ALBERT

Description: Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically

Description: Introduction: Very advanced age (≥80 years) DLBCL patients have worse prognosis. These unfavorable outcomes are largely considered to be a result of the combined effects of increased comorbidities, frailty, diminished tolerance and access to effective chemoimmunotherapy. It is not clear yet whether DLBCL patients of very advanced age have disease that is intrinsically more aggressive. Methods: We accessed the Stem Cell Transplant and Hematologic Malignancies database of University Hospitals Seidman Cancer Center for DLBCL patients diagnosed between 2000 and 2016. Information collected included demographic characteristics, baseline laboratory and disease information, as well as treatment details. Progression free survival and overall survival were calculated from time of diagnosis using Kaplan Meier methodology, comparisons were done with log rank. Cumulative incidence of relapse with death as competing risk was calculated for patients who underwent treatment, comparisons between age groups were done with the Gray test. Results: A total of 542 DLBCL patients were identified, 85 (16%) were older than 80 years. Table 1 shows the baseline demographic and disease characteristics. Older patients had a higher incidence of comorbidities, specifically cardiovascular comorbidities, prior renal insufficiency, and hyperlipidemia. Expectedly, very elderly patients had higher R-IPI, with a trend towards worse performance status that did not reach statistical difference. The proportion of patients diagnosed with non - germinal center DLBCL was not different than younger DLBCL patients, and there was no statistical difference in the incidence of double expressor or double hit lymphomas, possibly secondary to the small number of patients tested. A smaller proportion of patients ≥ 80 years received antineoplastic therapy (89% vs. 98%, p = 0.001), and use of less intense therapy was more common (table 2). Sixty one percent of patients, however, were still treated with R-CHOP (38.8%) or R-miniCHOP (22.2%). The overall response rate (ORR) for any therapy was 68.2%, lower than the ORR for younger patients (85.9%, p = 0.007). When only patients treated with RCHOP/R-miniCHOP were included, the difference in ORR was smaller, though still statistically significant (77.5% vs. 89.8%, p = 0.021). Median number of cycles was similar (5 vs. 6 cycles, respectively). Patients of all ages treated with single agent rituximab presented an ORR of 43%. After a median of 40 months follow up, estimated 4-year overall survival was 42% (95% CI 31-54%) for patients ≥ 80 years, 67% for patients aged between 60 and 79 years (95% CI 61-74%) and 78% for patients 〈 60 years (95% CI 73-84%) (Figure 1). Four - year survival for patients ≥80 years treated with R-CHOP or R-miniCHOP chemoimmunotherapy was 50% (95% CI 36-65%) vs. 75% for younger patients (95% CI 70-79%) (p

Description: Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma, but comprises a heterogenous group. Recent studies have identified aggressive subsets of DLBCL including double-hit lymphomas (DHL, with rearrangements of both MYC and BCL2 oncogenes and often classified in a separate DLBCL/Burkitt overlap category) and double-expressing lymphomas (DEL, which overexpress both MYC and BCL2). These subsets respond poorly to standard R-CHOP chemotherapy and account for most of the mortality associated with DLBCL. While recent studies have associated TP53 protein overexpression with worse prognosis in DLBCL, the effect of TP53 aberrations on these more aggressive DLBCL subsets is still uncertain. Design: We performed a retrospective single institution analysis of a cohort of 26 DHL and a cohort of 65 R-CHOP-treated DLBCL, including 10 DEL. We recorded clinical information, treatment, and patient outcome. The DHL cases were treated with either R-CHOP or a more intensive regimen. A tissue microarray or recuts from original blocks were used for immunostains for TP53, BCL2, MYC, and cell-of-origin determination by Hans algorithm, which were scored blindly. Results: TP53 expression (〉10% of tumor cells) was significantly associated with higher expression of BCL2 (p=0.02), MYC (p=0.0009), and DEL status (p=0.005) in the DLBCL group. With respect to the association of DEL with TP53 expression, 7/10 (70%) cases of DEL were TP53+ compared to 10/55 (18%) of non-DEL DLBCL. There was no association with TP53 expression and cell-of-origin. No statistically significant difference in overall or relapse free survival between TP53+ and TP53- cases was identified in either cohort. Conclusion: The findings in this small sample suggest that the relationship between TP53 staining and DLBCL outcome is more complex than previously reported, and may reflect an association of TP53 expression with DEL. The use of intensified treatment regimens (such as R-EPOCH) in the DHL cohort may abrogate any negative effects of TP53 overexpression in the TP53+ subset. Disclosures Abramson: Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Kite Pharma: Consultancy.

