Burkitt Type Research Articles

Burkitt Type Lymphoma in Palatine Tonsil. A report of a case

Burkitt Type Lymphoma in Palatine Tonsil. A report of a case

Survival of patients diagnosed with Burkitt-type lymphoma in human immunodeficiency virus carriers.

Introduction: Burkitt's lymphoma (BL) is one of the most common neoplasms in patients with human immunodeficiency virus (HIV), due to the immune compromise they present. Patients with BZL who are HIV carriers have a survival rate of approximately 69 % two years after diagnosis.Aim: to describe the survival of patients diagnosed with Burkitt's lymphoma in carriers of the Human Immunodeficiency Virus.Methodology: a narrative bibliographic review was carried out; for the bibliographic search information collected from the Pubmed database was used.Results: patients with HIV have a higher incidence of Burkitt type lymphoma due to their immunosuppression, so it is important that they adhere correctly to antiretroviral treatment and chemotherapy, since the survival of the mimics is between 45 % and 50 % 2 years after diagnosis.Conclusions: HIV carrier patients are approximately 100 times more likely to develop Burkitt's lymphoma due to their deficient immune system. Currently, antiretroviral treatment has played a very important role in giving HIV carriers a fairly good quality of life

Block of Counter-Regulation By Inhibition of Protein Synthesis Sensitizes Cancer Cells to IRE1α-Mediated Apoptosis Following Unfolded Protein Response

Background: Cellular stress responses like the unfolded protein response (UPR) decide over the fate of an individual cell. To prevent cell death, UPR induces expression of protective proteins that aim to restore homeostasis. A similar strategy is used by cancer cells to induce resistance against UPR-inducing drugs. Therefore, we hypothesized that a simultaneous block of protein synthesis prevents UPR counter-regulation and thus, enhances UPR-induced apoptosis. Methods: Tumor cell lines and patient-derived acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) cells were treated with several protein synthesis inhibitors and UPR-inducers. Synergy was determined as fold-increase over additivity. Mechanistic studies were performed using western blots, shRNA-mediated knock-down, and CRISPR/Cas9-mediated knock-out. In vivo synergy was tested using intravenously injected xenografts. Results: 2-deoxyglucose (2-DG), which competitively inhibits protein glycosylation in the endoplasmic reticulum (ER), induced UPR in B cell lymphoma cell lines. An additional block of protein synthesis by CD22-targeted immunotoxin Moxetumomab pasudotox (Moxe) prevented the upregulation of the protective binding immunoglobulin protein (BiP), although UPR signaling remained active. In line, 2-DG synergistically enhanced activity of protein synthesis inhibitors Moxe, cycloheximide, and puromycin suggesting a conserved mechanism of action. Furthermore, drug synergy was not only reversed by addition of mannose, which restores proper glycosylation, but was also mimicked by the two other UPR-inducers tunicamycin and bortezomib indicating UPR as cause of synergy. Mechanistically, Moxe and 2-DG induced synergistic mitochondrial apoptosis, which correlated with synergistic cleavage of PARP, synergistic reduction of BID, and additive fall in MCL-1. Knock-down of several UPR-associated proteins identified Inositol-requiring enzyme 1α (IRE1α) as responsible protein for synergy. Knock-out of IRE1α reversed synergistic cell death, PARP cleavage, and reduction of BID but not the fall of MCL-1 confirming IRE1α as key mediator of synergy. Suggesting broad applicability, immunotoxins and 2-DG induced synergy in seven distinct hematologic and three solid tumor entities, while healthy blood cells were insensitive towards the combination. Because UPR-induced cell death depends on a persisting stress signal and 2-DG has a short half-life, exposure time in vivo was increased by four injections of 2-DG per day. Against a systemic mantle cell lymphoma model, only high frequent 2-DG treatment, but not daily single injections, enhanced Moxe activity by 3-fold. The in vivo synergy was reproduced by combination with tunicamycin and bortezomib. Furthermore, the combination of 2-DG and Moxe induced a 35-fold synergy against a systemic Burkitt lymphoma model and an up to 37-fold synergy against two patient-derived B-ALL xenografts of the Burkitt's type. Conclusion: Blocking UPR counter-regulation by simultaneous inhibition of protein synthesis induces synergistic cell death in several malignancies. Synergy depends on IRE1α-mediated deregulation of BID which enhances MCL-1-mediated mitochondrial apoptosis. The broad applicability suggests a cancer cell-specific vulnerability which, together with a cell-targeted arrest of protein synthesis by immunotoxins, generates a unique therapeutic window supporting clinical evaluation.

