Treatment Of Burkitt Lymphoma Research Articles

TGF-β Induces Growth Arrest in Burkitt Lymphoma Cells via Transcriptional Repression of E2F-1

Transforming growth factor-beta (TGF-beta) is a potent regulator of tissue homeostasis and can act as both a tumor suppressor and a tumor promoter. The ability to induce cell cycle arrest is a major component of the tumor suppressor function of TGF-beta. Lung, mammary, and skin epithelial cells exhibit a common minimal cytostatic program in response to TGF-beta signaling involving the repression of the growth-promoting factors c-MYC, Id1, Id2, and Id3. Loss of c-MYC expression is a pivotal event in this process, resulting in derepression of the cyclin-dependent kinase inhibitors CDKN1A (p21) and CDKN2B (p15) and ultimately leading to growth arrest. It is not clear, however, which responses are necessary for TGF-beta-mediated growth arrest in other cell types. Here, in human Burkitt lymphoma cells transformed by deregulated c-MYC expression, we demonstrate that efficient TGF-beta-induced cytostasis can occur despite both maintenance of c-MYC levels and a lack of p21 and p15 induction. TGF-beta treatment also results in induction, rather than repression, of Id1 and Id2 expression. In this context, growth arrest correlates with transcriptional repression of E2F-1, and overexpression of E2F-1 in Burkitt lymphoma cells largely overcomes the TGF-beta-mediated G(1) arrest phenotype. These data indicate that deregulation of c-MYC in lymphoma cells does not overcome the tumor suppressor function of TGF-beta and that repression of E2F-1 transcription is sufficient for the efficient induction of cytostasis.

Patient compliance in the treatment of Burkitt′s lymphoma in rural Zambia: A retrospective study on 80 Burkitt′s lymphoma patients in Katete, Zambia

In African settings the treatment results of Burkitt's lymphoma (BL) seem to be less favourable compared with Western settings. The aim of this retrospective study was to analyse some factors that affect the treatment of BL. Over a 16 year period, data were extracted of 80 patients. Complete remission 5%, very good partial response 35%, partial response 16%, no response 10%, data missing 34%. Of all patients, 56% did have a positive response to treatment. However, 51% of this subgroup of patients did not finish treatment. There was no difference in completion of treatment between patients living in Katete district finishing treatment vs. living outside Katete district (respectively 25% vs. 32%, P = 0.7148). There is potential for higher cure rates for BL in tropical settings if full effort is put into compliance since a majority of patients, even while having a good prognosis, abandon treatment. Large distance to hospital makes no difference in completing the chemotherapy course.

Treatment of a CNS relapse while on therapy for Burkitt lymphoma

The treatment of Burkitt lymphoma (BL) has come a long way in regards to survival, with the majority of even the advanced stage patients being cured. The prognosis for relapsed BL remains dismal, despite attempts to further intensify therapy. We report on a patient with advanced stage BL who relapsed in the CNS while on therapy. The patient was successfully treated with an intensified regimen based on a concentration times time (C x T) CNS-directed model. Our experience shows both the feasibility and efficacy of such an approach in a patient with an otherwise very poor prognosis.

New EPOCH for Adult Burkitt Lymphoma Treatment

New EPOCH for Adult Burkitt Lymphoma Treatment

Rescue chemotherapy for patients with resistant or relapsed endemic Burkitt's lymphoma

Patients with endemic Burkitt's lymphoma who failed primary treatment with the Malawi 2002 or 2003 Burkitt's lymphoma treatment protocols, consisting of high frequency cyclophosphamide 40 mg/kg and intrathecal methotrexate, were offered rescue chemotherapy. Twenty-eight patients (14 boys and 14 girls; age range 3-13 years) with resistant disease (n=8) or relapse (n=20) presented to the Queen Elizabeth Central Hospital, Blantyre, Malawi. Treatment consisted of cyclophosphamide 60 mg/kg and vincristine 1.5 mg/m(2) i.v. on Days 1, 8 and 15, plus intrathecal methotrexate on the same days in those patients treated for a relapse. The majority of patients (81%) had St Jude stage III or IV disease. Twenty patients (71%) achieved a complete clinical remission. Day 8 treatment was delayed in eight children and Day 15 treatment in five patients, both for a median of 7 days, mainly due to neutropenia. Ten patients relapsed after 42-311 days (median 105 days). Ten patients (36%) remained in remission for 353-712 days (median 487 days). Patients whose first relapse occurred after 6 months as well as those with limited disease had the best outcome. This simple 15-day chemotherapy schedule salvaged 36% of patients and significantly increased the overall cure rate of our Burkitt's lymphoma patients.

