High-grade Diffuse Large B-cell Lymphoma Research Articles

DA-R-EPOCH May Mitigate the Adverse Prognostic Implication of the Diagnosis-to-Treatment Interval (DTI) in Large B-Cell Lymphomas

BackgroundShort diagnosis-to-treatment interval (DTI) is associated with high-risk disease and poor survival in diffuse large B-cell lymphoma (DLBCL). There is a paucity of literature on DTI and survival in DLBCL treated with first-line DA-R-EPOCH. We hypothesized that rapid initiation of DA-R-EPOCH in aggressive and high-risk DLBCL mitigates the adverse prognostic implication of short DTI. Patients and MethodsWe retrospectively examined the association of DTI, categorically (short DTI ≤ 14 and long > 14 days) and continuously, with clinical features and survival outcomes in DLBCL treated with first-line DA-R-EPOCH at our institution. ResultsA total 190 patients were analyzed, 21% with high-grade DLBCL subtypes, 56% IPI ≥ 3, and median DTI of 13 days. The short DTI cohort contained more patients with IPI ≥ 3, bulky disease, and elevated LDH. When analyzed categorically and continuously, DTI was not associated with significant differences in PFS or OS. There was significant multivariable interaction between bulky disease, DTI, and PFS (P = .033), with improved PFS in patients with bulky disease in the short DTI cohort. ConclusionWe found that negative prognostic implications of DTI are mitigated in DLBCL patients treated with first-line DA-R-EPOCH, suggesting that urgent initiation of DA-R-EPOCH in high-risk DLBCL, including bulky disease, may improve survival. Our study's shorter DTI compared with DTIs reported in prospective DLBCL trials highlights DTI as a marker of external validity in clinical trial results. Future trials should implement protocols encouraging shorter, realistic DTIs to avoid selection bias against high-risk patients who are unable to delay treatment.

Enhanced prognostic evaluation of diffuse large B-cell lymphoma: A comprehensive surveillance study incorporating Epstein-Barr virus infection status and immunohistochemical markers.

Emerging biologic subsets and new prognostic markers are significantly important for aggressive diffuse large B-cell lymphoma (DLBCL). Nevertheless, the high cost of testing limits the availability of these tests in most hospitals, thus making prognostic judgment based on basic immunohistochemical testing, whole blood Epstein-Barr virus DNA (WBEBV) surveillance and clinical features advantageous for hospitals and patients with poor medical conditions. We included 647 DLBCL patients treated in our hospital from January 2009 to March 2023. Non-germinal center B-cell like, Ki-67, and International Prognostic Index(IPI) scores were related to cMYC/B-cell lymphoma 2 (Bcl-2)-double expression. Age, Epstein-Barr virus-encoded small RNA(EBER) positivity, and IPIscores were associated with mortality. The cutoffs for differential overall survival (OS) of age, WBEBV, Bcl-2, and cMYC were 57 years, 1514 copies/mL (baseline), 5.89 × 104 copies/mL (treatment), 40%, and 55%, respectively. EBER positivity was significantly associated with a worse OS. Patients with newly defined DE (Bcl-2 ≥ 40 and cMYC > 55) had a worse prognosis than controls (p = 0.04). We found that cMYC with an optimal cutoff of 47.5 could effectively predict high-grade DLBCL with an area under the curve of 0.912, and the specificity and sensitivity were 70.7% and 100%, respectively. Our study provides valuable insights into the prognostic factors and biomarker cutoffs that influence OS in DLBCL patients, which may guide clinicians in tailoring treatment strategies and improving patient outcomes.

Molecular Mechanisms and Treatment Strategies for Helicobacter pylori-Induced Gastric Carcinogenesis and Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma.

