Abstract: Waldenström macroglobulinaemia ( WM ) is a rare and incurable lymphoma. Given that the survival of WM patients can be prolonged, our objective was to describe trends in overall survival ( OS ) and analyse competing risks of death in patients with WM . The analysis included 5784 patients diagnosed with WM between 1991 and 2010 from the S urveillance, E pidemiology and E nd R esults ( SEER ) database. Multivariate hazard models for OS and cumulative incidence of death were fitted according to epoch of diagnosis (1991–2000 vs. 2001–10) while adjusting for age, sex, race, histology, site of involvement and registry. Median OS for the 1991–2000 and the 2001–10 cohorts was 6 and 8 years, respectively ( P   〈  0·001). In the multivariate analysis, better OS [hazard ratio ( HR ) 0·73, 95% confidence interval ( CI ) 0·67–0·79; P   〈  0·001] was seen in the 2001–10 cohort. Survival benefits were identified, for the 2001–10 cohort, in almost every stratum analysed, with the exception of patients aged 〈 50 years and blacks. In the multivariate competing‐risk analysis, the 2001–10 cohort experienced lower rates of WM ‐related ( HR 0·57, 95% CI 0·49–0·66; P   〈  0·001) and non‐ WM ‐related deaths ( HR 0·72, 95% CI 0·66–0·79; P   〈  0·001). In conclusion, there have been significant improvements in OS , WM ‐related and non‐ WM ‐related mortality in patients with WM diagnosed in the last decade.

Abstract: Background : Relapsed or refractory (R/R) transformed indolent B-cell non-Hodgkin lymphoma (iB-NHL) is an uncommon clinical entity associated with poor prognosis. Unfortunately, most trials of aggressive B-NHL tend to specifically exclude transformed disease resulting in scant prospective data to guide therapy. We performed a prospective phase II trial of single agent ibrutinib in patients with previously treated transformed iB-NHL and now report the final results (NCT02207062). Methods : Eligibility included measurable, biopsy-proven transformed iB-NHL, no prior ibrutinib, ECOG 0-2, and prior receipt of ≥ 1 line of therapy for the transformed disease. Treatment consisted of oral ibrutinib 560 mg daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR, per Lugano criteria by independent radiology review), with a predefined threshold of success ≥ 30%. Secondary endpoints included clinical benefit rate (CBR, defined as ORR and/or stable disease of ≥ 6 months), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included ORR according to cell-of-origin (COO) of transformed lymphoma assessed by Hans algorithm and disease burden measured by computed tomography (CT) and metabolic tumor volume (MTV). Results : From October 2014 to March 2019, 20 patients were treated (Table 1). At enrollment, patients had received a median of 4 prior therapies (range 2 to 9) and were refractory to chemotherapy in 10 (50%) cases. Histology of transformed disease was diffuse large B cell lymphoma (DLBCL) in all patients. Two patients came off study prior to response assessment and without clinical evidence of disease progression: 1 after 1.3 months for intractable mucositis and 1 who died suddenly and without known cause 1.9 months into treatment. Median time on therapy was 3.1 months range (0.6 to 48.0) with 3 (15%) patients continuing on therapy 〉 1 year. Eighteen patients were evaluable for response. The ORR was 39% (complete response = 17%) and CBR was 44%. Median PFS and OS were 4.1 and 22.4 months, respectively, and median duration of response was 2.3 months; estimated 12-month PFS was 18% (Figure 1). ORR was more common in cases of low tumor burden but this association did not meet statistical significance on univariate analysis (p = 0.15 for maximum tumor 〈 5 cm by CT and p = 0.06 for MTV 〈 100 cm3). ORR was superior after prior autologous hematopoietic stem cell transplantation (auto-HSCT) (p = 0.01) and was not associated with DLBCL COO (p = 0.75). Dose holds for toxicity were required on 6 occasions in 5 (25%) patients for a median duration of 17.5 days (range 8 to 21); no reductions in dose were performed. Ibrutinib was resumed after resolution of toxicity at full dose in each case with the exception of an episode of pneumonia that, despite resolution, prompted the patient to stop treatment on study. Adverse events (AEs) considered related to ibrutinib were most commonly grade 1-2 and included fatigue (55%), bruising (55%), and diarrhea (35%). Grade ≥ 3 AEs included atrial arrythmia in 2 patients and the following AEs in 1 patient each: ventricular arrythmia, neutropenia, lymphopenia, mucositis/esophagitis, nausea, pneumonia, sepsis, and death of unknown cause. Conclusions : Ibrutinib appears active in R/R transformed iB-NHL and may provide extended disease control for a subset of patients or as part of a bridging strategy prior to CAR-T or transplant. The observed toxicity profile was consistent with other trials. Efficacy may be greater in cases of lower tumor burden and in patients previously treated with auto-HSCT. Further investigation of ibrutinib and focused study of agents in transformed iB-NHL is warranted. Disclosures Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Cassaday:Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests; Amgen: Consultancy, Research Funding. Lynch:Rhizen Pharmaceuticals S.A: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding. Krakow:Bellicum Pharmaceuticals: Research Funding; Highpass Bio: Research Funding; Magnolia Innovations: Consultancy. Smith:Denovo Biopharma: Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Pharmacyclics: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. OffLabel Disclosure: Ibrutinib is not approved for previously treated transformed indolent B-cell lymphoma.