Prostatic Burkitt Lymphoma, a Rare Secondary Location

Introduction: Non-Hodgkin’s malignant lymphoma is found primarily in African children. Prostate localization is a rare entity. We report the case of a secondary prostatic localization of Burkitt lymphoma in a 14-year-old child. Observation: the 14-year-old child NNJ was followed at the Libreville Cancer Institute (ICL) for Burkitt maxillo-facial stage II bilateral Murphy lymphoma. The clinical examination noted an alteration of the general state, total hematuria, a voluminous prostatic mass filling the rectal ampoule. The paraclinical assessment noted renal insufficiency, a prostatic mass on ultrasound. Anatomo-pathological examination of the prostatic biopsy diagnosed Burkitt type non-Hodgkin’s malignant lymphoma. He died a week later. Conclusion: Primary or secondary prostatic lymphoma is rare. Obstructive renal insufficiency is an additional complication that darkens its prognosis by delaying etiological treatment based on polychemotherapy.

RARE-29. PRIMARY CENTRAL NERVOUS SYSTEM NON-HODGKIN LYMPHOMA IN AN 11-YEAR-OLD BOY: A CASE REPORT

BACKGROUNDPrimary central nervous system lymphoma (PCNSL) are very rare in children. CLINICAL CASE: An 11-year-old male presented with a 2 months history with myoclonic movements in the upper right limb, and a sudden frontal headache, gait disturbance due to right hemiparesis and an ipsilateral convulsive episode. Upon admission he had critical condition, with hypertensive skull syndrome, Glasgow of 12, Karnofsky 40%, right hemiparesis, swallowing disorder, facial paralysis, and loss of photo motor reflex and unilateral amaurosis. A CT and MRI showed a huge tumor mass in the left tempo-parietal region, infiltrating the white matter and shifting the midline. A Tumor biopsy was done, and reported diffuse small cell non-Hodgkin lymphoma of high-grade, Burkitt type. Systemic lymphoma workup was negative. He received six cycles of chemotherapy based on high dose methotrexate, rituximab and triple intrathecal.After the second cycle an ophthalmologic evaluation was done, and found infiltration to the right retina, for which 6 cycles of intra vitreous chemotherapy with methotrexate were applied, he showed an excellent response, and recovered all his neurological functions except that right hemianopia persist. Control MRI showed partial response at 2nd cycle and complete response after the 4th cycle. No Radiation was performed.CONCLUSIONThis report highlights the fact that pediatric PCNSL may be effectively treated by a combination of HDMTX and rituximab-based chemoimmunotherapy without irradiation. Lack of awareness of this rare entity may lead to extense resections of brain, and potential permanent secuelae that were avoided in this illustrative case.

CD30 expression and survival in posttransplant lymphoproliferative disorders

Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of transplantation. For refractory and relapsed PTLD new therapies are needed, such as the antibody-drug conjugate brentuximab vedotin that targets CD30. There is limited knowledge of CD30 expression in various subtypes of PTLD and its correlation to clinicopathological features. Therefore, we studied the expression of CD30 in PTLD following solid organ transplantation and correlated CD30 expression to PTLD subtype, Epstein-Barr virus (EBV)-status, intratumoral regulatory T-cells (Tregs), clinical features, and outcome.Methods: We included 50 cases of PTLD from a nation-wide study of PTLDs following solid organ transplantation in Sweden. The tumor biopsies were reevaluated, and clinical data were collected. CD30 expression on tumor cells was analyzed by immunohistochemistry with the clone Ber-H2. Thirty-one cases were stained with clone 236 A/E7 for detection of forkhead box protein 3 (FoxP3, a Treg biomarker).Results: The case series consisted of 6% polymorphic, 88% monomorphic, and 6% Hodgkin lymphoma-like PTLDs and 53% of the cases were EBV+. Overall, 70% (35/50) of the PTLDs were CD30+ (≥1% CD30+ tumor cells) and 30% (15/50) were CD30-. All polymorphic PTLDs (n = 3) and Hodgkin lymphomas (n = 3), 88% (14/16) of non-germinal center type of diffuse large B-cell lymphoma (DLBCL), and 75% (9/12) of T-cell PTLDs were CD30+ whereas all germinal center-type of DLBCL (n = 5) and Burkitt type PTLD (n = 2) were CD30-. CD30+ PTLD tended to be EBV+ more frequently (p = .07) and occurred earlier posttransplant (2.1 vs. 8.2 years, p = .01) than CD30- PTLD. Type of transplant and localization of the tumor did not differ between the groups except that CNS engagement was more common in CD30- PTLD (p = .02). CD30-status was not associated with presence of intratumoral Tregs or overall survival.Conclusion: Expression of CD30 varied with PTLD subtype. There was no association between CD30 and survival, regardless of subtype.