Helicobacter pylori has been classified as a class I carcinogen by WHO because of its primary involvement in the development of gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. This review focuses on understanding the molecular pathophysiological mechanisms that operate within intracellular transduction pathways and their relevance in the treatment strategies for the two main diseases caused by H. pylori. H. pylori virulence factors such as cytotoxin-associated gene A and vacuolating cytotoxin A genotypes, inflammatory mediators, H. pylori-induced microRNA deregulation, alterations in autophagy proteins and regulators, and changes in DNA methylation are some of the molecular mechanisms that play essential roles in H. pylori infection and gastric carcinogenesis. The discovery of novel treatment strategies that target the deregulated intracellular transduction pathways in gastric carcinogenesis and MALT lymphoma is critical. H. pylori eradication (HPE) is not limited to H. pylori-dependent low-grade MALT lymphoma and may be used in patients with high-grade diffuse large B-cell lymphoma (DLBCL) (de novo or DLBCL-MALT lymphoma). The loss of H. pylori dependency and high-grade transformation appear to be distinct events in the progression of gastric lymphoma. Interestingly, patients with H. pylori-positive gastric DLBCL without histological evidence of MALT lymphoma (pure gastric DLBCL) may respond to HPE therapy.

Gastric lymphoma - epidemiology, clinical manifestations and current therapy management

Gastric lymphoma is a rare malignant disease, which in recent years has been showing an increasing incidence in the population. The development of MALT is most often the result of chronic Helicobacter pylori infection. Further chronic inflammation may result in malignant transformation of MALT to high-grade diffuse large B-cell lymphoma (DLBCL). However, DLBCL lymphomas most often arise de novo. The risk of primary gastric lymphoma increases with age. The symptoms of gastric lymphoma are very diverse and non-specific, which is why the knowledge about this disease and the differential diagnosis of diseases with similar symptoms play a very important role. The gold standard for diagnosing gastric lymphomas is upper GI endoscopy with biopsy, and sometimes additional imaging tests are necessary to make a proper diagnosis. It is very important to start treatment quickly - the first-line treatment is the eradication of Helicobacter pylori bacteria. Currently, we also have other therapeutic pathways that can change the course of the disease. The therapeutic plan should be individually selected for the needs of the individual patient. Changes detected in the early stages and treated quickly give patients a good chance of being cured. This publication is an attempt to summarize the current state of knowledge about the epidemiology, etiopathogenesis, clinical picture and therapeutic strategies in the case of gastric lymphoma.

Dissemination and genome characterization of a human adenovirus F41 in a patient with B-Cell lymphoma

Adenovirus (HAdV) F41 is a common cause of gastroenteritis and has rarely been reported associated with disseminated disease. In this report, an adult patient with a history of ulcerative colitis, cryptogenic cirrhosis, stage III adenocarcinoma, high-grade diffuse large B-cell lymphoma on chemotherapy was diagnosed with disseminated adenovirus infection. HAdV DNA was quantified in stool, plasma, and urine with viral loads of 7, 4, and 3 log10 copies/mL, respectively. The patient’s course was rapidly progressive and he passed away 2 days after initiation of antiviral therapy. The patient’s infecting virus was characterized as HAdV-F41 by whole genome sequencing.

Abstract #1312066: Transient Isolated Follicle-Stimulating Hormone (FSH) Deficiency Along With Azoospermia in a Patient Treated for Non-Hodgkin Lymphoma

Male subfertility can be due to diverse reasons, including anatomic, genetic, hormonal, iatrogenic causes, etc. Isolated FSH deficiency is a rare cause of male subfertility, reported only in a few cases till date. We report a case of a transient isolated FSH deficiency in a patient with azoospermia and subfertility with history of treated high-grade diffuse large B-cell lymphoma.