Abstract: Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). However, a substantial proportion of patients (pts) will relapse. The anti-PD-1 monoclonal antibody pembrolizumab has shown modest efficacy in previously treated DLBCL. We postulated that the first-line setting, with relatively intact host immunity and coexistence of malignant cells with T-cells in the microenvironment, may represent an opportunity for effective immune checkpoint inhibition. We carried out the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma, to evaluate the safety of this combination. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3B follicular lymphoma with a plan for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. A 30-pt sample size permitted estimation of the rate of clinically relevant grade 3-5 toxicity, assumed to occur in 40% of pts with RCHOP alone. A stopping rule for more than 3 instances of non-relapse death or inability to complete 6 cycles of RCHOP for any reason was applied. Secondary endpoints included response rates, overall (OS) and progression-free survival (PFS). Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). Peripheral blood flow cytometry for changes in PD1, PDL-1, and PDL-2 subsets were performed. After PET-based response assessment, pts were followed for relapse and survival. Results: Since March 2016, 29 pts were treated on study; 28 have finished all therapy. One is currently on therapy, and 1 remains to be enrolled. Pt characteristics are in Table 1. In 29 pts to date, 18 grade 3-5 clinically significant AE's occurred in 13 unique pts (13/29, 45%). 16 SAE's occurred in 11 pts (11/29, 38%); none qualified as unanticipated events. Two deaths occurred: One in the first accured patient, who had extensive gastric involvement by DLBCL, and died during cycle 1 of bleeding from the responding tumor bed despite maximal inpatient intervention. The other death occurred due to steroid-refractory GVHD after haploidenticial allogeneic transplant for relapsed disease. Four immune-related adverse events (IRAE) occurred: grade 3 rash, resolving with oral steroids and not recurring with further pembrolizumab, grade 1 hyperthyroidism, grade 2 colitis, and 1 episode of grade 3 pneumonitis. This case of pneumonitis was the only immune-related SAE, occurring in a 78 yo with a history of tobacco use and COPD, and resulted in stopping therapy after cycle 3. Among 27 completing treatment (excluding the pt who died during cycle 1), average anthracycline dose was 95% of expected; anthracycline relative dose intensity (RDI: delivered dose intensity/standard dose intensity) was 94%. PET response assessment among 26 evaluable pts showed 18 CR (69%), 7 PR, and 1 primary refractory disease. Among 7 PR, 1 relapsed, 3 had negative biopsies, and 3 remain in remission. Median follow-up of survivors is 13 months and 2 relapses (1 primary progressive disease, 1 after PET PR) occurred. One-year PFS is 87% (Figure 1). Baseline PDL-1 staining available for 19 pts showed a median % tumor cell staining of 30% (moderate 2+ plus strong 3+ staining; range, 0-100%). Tumor PDL1 was ≤5% in 4, 10-29% in 5, 30-49% in 4, and ≥50% in 6 pts. Both EBV+ DLBCL had 60% tumor PDL1 expression. 1 relapsing pt had no detectable tumor PDL1, and the THRLBL failed for technical reasons. Conclusions: RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles is safe, with toxicity similar to RCHOP alone and only 4 IRAE's. Anthracycline dose intensity, CR rate, and PFS are favorable. PDL1 tumor cell expression of 10% or more was observed in 15/19 pts. These data support further study of pembrolizumab with chemotherapy in untreated lymphoid malignancies. Final response/progression, correlative studies, and survival data will be presented in December after final accrual. Disclosures Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Cowan:Sanofi: Research Funding; Juno Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Shadman:Acerta Pharma: Research Funding; Genentech: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy; Beigene: Research Funding; Pharmacyclics: Research Funding; AbbVie: Consultancy; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy. Shustov:Seattle Genetics: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding. Gopal:Pfizer: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Takeda: Research Funding; Incyte: Consultancy; Spectrum: Research Funding; Gilead: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Teva: Research Funding.

