Treatment Advances For Burkitt Lymphoma - Longdom

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JouOPENamial of LeukernACCESS Freely available onlineJournal of LeukemiaISSN: 2329-6917Research ArticleTreatment Advances for Burkitt LymphomaIssa Hajji Ally1,2, Ting Yang1,2* and Jianda Hu1,2Department of Hematology, Union Hospital, People’s Republic China; 2Laboratory Department, Fujian Medical University UnionHospital, Fuzhou, People’s Republic Chinat1ABSTRACTBurkitt Lymphoma (BL) is an uncommon but highly aggressive B-cell Non-Hodgkin Lymphoma (NHL). It is a subtypeof mature B-cell lymphoma and can be treated successfully within a short period via high-intensity chemotherapeuticregimens. Diagnosis and initial work-up must be completed rapidly to begin treatment due to high proliferation. BLis associated with the Epstein-Barr Virus (EBV) and with a chromosomal translocation that activates the c-MYC gene.However, by implementing chemotherapy regimens, complete remission and overall survival for young patients withBL remains high. In contrast, in elderly patients and those with relapsed/refractory disease, the prognosis remainsa medical challenge.Rituximab, the chimeric monoclonal antibody against CD20, has improved the clinical management of B-cellmalignancies. Because BL expresses a CD20 positive marker in their cell surfaces, rituximab has been shown toimprove patient survival rate. However, because resistance can still occur, further treatment and evaluation isrequired, including inhibition of the MYC proto-oncogene through the use of bromodomain inhibitors. In thisreview, we highlight the treatment advances and progress in BL.Keywords: Burkitt lymphoma; MYC; Epstein-Barr virus; RituximabINTRODUCTIONBurkitt Lymphoma (BL) is a highly aggressive but potentiallycurable type of B-cell Non-Hodgkin Lymphoma (NHL) witha cellular doubling time of 24-48 hours. Derived from B-cellgerminal centers [1], BL was first described as a distinct clinicalentity in 1958. It was one of the first human tumors found to havea relationship with a viral infection (EBV). BL is also associatedwith a chromosomal translocation that activates the MYC protooncogene and is the first lymphoma reported to be associated withHuman Immunodeficiency Virus (HIV) infection [2]. BL is one ofthe most common pediatric malignancies in sub-Saharan Africancountries, with an incidence rate as high as 4.7 cases per year formales and 3.0 cases per year for females (per 100, 000 childrenunder 15 years of age) [3]. Three subtypes of BL are recognized:Endemic, Sporadic, and Immunodeficiency-associated.Endemic (African) BL, which mainly occurs in equatorial Africa(it also occurs in Papua Guinea), is the most common subtypein childhood and boys are more likely to be affected than girls(approximate ratio of 2:1). Endemic BL accounts for nearly 30%50% of all childhood cases [4,5], and infection by EBV is foundin nearly 100% of all patients with endemic BL [6]. Moreover,although Plasmodium falciparum is not an agent of the MYCproto-oncogene, its possible oncogenic development of BL hasbeen demonstrated through the shared geographic distribution ofBL and malaria [7].Sporadic BL is primarily observed in young adults, with anincidence of 1%-2% of all lymphomas occurring at a median age of30 (M:F is 3:1 or 4:1), although in pediatrics, it represents 40% ofall lymphomas. Moreover, EBV is detectable in 30% of sporadicBL [8-10] and the disease is more common in Caucasians thanAfricans or Asian-Americans. It may also be common in some areasof Central America (Guatemala) [11].Immunodeficiency-associated BL, the third subtype, is seenprimarily in HIV patients, often occurring as the initial clinicalmanifestation of AIDS. Indeed, an EBV infection is detected inapproximately 40% of cases. Interestingly, immunodeficiencyassociated BL is unlike other HIV-associated B-cell lymphomasbecause it typically occurs in patients with CD4 counts greater than200 cells per μL. As a result of antiretroviral therapy, the incidencehas decreased, but it may also be seen in other immunodeficiencyCorrespondence to: Ting Yang, Department of Hematology, Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, People’s RepublicChina, Tel: 0086-1395021357; E-mail: [email protected] Hu, Department of Hematology, Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, People’s Republic China, Tel: 008613959169016; E-mail: [email protected]: March 04, 2019, Accepted: March 14, 2019, Published: March 21, 2019Citation: Ally IH, Yang T, Hu J (2018) Treatment Advances for Burkitt Lymphoma. J Leuk 7:255. doi: 10.35248/2329-6917.7.255Copyright: 2019 Ally IH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.J Leuk, Vol. 7 Iss. 2 No: 2551

