Treatment Outcome of Burkitt ’ s Lymphoma in Adolescents and Adults: A Retrospective Study

Introduction Burkitt ’ s lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma (NHL) having three distinct subtypes: endemic, sporadic, and immunode ﬁ - ciency-associated BL. Sporadic BL accounts for only 1 to 2% of adult NHL. Objectives The objective of this article was to study the clinical pro ﬁ le and treatment outcome of patients with BL. Materials and Methods This was a retrospective study of 60 patients with BL conducted in the department of medical oncology at a tertiary cancer center in India during a 10-year period. Patients with BL/leukemia above 14 years of age diagnosed during the study period were included and their clinical presentation, treatment details, and outcome were studied. Results Among 60 cases with BL, there were 41 males and 19 females. The median age at presentation was 42 years (range: 14 – 81 years). The main symptoms were lymphadenopathy, abdominal pain, and abdominal distension. Two patients each had paraparesis, breast lump, and jaw swelling and one patient had involvement of the cervix. Thirteen patients had features of tumor lysis at presentation. The


Introduction
Burkitt's lymphoma (BL) is an aggressive B-cell lymphoma characterized by a high degree of proliferation of the malignant cells and deregulation of the proto-oncogene c-myc. 1 BL is predominantly a disease of childhood, but it is also seen in the adult population.The World Health Organization (WHO) classification of BL describes three clinical variants: endemic, sporadic, and immunodeficiency-related. 2 These types are similar in morphology, immunophenotype, and genetic features.Endemic BL is the most common childhood cancer in equatorial Africa associated with Epstein-Barr virus (EBV) and plasmodium falciparum malaria.The sporadic type predominates in the rest of the world with no special climatic or geographical links, and is rarely associated with EBV infection.Sporadic BL (sBL), accounts for 1 to 2% of all adult lymphomas in Western Europe and the United States. 3The diagnostic and therapeutic principles of BL in adults are the same as those in the pediatric population.A recent study of the Swedish Lymphoma Registry confirmed advanced age, poor WHO performance status, and elevated serum lactate dehydrogenase (LDH) as significant prognostic factors for adult BL. 4 The present retrospective analysis provides information on clinical presentation, histology patterns, and outcome of adolescents, adults, and elderly patients with BL treated at a tertiary cancer center in India.

Objectives
The objectives of this article were to study the clinical characteristics, treatment response, and survival of BL in adolescent and adult patients.The primary outcome measures were treatment response and progression-free survival (PFS).The secondary outcome measure was overall survival (OS) at 8 years.

Materials and Methods
Study Setting: This was a retrospective study conducted in the department of medical oncology at a tertiary cancer center in India during a 10-year period (January 2005 to December 2014).Patients with BL/leukemia above 14 years of age treated during the study period were included.We analyzed 60 patients with BL.
Inclusion/ Exclusion Criteria: Eligibility criteria included all patients aged above 14 years with a histological diagnosis of BL/leukemia.Patients with relapsed BL and who received some prior treatments were excluded from the study.
Methodology: Medical records of patients were studied with respect to the demographic details, clinical history, physical examination, baseline investigations like complete hemogram, serum chemistry, and serum LDH.Staging workup including histopathology report, bone marrow study, cerebrospinal fluid analysis, and imaging studies were noted.The disease was staged according to the Ann Arbor staging system.The treatment response at the end of induction and on completion of treatment was obtained.Clinical response was classified as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease based on modified Cheson lymphoma response evaluation criteria. 5S was assessed from the initiation of definitive chemotherapy to the last follow-up or death and PFS was calculated from the initiation of chemotherapy till disease progression.
Statistical Analysis: The baseline patient characteristics, treatment details, and response assessment were analyzed using descriptive statistics.OS and PFS were obtained by Kaplan-Meier method, using SPSS v. 11.The risk analysis for OS and PFS was done using Cox regression analysis.Statistical significance was defined as a p-value less than 0.05.
Ethics: The study was approved by the Institutional Review Board (IRB No. 09/2016/03, dated September 1, 2016).Informed consent was waived off due to retrospective nature of the study.All procedures performed in study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Results
Baseline Patient Characteristics (shown in ►Table 1) During the period 2005 to 2014, 3,811 cases of non-Hodgkin lymphoma (NHL) above 14 years of age were treated in our
Thirty-five patients received HCVAD AE R among them, 22 (63%) attained complete remission, 9 (26%) had progressive disease, 2 (6%) relapsed, and 4 (11%) patients died during the treatment.The median cycles of HCVAD regimen were 8 (4 cycles of A and 4 cycles of B).Twenty-two out of thirty-five patients (63%) were able to complete all planned cycles of chemotherapy with a median duration of 7 months (range: 6-10 months).Out of thirteen patients who received CHOP/ CVP AE R chemotherapy, only six (46%) patients attained complete remission, three (23%) had disease progression, and four patients (31%) died during chemotherapy.All patients on R CODOX-M/IVAC, Murphy's protocol and three of four patients on BFM protocol attained complete remission.
Among the 34 patients who achieved remission, four patients (12%) relapsed and received palliative chemotherapy later.Two patients with central nervous system (CNS) disease at diagnosis, two with extra nodal primary and one patient with residual disease after chemotherapy received RT after completion of the chemotherapy.

Survival (►Table 3)
The PFS was 58.3 at 2 years and 56.2 at 5 and 8 years.The 2year OS was 61.6% and 58.2% at 5 and 8 years (►Fig.

