a median of 52% (range 26%-87%).
Abandonment, which was differently defined among the studies, was reported in 15 out of the 33 papers, with rates ranging from 1% to 17% (median 7.5%).
The most commonly used regimen was ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), alone or alternated with COPP (cyclophosphamide, oncovin, procarbazine, prednisone), with or without dacarbazine (COPP/ABV(D)). After the 2000s, other schemes derived from the European pediatric protocols, particularly OEPA (oncovin, etoposide, prednisone, adriamycin) and COPDAC (cyclophosphamide, oncovin, prednisone, dacarbazine), have been introduced.
The total number of cycles varied from 3 to 12 (median 6), generally depending on medical decisions according to stage, response to treatment, and availability of radiotherapy. In the absence of radiotherapy, more cycles of chemotherapy were administered (Table 1).
Table 1 describes the studies based on chemotherapy alone. Chemotherapy alone was delivered in six studies due to the unavailability of Radiotherapy[38,43-47]. In four further studies, radiotherapy was sporadically delivered to a very small number of patients based on clinical decisions related to bulky disease at presentation or residual mass after chemotherapy.[20,21,42,48]
Table 2 (A, B, C) reports the studies based on a combined chemo-radiotherapy modality. In some studies, involved field (IF) radiotherapy was planned for patients with bulky or residual disease.[49-55] In other studies, radiotherapy, generally IF, was administered to all patients[34,41,56-58] or to patients selected according to risk.[39,40,59,60] Since 2010, in the most recent prospective protocols, radiotherapy (generally IF) was pre-planned based on ERA and in case of bulky disease[35-37,61-63] (Table 3).
Results according to therapeutic strategies. In the studies based on chemotherapy alone (generally COPP, COPP/ABV(D) or ABVD), the overall 5-year EFS and overall survival (OS) ranged from 69% to 87% (median 77.8%) and from 76.3% to 92.7% (median 91.5%), respectively, with good results (EFS up to 92% and OS up to 100%) in children presenting with localized disease. As previously mentioned, these patients received a high number of chemotherapeutic cycles, up to 10-12. Despite the high chemotherapy burden, the reported therapy-related deaths (TRD) are low (Table 1). However, little information on the long-term side effects is available. The median rate of abandonment is 12%. In the two studies in which abandonment was considered as an event, the 10- and 15-year EFS were 56.8% and 70.3%, respectively.[46,47]    
When a chemo-radiotherapy combination was used, the chemotherapy regimens included mainly ABVD, COPP, and COPP/ABVD. Other schemes such as COPDAC and OEPA or OPPA (oncovin, procarbazine, prednisone, adriamycin), derived from pediatric European experiences, have been used in studies from Pakistan and South Africa since 2000. The overall 5-10-year EFS ranged from 60% to 91% (median 81.5%), and the OS ranged from 72% to 96.6% (median 91.6%), with EFS up to 91.7% and OS up to 100% in children with early-stage disease. The median rate of abandonment, reported only in a few papers, was 8%. In the two studies in which abandonment was considered as an event, the 5-year EFS was 46% and 70%, respectively.[34,64]    
In the more recent studies, with different combined chemo-radiotherapy programs modulated according to the initial stage and ERA, the 3-5-year EFS and OS were 83.3% and 92.2%, respectively. Patients with localized disease reached a 3-year EFS and OS of 100%.[62,63]
No significant differences were observed among the three treatment strategies (Tables 1-3), with a median EFS of 72.8%, 81.5%, and 83.3% and OS of 91.5%, 91.6%, and 92%, respectively, for chemotherapy alone, chemo-radiotherapy, and ERA-based chemo-radiotherapy groups.

Discussion

Most children in the world live in LMICs, where over 80% of pediatric cancers occur.[65] Unfortunately, the good results of pediatric cancer treatment achieved in HICs are still not attained in the other parts of the world.[66] This is also true for a highly curable disease like HL. In LMICs, the survival rates reported in the published papers are acceptable, particularly for children with early-stage disease, though lower compared to those achieved in HICs and often at the cost of a high therapeutic burden. Moreover, we must consider that data on HL - and all pediatric cancers - are completely lacking for most LMICs. More data are recently emerging from Latin America with the implementation of cooperative studies and from the Indian subcontinent.
The data that emerge from this review confirm:
-  Lower age and the high incidence of MC in the pediatric HL cohorts.
-  The high incidence of MC is probably related to the high incidence of early EBV infection in LMICs.
-  The high M: F ratio. Cultural reasons, with a lower interest in female children, are evident, particularly in the reports from India. The M: F ratio appears to be reducing, though remaining high also in the more recent studies.
