Go, Ronald S.

Introduction Immune-mediated hematologic disorders are relatively rare but potentially life-threatening immune-related adverse events (irAE) with immune checkpoint inhibitor (ICI) therapy (Shiuan, Beckermann et al 2017). The management strategy often relies on systemic corticosteroids and other immunosuppressant agents in steroid-refractory cases (Brahmer, Lacchetti et al 2018). We hereby describe our institution's experience in diagnosing and managing immune-related hematologic adverse events (ir-h-AE). Methods We retrospectively searched the electronic health record for all ir-h-AE diagnosed by treating providers and confirmed by study authors between 2015 and 2020. The search included patients on ICI and the following conditions: immune-related neutropenia (IRN), autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), immune thrombocytopenia (ITP), immune-related pancytopenia, aplastic anemia (AA), and pure red cell aplasia (PRCA). For AIHA, PRCA, and CAD, partial response (PR) was defined as hemoglobin greater than 10 g/dL but < 12 g/dL and 2 g/dL above the nadir without blood product transfusion. Complete response (CR) was defined as hemoglobin of ≥ 12 g/dL and 2 g/dL above the nadir without blood product transfusion (Peñalver, Alvarez-Larrán et al. 2010). For ITP, CR was defined as platelet count ≥ 100 × 109/L and absence of bleeding. PR was defined as platelet count ≥ 30 × 109/L and ≥ two-fold increase from the baseline count and absence of bleeding (Gómez-Almaguer, Tarín-Arzaga et al. 2013). For IRN, CR was defined as absolute neutrophil count (ANC) ≥ 1500/ mm3 on 2 consecutive measurements separated by 7 days; PR was defined as ANC ≥ 500/ mm3 sustained over 7 days. JMP® 14.1 was used for data analysis. Results Seventeen patients were identified, 9 (52.9%) of whom were female (table 1). Median age was 68 years (range 26-78). The most common pre-existing malignancies were melanoma (6 patients, 35.3%), non-small cell lung cancer (4 patients, 23.5%), and gastrointestinal cancer (3 patients, 17.6%). The ir-h-AE included 7 patients (41.2%) with warm AIHA, 4 (23.5%) with ITP (1 had immune-related pancytopenia that resolved with ITP persisting), 3 (17.6%) with IRN, 1 with AA, 1 with CAD, and 1 with PRCA and mild ITP. All patients had received an ICI dose within 60 days of diagnosis (range 3-52 days, median 18 days). Only 1 patient had a concomitant chronic autoimmune disorder (antinuclear antibody-positive arthritis). Four patients (23.5%) were receiving chemotherapy. Sixteen patients (94.1%) required treatment and received corticosteroids. Eight out of 15 evaluable patients (53.3%) responded to corticosteroids only. Another 4 responders (26.7%) required additional therapies including intravenous immunoglobulins (IVIG) (4, 23.5%) and/or rituximab (4, 23.5%). Overall response rate was 71.4% for AIHA and 100% for IRN. ITP was likely underrepresented in our cohort, and the response rate of 66.7% is likely lower than the response rate in clinical practice. This could be related to the fact that many mild thrombocytopenia cases are not further evaluated in clinical practice. None of our patients died from the sequelae of an ir-h-AE. Two patients (11.8%) died within 30 days of ir-h-AE diagnosis (disseminated intravascular coagulation likely due to the underlying malignancy and sepsis from bacterial pneumonia). At the time of ir-h-AE diagnosis, the malignancy was showing evidence of response in 9 patients (52.9%), progression in 6 patients (35.3%), and stability in 2 patients (11.8%). ICI therapy was permanently discontinued in 9 patients (52.9%) and temporarily held in 6 patients (35.3%). Three of the 5 patients (60%), who were rechallenged with ICI therapy, had recurrence of the same ir-h-AE (AIHA) with adequate response to therapy. Non-hematologic irAE (7 patients, 41.2%) included 3 patients with hepatitis, 2 with thyroiditis, 2 with pneumonitis, 1 with colitis, and 1 with dermatitis. Conclusion Our clinical experience with ir-h-AE highlights the importance of exercising vigilance in assessing the hematologic parameters of patients receiving ICI therapy. While relatively rare, ir-h-AE may impact the clinical course of patients with cancer and their eligibility for therapies that have the potential of offering durable control of the underlying malignancy. ir-h-AE respond to classical therapies including corticosteroids, IVIG, and rituximab. Disclosures Block: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Marker Therapeutics: Research Funding; Transgene: Research Funding; Immune Design: Research Funding. Kottschade:Bristol-Myers Squibb: Consultancy, Research Funding.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.