Motor and functional outcome of myelopathy following intrathecal chemotherapy

Intrathecal (IT) chemotherapy is a widely used treatment for hematologic tumors with central nervous system involvement. We describe a 50-year-old patient with Burkitt type acute lymphocytic leukemia who developed a neurotoxic myelopathy after IT chemotherapy with methotrexate (MTX) and cytarabine (Ara-C). This type of adverse event is rare, is usually unresponsive to pharmacologic treatment and can be potentially devastating for the patient. Although rehabilitation was effective in restoring functional independence, only partial neurological recovery was achieved. Proper classification of spinal cord injury and outcome measures are essential to assess prognosis and treatment outcome in these patients.

Histopathological and immune-histochemical diagnosis of Burkitt Type Lymphoma in a cross bred cow

Histopathological and immune-histochemical diagnosis of Burkitt Type Lymphoma in a cross bred cow

PS1316 UNFOLDED PROTEIN RESPONSE AFTER TREATMENT WITH 2‐DEOXYGLUCOSE CREATES SUBSTANTIAL SYNERGY WITH IMMUNOTOXIN MOXETUMOMAB PASUDOTOX IN B‐CELL LYMPHOMA AND LEUKEMIA XENOGRAFTS

Background:Compared with healthy B‐cells, lymphoma cells commonly present with increased rate of protein synthesis and of glycolysis. 2‐Deoxyglucose (2‐DG), an inhibitor of the key enzyme of glycolysis, irreversibly blocks glucose metabolism. Despite promising in vitro activity, 2‐DG alone showed little clinical activity against various cancers. Immunotoxins are fusion proteins of an antibody fragment and pseudomonas exotoxin and kill lymphoma cells by arresting protein synthesis. The CD22‐targeted immunotoxin Moxetumomab pasudotox (Lumoxiti) was approved for the treatment of relapsed/refractory hairy cell leukemia where it produces over all response rates of 86%. In various animal models of B‐cell acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL), efficacy of Moxetumomab substantially increases when serum levels are kept high by repeated or continuous administration, compensating for the short serum half‐life after bolus injection.Aims:By targeted inhibition of protein synthesis and of glycolysis, we aimed to induce synthetic lethality in aggressive B‐cell malignancies.Methods:MCL, ALL, Burkitt's lymphoma (BL) cell lines, and patient‐derived B‐ALL were treated in vitro with 2‐DG and Moxetumomab alone or in combination. Drug synergy was determined mathematically as fold‐increase over additive synergy. Biochemical studies were performed using western blot. A systemic JeKo‐1 and a newly established systemic Ramos xenograft model were used to test the combination in vivo.Results:Moxetumomab alone was cytotoxic in the low pico‐molar range against MCL, ALL, and BL cell lines. 2‐DG alone showed cytotoxicity against some cells which was completely reversed by mannose. In combination, 2‐DG enhances Moxetumomab highly synergistically, increasing cytotoxicity of Moxetumomab by three to nine‐fold. Tested against patient‐derived primary ALL of the Burkitt's type in vitro, the high synergy of Moxetumomab and 2‐DG was reproduced. As for cytotoxicity of 2‐DG, the synergistic effects of 2‐DG on Moxetumomab was blocked by mannose. Mechanistically, Moxetumomab alone and 2‐DG alone resulted in a fall of MCL1 protein levels in an additive manner which did not explain synergy. In addition to changes in MCL1 levels, 2‐DG induced unfolded protein response (UPR) as determined by the upregulation of BIP and CHOP. The addition of mannose blocked 2‐DG induced UPR but not the fall of MCL1. Synergy was reproduced when combining Moxetumomab and the UPR inducer tunicamycin. In vivo, 2‐DG or tunicamycin alone had no activity against systemic JeKo‐1 or Ramos xenografts. Moxetumomab alone reduced bone marrow tumor burden by 5‐fold in the JeKo‐1 and by 16‐fold in the Ramos xenograft model. In vivo, efficacy of Moxetumomab was enhanced in a dose dependent manner up to 3‐fold in the JeKo‐1 model and the combination achieved an MRD‐negative bone marrow status in the Ramos model.Summary/Conclusion:The combination of 2‐DG and Moxetumomab is well tolerated, produces substantial drug synergy, and may be an interesting combination for future clinical testing.