-  The advanced stage of disease presentation is often due to delayed referral and diagnosis for social and economic reasons.
In these countries, the most used therapeutic regimens were the well-known ABVD, COPP, or COPP/ABV regimens, which are less toxic and can be administered as outpatients. Radiotherapy was not always available, and the number of chemotherapy cycles administered was frequently high, with a risk of late side effects, usually not reported in the published papers. In more recent years, treatment has also been modulated according to ERA with a consequent decrease in the chemo/radiotherapy burden. Based on the ERA evaluation, PET-CT should be the optimal choice, but unfortunately, it is not always available in LMICs where contrast-enhanced CT may be a valid option.[67] With the ERA-based strategies, good results were achieved in India with the ABVD protocol.[35,36] More aggressive schemes (OEPA/COPDAC), according to the European protocols, gave good results but increased the TRD due to the absence of appropriate supportive therapy.[37,61,62] In a very interesting study from South Africa, in high-risk patients, the more toxic OEPA scheme was replaced by ABVD[63] according to a EuroNet-CHL-inspired protocol. This was associated with a 2-year OS of 92.6% and very good results also in high-risk patients (OS 91%).

Key Points

Unavailability of radiological facilities. Proper staging and response evaluation with PET is often not possible, limiting therapy modulation and potentially leading to overtreatment.
Inconsistent Availability of Chemotherapy Drugs. Treatment cycles are sometimes inadequate due to the omission or substitution of unavailable drugs.
Inadequate supportive treatment. Intensive treatments used in advanced stages in HICs can cause excessive toxicity without proper patient compliance and supportive measures.
Inconsistent Quality of Radiotherapy. Radiotherapy in LMICs, even when available, may not always meet the quality requirements necessary for safe delivery.
Difficulties in solving the Problem of gonadal toxicity. Implementing fertility preservation measures, now widely adopted in HICs, can be difficult or impossible in LMICs.[68,69]
Difficulties in long-term follow-up. Without long-term follow-up, obtaining information on the rate and severity of late treatment effects is particularly challenging in LMICs, making it difficult to modulate HL treatment effectively while maintaining good outcomes.

Which strategy for LMICs? The ARIA Guidelines

The St. Jude Global and the International Society of Pediatric Oncology (SIOP) created the adapted Resource and Implementation Application (ARIA) guidelines to provide pediatric oncologists worldwide with safe and evidence-based guidelines for diagnosing and treating pediatric cancers. The Aria guidelines for childhood HL identify three categories of centers according to resource availability, detailing the minimal requirements for diagnosis, staging, and treatment for each category. Treatment recommendations are tailored according to patient risk groups (low-risk, intermediate-risk, or high-risk) and center resource categories, with more intensive treatments reserved for high-resource centers. Caution is advised in radiotherapy indications, requiring precise quality assessment for safe delivery. Adapted radiotherapy guidelines for LMICs were recently implemented by the Pediatric Oncology in Developing Countries (PODC) committee of SIOP in collaboration with the Pediatric Radiation Oncology Society (PROS).[70]
The novel immunotherapeutic drugs could play an important role in LMICs, especially for high-risk and non-responding patients, offering more effective treatments without increasing chemotherapy-related TRD. However, the primary obstacles remain the costs and availability of these approaches in LMICs.

Conclusions

The so-far reported survival data obtained in LMICs for childhood HL may be considered satisfactory, particularly in early-stage patients. However, these results are obtained in most studies at the cost of a high chemotherapy or radiotherapy burden. The lack of long-term follow-up data means insufficient information on the late effects of these extensive treatments. To improve these results, contrarily to what has been described for aggressive non-Hodgkin lymphoma,[66] the main issue is not to deliver aggressive treatment to all patients, but rather a timely hospital referral and the modulation of treatment based on an accurate evaluation of the extension of the disease and, subsequently, on the response to treatment over time. This “modulation strategy” will need to be adapted to the different realities within LMICs. The availability of diagnostic tools such as PET or only CT, the possibility of safely delivering aggressive treatment for high-risk/not-responding patients, and finally, the availability of affordable radiotherapy may be different between countries and between hospitals in the same country. For these reasons, it is important to implement practical guidelines for the treatment of pediatric HL in LMICs that take into account the heterogeneity of the different realities. The ARIA guidelines for pediatric HL give harmonized, evidence-based general indications that will help pediatric oncologists worldwide. However, only local pediatricians, with their profound knowledge and experience of their specific local contexts, can correctly adapt these guidelines to each unique situation.

Acknowledgements

The authors received no financial support for the research, authorship, and/or publication of this paper.