Resistência ao tratamento no linfoma de Burkitt: associação com mutações específicas no gene TP53?

O linfoma de Burkitt (LB) surge a partir de uma celula do centro germinativo que perde o controle da proliferacao devido a ativacao do gene c-myc. A resistencia a apoptose e uma causa importante da falha a quimioterapia na maioria dos cânceres e tambem no LB. A taxa alta de apoptose observada no LB em fases iniciais da genese do tumor e seguida pelo desenvolvimento subsequente de inativacao de vias que levam a apoptose da celula. Uma importante via que se encontra alterada no LB e a via mediada pela proteina p53. Essa via e importante para o controle da proliferacao celular em resposta ao dano no DNA. Dados da literatura mostram uma correlacao entre mutacoes do gene TP53 com resistencia ao tratamento. No entanto, alguns estudos tem demonstrado que diferentes tipos de mutacoes podem conferir respostas diferentes das celulas a quimioterapia. Isso tem sido observado em nossos estudos que mostram que linhagens celulares do LB com mutacoes diferentes da p53 apresentam uma resposta diferenciada a apoptose induzida por drogas que atuam por essa via, como, por exemplo, a doxorrubicina. Diferentes tipos de mutacoes conferem fenotipos funcionais distintos, embora nem sempre ocorra uma perda da funcao, o que pode ser um importante componente da resistencia a quimioterapia no LB. Nesse artigo revisamos a literatura com relacao a resposta ao tratamento no LB e discutimos o papel das mutacoes do gene TP53 na resistencia a quimioterapia nesses tumores.

Pilot study of sodium phenylbutyrate as adjuvant in cyclophosphamide-resistant endemic Burkitt's lymphoma

Burkitt's lymphoma (BL) accounts for the majority of childhood malignancies seen in sub-Saharan Africa. In Malawi, cyclophosphamide (CPM), the mainstay of treatment for endemic BL, is effective in around 50% of cases. Evidence exists in support of an association between activation of replication of Epstein-Barr virus (EBV) in the tumour and response to this chemotheraupeutic agent. Phenylbutyrate (PB), approved for treatment of inborn errors of the urea cycle with minimal toxicity in children, induces EBV replication and cell lysis in BL-derived cell cultures. It has also shown some success as adjuvant in treatment of chronic leukaemia and lymphoma. We tested in African BL patients with CPM-resistant tumours, and thus unlikely to survive, the hypothesis that PB can reverse this resistance. A study of five patients showed PB before CPM to induce shrinkage of CPM-resistant tumours in two of them. Findings suggested that for this effect PB pre-treatment should be given for a week before CPM treatment. A larger study is indicated.

P066 The combination of rituximab and HyperCVAD in treatment of Burkitt lymphoma – a single institution expirience

P066 The combination of rituximab and HyperCVAD in treatment of Burkitt lymphoma – a single institution expirience

Ectopic Thymic Hyperplasia in a Patient Treated for Burkitt Lymphoma

Thymic hyperplasia results from thymic regrowth after atrophy during stressful conditions such as burns, surgery, infection, and chemotherapy. Although thymic lesions are relatively common causes of anterior mediastinal masses, they also can develop in other mediastinal compartments on rare occasions. It is well known that thymic tissue can develop in ectopic intrathoracic lesions. Few cases of ectopic thymus associated with disturbance during thymus embryogenesis have been reported as incidental findings. We report the case of a 4-year-old boy with true thymic hyperplasia from an ectopic thymus after successful treatment for Burkitt lymphoma. This is a rare finding in the differential diagnosis of a middle mediastinal mass in a child following chemotherapy for lymphoma. The diagnosis of thymic hyperplasia from an ectopic thymus can be confirmed only histologically.