Discussion
BL is one of the most aggressive types of cancer and yet one of the most curable.Mostly, BL originates from B cells in the  Burkitt's Lymphoma in Adolescents and Adults Sugeeth et al. 25 follicular germinal center.BL is the first lymphoma reported to be associated with HIV infection. 6sBL in North America and Europe makes up 30 to 40% of childhood NHL and 1 to 5% of adult NHL. 7 sBL attacks regions outside Africa, with an incidence of about 4 per million in the United States. 8In India, BL constitutes 1.8 to 3.4% of all adult NHL. 9 BL is a classic example of a human malignancy whose pathogenesis involves a specific cellular genetic change characterized by a chromosomal translocation deregulating expression of the c-myc oncogene, complemented in many cases by the action the EBV. 10 This is the largest case series from India describing the treatment outcome of adolescent and adult patients with BL.In our series, the median age at presentation was 42 years (range: 14-81 years) with 11% patients above 65 years of age.These findings are consistent with other case series. 3,11,12In an Indian study including pediatric patients, BL constituted 3.5% of all NHL and the median age at presentation was 22 years. 13In this study, patients have a higher frequency of B-symptoms (65%) and advanced disease compared to European studies. 14In our study, bone marrow involvement was the most common extranodal site (30%) followed by gastrointestinal tract (22%).CNS involvement in our study was 3% compared to 15% in a study by Saleh et al. 14 Eleven patients (18%) had BL at presentation that was comparable with another study by Mbulaiteye et al. 7 Treatment success of BL resulted from the introduction of dose-intense multidrug chemotherapy, prophylaxis of CNS disease, and improvements in supportive care.The management of this aggressive lymphoma is a challenge in our resource-limited setting and the published data from the Indian population is scarce.The frequently used regimens in adolescent and adults based on pediatric protocols are CODOX-M/IVAC, the German BFM, and the French Lymphome Malins B regimens.6][17] In our study, most of the young and fit patients received HCVAD AE R (63.5%) and elderly patients with poor performance status received CHOP/CVP AE R (22%).The complete response rate in the entire population was 62%, 2-year PFS of 58.3%, and a 2-year OS of 61.6%.A study from India showed similar results with a complete response rate of 63% with 2-year PFS of 56%. 18atients above 65 years of age and frail patient who received less intense therapy, the 8-year OS was 46% that makes it an alternate option in elderly and frail patients.Similar studies in BL in adult patients receiving CHOP-based chemotherapy had a 2-year OS of 33 to 39%. 19,20Patients who received HCVAD AE R chemotherapy had a complete response rate of 63%, 8-year PFS and OS of 60%.Review on treatment outcome in BL is given in ►Table 4. 12,17,[21][22][23][24][25] In this study, only a few patients received other chemotherapy regimens like CODOX-M/IVAC, BFM, and Murphy's protocol to compare on survival.►Table 4 shows review of treatment outcome in BL.

Limitations
The study period was January 2005 to December 2014, during this period molecular study for BL was not available at our center.This is a retrospective data analysis.Patients were not treated with uniform protocol as they received different protocols depending on the time period the diagnosis was made.

Future Research Directions
Risk-adapted treatment that limits early and late drug toxicity ensuring optimal outcome should be adopted for BL.In elderly patients, R DA EPOCH is the preferred choice with better outcomes.Randomized control trials in Indian population are required to better define the treatment for elderly patients with BL.

Conclusions
BL accounts for 1.57% of NHL above the age of 14 years with male preponderance.Intensive, short-duration chemotherapy is the standard treatment.Treatment with HCVAD AE R gives 8-year PFS of 60% at 8 years.Treatment with R CHOP is an alternative option in elderly frail populations with an 8year OS of 46%.

Table 1
Baseline patient characteristics Complete IHC marker panel was done in 40 patients.Out of 11 patients with BL, four patients were diagnosed as acute lymphoblastic leukemia L3 on flow cytometry (►Supplementary Material TableB, available in the online version).Thirty-nine patients had a MIB labeling index of 100% and the lowest MIB labeling index was 80%.
Abbreviations: Hb, hemoglobin; LDH, lactate dehydrogenase; M: F, male: female ratio; S. Bil, serum bilirubin; S. Ca, serum calcium; S. Cr, serum creatinine; S. K, serum potassium; S. Ph, serum phosphorus; S. UA, serum uric acid; TLS, tumor lysis syndrome; ULN, upper limit of normal.department, of which 60 were BL (1.57%).The median age at presentation was 42 years (range: 14-81 years).There were 41 males and 19 females, with the male to female ratio of 2.16: 1. Twenty-five patients (42%) were less than 40 years of age and elderly patients above more than 65 years constituted 10% of our study population.The most common presenting symptoms were lymphadenopathy, abdominal pain and abdominal distension.Two patients each presented with paraparesis, breast lump, jaw swelling and one patient presented with vaginal mass.(►SupplementaryMaterialTableA, available in the online version).Three patients presented to us following surgery for acute intestinal obstruction and diagnosis of BL was confirmed on histopathological examination of the surgically resected specimen.B symptoms were present in 39 patients (65%).The median duration of symptoms was 4 weeks (range: 1-16 weeks).Eleven patients had BL at presentation (18%) and 13 patients had features of tumor lysis syndrome (22%).Laboratory tumor lysis syndrome was present in all 13 patients and clinical tumor lysis syndrome in 6 patients (10%).Patient had a mean hemoglobin of 11.6 g/dL, mean total leucocyte count of 8,586/mm 3 , and a mean platelet count of 2.8 lakhs/mm 3 .In our study population, only one patient tested positive for human immunodeficiency virus (HIV) infection.Cerebrospinal fluid was positive