ABCL-286 Abrupt Obstruction of the Central Airway by a Relapse of Thyroid Gland Diffuse Large B-Cell Lymphoma: An Unusual Presentation

Primary thyroid lymphoma is a rare neoplasm comprising 1%-5% of all thyroid malignancies and 1%-7% of all extra-nodal lymphomas. Most thyroid lymphomas are of B-cell origin. Sharing a rare case of relapsed primary thyroid gland diffuse large B-cell lymphoma (DLBCL) and its diagnostic and therapeutic outcome, emphasizing the airway obstruction event. A case report. In March 2019, a 69-year-old man was admitted to our hospital with the following results of the thyroid gland biopsy-HP/Dg. High-grade DLBCL of the thyroid gland (CD20+, CD23+, Ki67=95%) was led by the endocrinologist because of the swelling symptoms around the neck and the changes in the thyroid gland ultrasound. The patient had no family history of any chronic or malignant disorders. Since the patient's laboratory tests and physical examination findings were normal, we decided to immediately start treating him with RCHOP protocol. After 8 rounds of chemotherapy, the patient was stable, and we planned to continue with maintenance therapy. Unfortunately, the patient came back before suggested with severe dyspnea, and the neck CT revealed a paravertebral/retrotracheal mass of 10.4×9.7×8.0 cm that was dislocating the trachea in the anterior plan and compromising the trachea and esophagus in T2 level. In the following days, there was an exacerbation of the dyspnea leading to total airway obstruction with SpO2 decreasing below 65%, and we needed to intubate the patient. Immediately after that, a tracheostomy was performed by an otorhinolaryngologist. When the patient's condition stabilized, we decided to treat his relapse with 4 cycles of salvage therapy-R-ESHAP-because of the lack of a transplant procedure in our country. After salvage chemotherapy, a PET-CT revealed no pathological FDG absorption, and a repeated neck CT showed a total reduction of the retrotracheal mass. The patient is still being followed every 6 months and has been in complete remission ever since. Seventeen months after completing the R-ESHAP treatment protocol, the patient is still in remission with no signs of disease and a normal CT scan. Despite the rare presentation of DLBCL, optimal early management and a multidisciplinary approach had a great impact on the patient's prognosis.

The Oncogene MYC Regulates the Branched Chain Amino Acid Metabolism and mTOR Signaling in Diffuse Large B Cell Lymphoma

Diffuse large B‐cell Lymphoma (DLBCL) is the most common type of aggressive non‐Hodgkin lymphoma (NHL) worldwide. While therapeutic strategies to combat DLBCL have advanced, these malignancies continue to be challenging to treat due to their heterogeneity and frequently recurring mutations. Aberrations in the oncogene MYC are commonly found in high grade DLBCL and are associated with poor responses to standard therapy.In search of downstream targets of MYC in DLBCL, we found MYC‐binding sites in the promoter regions of BCAT1, BCAT2, and BCKDHA. These genes encode enzymes in the metabolism of the branched chain amino acids (BCAAs), and they have been previously linked to cancer progression. BCAT1 and 2 encode the cytosolic (BCATc) and mitochondrial (BCATm) branched‐chain aminotransferases, while BCKDHA encodes the E1α subunit of the branched‐chain ketoacid dehydrogenase complex. We hypothesized that MYC activates these genes in DLBCL tissues leading to upregulation of BCAA metabolism and lymphoma growth.Human tissues collected from DLBCL patients (n=89) or controls (n=33) were used to analyze the gene expression of MYC, BCAT1, BCAT2 and BCKDHA followed by correlative analysis of the expression of these genes and the survival of DLBCL patients. Next, human DLBCL and B‐lymphoblast (control) cells were treated with the MYC inhibitor 10058‐F4 (0, 25, 50, 100 µM), the BCAA antagonist N‐acetyl leucine amide (NALA, 0, 10, 20, 40 mM) and the BCATc inhibitor gabapentin (0, 5, 10, 20 mM). 24 hours post treatment, the cell viability and cell proliferation, as well as the protein expression of BCATc, BCATm, and E1α, and the total and phosphorylation states of the ribosomal protein S6 (a downstream target of the mammalian target of rapamycin, mTOR) were determined.Results showed that the gene expression of BCAT1, BCAT2and BCKDHA were significantly elevated in tumor tissues from DLBCL patients compared to controls, and there was a positive correlation between their expression and the upregulation of MYC in DLBCL tissues. The high expression of MYC and BCAT2, but not that of BCAT1 and BCKDHA, correlated with poor overall cancer survival. Inhibiting the MYC function by 10058‐F4, the BCAA uptake by NALA, and the BCATc activity by gabapentin led to concentration dependent reductions in the cell viability and proliferation of the DLBCL cells. The protein expression of BCATm and E1α were reduced in the presence of 10058‐F4, which correlated with downregulation of mTOR signaling as measured by the deceased phosphorylation state of S6 in treated DLBCL cells. These results support the hypothesis that MYC is an upstream regulator of genes associated with BCAA metabolism. The results also demonstrate that DLBCL cells need MYC and BCAAs to upregulate mTOR signaling and to survive and may represent a new molecular mechanism via which MYC exerts its effects in DLBCL lymphoma.