Ally IH, et al.states (e.g. post organ transplant). These patients typically presentwith BL 4-5 years after organ transplantation [11,12]. This reviewdiscusses the treatment of advanced BL. In recent decades,researchers have discovered different combination chemotherapyregimens and combined them with rituximab as a new form of BLtreatment. However, resistance can occur in some cases. We believethat this is the most up-to-date study to discuss the treatment of BL.METHODSA literature search of treatment advances for Burkitt lymphomawas performed for English-language review articles, using theelectronic database of Pubmed. The following search terms wereinput: (Burkitt lymphoma) or (Burkitt’s lymphoma) and (treatment)in (Title/Abstract). The first author and corresponding authorinvestigated all relevant studies for quality and publication date.Importantly, a list of references was added manually.Epstein-Barr virus and Burkitt lymphomaEpstein-Barr Virus (EBV) is a ubiquitous virus that belongs tothe γ herpes virus subfamily, which is well-known for comprisingtumor viruses that express viral cancer genes and immortalizeinfected-lymphocytes. Of these, EBV is the most commonpersistent viral infection in humans, with approximately 95% ofthe world’s population exposed. Initial infection with EBV is oftenasymptomatic, but it can manifest as infectious mononucleosis [13].In past decades, EBV was detected in cultured cells derived from apatient with BL [14]. However, EBV is not completely critical in thedevelopment of BL, which can develop in its absence. Nevertheless,the etiological role of virus infection is supported by the findingthat, in EBV-positive cases, every tumor cell harbors monoclonalEBV genomes. More research is required regarding the precisedetails of BL pathogenesis, specifically in terms of the nature of theB-cell initially infected with EBV, whether EBV infection precedesor follows the c-MYC translocation, and which viral genes areinvolved at different stages of the tumor transformation process[15,16].Clinical presentation and evaluation of BLBecause BL is highly aggressive, patients usually present withenlarged masses and signs of tumor lysis syndrome, withsignificantly elevated serum LDH and Ki-67 staining up to 95%.Bone marrow and Central Nervous System (CNS) involvement canbe found in 15%-30% of all cases. Sporadic BL patients generallypresent with abdominal involvement, while endemic BL patientspresent with intra-oral masses, such as of the jaw or maxilla.Immunodeficiency-associated BL is primarily seen in patients whoare HIV-positive, particularly in those with low CD4 counts. Theclinical presentation includes CNS involvement or peripheralblood and bone marrow involvement.The clinical evaluation of BL is always an emergency procedure.Bone marrow aspiration and biopsy and lumber puncture arenecessary to diagnose BL, in addition to liver and renal functiontests and radiographic staging with Computed Tomography scan(CT) and Positron Emission Tomography (PET) of the chest, pelvis,and abdomen. The Ann Arbor staging system for the extent ofdisease evaluation is currently widely used. In recent years, however,the Lugano classification has emerged for staging of NHL [17,18].J Leuk, Vol. 7 Iss. 2 No: 255OPENACCESS Freely available onlineMorphology and cytogeneticsBL tumor cells are usually monomorphic with very limitedpleiomophism. Importantly, the diagnosis of BL demonstratescytogenetic characteristics of t(8;14) (q24;q32) and its varianttranslocation t(2;8) (p12;q24) and t(8;22) (q24;q11), occurringin 90% of cases, or c-MYC rearrangement. The rate of Ki-67proliferative index is usually 90%, and up to 100% in BL.However, a high Ki-67 by itself does not equate with BL. Therefore,when diagnosing BL, karyotyping and FISH are commonly used todetect MYC translocation [19-21].Immunophenotype and molecular signatureBL is a subtype of B-cell NHL, for which positive B-cell markersare typically detected, including CD10, CD19, CD20, CD22, andCD79a; BCL6 and monotypic surface IgM with kappa and lambda.BL cells do not usually express CD5 and CD23 or Terminaldeoxynucleotidyl Transferase (TdT). Meanwhile, BCL2 is negativein most patients. The over proliferation of B-cells derived from thelymphoid cells’ Germinal Center (GC) are separated into blast(centroblast) and centrocyte. The somatic hypermutation expressimmunoglobulin gene variable (IgV) region transforms B-cellsinto neoplasm with either BL or diffuses, Large B-Cell Lymphoma(DLBCL) [22].TREATMENT