AbstractInduction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment‐emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first‐line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty‐five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21‐day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22–56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

AbstractIntroductionLittle is known on continued response following completion of therapy in light chain (AL) amyloidosis.MethodsWe studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first‐line therapy.ResultsBy end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10‐year OS 87% vs 71% vs 56%, P < .001).ConclusionsThis study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease (“R” group), and 9 patients with lesions limited to the skin or subcutaneous tissue (“C” group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the “R group” of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease ( P <0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.

INTRODUCTION: Autoantibody effects of monoclonal proteins have been described in multiple organ systems. We previously found a 5-fold higher prevalence than expected of monoclonal gammopathy (MG) in adults with TMA (21% versus 4.2%; Ravindran A et al, Kidney Int 2017). Here we investigated the prevalence of MG in patients undergoing evaluation for TMA with an ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) activity assay performed as part of routine clinical care to evaluate for a signal of possible autoantibody pathophysiology in patients with immune thrombotic thrombocytopenic purpura (iTTP). METHODS: WAfter IRB approval, waste plasma samples from patients who had ADAMTS13 activity and inhibitor assay (Lifecodes, ATS-13, Immucor) were archived. Eligible patients included those with the following: i) ADAMTS13 activity level &lt; 30% (n=26), ii) ADAMTS13 activity level &gt;30% but with prior documentation of a value &lt; 30% (n=4). A control cohort (n=49) of patients with ADAMTS13 activity level &gt;30% (and no prior samples with a level &lt; 30% recorded) was also included. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry detection (MALDI-TOF) was used for MG assessment. Mass spectrometry findings of only an IgG kappa MG appearing consistent with rituximab were reviewed and considered negative for MG if the patients had received rituximab prior to sample collection. Medical records were retrospectively reviewed and the following patients were excluded: i) &lt;18 years of age (n=4), ii) iTTP in remission (n=4) at the time of sample collection, and iii) absence of microangiopathy (n=11). RESULTS: Sixty patients met eligibility criteria with the following final diagnoses: iTTP (n=14), transplant-associated TMA (n=12), infection (n=11), malignancy (n=6), complement-mediated TMA (n=5), drug-induced TMA (DITMA; n=5), shock liver (n=2), pancreatitis (n=1), cryoglobulinemia (n=1), and multifactorial (n=3). The median age was 56.5 years (yr) (standard deviation 14.4, range18-81) and 58% of patients were female. The median age was similar among patients with (57 yr) and those without MG (56 yr). Median ADAMTS-13 activity of the whole study population was 52% (0-100%); 6/14 patients with an inhibitor screen performed on the same sample had a positive result; median titer was 1.2 Bethesda units (range &lt;0.4 - 2.8). Treatments of the acute presentation included corticosteroids (n=32), plasma exchange (n=21), rituximab (n=9), and eculizumab (n=4). None of these patients received a multiple myeloma-type treatment regimen as part of their acute management. A MG was identified in 25 patients: monoclonal in 14 patients, biclonal in 10 patients, and triclonal in 1 pt. Among the 14 patients with a single monoclonal protein, the distribution of heavy and light chains was as follows: IgG (9; 64%), IgM (3; 21%), IgA (2; 14%), lambda (8; 57%), kappa (6; 43%). Receipt of immune-modifying treatment at the time of sample draw was identified in 24 patients (9/25 with a monoclonal protein, 15/35 without a monoclonal protein; not statistically significant by 2-tail Fisher's exact test [p=0.79]), including cancer-directed therapy (n=9), graft-versus-host disease prophylaxis (n=8), solid organ transplant anti-rejection therapy (n=5), and autoimmune disease treatment (n=2). Overall, the proportion of patients with monoclonal gammopathy was similar between iTTP and other diagnoses, detailed in Table 1. Among the 14 pt with iTTP, 4 had a monoclonal protein (IgG kappa [n=2], IgA lambda [n=2]). Additionally, 1 pt with iTTP had biclonal proteins (IgG kappa and IgA kappa), which was consistent with a known prior history of monoclonal gammopathy of undetermined significance. A monoclonal protein was present in 2 of the 6 pt with a detectable inhibitor titer (0.6 and &lt;0.4 Bethesda units). CONCLUSIONS: Patients undergoing evaluation for iTTP with ADAMTS-13 activity testing had a high prevalence of monoclonal proteins across variable underlying diagnoses. In this heterogeneous cohort there was no significant association between iTTP and the presence of MG to support an autoantibody pathophysiologic role. Disclosures Murray: The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Pruthi:HEMA Biologics: Honoraria; Instrumentation Laboratory: Honoraria; Merck: Honoraria; CSL Behring: Honoraria; Genentech Inc.: Honoraria; Bayer Healthcare: Honoraria.