Abstract: Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.

Abstract: Bortezomib is active in Waldenstrom’s macroglobulinemia (WM) but associated with considerable peripheral neuropathy (PN). The proteasome inhibitor carfilzomib (CFZ) is approved in the USA for relapsed/refractory myeloma. Herein, we examined the efficacy and safety of carfilzomib, rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor and rituximab naive WM patients with symptomatic disease. Median baseline characteristics: age 61, prior therapies 0 (range 0-1), hematocrit 32.3%, hemoglobin 10.7 g/dL, serum IgM 3375 mg/dL, serum M-protein 2.185 g/dL, B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV CFZ 20 mg/m2 (cycle 1) then 36 mg/m2 (cycles 2 and beyond) with IV dexamethasone (dex) 20 mg given on days 1,2,8,9 and rituximab 375 mg/m2 on days 2,9 of each 21-day cycle. Treatment consisted of six induction cycles, then maintenance beginning 8 weeks after induction (given every 8 weeks for eight cycles; consisted of CFZ 36 mg/m2, and IV dex 20 mg on days 1,2 and rituximab 375 mg/m2 on day 2). Patients with IgM level 〉 4000 mg/dL underwent plasmapheresis and/or had rituximab held until IgM 〈 4000 mg/dL to prevent symptomatic IgM flare. Patients received oral acyclovir (400 mg twice daily) and famotidine (20 mg twice daily) as concomitant medications. For all 31 patients, median serum IgM levels and M-protein declined to 749 mg/dL and 0.7 g/dL, respectively (p 〈 0.00001). Median hematocrit and hemoglobin rose to 40.9% and 13.7 g/dL, respectively (p 〈 0.00001). A total of 30 patients concluded induction therapy with bone marrow tumor involvement reduced to a median of 7.5% (p=0.0003). The best overall response rate using criteria adapted from the 3rd International Workshop on WM was 81% (1 CR, 8 VGPR, 12 PR, 4 Minor Responses). With a median follow-up of 8 cycles, 22 patients remain on study, including 20 currently on maintenance therapy. Median time to response (for minor responders or better) was 2.1 months. Grade 〉 2 treatment related toxicities included asymptomatic elevation in lipase (12.9%), dex-related hyperglycemia (6.45%), reversible neutropenia (9.67%), and cardiomyopathy (3.22%). There were no grade 2 or greater PN events. Treatment discontinuation occurred for non-response (n=8), cardiomyopathy in a patient with multiple cardiac risk factors (n=1), and progressive disease (n=1). CaRD is highly active and offers a neuropathy sparing approach for proteasome-inhibitor based therapy in WM. Disclosures: Off Label Use: Carfilzomib is a novel proteasome inhibitor, which offers a neuropathic sparing approach on waldenstrom macroglobulinemia disease when used in a combination therapy with rituximab and dexamethasome.