OPTIONSDue to the aggressive nature of BL, diagnosis and workup should becompleted as soon as possible to begin chemotherapy. Interestingly,different types of chemotherapy protocols are recommended, andthe prognosis for this disease is good.Treatment must be started promptly (ideally within 48 hours afterdiagnosis) including the prevention of Tumor Lysis Syndrome(TLS). The unavoidable first step of treatment is the applicationof the prophase, with low-dose cyclophosphamide and prednisone.This pre-phase helps limit the risk of TLS by decreasing the releaseof cytokines, particularly in case of high tumor burden-a situationthat can be lethal given the aggressiveness and chemo-sensitivity ofthe tumor burden. The anti-CD20 monoclonal antibody rituximabtransforms the management of other mature B-cell malignancies[23-25]. Clinical trials have demonstrated that adding rituximabto chemotherapy can improve patients’ Overall Survival (OS).An efficacy benefit has also been shown in patients with BL andother aggressive lymphomas. However, in pediatrics, rituximab isgiven prior to chemotherapy. Because BL expresses CD20 positivemarkers in their cell surfaces, rituximab has been shown to improvethe survival rate in this disease (Table 1).ChemotherapyHyper-CVAD regimen: The MD Anderson Cancer Centerdeveloped a hyper- CVAD regimen (hyper-fractionatedcyclophosphamide, adriamycin, vincristine, and dexamethasonealternating with methotrexate plus cytarabine), which has beenused to treat B-cell aggressive neoplasms in addition to rituximab.This regimen was evaluated prospectively in 31 adult patients witheither ALL or BL. The outcomes were excellent. The achievedresponse rate was 81%, with an overall survival of 89%; Only oneinduction death was observed [26,27]. The hyper-CVAD regimen isoften used in adult patients.CODOX-M/IVAC regimen: Although BL is highly invasive, it is2

Ally IH, et al.OPENACCESS Freely available onlineTable 1: Treatment results of Rituximab combined with different chemotherapy regimens.RegimenPatientnumberMedian age(year)[26]Hyper-CVAD265821 (81)49 (3)61 (3)[27]R-Hyper-CVAD314624/28 (86)89 (3)80 (3)92 (2)ReferenceComplete remissionrate (%)Overall survival % (year)EFS/PFS, % (year)[28]CODOX-M IVAC412539 (95)No report[25]R-CODOX-M-IVAC2544100 (92)84 (2)80 (2)[24]RD-CODOX-M/IVAC30529082 (4)78 (4)[29]CALGB (GMALL type)924768 (74)No reportNo report[30]GMALL B-NHL 20021054783 (79)67 (3)75 (3)[31]CALBG 10002 (GMALLtype)1054477 (73)79 (2)74 (2)[32]DA-EPOCH R1925No report100 (7.1)95 (7.1)chemosensitive. Multiagent chemotherapeutic regimens yieldedsignificant impacts in the treatment of BL. One such regimen isreferred to as CODOX-M/IVAC, as demonstrated by Magrathet al. at the National Cancer Institute (NCI) in 1996. Thisregimen consists of cyclophosphamide, vincristine, doxorubicin,and methotrexate alternating with ifosfamide, etoposide andcytarabine, along with intrathecal methotrexate and cytarabine.This regimen was reported in 72 patients, consisting of 39 adultsand 33 children, stratified into low- and high-risk groups. Thelower risk stratification was described as an extra-abdominal massor resected abdominal disease with normal LDH, and the patientswere given three cycles of treatment. Patients considered to be highrisk were given two cycles each of CODOX-M/IVAC, which yieldedfavorable outcomes, with an Event-Free Survival (EFS) rate of 92%after two years. According to Evens et al. 25 patients (20 high-riskand 5 low-risk) were enrolled and treated with this regimen, whichresulted in 2-year PFS and OS rates of 80% and 84%, respectively.The CODOX-M/IVAC was reported as achieving a better outcomecompared with that of children and younger adults [24,25,28].Cancer and leukemia group B (CALGB): Another short-durationchemotherapy regimen was introduced by the Cancer and LeukemiaGroup B (CALGB) phase, which involved two multi-institutiontrial that included 105 patients with BL/BLL with median ageof 43 (range 19-79). Patients received one week of cytoreduction,including cyclophosphamide and prednisone with allopurinol (onecycle), and subsequently undertook six cycles of cyclophosphamide,ifosfamide, methotrexate, vincristine, cytarabine, etoposide,glucocorticoids, and intrathecal plus rituximab. Patients alsoreceived intrathecal therapy. Nearly 80% completed at least six ofthe seven planned cycles of therapy. There were seven treatmentrelated deaths. The rate of complete remission was 83%, withno differences observed related to age. The EFS at two years was78% and OS was 80%, with a few relapses occurring after twoyears. Interestingly, s