Introduction: In general, the use of an immunomodulator (IMiD), proteasome inhibitors (PI) and dexamethasone (dex) for the treatment of MM is associated with better outcomes. The management of elderly patients with multiple myeloma (MM) is challenging due to difficulty in managing their co-morbidities and inability to tolerate treatment side effects. We evaluated therapies and outcomes of elderly patients with newly diagnosed MM. Methods: This is a retrospective study of patients with MM who were &gt;75 years old treated at the Mayo Clinic, Rochester from January 2004 to January 2018. We included patients who were treated on clinical trials as well as off-trials. Patients were classified as receiving treatment with IMiD+PI+dex, alkylator+PI+steroid, IMiD+dex, PI+dex, alkylator+IMid+steroid, and other (alkylator with steroid or steroid only). Treatment response was documented as well as the progression-free (PFS), defined as the time from therapy initiation to disease relapse or death from any cause and overall survival (OS), defined as the time from start of treatment to death from any cause. A multivariate analysis for factors affecting OS was done including the following variables: being on a triplet combination (alkylator+PI+steroid, IMid+PI+dex, or alkylator +IMiD+steroid), revised international staging system (R-ISS)(stage 3 vs. 1-2), bone marrow plasma cell percentage (BMPC%)(&gt;60% vs. ≤60%), and receiving treatment during or after 2010 vs. before 2010. Analysis was done for patients treated off-trials, as well as, including trial patients. Results: We identified 394 patients with MM who were &gt;75 years old and 246 (62%) were male. For non-trial patients (n=350), IMiD+dex (32%) was the most commonly used regimen followed by alkylator with steroid or steroid only (20%), alkylator+PI+steroid (18%), and IMid+PI+dex (13%). The remaining patients were treated with PI+dex (12%) and alkylator +IMiD+steroid (5%). Forty-four patients (11%) were treated in clinical trials with alkylator+IMid+steroid (47%), IMiD+dex (25%), IMiD+PI+dex (14%), and alkylator+PI+steroid (14%). The median follow up was 45.9 months with an interquartile range of 28.2 to 75.6 months. Overall, achieving very good partial response or complete response was more likely in patients who were treated with an IMid+PI+dex (58%) or alkylator+PI+steroid (47%), compared to in other therapies (5-30%)(P&lt;0.0001). The PFS and OS for non-trial patients are displayed in Figure 1 (A,B) and for all, including trial patients in (C,D). Overall, the median OS was significantly longer in patients who were treated with a triplet in non-trial as well as all patients. In a multivariate for OS including non-trial patients, predictors for better OS included receiving a triplet (HR: 0.63, P=0.02) and not having an R-ISS stage 3 (HR: 0.39, P=0.001). This was also found when including trial patients (using a triplet, HR: 0.65, P=0.01 and not having an R-ISS stage 3, HR: 0.35, P=0.0002). Conclusion: In MM patients &gt;75 years old, being able to receive triplet therapy is associated with better survival. This study provides better understanding of the natural history of MM outside of trials in the elderly age group. Disclosures Dispenzieri: Celgene: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Dingli:Bristol Myers Squibb: Research Funding; Alexion: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Sanofi-Genzyme: Consultancy; Apellis: Consultancy; Janssen: Consultancy; Karyopharm Therapeutics: Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Celgene: Honoraria. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee; Springer Publishing: Patents & Royalties; Proclara: Other; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau; Sanofi: Other; Research to Practice: Other; Celgene: Other; Abbvie: Other; Aurora Bio: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Amgen: Other: personal fee; Appellis: Other: personal fee; Annexon: Other: personal fee. Kumar:Carsgen: Other, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Cellectar: Other; Genecentrix: Consultancy.