Non Hodgkin Lymphomas (NHL) in the Pediatric Oncology Unit of the Gabriel Touré Teaching Hospital, Bamako Mali

Background :Non-Hodgkin lymphomas are the first childhood cancer in sub-Saharan Africa. Objective: The purpose of this study was to assess non-Hodgkin lymphomas cases in our setting. Methodology: A retrospective and descriptive study carried out in the pediatric oncology unit of the Gabriel Toure Teaching Hospital Bamako over 10 years from 1st January 2005 to 31th December 2015. Results: We exploited 274 (21.6%) cases of Non-Hodgkin Lymphoma out of 1295 cancer cases registered, the age group 6 - 10 years was the most represented (46.4%); the male sex was predominant with a sex-ratio of 1.8; digestive signs were the most common signs of discovery (44.2%) followed by maxillary swelling (42.7%); the majority of patients (52.9%) consulted between 1 and 3 months after the onset of signs; the malnutrition rate was 39.8%, of which 24.1% were severe cases and 15.7% were moderate rate. Abdominal localization was the most common (43.1%) followed by maxillofacial localization (33.9%). Almost all were Burkitt type cytology (92.7%), the majority (73.4%) were in Murphy stage III. Almost all (96%) had received chemotherapy and the modified LMB 01 protocol was widely used (62.4%). The majority of patients (85%) were chemosensitive at day 7 or after the third cyclophosphamide injection but at the end of induction only 31% were in complete remission. Gastrointestinal toxicity was the most common (37.13%) followed by hematologic toxicity 35.09 %; 9.12 % of patients were lost of follow-up and 22.26% died. Tumor progression was the most common cause of death (60.66%) followed by infection (21.31%). Conclusion: In light of these findings, the late diagnosis and the poor management of NHL, as well as the limited ability to primarily treat metabolic complications, explain the high case-fatality rate, hence the important role of early diagnosis and treatment multidisciplinary.

Methotrexate-Loaded Biodegradable Polymeric Micelles for Lymphoma Therapy in Mouse Model

Purpose: Methotrexate (MTX), a folate antimetabolite, competitively inhibits dihydrofolate reductase, the intracellular enzyme responsible for converting folic acid to folate cofactor, thus blocking the synthesis of thymine and purine, causing impairment of tumor growth and induction of cell death. High dose MTX (HD-MTX) is infused in doses of 3-5g/m2 and over a period of 6-24h to maintain the serum MTX at high levels, which shows benefit in the treatment of childhood leukemia and certain adult NHL, particularly the Burkitt type. However, the clinical implication of MTX is hampered for some reasons. On the one hand, the adverse effects of HD- MTX are severe, including bone marrow suppression, mucositis, hepatotoxicity, nephrotoxicity and neurological symptoms. On the other hand, leucovorin rescue, adequate hydration, urinary alkalization and monitoring of MTX concentration is required to avoid life-threating side effects of HD-MTX, which makes the administration rather complicated. In addition, the poor water solubility also impedes the application of MTX. To overcome these obstacles, a new drug delivery system is required to reduce the side effects of HD-MTX as well as to increase the solubility of the drug. So we designed a self-assembled micellar system to load MTX to overcome water solubility and to enhance therapeutic efficacy while reduce toxicity.Materials and Methods: Monomethyl poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) our group previously synthesized was employed to load MTX through a one-step solid dispersion method. The preparation was done without any surfactants, organic solvents, or vigorous stirring.Results: MTX loaded micelles had a small particle size of 25.64±0.99nm and polydisperse index (PDI) of 0.176±0.05. Drug loading and encapsulation efficiency of MTX loaded micelle were 5.57±0.14% and 92.46±2.38%, respectively. Compared with free MTX, MTX loaded micelles demonstrated a much slower and sustained release behavior in vitro. MTT assay and cell apoptosis study suggested that MTX loaded micelles were more effective in inhibiting proliferation (IC50 value 137.8ug/ml vs 86.5ug/ml, p<0.05) and inducing apoptosis (p<0.01) on Raji lymphoma cells than MTX treatment, which was especially distinct in high dose groups (38.78% vs 22.17%). Cellular uptake study indicated that MPEG-PCL micelle had a 1.5 times higher uptake rate in Raji cells. As for in vivo studies, MTX loaded micelles were more competent to suppress tumor growth (p<0.01) and prolong survival time than MTX injection (p<0.05) in the subcutaneous Raji lymphoma mouse model. Notably, the high dose group of micelle formulation exhibited the strongest anti-tumor effect without additional toxicity. As for body weight, which represented systematic toxicity, no difference between control group and two kinds of MTX formulation group was observed (p >0.05). Furthermore, immunofluorescent and immunohistochemical studies showed that tumors of MPEG-PCL-MTX treated mice had more apoptotic cells (p<0.05) and fewer proliferative cells (p<0.01).Conclusions: In this work, MPEG-PCL-MTX micelle was fabricated with a thin-film hydration method to improve the water solubility of MTX and to meet the requirements of intravenous administration, which was stable, safe, effective, easy to produce and scale up, and showed potential clinical application. The enhanced therapeutic efficiency of MPEG-PCL-MTX micelle might be attributed to enhanced permeability and retention (EPR) effect, which increased drug accumulation in the tumor site. Besides, compared with MTX injection with highest concentration in our experiment, MPEG-PCL-MTX micelle with lowest concentration achieved similar or better therapeutic outcome, which indicated the amount of drug could be reduced to achieve the same therapeutic efficiency and alleviate adverse effects towards normal tissues and organs. Moreover, MPEG-PCL-MTX micelle of high dose (7mg/ml) achieved great therapeutic advantage without obvious toxicity, which makes micelle an effective and safe choice when HD-MTX is clinically employed. DisclosuresNo relevant conflicts of interest to declare.

