Priyank Patel

Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable

Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC‐amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2‐year progression‐free survival rate (PFS) was 49% and 48% and 2‐year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2‐year PFS (59% vs. 23%, P = 0·006) but similar 2‐year OS as compared with SHL patients receiving R‐CHOP. SHL DLBCL patients treated with R‐CHOP, but not intensive induction, experienced significantly lower 2‐year PFS and OS (P < 0·001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction.

Rituximab-refractory thrombotic thrombocytopenic purpura responsive to intravenous but not subcutaneous bortezomib

Thrombotic thrombocytopenic purpura (TTP) is often characterized by formation of antibodies against a disintegrin and metalloprotease with thrombospondin repeat, member 13 (ADAMTS13). Therapeutic plasma exchange (PEX) is the basis of TTP therapy, with additional immunosuppression to eradicate ADAMTS13 antibody–producing B cells.

HER2 status in elderly women with breast cancer

OBJECTIVES HER2 (human epidermal growth factor receptor 2) is an important biomarker in breast cancer, but its prevalence in elderly women is not well established. Previous studies reported HER2 status based on either immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) interchangeably. However, the tests may give discordant results. We report the prevalence of HER2 amplification in elderly women using only FISH. MATERIALS AND METHODS We retrospectively identified women 65 years and older undergoing core biopsy, lumpectomy or mastectomy for primary breast malignancy at a single institution between 2009 and 2011. Data collected included age, histopathological type, hormone receptor status, and HER2 status. Descriptive statistics were performed using SAS Software, Version 9.2. RESULTS One hundred fifty-eight women were included in the study. Most had invasive ductal carcinoma (74.7%), and were positive for either estrogen (ER) or progesterone (PgR) receptors (82.3% and 70.0%, respectively). Only 17% were negative for both ER and PgR; 11.4% were triple negative. Nineteen samples (12.0%) were positive for HER2. In univariate analyses, hormone receptor and HER2 status did not vary with age. When stratified by age, 60% of women with hormone receptor/HER2 positive tumors were younger than 70 years, compared with 22.2-33.3% of women in other subgroups. The difference was not statistically significant (p=0.20). CONCLUSION This study adds to the knowledge of the biology of breast cancer in elderly women. Triple negative tumor incidence was similar to that previously reported for women under 70 years old, but HER2 positive tumors were less common. Additional prospective studies are needed to confirm our findings.

An Unusual Cause of Altered Mental Status in Elderly—Acute Cerebellitis: A Case Report and Review

Acute cerebellitis is a rare diagnosis found mostly in the pediatric population. The etiology, in most instances, is unknown. We describe the case of a 61-year-old woman who presented with acute mental status changes, signs of cerebellar dysfunction, and MRI findings of acute cerebellitis. A brief review of the existing literature and comparison of our case with previous reports are also presented.

A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma

Background To explore the role of augmenting neutrophil function in B‐cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low‐grade CD20+ B‐cell non‐Hodgkin lymphoma (B‐NHL). Patients and Methods Twenty patients with indolent B‐NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III‐IV disease. The median number of previous therapies was 2 (range, 0‐5); 90% had received previous anti‐CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab‐related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression‐free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9‐27.6 months); the median overall survival was not reached. A shorter time‐to‐peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion The pegfilgrastim‐rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time‐to‐peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B‐NHL. Micro‐Abstract The present phase II study has demonstrated that augmenting neutrophil function by the addition of pegfilgrastim can potentiate the clinical activity of rituximab in indolent B‐cell non‐Hodgkin lymphoma while retaining the excellent safety profile. Strategies to boost the innate immune system such as this combination warrant further study, especially in the frail, elderly population for whom therapeutic options are limited owing to poor tolerance.

Abstract 3038: Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)

Background: Molecular studies divide DLBCL into three subtypes with distinct pathogenesis and clinical outcomes: activated B-cell (ABC), germinal center B-cell (GCB) and primary mediastinal lymphoma (PML). Florescence in situ hybridization (FISH) studies identified another subgroup of DLBCL, classified as DH-DLBCL, with a poor clinical outcome harboring concurrent gene rearrangements of the c-MYC, BCL2 and/or BCL6 proto-oncogenes, resulting in the over-expression of c-Myc, Bcl2 and Bcl6 proteins. Previously, our retrospective review from single institution series revealed that 30 out of 611 DLBCL patients had aberrations in c-MYC and BCL2 or BCL6 by FISH. These patients exhibited inferior response rates (RR) to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS), suggesting that newer therapies are in dire need. DH-DLBCL is characterized by de-regulation of apoptosis and cell cycle progression, resulting in rapid cellular proliferation and resistance to apoptotic stimuli. In ABC-DLBCL, anti-apoptotic factor MCL-1 is implicated in poor prognosis leading to resistance to standard chemotherapy. C-MYC transcriptionally upregulates Mcl1. Translocation of c-MYC in DH-DLBCL may contribute to the aggressive phenotype and chemotherapy resistance via the MCL-1 pathway. We hypothesize that dual inhibition of both anti-apoptotic proteins BCL2 and MCL1 is an effective strategy in inducing lymphoma cell death in DH-DLBCL. Materials & Methods: At the pre-clinical level, we studied 3 novel therapeutic agents targeting BCL2 (ABT-199), c-MYC (JQ-1), and various cell cycle regulatory proteins (p21) and other BCL2 family members affecting ABT-199 activity (irreversible proteasome inhibitor carfilzomib(CFZ)) using DH lymphoma (DHL) cell lines (Val, DOHH-2, ROS-50). DHL cell lines were exposed to ABT-199 (0-10 uM), JQ-1 (0-100 uM) and carfilzomib (CFZ) (0-50 nM) at 24, 48 and 72 hours. Changes in cell viability were evaluated using Presto Blue assay. Subsequently, DHL cells were exposed to doublet combinations of ABT-199, JQ-1 and CFZ for 48 hours. Coefficient of synergy was calculated using CalcuSyn. Results: In vitro, ABT199, JQ-1, and CFZ induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed by combining ABT199 with CFZ and to a lesser degree with JQ-1. Conclusion: ABT199 exhibited strong synergistic activity with CFZ. Dual targeting of BCL2 and c-MYC pathways results in synergistic activity in DHL cell lines. Of interest, this pharmacological interaction could be related to the effects of proteasome inhibition on MCL1 and p21 levels in lymphoma cells, further enhancing the activity of ABT199. Using combination therapy to inhibit c-MYC and the proteasome and in turn decreasing MCL1 will render ABT-199 more effective and be a more potent combination in causing apoptosis and lymphoma cell death. Further pre-clinical work is ongoing. Citation Format: Priyank P. Patel, Alison Zeccola, Juan Gu, Cory Mavis, Sheila N. J. Sait, Vishala Neppalli, Francisco J. Hernandez-Ilizaliturri. Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3038.