Author contributions

MLM reviewed the literature and wrote the manuscript; AMT and RF critically reviewed and contributed to the final draft of the paper; SAH and MFAJ, with their extensive working experience at the Children Welfare Teaching Hospital in Baghdad, inspired and contributed to the discussion of the review.
All authors revised and approved the final version of the manuscript.

References   

  1. Belsky JA, Hochberg J, Giulino-Roth L. Diagnosis and management of Hodgkin lymphoma in children, adolescents, and young adults. Best Pract Res Clin Haematol. 2023;36(1):101445. https://doi.org/10.1016/j.beha.2023.101445  
  2. Lo AC, Dieckmann K, Pelz T, Gallop-Evans E, Engenhart-Cabillic R, Vordermark D, Kelly KM, Schwartz CL, Constine LS, Roberts K, Hodgson D. Pediatric classical Hodgkin lymphoma. Pediatr Blood Cancer. 2021;68 Suppl 2:e28562. https://doi.org/10.1002/pbc.28562  
  3. Mauz-Korholz C, Landman-Parker J, Balwierz W, mmann RA, Anderson RA, Attarbaschi A, Bartelt JM, Beishuizen A, Boudjemaa S, Cepelova M, Claviez A, Daw S, Dieckmann K, Fernández-Teijeiro A, Fosså A, Gattenlöhner S, Georgi T, Hjalgrim LL, Hraskova A, Karlén J, Kluge R, Kurch L, Leblanc T, Mann G, Montravers F, Pears J, Pelz T, Rajić V, Ramsay AD, Stoevesandt D, Uyttebroeck A, Vordermark D, Körholz D, Hasenclever D, Wallace WH. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol. 2022;23(1):125-137. https://doi.org/10.1016/S1470-2045(21)00470-8  
  4. Keller FG, Castellino SM, Chen L, Pei Q, Voss SD, McCarten KM, Senn SL, Buxton AB, Bush R, Constine LS, Schwartz CL. Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: a report from the Children's Oncology Group. Cancer. 2018;124(15):3210-3219. https://doi.org/10.1002/cncr.31519  
  5. Kelly KM, Cole PD, Pei Q, Bush R, Roberts KB, Hodgson DC, McCarten KM, Cho SY, Schwartz C. Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children's Oncology Group. Br J Haematol. 2019;187(1):39-48. https://doi.org/10.1111/bjh.16014  
  6. Friedman DL, Chen L, Wolden S, Buxton A, McCarten K, FitzGerald TJ, Kessel S, De Alarcon PA, Chen AR, Kobrinsky N, Ehrlich P, Hutchison RE, Constine LS, Schwartz CL. Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol. 2014;32(32):3651-3658. https://doi.org/10.1200/JCO.2013.52.5410  
  7. Metzger ML, Weinstein HJ, Hudson MM, Billett AL, Larsen EC, Friedmann A, Howard SC, Donaldson SS, Krasin MJ, Kun LE, Marcus KJ, Yock TI, Tarbell N, Billups CA, Wu J, Link MP. Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma. JAMA. 2012;307(24):2609-2616. https://doi.org/10.1001/jama.2012.5847  
  8. Kabahweza HM, Spencer A. Childhood Hodgkin Lymphoma in Sub-Saharan Africa: A Systematic Review on the Effectiveness of the Use of Chemotherapy Alone. Glob Pediatr Health. 2024;11:2333794X231223266. https://doi.org/10.1177/2333794X231223266  
  9. Macfarlane GJ, Evstifeeva T, Boyle P, Grufferman F. International patterns in the occurrence of Hodgkin's disease in children and young adult males. Int J Cancer. 1995;61(2):165-169. https://doi.org/10.1002/ijc.2910610204  
  10. Stiller CA, Parkin DM. Geographic and ethnic variations in the incidence of childhood cancer. Br Med Bull. 1996;52(4):682-703. https://doi.org/10.1093/oxfordjournals.bmb.a011577
  11. Grufferman S, Delzell E. Epidemiology of Hodgkin's disease. Epidemiol Rev. 1984;6:76-106. https://doi.org/10.1093/oxfordjournals.epirev.a036276  
  12. Mahajan A, Bakhshi S, Seth R, Verma N, Mandal P, Singh M, Jain S, Radhakrishnan V, Kanvinde S, Arora RS, Dinand V, Kalra M, Taluja A, Mallick S, Kumar R, Chandra J. Hodgkin Lymphoma in children < 5 years. Do they behave differently? J Pediatr Hematol Oncol. 2022 May 1;44(4):186-190. https://doi.org/10.1097/MPH.0000000000002423  
