Abstract: Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)—a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.

Abstract: BACKGROUND: The human c-MYC oncogene is rearranged or overexpressed in approximately 12% or 37% of aggressive B-cell non-Hodgkin lymphomas (NHL), respectively. Relapses within 18-24 months are observed in more than 50% of these patients when treated with standard chemoimmunotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that is FDA approved for multiple myeloma and has been shown to down-regulate MYC in lymphoma models (Ravi et al., 2016). It has also demonstrated preclinical activity in aggressive NHL, including double-hit (DH) lymphoma. Herein, we report results of a multicenter phase I/II study evaluating the safety and efficacy of induction chemotherapy with DA-EPOCH-R in combination with ixazomib followed by ixazomib maintenance in aggressive MYC-aberrant NHL. METHODS: Adult patients with aggressive MYC-aberrant NHL defined as MYC-overexpression ( & gt; 40%) by IHC, MYC-amplification ( & gt;4 copies) by FISH, and/or MYC-rearrangement by FISH were eligible. Ixazomib was administered in conjunction with 6 cycles of DA-EPOCH-R. Intrathecal methotrexate prophylaxis was administered using institutional guidelines. Ixazomib was continued as maintenance for up to one year in responders. During phase I, an accelerated titration design was employed to determine the MTD of ixazomib (doses of 2.3 mg, 3 mg or 4 mg) in combination with DA-EPOCH-R. During induction, ixazomib was administered twice per cycle (1 cycle = 21 day), day 1 and day 8 or 15 based on blood counts. For maintenance, ixazomib was dosed at 4 mg weekly. Based on phase I results, 3mg of ixazomib was chosen as the RP2D for phase II. The primary objective was to determine MTD in phase I and to evaluate the efficacy of ixazomib given with DA-EPOCH-R as measured by 12-month PFS rate in phase II. Secondary objectives were to evaluate safety and assess ORR post-induction and OS in all phase I/II patients. RESULTS: Thirty-eight patients were enrolled between 10/2015 and 9/2019 and 36 were evaluable for response. Median age was 63 years (range 31-77) and 27 were male (71%), 86% had advanced stage, 46% had DH or triple hit lymphoma (28% and 18%, respectively), and 89% had an IPI of 2 or higher (Table 1). Twenty-nine (76.3%) patients completed all 6 cycles of induction therapy with DA-EPOCH-R and 25 (65.8%) patients were able to undergo dose escalation of DA-EPOCH-R. Two (5.3%) patients had ixazomib dose reductions during induction and 10 (26.3%) patients had discontinuation of ixazomib during induction. Reasons for early discontinuation during induction included peripheral neuropathy, concomitant comorbidities, progressive disease, and death. Of the 21 (55.3%) patients who received maintenance therapy, 5 (23.8%) had ixazomib dose reductions, and 9 (42.9%) had discontinuation of ixazomib during maintenance. Reasons for early discontinuation during maintenance included peripheral neuropathy, patient preference, and progressive disease. Treatment-related adverse events (TRAEs) of interest occurring in b % 10 % of patients are noted in Table 2. The ORR after induction was 89% with an associated CR rate was 61%. One patient received autologous transplant as consolidation and did not pursue maintenance as a result. Estimated 24-months PFS and OS were 66.9% (95% CI, 50.7% to 88.4%) and 78.7% (95% CI, 65.10% to 95.52%), respectively. Of the 21 patients who received maintenance, sixteen had a CR while 5 had a PR. In those who achieved a PR and went on to receive maintenance, 1 patient converted to CR and 1 maintained a PR with ongoing response at last follow-up. Two patients progressed and 1 has not yet been re-evaluated for response. At a median follow up of 17.6 months (range: 14-19 months), 7 patients had PD. Six patients died, 3 from PD, 1 from respiratory failure, 1 from sepsis, and 1 from natural causes considered unrelated to study drug. CONCLUSION: In this older population with aggressive MYC-aberrant NHL, DA-EPOCH-R induction with adjunctive ixazomib followed by maintenance ixazomib appears to be safe and effective. It is notable that 31% of patients had ixazomib dose reduction or discontinuation during induction and only 55% of patients initiated maintenance, which may have compromised the efficacy of this approach. Exploratory analysis of clinical and histological variables is ongoing and will be presented at the meeting. Improving frontline outcomes for this subset of patients remains a critical unmet need. Disclosures Karmali: Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Takeda: Research Funding; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R & D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Ma:TG Therapeutics: Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding. Fenske:Medical College of Wisconsin: Current Employment. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria. Jagadeesh:Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Petrich:AbbVie: Current equity holder in publicly-traded company; Daiichi-Sankyo: Current Employment. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Pro:Verastem Oncology: Research Funding. OffLabel Disclosure: Ixazomib is an orally bioavailable proteasome inhibitor that is FDA approved for multiple myeloma. It has also demonstrated preclinical activity in aggressive NHL, including double-hit (DH) lymphoma.