Orbital apex syndrome secondary to sinonasal diffuse large B cell lymphoma: how rare is it?

A sinonasal lymphoma is an uncommon form of non-Hodgkin lymphoma (NHL), comprising only 1.5% of all lymphomas. We report a rare case of primary sinonasal diffuse large B cell lymphoma (DLBCL) found accompanying orbital apex syndrome. A 75-year-old Chinese man presented with progressively reduced visualacuity in the left eye for over 2 months and frequent rhinorrhoea for the previous 4 months. Upon examination, his left eye was noted with poor vision with incomplete ptosis, periorbital fullness, and ophthalmoplegia. Computed tomography scan of the brain and orbit showed nasal soft tissue mass with local extension to the left extraconal space. Histopathological examination of the nasal biopsy tissue showed high-grade DLBCL. The distal cranial neuropathy caused by the lymphomatous infiltration of the left paranasal sinuses had preceded the systemic manifestation. The patient was initiated on chemotherapy and has been, at the time of writing, in remission for 8 months after presentation.

Primary high-grade diffuse large B-cell lymphoma of the breast.

Primary high-grade diffuse large B-cell lymphoma of the breast.

S2647 An Unfortunate Association: Diffuse Large B-Cell Lymphoma With Chronic Hepatitis C

INTRODUCTION: Hepatitis C virus (HCV) is among the most common chronic viral infections, with potential sequelae of cirrhosis and hepatocellular carcinoma. In addition to hepatic complications, there are well established links from multiple studies between HCV and B-cell malignancies. While direct-acting antiviral (DAA) therapy is effective inducing regression in low-grade B-cell malignancies, for high-grade diffuse large B-cell lymphoma (DLBCL) associated with HCV treatment includes chemotherapy in addition to DAA therapy. Here we present a case of a newly diagnosed DLBCL in the setting of chronic HCV. CASE DESCRIPTION/METHODS: A 44 y.o male with a PMH of chronic HCV, h/o renal transplant, and CKD 3 presented with complaints of R-sided posterior chest mass which grew suddenly over 3 weeks. Patient reported a renal transplant approximately 20 years ago for congenital vesicoureteral reflux from a living, non-related donor and was on immunosuppression with prednisone, azathioprine, and cyclosporine. CT chest showed a large, irregular soft tissue mass in the posterior right chest wall encasing the right 11th rib with several enlarged mediastinal and periportal lymph nodes. He underwent a core biopsy of the mass which showed a new diagnosis of DLBCL, double expressor subtype with double/triple hit negative by FISH. Outpatient HCV workup showed genotype 4 with RNA levels 4.4 million; U/S liver showed no signs of cirrhosis. Patient was followed by oncology outpatient with initial labs showing concern for spontaneous tumor lysis syndrome and advised to return to ER. On presentation to ER, patient’s labs were unremarkable except for mild AKI on CKD3 which eventually resolved and was started on dose-adjusted R-CHOP therapy. He was discharged with plans to start DAA therapy with Epclusa and close follow-up with GI to monitor for sustained virological response. DISCUSSION: It’s hypothesized HCV plays a role in sustained B-cell activation and prevention of apoptosis by chronic antigenic stimulus rather than direct oncogenic effect, thereby predisposing to B-cell lymphoid malignancies. Treatment with DAAs stops persistent activation of B-cell lymphocytes. In addition, the combination of DAAs with chemotherapy including rituximab is well-tolerated without pharmacological interactions or significant hepatotoxicity, especially in patients without abnormal LFTs at baseline. Finally, initiating DAAs after chemotherapy in these cases helps to prevent recurrence of DLBCL once SVR is achieved.Figure 1.: CT Scan of R-posterior Rib Mass 60 mm × 64 mm.Figure 2.: Rib Mass Biopsy DLBCL 100X H&E.Figure 3.: Rib Mass Biopsy DLBCL 200X Ki-67 IHC.