  13. Claviez A, Tiemann M, Lüders H, Krams M, Parwaresch R, Schellong G, Dörffel W. Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma. J Clin Oncol. 2005;23(18): 4048-4056. https://doi.org/10.1200/JCO.2005.01.701  
  14. Lee JH, Kim Y, Choi JW, Young-Sik K. Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin's lymphoma: a meta-analysis. Arch Med Res. 2014;45(5):417-431. https://doi.org/10.1016/j.arcmed.2014.06.001  
  15. Jarrett RF, Stark GL, White J, Angus B, Alexander FE, Krajewski AS, Freeland J, Taylor GM, Taylor PRA. Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood. 2005;106(7):2444-2451. https://doi.org/10.1182/blood-2004-09-3759  
  16. Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P, Pallesen G, Gulley ML, Khan G, O'Grady J, Hummel M, Preciado MV, Knecht H, Chan JK, Claviez A. Epstein-Barr virus associated Hodgkin's disease: epidemiologic characteristics in international data. Int J Cancer. 1997;7084:375-382. https://doi.org/10.1002/(SICI)1097-0215(19970207)70:4<375::AID-IJC1>3.0.CO;2-T  
  17. Chabay PA, Barros MH, Hassan R, De Matteo E, Rey G, Carrico MK, Renault IZ, Preciado MV. Pediatric Hodgkin lymphoma in 2 South American series: a distinctive epidemiologic pattern and lack of association of Epstein-Barr virus with clinical outcome. J Pediatr Hematol Oncol. 2008;30(4):285-291. https://doi.org/10.1097/MPH.0b013e3181647bc3
  18. Naresh KN, Johnson J, Srinivas V, Soman CS, Saikia T, Advani SH, Badwe RA, Dinshaw KA, Muckaden M, Magrath I, Bhatia K. Epstein-Barr virus association in classical Hodgkin's disease provides survival advantage to patients and correlates with higher expression of proliferation markers in Reed-Sternberg cells. Ann Oncol. 2000;11(1):91-96. https://doi.org/10.1023/A:1008337100424
  19. Dinand V, Dawar R, Arya LS, Unni R, Mohanty B, Singh R. Hodgkin's lymphoma in Indian children: prevalence and significance of Epstein-Barr virus detection in Hodgkin's Reed-Stemberg cells. Eur J Cancer. 2007;43(1):161-168. https://doi.org/10.1016/j.ejca.2006.08.036  
  20. Chandra J, Naithani R, Singh V, Saxena YK, Sharma M, Pemde H. Developing anticancer chemotherapy services in a developing country: Hodgkin lymphoma experience. Pediatr Blood Cancer. 2008;51(4):485-488. https://doi.org/10.1002/pbc.21609
  21. Trehan A, Singla S, Marwaha RK, Bansal D, Srinivasan R. Hodgkin lymphoma in children: experience in a tertiary care centre in India. J Pediatr Hematol Oncol. 2013;35(3):174-179. https://doi.org/10.1097/MPH.0b013e318271f587  
  22. Nandakumar A, Anantha N, Appaji L, Swamy K, Mukherjee G, Venugopal T, Reddy S, Dhar M. Descriptive epidemiology of childhood cancers in Bangalore, India. Cancer Causes Control. 1996;7(4):405-410. https://doi.org/10.1007/BF00052665  
  23. Ehrhardt MJ, Flerlage JE, Armenian SH, Castellino SM, Hodgson DC, Hudson MM. Integration of Pediatric Hodgkin Lymphoma Treatment and Late Effects Guidelines: Seeing the Forest Beyond the Trees. J Natl Compr Canc Netw. 2021;19(6):755-764. https://doi.org/10.6004/jnccn.2021.7042   
  24. Nachman JB, Sposto R, Herzog P, Gilchrist GS, Wolden SL, Thomson J, Kadin ME, Pattengale P, Davis PC, Hutchinson RJ, White K. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol. 2002;20(18):3765-3771. https://doi.org/10.1200/JCO.2002.12.007   
  25. Mauz-Korholz C, Hasenclever D, Dorffel W, Ruschke K, Pelz T, Voigt A, Stiefel M, Winkler M, Vilser C, Dieckmann K, Karlén J, Bergsträsser E, Fosså A, Mann G, Hummel M, Klapper W, Stein H, Vordermark D, Kluge R, Körholz D. Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin Oncol. 2010;28(23):3680-3686. https://doi.org/10.1200/JCO.2009.26.9381  