Efficacy and toxicity of dose-adjusted EPOCH-rituximab in adults with newly diagnosed Burkitt lymphoma

8035 Background: Burkitt Lymphoma (BL) is a rare and highly aggressive lymphoma, characterized by a high tumor proliferation rate. While the standard therapy of BL is highly effective, it involves intensive, multi-agent chemotherapy that is associated with considerable treatment-related toxicity and mortality, especially in older patients. We hypothesized that the regimen DA-EPOCH may be effective in BL, based on the observation that it overcomes the adverse effect of high proliferation in diffuse large B-cell lymphoma. Methods: We investigated DA-EPOCH-rituximab (R) in untreated BL in an attempt to maintain the high cure rates of standard therapy with minimal treatment related toxicity. Eligible patients had a diagnosis of untreated BL and could be HIV negative or positive with HIV negative patients (n=13) receiving 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002) and HIV positive (n=6) patients receiving 3–6 cycles of DA- EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and outpatient therapy where possible. Results: The characteristics of 19 enrolled patients are: median age (range) 29 (18–66) and ECOG PS 1(1–3); stage III/IV 10 (53%); LDH > N 11 (61%); male sex 15 (79%); extranodal sites 13 (68%) and ileocecal disease 13 (68%). No patients so far had CNS involvement at diagnosis. Response is CR/CRu in 100% of patients with one patient receiving consolidative radiotherapy to a site of residual disease. OS and PFS are both 100% and EFS 93.3% at a median potential follow-up time of 29 months. Toxicities were fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There was one case of tumor lysis syndrome and no treatment related deaths. Conclusions: DA-EPOCH-R is highly effective in BL. It appears to be associated with much lower toxicity compared to standard high-dose regimens and may significantly advance the therapeutic index of BL treatment. Accrual continues. No significant financial relationships to disclose.

Successful treatment of a bowel perforation after chemotherapy for Burkitt lymphoma

Chemotherapy-induced intestinal perforation after treatment for Burkitt lymphoma is a known potential complication. However, there are very few reports in the pediatric literature that discuss this complication in any detail, and most incidents are secondary to surgical complications such as anastomotic leaks. Furthermore, there are no reports of children that have survived chemotherapy-induced perforation, and thus, guidelines for the diagnosis and treatment of this complication or for the continuation of chemotherapy are lacking. We present a case of a 5-year-old boy who survived jejunal perforation after treatment for his Burkitt lymphoma, and the critical aspects of his care are discussed.

Treatment of Burkitt lymphoma in children and adults: Lessons from Africa

Modern chemotherapy for childhood Burkitt lymphoma has its origins in Africa, where treatment evolved from one or two doses of single agents, which were curative in some patients, to combinations of non-cross-resistant drugs. Subsequently, in Europe and the United States, high-dose methotrexate, high-dose cytarabine, etoposide, and ifosfamide were found to be active in children with recurrent disease and were incorporated into primary therapy for patients with high-risk disease. These third-generation protocols produce overall cure rates around 90%. Therapy regimens for adults with Burkitt lymphoma have been developed by modifying second-generation pediatric protocols, and few investigators have used the third-generation pediatric regimens that include higher doses of methotrexate and additional agents. The weight of evidence strongly suggests that high-dose therapy with stem cell rescue in first remission cannot substitute for intensive therapy from the outset. Tolerance of intensive regimens by the elderly is a legitimate concern, but it seems appropriate to modify therapy only when necessary in individual patients. The value of rituximab and granulocyte colony-stimulating factor in patients undergoing intensive therapy (particularly the elderly) is worthy of further exploration. Because childhood diffuse large-B-cell leukemia (DLBCL) responds equally well to therapy for Burkitt lymphoma, more intensive therapy and intensive support might also give better results in at least a subset of adults with advanced DLBCL-perhaps defined on the basis of limited molecular profiling, which has provided new information about the categories of aggressive B-cell lymphomas.