Abstract: There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS & gt; 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup. (Blood. 2003;102:2373-2378)

Abstract: Predictive models that take race into account like the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPT RC) and the new Prostate Biopsy Collaborative Group (PBCG) RC have been developed to equitably mitigate the overdiagnosis of prostate specific antigen (PSA) screening. Few studies have compared the performance of both calculators across racial groups. Methods From 1485 prospectively recruited participants, 954 men were identified undergoing initial prostate biopsy for abnormal PSA or digital rectal examination in five Chicago hospitals between 2009 and 2014. Discrimination, calibration, and frequency of avoided biopsies were calculated to assess the performance of both risk calculators. Results Of 954 participants, 463 (48.5%) were Black, 355 (37.2%) were White, and 136 (14.2%) identified as Other. Biopsy results were as follows: 310 (32.5%) exhibited no cancer, 323 (33.9%) indolent prostate cancer, and 321 (33.6%) clinically significant prostate cancer (csPCa). Differences in area under the curve (AUC)s for the detection of csPCa between PCPT and PBCG were not statistically different across all racial groups. PBCG did not improve calibration plots in Blacks and Others, as it showed higher levels of overprediction at most risk thresholds. PCPT led to an increased number of avoidable biopsies in minorities compared to PBCG at the 30% threshold (68% vs. 28% of all patients) with roughly similar rates of missed csPCa (23% vs. 20%). Conclusion Significant improvements were noticed in PBCG’s calibrations and net benefits in Whites compared to PCPT. Since PBCG’s improvements in Blacks are disputable and potentially biases a greater number of low risk Black and Other men towards unnecessary biopsies, PCPT may lead to better biopsy decisions in racial minority groups. Further comparisons of commonly used risk calculators across racial groups is warranted to minimize excessive biopsies and overdiagnosis in ethnic minorities.

Abstract: A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Abstract: The Prostate Imaging Reporting and Data System (PIRADS) has shown promise in improving the detection of Gleason grade group (GG) 2–5 prostate cancer (PCa) and reducing the detection of indolent GG1 PCa. However, data on the performance of PIRADS in Black and Hispanic men is sparse. We evaluated the accuracy of PIRADS scores in detecting GG2-5 PCa in White, Black, and Hispanic men. Methods We performed a multicenter retrospective review of biopsy-naïve Black (n = 108), White (n = 108), and Hispanic (n = 64) men who underwent prostate biopsy (PB) following multiparametric MRI. Sensitivity and specificity of PIRADS for GG2-5 PCa were calculated. Race-stratified binary logistic regression models for GG2-5 PCa using standard clinical variables and PIRADS were used to calculate area under the receiver operating characteristics curves (AUC). Results Rates of GG2-5 PCa were statistically similar between Blacks, Whites, and Hispanics (52.8% vs 42.6% vs 37.5% respectively, p  = 0.12). Sensitivity was lower in Hispanic men compared to White men (87.5% vs 97.8% respectively, p  = 0.01). Specificity was similar in Black versus White men (21.6% vs 27.4%, p  = 0.32) and White versus Hispanic men (27.4% vs 17.5%, p  = 0.14). The AUCs of the PIRADS added to standard clinical data (age, PSA and suspicious prostate exam) were similar when comparing Black versus White men (0.75 vs 0.73, p  = 0.79) and White versus Hispanic men (0.73 vs 0.59, p  = 0.11). The AUCs for the Base model and PIRADS model alone were statistically similar when comparing Black versus White men and White versus Hispanic men. Conclusions The accuracy of the PIRADS and clinical data for detecting GG2-5 PCa seems statistically similar across race. However, there is concern that PIRADS 2.0 has lower sensitivity in Hispanic men compared to White men. Prospective validation studies are needed.

Abstract: To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. Patients and Methods We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. Results Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus 〈 10 were 45% versus 100%, respectively ( P 〈 .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% ( P 〈 .001), respectively, the latter persisting on multivariable analyses. Conclusion Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.