ABCL-237: Treatment of High-Grade Diffuse Large B-Cell Lymphoma (HG-DLBCL) of the Elderly with Lenalidomide, Rituximab, Cyclophosphamide, and Prednisone

The treatment of HG-DLBCL in elderly patients is challenging in contemporary oncology. Afflicted by cardio-vascular and other co-morbidities, elderly patients often cannot receive important agents such as anthracyclines. In addition, myelosuppression and severe constitutional effects limit their therapeutic possibilities. Thus, elderly patients often receive palliative treatments or none. IMiDs (immunomodulatory imide drugs) with thalidomide as the parent compound, have activity in the treatment of several inflammatory, autoimmune and neoplastic diseases. Their antiangiogenic and T-cell co-stimulatory functions has given them an important place in the treatment of hematologic neoplasms such as multiple myeloma and myelodysplastic syndromes. Lenalidomide, a second generation IMiD, has activity against DLBCL alone and in combination with rituximab, an anti-CD20 antibody. We have observed significant therapeutic activity of lenalidomide when combined with rituximab, cyclophosphamide, prednisone + vincristine in five elderly patients with high-grade DLBCL who were anthracycline-ineligible. Clinical Data: Five elderly patients, 87 years median age, and the diagnosis of high grade (Ki-67 >60%) DLBCL, clinical stage IV were treated with six cycles of rituximab 375mg/m2cyclophosphamide 750mg/m2and prednisone 100mg a day by mouth in combination with lenalidomide 10mg a day for 21 days of a 28 day cycle. Two of the five patients received vincristine at a dose not to exceed 2mg total dose. Four achieved a complete remission after 2 courses of treatment and one a partial remission. The median duration of response is 46 weeks and there has been no relapses. One died at 90 weeks of his established cardiomyopathy. Conclusion: The standard of care for HG-DLBCL is a combination of an anti-CD20 antibody with an anthracycline, doxorubicin together with cyclophosphamide, vincristine, and prednisone (R-CHOP). In these five elderly patients reported here, we have observed a dramatic impact of lenalidomide in HG-DLBCL when combined with rituximab, cyclophosphamide, prednisone + vincristine (ORR:100%). None of the five treated patients has relapsed. The regimen is well tolerated with no significant complications. The addition of cyclophosphamide and prednisone may greatly enhance the already known activity of lenalidomide alone or in combination with rituximab in DLBCL (ORR: 27 and 33% respectively) in anthracycline-ineligible patients.

Analysis of primary central nervous system large B-cell lymphoma in the era of high-grade B-cell lymphoma: Detection of two cases with MYC and BCL6 rearrangements in a cohort of 12 cases