Novel Treatment of Burkitt Lymphoma with Dose-Adjusted EPOCH-Rituximab: Preliminary Results Showing Excellent Outcome.

Burkitt Lymphoma (BL) is a highly proliferative lymphoma with a propensity to present in extranodal sites. Standard treatment for BL involves intensive, multi-agent chemotherapy that is highly effective but associated with considerable toxicity and treatment-related mortality, particularly in older patients. Based on the observation that DA-EPOCH overcomes the adverse effect of high proliferation in diffuse large B-cell lymphomas, we hypothesized it may be effective in BL. We have undertaken a study of DA-EPOCH-Rituximab in untreated BL in an attempt to maintain a high cure rate with low treatment related toxicity. Eligible patients had untreated BL and could be HIV positive or negative. HIV negative patients (n=13) received 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002). Patients with HIV-associated BL (n=4) received 3–6 cycles of DA-EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and therapy was administered in the outpatient clinic where possible. Characteristics of 17 patients include median age (range) 27 (18–66) and ECOG PS 1 (1–3); stage III/IV 9 (53%); LDH > N 9 (53%); male sex 13 (76%) and; extranodal sites 11 (65%). All 11 (65%) patients with extranodal disease had abdominal or pelvic involvement at diagnosis. No patients had central nervous system disease on presentation. Response is CR/CRu in 100% of patients. One patient received consolidative radiotherapy to a single site of residual disease. At a median potential follow-up of 28 months, OS and PFS are both 100% and EFS is 92.3%. Significant toxicities include fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There were no treatment related deaths and no tumor lysis syndrome. In conclusion, DA-EPOCH-R appears to be highly effective with relatively low toxicity compared to standard intensive high-dose regimens for BL. Infusional chemotherapy may reduce or eliminate the risk of tumor lysis syndrome. Accrual continues. [Display omitted]

Treatment of Burkitt's Lymphoma During Pregnancy

To report a case of both successful maternal treatment outcome and normal fetal outcome in a patient who was diagnosed with Burkitt's lymphoma (BL) and aggressively treated with 6 different chemotherapy agents during the second and third trimesters of pregnancy. A 21-year-old white woman was diagnosed with stage II BL of the head and neck at 26 weeks' gestation. She was treated with 2 cycles of systemic intensive polychemotherapy, including cyclophosphamide, vincristine, doxorubicin, cytarabine, etoposide, ifosfamide, mesna, and intrathecal cytarabine with growth factor support during the second and third trimesters. She delivered a healthy, premature boy 6 weeks after diagnosis. At a follow-up 1 year after diagnosis, the patient remained disease-free and the baby remained healthy. The prognosis of BL depends on the stage at diagnosis, as well as treatment aggressiveness. Previous reports indicate that most patients diagnosed with BL during pregnancy received either no treatment or only one chemotherapy agent, and the majority ultimately died of rapidly progressive diseases. The fetal outcomes seem to depend primarily on the time of exposure to chemotherapy and/or radiation, doses, specific chemotherapy agent given, and frequency of treatment during pregnancy. Limited retrospective data suggest that chemotherapy given after the first trimester is relatively safe and does not adversely affect the short- and long-term fetal outcomes. Treatment of BL during pregnancy can be very challenging because an aggressive approach is the main key to maximize the patient's long-term disease-free survival. However, the health of the unborn child should also be a concern when choosing treatment. This case demonstrates that combination chemotherapy given after the first trimester did not result in any congenital malformations or acute adverse effects in the fetus. Long-term follow-up of the child remains necessary to evaluate possible long-term complications.

Treatment of Burkitt lymphoma in adults

Since its initial description in 1958, Burkitt lymphoma has become a prototype for our understanding of the pathogenesis and optimal treatment of aggressive lymphomas. The evolution of the treatment of this disease is explored and current therapeutic approaches evaluated. Special issues in the treatment of Burkitt lymphoma will also be discussed, including considerations in patients infected with HIV and current views on prophylactic measures and treatment of tumor lysis syndrome.