Breast cancer cases of female patients under 35 years of age in Togo: A series of 158 cases.

Breast cancer in young female patients represents a public health problem in developing countries. The objectives of the study were to study the epidemiological and histological characteristics of breast cancer in female patients under 35 years of age. This was a retrospective analytical study of a series of 158 cases of breast cancer in female patients under 35 years of age, conducted at the University Teaching Hospital of Lomé between 2000 and 2015. A total of 158 cases were collected, representing 36.2% (436) of all breast cancer cases. The average age of the patients was 30.9 years (range, 16-35 years). A family history of breast cancer at the 1st or 2nd degree was identified in 13.9% of cases. Genetic mutation studies were carried out for 7 patients, 5 of which revealed mutations (4 BRCA1 and 1 BRCA2). According to the locus, the cancer was located preferentially in the left breast in 88 cases (55.7%). Malignant mammary lesions were epithelial tumors (n=144 cases, 91.1%), infiltrating (n=125 cases, 79.1%) and non-infiltrating (n=19 cases, 12.0%). The other histological groups consisted of 8 cases of sarcomas (5 cases of angiosarcoma, 2 cases of fibrosarcoma and 1 case of Kaposi's sarcoma), 5 cases of lymphomas and one case of melanoma. Not otherwise specified infiltrating ductal carcinomas were SBR II and III in 43.2 and 35.2% of cases, respectively. The tumors classified as T4 were the most frequent (30.4%). Regarding the lymph node status, lymph node metastasis was noted in 22.8% of cases. Studies of hormone receptors were carried out in 23 patients and were positive for 11 patients: Estrogen receptor (ER)+plus progesterone receptor (PR)+(7 patients), ER+PR-(4 patients). Of the aforementioned 8 cases of sarcoma, 5 were angiosarcoma. The lymphomas were predominantly Burkitt's type for 4 cases. Mammary ultrasonography was performed in 45.6% of the patients and 54.4% underwent the combined ultrasonography and mammography. Ultrasound identified one or more sign of malignancy in 67 patients (42.4%), and combined ultrasonography and mammography classified 51.9% of lesions in BIRADS 4 and 5. The incidence of breast cancer in young Togolese patients is high. It is a disease distinguished by a delay in diagnosis, which contributes to the high number of cases that initially diagnosed at an advanced stage, particularly the high histo-prognosis grades of infiltrating ductal carcinoma. These results indicate a genetic origin; therefore, a thorough investigation into genetic mutations should be carried. In addition, further collaborative studies are required to verify these results.