High-grade diffuse large B-cell lymphoma (HG-DLBCL) refers to DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit DLBCL) that exhibits poor prognosis. Double-expressor DLBCL (c-myc+/bcl-2+) has intermediate prognosis when compared to HG-DLBCL. Primary central nervous system lymphoma (PCNSL) has distinct pathophysiology (frequent non-germinal center-like subtype and double-expressor) and has worse prognosis than systemic DLBCL. By fluorescence in situ hybridization (FISH), 25–30% of PCNSLs harbor BCL6 abnormalities with rare alterations in MYC, BCL2, double-hit or triple-hit events. We describe the clinicopathologic features and status of MYC, BCL2 and BCL6 in 12 PCNSLs (7 women, 5 men; median age 63 years; range: 28–79). Six cases showed focal starry-sky pattern. Immunohistochemically, all (100%) were of non-germinal center-like subtype, and 8/10 (80%) cases were double-expressors. Ki-67 ranged from 70 to 100%. FISH was positive in 9/12 (75%) cases: 4 (33%) harbored a BCL6 rearrangement, 3 (25%) had a gain of BCL2, 2 (17%) cases each had a gain of BCL6 and gain of IGH, and gain of MYC and deletion of MYC were observed in 1 case each (8%). Two (16%) cases were MYC/BCL6 double-hit PCNSLs. No MYC/BCL2 or triple-hit cases were identified. Eleven (92%) patients received chemotherapy and one also received whole brain radiation. The median time of follow-up was 4.4 months (range, 0.3–40.3). Seven (58%) patients are alive, 4 (33%) have died, and 1 (8%) had no follow-up. Five alive patients are in remission, including one MYC/BCL6 double-hit PCNSL. Our results add two new cases of rare double-hit PCNSL to the literature.

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

AbstractMYD88L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

1541 Colorectal Lymphoma: A Wolf in Sheep's Clothing

INTRODUCTION: Although extranodal lymphomas are most commonly found in the gastrointestinal (GI) tract, colorectal lymphomas are a rare diagnosis accounting for only 0.2% of large intestinal malignancies and 4% of malignancies in the entire GI tract. We report a case of a female patient with vague abdominal symptoms, ultimately diagnosed with diffuse large B-cell lymphoma (DLBCL) of the colon. CASE DESCRIPTION/METHODS: A 55 year old African American female with HIV (CD4 164) was admitted for acute shortness of breath and 4 months of intermittent diffuse abdominal pain. She denied any diarrhea, changes in bowel habits, hematochezia, melena, or weight loss. Imaging revealed a pneumonia and nonspecific mesenteric lymphadenopathy (LAD), but no bowel abnormalities. Her abdominal pain initially improved with treatment of the pneumonia, but she was readmitted to the hospital one month later with recurrence of the abdominal pain and worsening shortness of breath. Vitals included BP 136/94, HR 125, RR 25, SpO2 90%, T 98.5. Exam showed bibasilar crackles and accessory muscle use with respirations. She had diffuse abdominal tenderness without obvious hepatosplenomegaly or LAD. Laboratory workup showed WBC 5.2 (normal differential), Hb 11.0, Platelets 361, normal CMP, BNP 300, LDH 9,845. CT revealed new bilateral pleural effusions, nonspecific mesenteric LAD, and mild transverse colon thickening (Figure 1). Colonoscopy revealed a non-obstructive 4 cm mass in the transverse colon. Biopsies revealed high-grade DLBCL. Thoracentesis confirmed the diagnosis. Before treatment could be initiated, the patient expired from tumor lysis syndrome and subsequent cardiac arrest. DISCUSSION: Colorectal lymphoma is extremely rare. Early recognition is crucial as stage I and II disease can be treated with surgery and chemotherapy, and if not treated, the mortality rate is 58%. Though DLBCL can occur in 5-10% of patients with HIV, the incidence of GI involvement in this population is still as low as 3%. As with our patient, diagnosis is often delayed due to nonspecific and non-localizing symptoms and signs. Imaging can be helpful, but can have a wide variety of characteristics–bulky masses, diffuse infiltration, multi-site involvement, and lymphadenopathy. Definitive diagnosis relies on histologic analysis. Later diagnosis also limits treatment. Management of stage I and II include chemotherapy and surgery while stage III and IV often require clinical trials. This case presentation highlights the importance of early diagnosis.