Complete Loss or Severely Compromised Expression of the Pro-Apoptotic Protein Bax Leads to Resistance to Curcumin-Induced Apoptosis in Burkitt's Lymphoma Cells.

This report compares in detail, the role of curcumin treatment in a panel of Burkitt's lymphoma (BL) cell lines that are either expressing full length Bax with a group of cell lines that are either completely deficient or have decreased expression of Bax. Multiple apoptotic stimuli induce conformational changes in Bax, a pro-apoptotic protein from the Bcl-2 family and its deficiency is a frequent cause of chemo-resistance in a variety of malignancies including Burkitt's lymphoma. We extent our previous studies on Burkitt's lymphoma to determine the role of curcumin treatment on BLs. Curcumin (diferuloymethane) is a naturally occurring yellow pigment isolated from the rhizomes of the plant curcuma longa. The medicinal value of curcumin has been well recognized with its anti-oxidant, anti-inflammatory and anti-tumor activities. Curcumin is also known to induce apoptosis in a variety of cancer cells including multiple myeloma and primary effusion lymphomas. To understand the role of Bax in curcumin-induced apoptosis, we used two groups of Burkitt's lymphoma cell lines, one that expressed the Bax protein (AS283A, KK124 and Pa682PB) and the other group either did not or had decreased expression of Bax (BML895 CA46, and LW878). Cell viability decreased in a dose-dependent manner in AS283A, PA682PB and KK124 with curcumin treatment ranging between 0–40mM whereas only minimal changes in viability was observed in BML895, CA46 and LW878 after treatment. Curcumin induced a dose-dependent apoptosis in the Bax expressing group of cell lines while the cell lines that were either completely deficient or had decreased expression of Bax did not respond to curcumin treatment and remained refractory. In AS283A, KK124, and PA682PB, curcumin induced apoptosis through truncation of BID, loss of mitochondrial potential as determined by JC1 staining with subsequent activation of caspase3 followed by cleavage of PARP. However, in the curcumin resistant cell lines, there was no change in the mitochondrial potential after curcumin treatment and therefore apoptosis did not occur. In addition, zVAD-fmk, a universal inhibitor of caspases prevented caspase3 cleavage as well as cell death in the sensitive cell lines after curcumin treatment suggesting that curcumin-induced apoptosis is caspase dependent. Our findings suggest that Bax integrity is necessary for curcumin to induce apoptosis in Burkitt's lymphoma cells. These results provide the molecular basis and preliminary data for new treatment strategies that may incorporate curcumin in regimens for Burkitt's lymphoma treatment.

Treatment of Burkitt lymphoma: A single institution’s experience

6742 Background: Burkitt lymphoma (BL) is one of the clinically aggressive NHLs. McMaster et al. (JCO 9:941–6, 1991) presented an 8-week, 7-drug regimen for aggressive lymphomas, with a CR of 81% for BL. Cabanillas et al (PASCO 2003, abs# 2309, 2003) treated BL with hyper-CVAD plus rituximab, delivered over 32 weeks, with a CR rate of 89%. One year survival, however, is only approximately 60% by these or other regimens. Our medical center serves a largely indigent urban population; we report here a retrospective study of our experience with these two regimens. Methods: Over the past 7 years, 9 cases were identified: median age 42 years (range 26–55); male: female ratio 8:1; HIV infection 6 pts; stage I-II (2 pts); III-IV (7 pts); and ECOG 0–1 (8 pts) and 2 (1 pt). Patients were treated by McMaster regimen (McM), hyper-CVAD, CHOP or EPOC regimens with rituximab at the discretion of the treating physician. Results: Two pts. treated with CHOP achieved a PR; one was unsuccessfully salvaged with EPOCH (died at 3 mos.), and one was successfully salvaged with McM with rituximab (McM+R) (NED at 51 months). One pt. treated with EPOCH+R achieved a PR and failed salvage with McM+R. One pt. treated with hyper-CVAD+R achieved a CR. Four pts. were treated by McM, 1 with and 3 without rituximab, with 3 of 4 achieving a durable. All received CNS prophylaxis. Pt.#5 presented with CNS disease. Pt. #2 suffered a CNS relapse at 17 mos. and was salvaged with high dose MTX. One patient refused therapy. Primary prophylaxis with G-CSF was done throughout. Grade 4 hematological toxicities occurred in all patients; septic deaths occurred only in PR/NR pts. Conclusions: At our institution, 4 of the 6 patients treated with McM regimen had a durable CR. This regimen remains an attractive option for the treatment of BL. No significant financial relationships to disclose.