  26. Dorffel W, Rühl U, Lüders H, Claviez A, Albrecht M, Bokkerink J, Holte H, Karlen J, Mann G, Marciniak H, Niggli F, Schmiegelow K, Schwarze E-W, Pötter R, Wickmann L, Schellong G. Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: final results of the multinational trial GPOH-HD95. J Clin Oncol. 2013;31(12):1562-1568. https://doi.org/10.1200/JCO.2012.45.3266  
  27. Giulino-Roth L, Keller FG, Hodgson DC, Kelly KM. Current approaches in the management of low risk Hodgkin lymphoma in children and adolescents. Br J Haematol. 2015;169(5):647-660. https://doi.org/10.1111/bjh.13372  
  28. Vassilakopoulos TP, Liaskas A, Pereyra P, Panayiotidis P, Angelopoulou MK, Gallamini A. Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma. Int J Mol Sci. 2023;24(17): 13187. https://doi.org/10.3390/ijms241713187  
  29. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2018;378(4):331-344. https://doi.org/10.1056/NEJMoa1708984
  30. Metzger ML, Link MP, Billett AL, Flerlage J, Lucas Jr JT, Mandrell BN, Ehrhardt MJ, Bhakta N, Yock TI, Friedmann AM, de Alarcon P, Luna-Fineman S, Larsen E, Kaste SC, Shulkin B, Lu Z, Li C, Hiniker SM, Donaldson SS, Hudson MM, Krasin MJ. Excellent outcome for pediatric patients with high-risk hodgkin lymphoma treated with brentuximab vedotin and risk-adapted residual node radiation. J Clin Oncol. 2021;39(20):2276-2283. https://doi.org/10.1200/JCO.20.03286  
  31. Hochberg J, Basso J, Shi Q, Klejmont L, Flower A, Bortfeld K, Harrison L, van de Ven C, Moorthy C, Islam H, Gerard P, Voss S, Cairo MS. Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin's lymphoma: a phase II, non-randomized controlled trial. J Immunother Cancer. 2022;10(5) e004445. https://doi.org/10.1136/jitc-2021-004445  
  32. Castellino SM, Pei Q, Parsons SK, Hodgson D, McCarten K, Horton T, Cho S, Wu Y, Punnett A, Dave H, Henderson TO, Hoppe BS, Charpentier A-M, Keller FG, Kelly KM. Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma. New Engl J Med. J Clin Oncol. 2022;387(18):1649-1660. https://doi.org/10.1056/NEJMoa2206660
  33. Vinti L, Daw S, Sabado Alvarez C, Mauz-Korholz C, Fagioli F, Beishuizen A, Michel G, Moleti M, Cepelova M, Thorwarth A, Rigaud C, Plaza Lopez De Sabando D, Landman-Parker J, Shen J, Pillai P, Marinello P, Mauz-Koerholz C. Pembrolizumab in children and young adults with classical hodgkin lymphoma (chl) with slow early response (ser) to front-line chemotherapy (KEYNOTE-667). Pediatr Blood Cancer. 2023; Volume 70, Issue S8. Abstract 0053/#1080; 55th Congress of the International Society of Paediatric Oncology (SIOP) October 11-14, 2023.
  34. Luna-Fineman S, Castellanos M, Metzger ML, Baez LF, Peña Hernandez A, Bonilla M, Fuentes-Alabi S, Nieves R, Blanco J, Rossi E, Devidas M, Chen Y, Arreola M, de Alarcon PA. Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes. Pediatr Blood Cancer. 2024;71(2):e30792. https://doi.org/10.1002/pbc.30792  
  35. Mahajan A, Singh M, Bakhshi S, Jain S, Radhakrishnan V, Verma N, Seth R, Arora RS, Dinand V, Kalra M, Mandal P, Kapoor G, Sajid M, Thulkar S, Arora A, Taluja A, Chandra J. Treating early-stage Hodgkin lymphoma in resource-limited settings: InPOG-HL-15-01 experience. Pediatr Blood Cancer. 2021;68(10):e29219. https://doi.org/10.1002/pbc.29219  
  36. Jain S, Bakhshi S, Seth R, Verma N, Singh M, Mahajan A, Radhakrishnan V, Mandal P, Arora R, Dinand V, Kalra M, Sharma A, Taluja A, Thulkar S, Biswas A, Chandra J. Risk based and response adapted radiation therapy for children and adolescents with newly diagnosed advanced stage Hodgkin lymphoma treated with ABVD chemotherapy: a report from the Indian pediatric oncology group study InPOG-HL-15-01. Leuk Lymphoma. 2022;63(5):1111-1118. https://doi.org/10.1080/10428194.2021.2012659  
