Abstract
              Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26–71), seven (58%) were male, and six (50%) were HIV-positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24–79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA

Chikasema, Maria

Chimzimu, Fred

Chiyoyola, Sarah

Dhungel, Bal M

Fedoriw, Yuri

Gopal, Satish

Kaimila, Bongani

Kampani, Coxcilly

Kasonkanji, Edwards

Krysiak, Robert

Kudowa, Evarista

Montgomery, Nathan D

Mulenga, Maurice

Ntangwanika, Asekanadziwa

Painschab, Matthew S

Seguin, Ryan

Tewete, Blessings

Tomoka, Tamiwe

Zuze, Takondwa

Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26–71), seven (58%) were male, and six (50%) were HIV-positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24–79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA

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SHORT REPORT Open AccessPlasmablastic lymphoma in MalawiTakondwa Zuze1, Matthew S. Painschab1,2, Ryan Seguin1,2, Evarista Kudowa1, Bongani Kaimila1,Edwards Kasonkanji1, Tamiwe Tomoka1,3, Bal Mukunda Dhungel1,2, Maurice Mulenga4, Maria Chikasema1,Blessings Tewete1, Asekanadziwa Ntangwanika1, Sarah Chiyoyola1, Fred Chimzimu1, Coxcilly Kampani1,Robert Krysiak1,2, Nathan D. Montgomery2, Yuri Fedoriw2 and Satish Gopal1,2,3*AbstractPlasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV andEBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort inLilongwe, Malawi. Median age was 46 (range 26–71), seven (58%) were male, and six (50%) were HIV-positive. Eightpatients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was56% (95% CI 24–79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA.Keywords: Plasmablastic lymphoma, HIV, EBV, EPOCH, Sub-Saharan AfricaIntroductionPlasmablastic lymphoma (PBL) is an aggressivenon-Hodgkin lymphoma (NHL) subtype associated withhuman immunodeficiency virus (HIV) infection [1], con-stituting 2% of all HIV-associated lymphomas [2]. Des-pite strong association with HIV, PBL is also seen inHIV-negative patients [3, 4]. Epstein-Barr virus (EBV)increases plasmablasts in blood and lymph nodes in thepresence or absence of HIV, and may play a direct rolein PBL development [5].Despite high prevalence of HIV infection insub-Saharan Africa (SSA), PBL descriptions from the re-gion are scarce. We describe characteristics, treatment,and outcomes of PBL patients enrolled in a prospective,observational cohort in Malawi. This is among the firstdetailed clinical descriptions of this unique and aggres-sive NHL subtype from SSA, where HIV and EBV areendemic.MethodsWe identified patients with PBL enrolled in the prospect-ive Kamuzu Central Hospital Lymphoma Study betweenMay 2013 and May 2017 in Lilongwe, Malawi. PBL diag-noses were histologically and immunophenotypicallyconfirmed, and underwent subsequent secondary reviewin the United States [6]. All cases were positive for CD138and negative for CD20 with Ki67 > 90%.Following diagnosis, all patients underwent standardizedclinical, laboratory, and radiologic assessments as previ-ously described [7]. Before August 2016, patients weretreated with CHOP (cyclophosphamide 750 mg/m2, doxo-rubicin 50 mg/m2, vincristine 1.4 mg/m2 day 1, and pred-nisone 40 mg/m2 days 1–5; 21 day cycles). After August2016, patients received a modified EPOCH regimen (eto-poside 50 mg/m2, vincristine 0.4 mg/m2, and doxorubicin10 mg/m2 days 1–4, prednisone 60 mg/m2 days 1–5, andcyclophosphamide 750 mg/m2 day 1; 21-day cycles). Be-cause the local clinical environment does not allow safeadministration of 24-h continuous infusions, 24-h dosesof etoposide, vincristine, and doxorubicin were instead ad-ministered over 6–8 h on successive days. Hematopoieticgrowth factors were not available. All HIV-infected pa-tients received antiretroviral therapy (ART) concurrentwith chemotherapy.Cohort characteristics were summarized using simpledescriptive statistics. Patients were followed until deathor administrative censoring on September 30, 2017. Ad-verse events were reported using National Cancer Insti-tute Common Terminology Criteria for Adverse Eventsversion 4.0. Kaplan-Meier methods were used to esti-mate overall survival (OS). Analyses were conductedusing Stata version 14.1 (College Station, Texas).