Association of a Giant Lymphoma Mass With Occupational Benzene Exposure

Benzene is a chemical widely used in industrial settings and known to have hematopoietic toxicity. Previous literature has been inconsistent regarding a direct association of benzene exposure with lymphoma. A young patient with a strong history of benzene exposure presented with a 17-cm chest wall lymphoma and purulent drainage from the mass. He underwent resection of the mass. Pathologic analysis revealed a high-grade diffuse large B-cell lymphoma. The wound ultimately healed well and the patient received adjuvant chemotherapy. Though the overall literature has been inconsistent regarding the association of benzene with lymphoma, our report highlights the possibility that a very extensive exposure history may be a risk factor for the development of lymphoma. J Med Cases. 2019;10(9):274-276 doi: https://doi.org/10.14740/jmc3364

Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma.

Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape cell death during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanism that underlie treatment resistance. We isolated aneuploid/polyploid populations of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells revealed that following drug removal, a subset of these DIAP cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling demonstrated that alisertib-induced aneuploid/polyploid cells up-regulate DNA damage, DNA replication and immune evasion pathways. In addition, we identified amplified receptor tyrosine kinase and T-cell receptor signaling, as well as MYC-mediated dysregulation of the spindle assembly checkpoints RanGAP1, TPX2 and KPNA2. We infer that these factors contribute to treatment resistance of DIAP cells. These findings provide opportunities to develop novel DH/DE-DLBCL therapies, specifically targeting DIAP cells.Key Points● MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells.● Drug-induced polyploid cells re-enter the cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.

Long-Term Results of Russian Prospective Multicenter Trial of the Addition R-HMA to R-DA-EPOCH in Patients with Untreated High-Grade Diffuse Large B-Cell Lymphoma

Long-Term Results of Russian Prospective Multicenter Trial of the Addition R-HMA to R-DA-EPOCH in Patients with Untreated High-Grade Diffuse Large B-Cell Lymphoma

A retrospective study of double-hit lymphomas in elderly patients (> 70 years): Overall outcomes.

e19530Background: Double-hit lymphomas (DHLs) are high-grade diffuse large B-cell lymphomas with concurrent translocations involving myc and bcl-2 and/or bcl-6. A patient with DHL often has advance...

A Retrospective Study of Double-hit Lymphomas in Elderly Patients (Aged > 70 Years): Overall Outcomes

BackgroundDouble-hit lymphomas (DHLs) are high-grade diffuse large B-cell lymphomas with concurrent translocations involving myc and bcl-2 and/or bcl-6. A patient with DHL often has advanced disease at presentation and typically responds poorly to standard therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). More intensive treatment regimens have been studied; however, few data are available on the outcomes in elderly patients (aged > 70 years) treated with these therapies. We retrospectively studied the efficacy and tolerability of chemotherapy regimens in elderly patients within the Advocate Healthcare System. Materials and MethodsA system-wide search of patients treated from 2012 to 2017 was completed to identify patients with c-myc with bcl-2 and/or bcl-6 translocations using fluorescence in situ hybridization. The patients were reviewed for the following: age at diagnosis, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, chemotherapy details, grade 3/4 toxicities, and response to therapy. Overall survival (OS) and event-free survival (EFS) were calculated. ResultsWe identified 17 patients (9 men and 8 women) with a median age of 73 years (range, 70-89 years). Six patients received R-EPOCH (rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin), 5 received R-CHOP, 1 received bendamustine and rituximab, 1 received the MaGrath regimen, and 1 received cyclophosphamide and rituximab. Three patients were not treated and were referred to hospice care. For all patients, the median follow-up period was 25 months, the EFS and OS were 28% at 36 months, and the median survival was 7.5 months. For patients treated with R-EPOCH, the EFS was 33% at 24 months. For the R-CHOP group, the EFS was 40% at 24 months. Most common grade 3/4 toxicities were neutropenia, anemia, thrombocytopenia, and infections and were more common in the R-EPOCH group. Three patients each died in the R-EPOCH and R-CHOP groups. ConclusionAlthough the numbers are small, elderly patients with DHL can achieve durable EFS and OS. Using the comprehensive geriatric assessment can aid in decision making in the treatment options for elderly patients. Our retrospective analysis, given a small sample size, suggests that intensive treatment regimens can be offered to elderly patients with DHL.