Long distance polymerase chain reaction of ascites lymphoma cells aids diagnosis establishment of abdominal Burkitt's lymphoma and Burkitt-like lymphoma

Burkitt's lymphoma (BL) and its variants, including Burkitt-like lymphoma (BLL), can be difficult to distinguish morphologically and immunophenotypically from diffuse large B-cell lymphoma (DLBCL). Because the treatment of BL differs markedly from that of other types of non-Hodgkin's lymphoma (NHL), exact pathological diagnosis is crucial. We report 2 cases of patients with BL initially diagnosed as DLBCL. Due to clinical features typical of BL, long distance polymerase chain reaction (PCR) for detecting the t(8;14) translocation involving the c-myc proto-oncogene was performed on ascites lymphoma cells. Re-evaluation by a reference hematopathologist, together with long distance PCR in both patients revealing the t(8;14) translocation, resulted in diagnosis modification to BL and BLL. Consequently, the patients were treated with intense high-dose chemotherapy regimens including central nervous system (CNS) prophylaxis, and complete remission was initially achieved in both patients. Both BL and BLL should be considered in the differential diagnosis of DLBCL if abdominal spread with ascites and metabolic disorders are present. Long distance PCR analysis of ascites lymphoma cells for the detection of the BL-typical c-myc rearrangement offers a convenient and rapid possibility of diagnosis verification in atypical or borderline cases of BL.

Pseudomembranous colitis presenting as acute colonic obstruction without diarrhea in a patient with gastric Burkitt lymphoma

Pseudomembranous colitis (PMC) usually manifests as fever and diarrhea in hospitalized patients treated with systemic antibiotics. We described a case of PMC with intestinal obstruction but without diarrhea. A 60-year-old man was hospitalized for chemotherapy for the treatment of Burkitt lymphoma of the stomach. The patient became febrile and complained of crampy abdominal pain during the post-chemotherapy nadir. Plain abdominal radiography showed some intestinal gas and niveau. Because stool cytotoxin assay for clostridium difficile was positive and colon fiberscopic examination showed a pseudomembrane at the left side of the colon, and a diagnosis of PMC was made. Treatment with intracolonic vancomycin administration by colonoscopy and nasoileus tube was successful. Physicians should take into account the possibility of bowel obstruction due to PMC occurring in patients undergoing chemotherapy and perform emergency colonoscopy examination of suspected cases.

Clinical Presentation and Treatment Outcome of Children With Burkitt Lymphoma in Lebanon

The authors reviewed the medical records of 42 children younger than 13 years of age diagnosed with Burkitt lymphoma at the American University of Beirut Medical Center between 1983 and 1993. The male:female ratio was 3.9. The abdomen was the most common site of disease (86%). Jaw, central nervous system, and bone marrow involvement occurred in 16.6%, 16.6%, and 9.5%, respectively. The mean LDH level was 447 U/L. The mean age at diagnosis was 6.9 years. Thirty-nine patients received a variation of the COMP protocol. The total duration of treatment ranged from 6 to 18 months. At a median follow-up of 5 years the event-free survival was 100% for children with stages I and II disease, 77.4% (+/- 2 SE) for stage III, and 0% for stage IV. Failures in stage III patients were due to tumor lysis (3/24) and progressive disease (2/24). Aggressive therapy with high doses of methotrexate and anthracyclines may not be necessary for the treatment of children with extensive abdominal disease (stage III) in Lebanon. If confirmed in a larger series of patients, this study could have a major impact on the treatment of Burkitt lymphoma in Lebanon and other countries with limited resources.