  37. Palayullakandi A, Trehan A, Jain R, Kumar R, Mittal BR, Kapoor R, Srinivasan R, Kakkar N, Bansal D. Retrospective single-center experience with OEPA/COPDAC and PET-CT based strategy for pediatric Hodgkin lymphoma in a LMIC setting. Pediatr Hematol Oncol. 2022 Oct;39(7):587-599. https://doi.org/10.1080/08880018.2022.2044418  
  38. Al-Tonbary Y, Sarhan MM, El-Ashry RA, Salama E, Sedki M, Fouda A. Comparative study of two mechlorethamine, vincristine, procarbazine, and prednisone derived chemotherapeutic protocols for the management of pediatric Hodgkin lymphoma (HL): single-center 5-year experience. Leuk Lymphoma. 2010;51(4):656-663. https://doi.org/10.3109/10428191003624249  
  39. Sherief LM, Elsafy UR, Abdelkhalek ER, Kamal NM, Elbehedy R, Hassan TH, Sherbiny HS, Beshir MR, Saleh SH. Hodgkin lymphoma in childhood: clinicopathological features and therapy outcome at 2 centres from a developing country. Medicine (Baltimore). 2015;94(15):e670. https://doi.org/10.1097/MD.0000000000000670  
  40. Alebouyeh M, Moussavi F, Haddad-Deylami H, Vossough P. Successful ambulatory treatment of Hodgkin's disease in Iranian children based on German-Austrian DAL-HD 85-90: single institutional results. Ann Oncol. 2005;16(12):1936-1940. https://doi.org/10.1093/annonc/mdi401  
  41. Sackmann-Muriel F, Zubizarreta P, Gallo G, Scopinaro M, Alderete D, Alfaro E, Casak S, Chantada G, Felice MS, Quinteros R. Hodgkin disease in children: results of a prospective randomized trial in a single institution in Argentina. Med Pediatr Oncol. 1997;29(6):544-552. https://doi.org/10.1002/(SICI)1096-911X(199712)29:6<544::AID-MPO5>3.0.CO;2-K
  42. Arya LS, Dinand V, Thavaraj V, Bakhshi S, Dawar R, Rath GK, Singh R, Vats TS. Hodgkin's disease in Indian children: outcome with chemotherapy alone. Pediatr Blood Cancer. 2006; 46(1):26-34. https://doi.org/10.1002/pbc.20157  
  43. Lobo-Sanahuja F, García I, Barrantes JC, Barrantes M, González M, Jiménez R. Pediatric Hodgkin's disease in Costa Rica: twelve years' experience of primary treatment by chemotherapy alone, without staging laparotomy. Med Pediatr Oncol. 1994;22(6):398-403. https://doi.org/10.1002/mpo.2950220609  
  44. Sripada PV, Tenali SG, Vasudevan M, Viswanadhan S, Sriraman D, Kandasamy R. Hybrid (COPP/ABV) therapy in childhood Hodgkin's disease: a study of 53 cases during 1989-1993 at the Cancer Institute, Madras. Pediatr Hematol Oncol. 1995;12(4):333-341. https://doi.org/10.3109/08880019509029583  
  45. Baez F, Ocampo E, Conter V, Flores A, Gutierrez T, Malta A, Pacheco C, Palacios R, Biondi A, Riva L, Sala A, Silvestri D, Cavalli F, Sessa C, Casanova M, Masera G. Treatment of childhood Hodgkin's disease with COPP or COPP-ABV (hybrid) without radiotherapy in Nicaragua. Ann Oncol. 1977;8(3):247-250. https://doi.org/10.1023/A:1008200210674  
  46. Castellanos EM, Barrantes JC, Báez LF, Gamboa Y, Peña A, Alabi S, Bonilla M, Wang H, Metzger ML, de Alarcón PA. A chemotherapy only therapeutic approach to pediatric Hodgkin lymphoma: AHOPCA LH 1999. Pediatr Blood Cancer. 2014;61(6):997-1002. https://doi.org/10.1002/pbc.24905  
  47. Testi AM, Al Jadiri MF, Moleti ML, Uccini S, Al-Darraij AF, Al-Saeed RM, Ghali HH, Sabhan AH, Fadhil SA, Al-Badri SA, Alsaadawi AR, Hameedi AD, Shanshal MH, Al-Agele YS, Al-Saffar FAR, Yaseen NK, Piciocchi A, Marsili G, Al-Hadad SA . Hodgkin Lymphoma in children: a 16-year experience at the Children's Welfare Teaching Hospital of Baghdad, Iraq. Mediterr J Hematol Infect Dis. 2024;16:e2024o53. https://doi.org/10.4084/MJHID.2024.053  