Hepatitis B virus reactivation after cessation of prophylaxis with entecavir in a patient with Burkitt type acute lymphoblastic leukaemia treated with rituximab

Hepatitis B virus reactivation after cessation of prophylaxis with entecavir in a patient with Burkitt type acute lymphoblastic leukaemia treated with rituximab

Primary Burkitt lymphoma of the supraglottic larynx: a case report and review of the literature

BackgroundBurkitt lymphoma is a high-grade B cell lymphoma which accounts for less than 1% of all adult cases of non-Hodgkin lymphoma. Rare instances of Burkitt lymphoma developing secondary to prior irradiation have been described in the literature.Case presentationWe report a case of a 90-year-old white woman with a recent history of irradiation for Hodgkin lymphoma, who presented with primary Burkitt lymphoma of the supraglottic larynx. She underwent emergency awake tracheostomy with biopsy. A histopathological examination confirmed non-Hodgkin, B cell lymphoma of Burkitt type. Given her age and poor functional status, she underwent treatment with palliative radiotherapy.ConclusionsA literature review was performed to clarify the clinical characteristics of radiation-induced Burkitt lymphoma in the head and neck, as well as its diagnosis and management. The present case represents the second case of radiation-induced Burkitt lymphoma in the head and neck in the reported literature, and the first in the supraglottic larynx. It highlights the need to maintain a broad differential in the assessment of malignancies of the larynx, particularly in patients with a prior history of radiation treatment.

回腸原発悪性リンパ腫 (Burkitt's type) の 2 症例

回腸原発悪性リンパ腫 (Burkitt's type) の 2 症例

A Pediatric-Inspired Regimen Containing Multiple Doses of Intravenous Pegylated Asparaginase Appears Safe and Effective in Newly Diagnosed Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Adults up to Age 60: Results of a Multi-Center Phase II Clinical Trial

▪Background: The U.S. Intergroup C10403 trial has demonstrated that treating acute lymphoblastic leukemia (ALL) in adolescents and young adults up to age 39 using a pediatric regimen improves event-free and overall survival compared with adult regimens (Stock W et al. ASH 2014). However, the safety and efficacy in implementing pediatric regimens in older adults above age 40 have not been well studied. Herein, we report the results from a phase II multicenter study of pediatric-inspired regimen in newly diagnosed adult patients (pts) with ALL up to age 60 (NCT01920737).Methods: Newly diagnosed adult pts aged 18 to 60 with ALL were eligible. Burkitt type and Ph+ ALL were excluded. The treatment regimen consisted of induction 1 (I1), induction 2 (I2) followed by several cycles of intensifications and re-inductions and 3 years of maintenance therapy. The treatment contained a total of 6 doses of 2,000 IU/m2 pegylated asparaginase (Peg-ASP), administered IV at various intervals of ³4 weeks based on our previous pharmacokinetics (PK) data (Douer D et al. Blood 2007). Minimal residual disease (MRD) was assessed after I1 and I2 by multiparameter flow cytometry. Serum asparaginase enzymatic activity and presence of anti-asparaginase antibody (Ab) were assessed on day 7 after each Peg-ASP dose.Results: 27 pts were enrolled between 4/2014 and 4/2016. The median age at diagnosis was 43.6 (range, 20-60) years: 52% were 40-60 years. The majority had precursor B-ALL (70%) and rest T-ALL. Four pts (15%) had extramedullary disease only (mediastinal mass, lymph nodes, bone). Of the 27 pts, 26 pts (96%) achieved complete remission (CR) after I1. MRD was assessed in 20 pts; 8 (40%) and 15 (75%) pts achieved MRD neg CR after I1 and after I2, respectively. Six pts proceed to allogeneic HSCT. With a median follow-up of 7.8 months (range, 0.9-22.5), 3 patients (12%) relapsed: 2 occurred among the 12 MRD+CR group (17%) after I1 at 4.5 and 8.8 months, and 1 occurred among the 8 MRD negative CR group (13%) after I1 at 7 months from I1 completion. No relapses occurred among the 6 MRD unknown pts. No pt died on study. Grade 3-4 Peg-ASP-related toxicities (Table 1) included hypertriglyceridemia (59%), transaminitis (52%), hyperglycemia (41%), hyperbilirubinemia (30%), and pancreatitis (4%). Notably, all cases of hyperbilirubinemia occurred during I1 but despite continued use of Peg-ASP, grade 3-4 hyperbilirubinemia did not recur. Four pts (15%) developed hypersensitivity reactions to Peg-ASP and subsequently received Erwinia asparaginase without reaction and completed the full intended doses of Peg-Asp treatments. Three pts (11%) discontinued Peg-ASP due to toxicity (n=2; hyperbilirubinemia, transaminitis) and physician preference (n=1). Asparaginase PK and anti-ASP Ab data were available in 16 pts. In pts without hypersensitivity to Peg-ASP, a median asparaginase enzymatic activity was 0.58 IU/ml (range, 0.30-0.88) and 0.73 IU/ml (range, 0.53-0.88) on day 7 of Peg-ASP during I1 and I2, respectively. One pt developed silent inactivation after I1 with the activity level <0.01 IU/ml during I2 but without detectable anti-ASP Ab; 3 pts with hypersensitivity reactions had no or lowest activity levels, ranging from <0.01-0.1 IU/ml. Four pts (15%) had pre-existing anti-ASP Ab at pre-treatment; none of these was neutralizing and all 4 pts had adequate enzymatic activity.Conclusions: This phase 2 study suggests that a pediatric-inspired regimen containing rationally synchronized 6 doses of 2,000 IU/m2 IV Peg-ASP is safe and effective in older adults with newly diagnosed Ph-negative ALL up to age 60. Although follow-up remains short, we have observed high CR rates and few relapses. Hypertriglyceridemia, hyperglycemia, transaminitis and hyperbilirubinemia occurred frequently but few discontinued treatment due to toxicities. The rate of silent inactivation of asparaginase was low (6%), and almost all pts without hypersensitivity had adequate activity on day 7. Further results of asparaginase PK analysis and silent inactivation will inform the appropriate dosing of Peg-ASP and utility of PK/Ab tests in future adult ALL trials. [Display omitted] DisclosuresPark:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ritchie:Arian: Speakers Bureau; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Speakers Bureau; Incyte: Speakers Bureau. Rao:Gilead Sciences: Employment, Equity Ownership. Douer:Jazz Pharmaceuticals: Honoraria; Gilled Sciences, Inc: Consultancy; Shire: Consultancy, Speakers Bureau; Pfizer: Consultancy; Spectrum: Consultancy.