* Correspondence: satish_gopal@med.unc.edu1UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi2University of North Carolina, Chapel Hill, USAFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Zuze et al. Infectious Agents and Cancer  (2018) 13:22 https://doi.org/10.1186/s13027-018-0195-4ResultsOf 183 adults with pathologically confirmed NHLduring the study period, we identified 12 patientswith PBL (Table 1). Median age was 46 years (range26–71), seven (58%) were male, and six (50%) wereHIV-positive. Of HIV-positive patients, three were di-agnosed with HIV prior to PBL diagnosis, and hadbeen on ART for 6, 10, and 14 months. AmongHIV-positive patients, median CD4 cell count was147 cell/μL (range 9–460) and three (50%) had sup-pressed HIV RNA < 400 copies/mL at PBL diagnosis.Of seven patients whose tumors were tested forEBV-encoded RNA (EBER) by in situ hybridization,five (71%) were positive: 3/3 HIV-positive, 2/4HIV-negative. All patients had a primary site of dis-ease in the head and neck. Nine (75%) patients hadAnn Arbor stage I/II disease. Median lactate dehydro-genase was 339 IU/L (range 186–2522 IU/L, upperlimit of normal 250 IU/L).Eight patients were treated with CHOP for a medianof six cycles (range 1–8). Four patients received themodified EPOCH regimen for a median of five cycles(range 2–6). All patients receiving EPOCH and 50% ofCHOP recipients experienced treatment delay due tograde 3/4 neutropenia and one CHOP recipient experi-enced delay due to grade 3 anemia. Overall, five (42%)patients achieved a complete response (CR) after chemo-therapy [CHOP 2/8 (25%); EPOCH 3/4 (75%)]. Both pa-tients who achieved CR after CHOP relapsed 4 monthsafter treatment completion.As of September 30, 2017, vital status was known forall patients and median follow-up was 13 months (range1–35) among patients still alive. One-year OS was 56%(95% CI 24–79%, Fig. 1). No differences were observedbetween HIV-positive patients (1-year OS 67, 95% CI19–90%) and HIV-negative patients (1-year OS 42, 95%CI 6–77%, p = 0.53). Of seven deaths, one was due toneutropenic sepsis and six due to lymphomaprogression.DiscussionIn resource-rich settings, PBL is a rare lymphoma subtypewith poor outcomes [8, 9]. The current National Compre-hensive Cancer Network guidelines recommend intensivechemotherapy regimens such as dose-adjusted EPOCH,hyper-CVAD (cyclophosphamide, vincristine, doxorubicin,dexamethasone alternating with cytarabine, methotrex-ate), or CODOX-M/IVAC (cyclophosphamide, vincristine,doxorubicin, methotrexate alternating with ifosfamide,etoposide, cytarabine). Consolidative high-dose chemo-therapy and autologous stem cell rescue in first remissionis also recommended by some [10]. Ongoing studies inhigh-income countries are attempting to investigateanti-myeloma agents (bortezomib, daratumumab, etc.)added to aggressive NHL chemotherapy regimens to im-prove outcomes, based on plasmacytic differentiation ofPBL tumor cells [11, 12]. Conversely, other studies havedemonstrated similar or worse results after intensivechemotherapy regimens compared with CHOP due to ex-cess treatment-related complications [10, 13].Table 1 Baseline characteristics of plasmablastic lymphoma patients from the Kamuzu Central Hospital Lymphoma Cohort studyTotal (n = 12) HIV+ (n = 6) HIV- (n = 6)Age, years, median (range) 46 (26–71) 39 (30–60) 53 (26–71)Male sex, n (%) 7 (58) 2 (33) 5 (83)Largest tumor location head and neck, n (%) 12 (100) 6 (100) 6 (100)CNS involvement, n (%) 1 (8) 0 (0) 1 (17)Bone marrow involvement, n (%) 3 (25) 2 (33) 1 (17)Largest diameter of mass, cm, median (range) 10 (3–22) 8 (3–15) 11 (10–22)Ann Arbor stage I/II, n (%) 9 (75) 6 (100) 3 (50)Performance score≥ 2, n (%) 1 (8) 0 (0) 1 (17)White blood cells, 103/uL, median (range) 4.6 (2.7–14.9) 11.6 (6.2–12.5) 6.1 (2.7–14.9)Absolute neutrophils, 103/uL, median (range) 2.74 (0.92–10.6) 2.55 (0.9–4.07) 2.48 (1.3–10.6)Hemoglobin, g/dL, median (range) 11 (6.2–14.9) 11.6 (6.2–12.5) 10.9 (10.1–14.9)Platelets, 103/uL, median (range) 206 (103–666) 210 (176–666) 233 (103–458)Lactate dehydrogenase (LDH), IU/L, median (range)a 338 (186–2522) 328 (240–2522) 226 (186–1803)CD4 count, cells/μL, median (range) ― 147 (9–460) ―HIV RNA < 400 copies/mL, n (%) ― 3 (50) ―EBER expression n (%) 5 (71) 3 (100) 2 (50)Abbreviations: CNS Central nervous system, EBV Epstein Barr virus, EBER EBV encoded RNA, ECOG PS Eastern oncology cooperative group performance status, HIVhuman immunodeficiency virus, LDH lactate dehydrogenaseaLDH normal range = 0–250 IU/LZuze et al. Infectious Agents and Cancer  (2018) 13:22 Page 2 of 4Upon first recognition of PBL in Malawi, and due tosupportive care constraints, we initially treated partici-pants with CHOP resulting in a 25% CR rate, with nearlyall patients dying of progressive disease rather thantreatment-related complications. Given these poor out-comes, we intensified our approach to a modifiedEPOCH regimen adapted as required by clinic infra-structure, resulting in a 75% CR rate, although