  48. Sagar TG, Chandra A, Raman G. Childhood Hodgkin disease treated with COPP/ABV hybrid chemotherapy: a progress report. Med Pediatr Oncol. 2003;40(1):66-69. https://doi.org/10.1002/mpo.10017  
  49. Radhakrishnan V, Dhanushkodi M, Ganesan TS, Ganesan P, Sundersingh S, Selvaluxmy G, Swaminathan R, Rama R, Sagar TG. Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome. J Glob Oncol. 2016;3(5):545-554. https://doi.org/10.1200/JGO.2016.005314  
  50. Jain S, Kapoor G, Bajpai R. ABVD-Based Therapy for Hodgkin Lymphoma in Children and Adolescents: Lessons Learnt in a Tertiary Care Oncology Center in a Developing Country. Pediatr Blood Cancer. 2016;63(6):1024-1030. https://doi.org/10.1002/pbc.25935 
  51. Ashraf MS, Naz F, Yakoob MY. Characteristics and Survival Outcomes of Children With Hodgkin Lymphoma Treated Primarily With Chemotherapy. J Pediatr Hematol Oncol. 2019:41(6):452-456. https://doi.org/10.1097/MPH.0000000000001496  
  52. Muwakkit S, Geara F, Nabbout B, Farah RA, Shaab NS, Hajjar T, Khogali M. Treatment of pediatric Hodgkin's disease with chemotherapy alone or combined modality therapy. Radiat Oncol Investig. 1999;7(6):365-373. https://doi.org/10.1002/(SICI)1520-6823(1999)7:6<365::AID-ROI7>3.0.CO;2-W
  53. Belgaumi A, Al-Kofide AA, Khafaga Y, Joseph N, Jamil-Malik R, Siddiqui KS, Sabbah RS. Clinical characteristics and outcome of pediatric patients with stage IV Hodgkin lymphoma. Hematol Oncol Stem Cell Ther. 2009;2(1):278-284. https://doi.org/10.1016/S1658-3876(09)50038-6
  54. Baharvand M, Mortazavi H. Characteristics of Hodgkin lymphoma in a defined group of Iranian pediatric patients. Asian Pac J Cancer Prev. 2014;15(13):5167-5169. https://doi.org/10.7314/APJCP.2014.15.13.5167  
  55. Mehreen A, Wali RM, Sindhu II, Asad M, Ria S. Retrospective analysis of clinical features and treatment outcomes of children with Hodgkin's Lymphoma treated with different chemotherapy protocols at a tertiary care center in Pakistan. J Pak Med Assoc. 2019;69(9):1266-1272.  
  56. Kapoor G, Advani SH, Dinshaw KA, Muckaden MA, Soman CS, Saikia TK, Gopal R, Nair CN, Kurkure PA, Pai SK, et al. Treatment results of Hodgkin's disease in Indian children. Pediatr Hematol Oncol. 1995;12(6):559-569. https://doi.org/10.3109/08880019509030770  
  57. El-Badawy S, Aboulnaga S, Abou Gabal A, Mokhless A, Zamzam M, Sidhom I, Ebeid E, Hussein H.. Risk adapted combined modality treatment in children with Hodgkin's disease: NCI, Cairo. J Egypt Natl Canc Inst. 2008;20(2):99-110.  
  58. Büyükpamukçu M, Varan A, Akyüz C, Atahan L, Ozyar E, Kale G, Köksal Y, Kutluk T. The treatment of childhood Hodgkin lymphoma: improved survival in a developing country. Acta Oncol. 2009;48(1):44-51. https://doi.org/10.1080/02841860802310991  
  59. Zubizarreta PA, Alfaro E, Guitter M, Sanchez La Rosa C, Galluzzo ML, Millán N, Fiandrino F, Felice MS. Children and Adolescent Hodgkin Lymphoma in Argentina: long-term Results After Combined ABVD and restricted Radiotherapy. J Pediatr Hematol Oncol. 2017;39(8):602-608. https://doi.org/10.1097/MPH.0000000000000943  
  60. Geel JA, Chirwa TC, Rowe B, Eyal KC, Omar F, Stones DK, et al. Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children's Cancer Study Group. Pediatr Blood Cancer. 2017;64(10). https://doi.org/10.1002/pbc.26536  
  61. Ghafoor T. Prognostic factors in pediatric Hodgkin lymphoma: experience from a developing country. Leuk Lymphoma. 2020;61(2):344-350. https://doi.org/10.1080/10428194.2019.1665666  
  62. Parambil BC, Narula G, Prasad M, Shah S, Shet T, Shridhar E, Khanna N, Laskar S, Gujral S, Sankaran H, Banavali S. Clinical profile and outcome of classical Hodgkin lymphoma treated with a risk-adapted approach in a tertiary cancer center in India. Pediatr Blood Cancer. 2020;67(2):e28058. https://doi.org/10.1002/pbc.28058  