Abstract B08: Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis

Abstract Objective: The Myc-interacting zinc finger protein 1 (Miz-1) is a ubiquitous BTB/POZ domain and zinc finger protein that acts as both a transcriptional repressor and activator. The POZ domain of Miz-1 enables protein-protein interactions and facilitates a stable association with chromatin. Miz-1 binds to the proto-oncogen c-Myc and modulates c-Myc target gene expression. Overexpression of c-Myc is an important feature of Burkitt-type B cell lymphomas (BL) caused by c-Myc gene rearrangements. The aim of this project is to determine if Miz-1 is a crucial collaborator of c-Myc in transcriptional regulation of B cells and in the development of c-Myc-dependent B-cell lymphomas. Methods: We are using the Eµ-Myc mouse model to generate Burkitt type c-Myc dependent lymphomas to study the implication of Miz-1 in a c-Myc driven process of malignant transformation. Mice carrying the Eµ-Myc transgene (c-Myc gene placed under the control of Eµ enhancer of the IgH locus) overexpress c-Myc in lymphoid cells and develop a disease similar to Burkitt's lymphoma. Mice that express a conditional non-functional Miz-1 allele lacking the part coding for the POZ domain in B cells (Mb1-Cre-Miz-1fl/fl mice, hereafter called ΔPOZ mice) were crossed with Eµ-Myc transgenic mice. We monitored Eµ-Myc animals expressing wild type or ΔPOZ Miz-1 protein over a period of 500 days. Incidence and latency periods of the development of tumors in both cohorts was compared. Pre-cancerous mice of all genotypes were also investigated to evaluate the influence of Miz-1 during the development of the c-Myc dependant lymphomas. To identify underlying molecular mechanisms, global mRNA expression profiles of pre-neoplastic and tumor cells derived from Eµ-Myc and ΔPOZ/Eµ-Myc mice were performed using high throughput sequencing (RNA-seq). To address the role of Miz-1 in the deregulation of chromatin associated with c-Myc overexpression, chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) was performed on B-lymphoma and pre-tumoral B-cells and compared to normal B-cells. Binding to chromatin of Miz-1 and c-Myc was assessed. Results: ΔPOZ/Eµ-Myc mice develop lymphomas with a significant longer latency and lower incidence than Eµ-Myc mice expressing functional Miz-1 proteins. Additionally, blood analysis of sick animals reveal a lower amount of Large Unstained Cells (LUC) when Miz-1 is mutated. Accordingly, in 40 day old pre-tumoral ΔPOZ/Eµ-Myc animals compared to Eµ-Myc mice, less pre-B and/or pro-B cells were observed in lymphoid organs and little or no LUC were present in the blood. This suggests that Myc driven lymphoma and leukemia is impaired when a ΔPOZ Miz-1 protein is expressed. Our RNA-seq analyses of pre-neoplastic and tumor cells revealed that the expression of ΔPOZ Miz-1 induces deregulation of several genes belonging to different GO (Gene Ontology) functions like “small GTPase-mediated signal transduction”. Interestingly, comparision of RNA-seq and Miz-1 ChIP-seq analyses indicates that some Miz-1 bound genes are deregulated in cells from ΔPOZ/Eµ-Myc mice (e.g: Aurora kinase A (Aurka)). Conclusion: Our data indicate that Miz-1 is required for the efficient development of aggressive c-Myc-driven lymphomas. Miz-1 is probably cooperating with c-Myc in the abnormal transcriptional program that is occuring in lymphoma cells. Therefore, targeting Miz-1 in B-lymphomas could lead to the development of new therapeutic approaches. Citation Format: Julie Ross, René Winkler, Charles Vadnais, Marissa Rashkovan, Christian Kosan, Tarik Möröy. Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B08.