Description: Background Philadelphia-like (Ph-like) B Lymphoblastic Leukemia (B-ALL) is a high-risk subtype of B-ALL that lacks the BCR-ABL1 fusion but has a gene expression profile similar to Philadelphia positive (Ph+) B-ALL. Gene expression profiling has previously identified Immunoglobulin Joining chain (IgJ) overexpression at the mRNA level in Ph-like B-ALL. This is surprising since IgJ is normally expressed by mature or maturing B cells. The normal function of IgJ protein is to concatenate monomers of immunoglobulin IgM or IgA into the mature pentameric and dimeric forms of these molecules respectively. IgJ also plays a crucial role in transport of IgA protein across mucosal epithelium to facilitate mucosal humoral immunity. In hematopathology, J chain immunohistochemistry (IHC) has been used to identify neoplastic cells in nodular lymphocyte predominate Hodgkin lymphoma (NLPHL) and can be used in distinguishing this disease from morphologic mimickers. It does not have known diagnostic utility outside of this context. Lymphoblasts do not typically express immunoglobulins at the protein level. Therefore, we sought to determine the protein expression of IgJ in B-ALL and to determine whether IgJ immunohistochemistry may be employed in identifying particular subtypes of B-ALL. Methods We selected a total of 46 B-ALL cases diagnosed from a bone marrow sample at our institution from 2016-2019 with adequate diagnostic material for IHC. This included 5 cases of Ph-like B-ALL, all with a CRLF2 rearrangement and overexpression, 7 de novo Ph+ B-ALL and 34 cases representing the other most commonly recognized WHO subtypes of B-ALL, determined based on cytogenetic studies performed at the time of diagnosis. No cases of B-ALL with t(5;14) and B-ALL with iAMP21 was represented. Our cohort included 23 pediatric cases and 24 adult cases and the patients ranged from 1 to 82 years old at the time of initial diagnosis. A total of 8 normal bone marrow cases (negative staging bone marrow biopsies for diffuse large B cell lymphoma, neuroblastoma or classic Hodgkin lymphoma) were used as controls. IgJ IHC was performed on B-plus fixed paraffin embedded bone marrow biopsy specimens using a commercially available and validated anti-IgJ monoclonal antibody (clone OTI3B3). Staining of bone marrow samples was performed at 2 different dilutions; tonsil secondary follicles and neoplastic cells from NLPHL were used as technical controls. Cellular staining in the lymphoblasts was scored in a blinded manner by a board certified hematopathologist and a pathologist in training as diffusely positive, partially positive, or negative. Results Cellular staining was distinguishable from background staining due to circulating immunoglobulins and there was almost perfect inter-observer concordance in identifying positive and negative cases (agreement of 98%, kappa test 0.94). All normal bone marrow controls cases were negative for IgJ cellular staining. A total of 11/46 (23%) B-ALL cases demonstrated partial or diffuse cellular staining for IgJ in the lymphoblasts. This included 4/5 (80%) Ph-like cases, 5/7 (71%) Ph+ cases, 1/3 MLL rearranged cases and 1/6 ETV6-RUNX1. All TCF3-PBX1 (0/4), hyperdiploid B-ALL (0/10), hypodiploid B-ALL (0/2), and B-ALL, NOS cases (0/9) were negative for IgJ. Diffuse IgJ staining was restricted to Ph-like (2/4) or Ph+ (2/5) B-ALL subtypes; the positive MLL rearranged and ETV6-RUNX1 B-ALL cases only showed weak partial staining. IgJ protein was significantly expressed in Ph+/Ph-like B-ALL (p