  63. Geel J, van Zyl A, Plessis JD, Hendricks M, Goga Y, Carr A, Neethling B, Hramyka A, Omar F, Mathew R, Louw L, Naidoo T, Ngcana T, Schickerling T, Netshituni V, Madzhia E, du Plessis L, Kelsey T, Ballot DE, Metzger ML. Improved survival of children and adolescents with classical Hodgkin lymphoma treated on a harmonised protocol in South Africa. Pediatr Blood Cancer. 2024;71(1):e30712. https://doi.org/10.1002/pbc.30712  
  64. Hessissen L, Khtar R, Madani A, El Kababri M, Kili A, Harif M, Khattab M, Sahraoui S, Benjaafar N, Ahid S, Howard SC, Benchekroun S. Improving the prognosis of pediatric Hodgkin lymphoma in developing countries: a Moroccan Society of Pediatric Hematology and Oncology study. Pediatr Blood Cancer. 2013;60(9):1464-1469. https://doi.org/10.1002/pbc.24534  
  65. Rodriguez-Galindo C, Friedrich P, Alcasabas P, Antillon F, Banavali S, Castillo L, Israels T, Jeha S, Harif M, Sullivan MJ, Quah TC, Patte C, Pui CH, Barr R, Gross T. Toward the cure of all children with cancer through collaborative efforts: pediatric oncology as a global challenge. J Clin Oncol. 2015;33(27):3065-3073. https://doi.org/10.1200/JCO.2014.60.6376
  66. Moleti ML, Testi AM, Foà R. Childhood aggressive B-cell non-Hodgkin lymphoma in low-middle-income countries. Br J Haematol. 2022;196(4):849-863. https://doi.org/10.1111/bjh.17979
  67. Kalra M, Bakhshi S, Singh M, Seth R, Verma N, Jain S, Radhakrishnan V, Mandal P, Mahajan A, Arora RS, Dinand V, Kapoor G, Sajid M, Kumar R, Taluja A, Mallick S, Chandra J. Response assessment by positron emission tomography-computed tomography as compared with contrast-enhanced computed tomography in childhood Hodgkin lymphoma can reduce the need for radiotherapy in low- and middle-income countries. Pediatr Blood Cancer. 2023;70(2):e30091. https://doi.org/10.1002/pbc.30091
  68. Mulder RL, Font-Gonzalez A, Green DM, Loeffen EAH, Hudson MM, Loonen J, Yu R, Ginsberg JP, Mitchell RT, Byrne J, Skinner R, Anazodo A, Constine LS, de Vries A, Jahnukainen K, Lorenzo A, Meissner A, Nahata L, Dinkelman-Smit M, Tournaye H, Haupt R, van den Heuvel-Eibrink MM, van Santen HM, van Pelt AMM, Dirksen U, den Hartogh J, van Dulmen-den Broeder E, Wallace WH, Levine J, Tissing WJE, Kremer LCM, Kenney LB, van de Wetering MD; PanCareLIFE Consortium. Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline harmonization Group. Lancet Oncol. 2021;22(2):e57-e67. https://doi.org/10.1016/S1470-2045(20)30582-9
  69. Mulder RL, Font-Gonzalez A, Hudson MM, van Santen HM, Loeffen EAH, Burns KC, Quinn GP, van Dulmen-den Broeder E, Byrne J, Haupt R, Wallace WH, van den Heuvel-Eibrink MM, Anazodo A, Anderson RA, Barnbrock A, Beck JD, Bos AME, Demeestere I, Denzer C, Di Iorgi N, Hoefgen HR, Kebudi R, Lambalk C, Langer T, Meacham LR, Rodriguez-Wallberg K, Stern C, Stutz-Grunder E, van Dorp W, Veening M, Veldkamp S, van der Meulen E, Constine LS, Kenney LB, van de Wetering MD, Kremer LCM, Levine J, Tissing WJE; PanCareLIFE Consortium. Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2021;22(2):e45-e56. https://doi.org/10.1016/S1470-2045(20)30594-5  
  70. Parkers J, Hess C, Burger H, Anacak Y, Ahern V, Howard SC, Elhassan M, Ahmed S, Ghalibafian M, Abbasi AN, Qureshi BM, Zaghloul M, Zubizarreta E, Bey P, Davidson A, Bouffet E, Esiashvili N. Recommendations for the treatment of children with radiotherapy in low- and middle-income countries (LMIC): A position paper from the Pediatric Radiation Oncology Society (PROS-LMIC) and Pediatric Oncology in Developing Countries (PODC) working groups of the International Society of Pediatric Oncology (SIOP). Pediatr Blood Cancer. 2017;64 Suppl 5. https://doi.org/10.1002/pbc.26903