Abstract: Background While kidney disease (KD) is a well described complication of multiple myeloma (MM), occurring in up to 40% of patients, the incidence, pathological manifestations, and clinical correlations associated with KD in patients with Waldenström's Macroglobulinemia (WM) or IgM MGUS remain to be clarified. Methods Out of 1,738 patients with consensus criteria defined WM (N=1,655) or IgM MGUS (N=83) diagnosis who were evaluated in the WM clinic at our institution from 2001-2015, we selected those individuals with at least one of the following abnormalities: serum creatinine ≥1.3; estimated GFR (eGFR) 〈 60; or proteinuria. Patients with non-WM/IgM MGUS related KD were excluded. Results Renal impairment and/or proteinuria were present in 259 patients. In 183 cases, KD was not related to WM/IgM MGUS (mainly diabetic and/or hypertensive nephropathy). Fifteen patients with kidney or bladder carcinoma, and 4 patients with peri-renal diffuse large B-cell lymphoma (N=3) or lymphoplasmacytic lymphoma (N=1) were also excluded. Therefore, a clinical diagnosis of WM/IgM MGUS associated KD was made in 57 (53 WM; 4 IGM MGUS) patients, of whom 41 had a confirmatory renal biopsy. The crude incidence of WM/IgM MGUS-associated KD in this cohort was 3.3% (2.4% for renal biopsy confirmed cases). Renal pathology in the 41 cases showed: amyloid deposition (N=10; 24%); parenchymal lymphoplasmacytic infiltrate (N=7; 17%); monoclonal light chain deposition (N=6; 15%); cryoglobulin deposition (N=6; 15%); light chain cast nephropathy (N=4; 10%); monoclonal IgM deposition (N=3; 7%), thrombotic microangiopathy (N=3; 7%), and minimal change disease (N=2; 5%). In 11 (27%) of these cases, multiple abnormalities were present in the renal biopsy. For patients who underwent renal biopsy, the median age was 66 (range 46-81 years), serum IgM was 2,053 (range 178-5,870 mg/dL), and eGFR was 30 (range 4-99 ml/min/1.73m2). Nephrotic syndrome was present in 13 (31%) of these patients. Four (10%) patients presented with hemoglobin ≤10 g/dL, while none had hypercalcemia. The median follow-up for these patients was 17 (range 1-162 months). A synchronous diagnosis of WM and KD was made in 17 patients (41%), while in the remaining 24 patients the median time to KD following the diagnosis of WM was 29 (range 5-88 months). KD was diagnosed in mainly untreated patients (N=29; 70%), while for the remaining 12 patients, KD occurred after a median of 2 prior therapies. Thirty-six patients received treatment associated with WM/IgM MGUS related KD as follows: proteasome-inhibitor based (N=19; 46%); alkylator based (N=11; 27%); nucleoside analogues (N=4; 10%); and rituximab monotherapy (N=2; 5%). Plasmapheresis was employed in 12 (31%) patients. Treatment responses based on consensus criteria were as follows: CR (N=1; 3%), VGPR (N=4; 11%), PR (N=27; 75%), MR (N=1; 3%) progressive disease (N=1; 3%), or unevaluable (N=5; 14%). Renal outcomes for the 36 treated patients based on at least a 10 ml/min/1.73m2 change in eGFR were as follows: improved (N=14; 34%); stable (N=12; 29%); decreased (N=9; 22%) and unknown (N=1; 2%). Patients with either amyloid or light chain deposition (N=16) showed worse outcomes: 1 died of refractory nephrotic syndrome; 5 went on to dialysis. None of the patients with other renal pathology either died of renal complications or required dialysis. Conclusions In contrast to MM, KD is uncommon and shows a different spectrum of renal pathology (including multiple pathological findings) in WM/IgM MGUS patients. Patients with amyloid or light chain deposition disease show worse outcomes, including the requirement for dialysis. While treatment is associated with either improved or stable renal function in most patients, the optimal approach to the management of WM/IgM MGUS related KD remains to be determined. Disclosures No relevant conflicts of interest to declare.