follow-uptime for this more recently treated group is limited.Nevertheless, this experience illustrates that even in aresource-limited country, sustained investments in cancerdiagnostic and treatment capabilities can lead to recogni-tion of new tumor types, foundational understanding ofoutcomes using standard approaches, and evidence-basedadjustment of therapeutic approaches.HIV-positive and HIV-negative patients with PBL havedifferent clinical and pathologic characteristics, includingbetter response to chemotherapy in HIV-positive patients[14]. HIV-positive PBL patients are younger, predominantlymale, and have more frequent oral involvement.HIV-positive PBL cases have significantly higher expressionof CD20, CD56, and EBER compared with HIV-negativePBL. HIV-positive patients with PBL have also been re-ported to have better survival than HIV-negative patientswith PBL [14]. We found no difference in OS betweenHIV-positive and HIV-negative patients, although our sam-ple size is small and trends in OS by HIV status were simi-lar to those described in high-income countries.Previous studies have indicated that PBL is closely as-sociated with EBV infection. A metanalysis of PBL casesdemonstrated EBV by in situ hybridization in 75% ofHIV-infected cases and 50% of HIV-uninfected cases [9].Similarly, our findings confirmed EBV presence in 3/3HIV-positive cases but only 2/4 HIV-negative cases.Strengths of our study include its prospective longitu-dinal nature, no loss to follow-up, standardized treatment,and pathologic confirmation using immunohistochemistryand telepathology consultation, all of which are not com-mon in studies of lymphoproliferative disorders in SSA.Limitations are small sample size and relatively shortfollow-up. Ongoing enrollment and long-term follow-upwill allow better understanding of prognostic factors andoutcomes.In conclusion, PBL occurs in SSA and may be under-diagnosed in many settings. Further study is needed toidentify best treatment approaches, but our early experi-ence suggests treatment intensification might lead tobetter outcomes for this population even in highlyresource-limited environments.AbbreviationsCD4: Positive for cluster of differentiation 4; CHOP: Cyclophosphamide,doxorubicin, vincristine, and prednisone; EBER: Epstein-Barr virus-encodedRNA; EBV: Epstein Barr virus; EPOCH: Etoposide, prednisone, vincristine,cyclophosphamide and doxorubicin; HIV: Human immunodeficiency virus;OS: Overall survival; PBL: Plasmablastic lymphomaAcknowledgementsWe wish to thank patients and their families for participating in this study.We also thank Wiza Kumwenda for developing the study database, ourpathology team and the University of North Carolina Translational PathologyLaboratory for performing additional stains.FundingThis work was supported by grants from the National Institutes of Health(K01TW009488, R21CA180815, and U54CA190152 to S.G.), the MedicalEducation Partnership Initiative (U2GPS001965), and the LinebergerComprehensive Cancer Center (P30CA016086).Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request.0.000.250.500.751.00Survival Probability6 6 4 4 4HIV+ 6 5 4 2 2HIV- Number at risk0 3 6 9 12monthsp = 0.6151HIV-HIV+Fig. 1 Overall survival of plasmablastic lymphoma patients in Lilongwe stratified by HIV status. No difference was found between HIV+ and HIV-patients by log-rank testZuze et al. Infectious Agents and Cancer  (2018) 13:22 Page 3 of 4Authors’ contributionsTZ performed research, analyzed data, and wrote the manuscript; MSP andRS wrote the manuscript; EK analyzed the data; BK, EK, TT, BMD, MM, MC, BT,SC, AN, FC, CK, RK, NDM, YF performed research; SG designed the study,performed research, and wrote the manuscript. All authors approved themanuscript for submission.Ethics approval and consent to participateAll patients provided written informed consent for participation in theKamuzu Central Hospital Lymphoma Study, which was approved by theMalawi National Health Sciences Research Committee (1107) and Universityof North Carolina Biomedical Institutional Review Board (12–2255).Consent for publicationNot applicableCompeting interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi. 2University ofNorth Carolina, Chapel Hill, USA. 3University of Malawi College of Medicine,Blantyre, Malawi. 4Kamuzu Central Hospital, Lilongwe, Malawi.Received: 23 May 2018 Accepted: 22 June 2018References1. STEIN & H. 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Plasmablastic lymphoma in Malawi

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Plasmablastic lymphoma in Malawi

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