T-cell acute lymphoid leukemia resembling Burkitt leukemia cell morphology: A case report.

Biphenotypic acute leukemia (BAL) is an uncommon type of cancer, which accounts for <5% of all adult ALs. Based upon a previously described scoring system, the European Group for the Immunological Classification of Leukemias (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based upon the number and degree of specificity of several markers for myeloid or T/B-lymphoid blasts. The present study describes a case of T-cell acute lymphoblastic leukemia (T-ALL) with Burkitt-like cytology, which according to the French-American-British classification, corresponded to a diagnosis of Burkitt type L3 ALL. Flow cytometry analysis demonstrated that the blasts were positive for T-lymphoid markers, cytoplasmic cluster of differentiation (CD)3, CD7 and CD56, and myeloid markers, CD13, CD33 and CD15. At first, a diagnosis of BAL was suggested by the EGIL score, however, according to the 2008 World Health Organization criteria, a case of T-ALL with aberrant myeloid markers was established. The study also reviewed the literature and discussed the limitations of the EGIL scoring system in clinical decision making, to aid in the selection of an appropriate therapeutic regimen.

Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403

▪Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children’s Oncology Group regimen (COG AALL0232) .Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL.Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04).Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. [Display omitted] [Display omitted] DisclosuresStock:Sigma-Tau: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity’s Board of Directors or advisory committees; Jazz: Membership on an entity’s Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity’s Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Consolidative Autologous Stem Cell Transplant for Double Hit Lymphoma

Double hit lymphoma (DHL), defined as B cell lymphoma with a c-MYC rearrangement plus a IGH/BCL2 rearrangement, confers a poor prognosis. Outcomes with R-CHOP are dismal with reported 2 year EFS <30% in multiple series. To improve upon these results, Burkitt type regimens such as R-HyperCVAD and dose adjusted (DA) R-EPOCH have been attempted, but 2 year EFS remains < 50% in early reports. In addition, the SWOG-9704 study found a benefit for consolidative autologous stem cell transplant (autoSCT) in high risk DLBCL, likely including some DHL, although this reported benefit has not been confirmed in three other randomized European studies.Since 2010 the treatment algorithm at Oregon Health & Science University for fit patients with DHL has been DA-R-EPOCH followed by consolidative autoSCT in responding patients. Here we report the first 16 patients treated with consolidative autoSCT. At diagnosis, the median age was 58, and the median IPI was 3. All patients had rearrangements of c-MYC and IGH/BCL2. One of the c-MYC rearrangements was a classical t(8;14); the translocation partners in the other cases were unknown. Three patients also had a ‘triple hit’ with an additional BCL6 rearrangement. Fourteen patients received DA-R-EPOCH with intrathecal prophylaxis for induction. One received R-CHOP at another institution, and one received R-HyperCVAD. 15 of 16 patients were in CR after induction. Stem cell mobilization was performed with G-CSF +/- plerixafor, and BEAM was utilized as the high dose conditioning regimen.With a median follow-up of 18 months, the estimated 2 year PFS is 91 %, and the 2 year OS is 91 % in the 16 patients who underwent consolidative autoSCT. There were no deaths from non-relapse mortality, and the only relapse was 6 months post-transplant. All other patients undergoing autoSCT remain alive and in remission.An additional 15 patients also underwent induction with DA-R-EPOCH but did not proceed to autoSCT. Four patients who had intended to undergo autoSCT were refractory to induction. Of the remaining 11 patients, 9 did not pursue autoSCT because of age and/or comorbidities, and 1 each declined out of personal preference or insurance denial. Four of these 11 have relapsed or died.Our results suggest that consolidative autoSCT, especially after DA-R-EPOCH induction, is an effective treatment strategy for DHL in fit patients and should be explored in prospective studies. DisclosuresNo relevant conflicts of interest to declare.