ALBERT

Description: Background: The fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has shown to be highly efficacious in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL). Initial results of a single-arm nivolumab monotherapy in heavily pretreated young adults with RR cHL, previously treated with autologous hematopoetic stem cell transplantation (autoSCT) and brentuximab vedotin are promising. However, demonstrating similar results in real-life experience in patients not on Pharma clinical studies are of major clinical importance. Aim: The aim of the current study was to evaluate the efficacy and safety of nivolumab in previously heavily pretreated patients with RR cHL not on Pharma clinical studies. Methods: The records of patients with RR cHL who were treated with nivolumab in seven medical centers were reviewed. The regimen consisted of nivolumab 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. Results: Between May 2015 and April 2016, 30 patients with RR cHL received nivolumab monotherapy. The median age was 35 years (range: 21 to 88). Patients were extremely heavily pretreated with median of 6 prior therapies (range: 3 to 11); 73% of them received ≥ 5 lines of therapy. Specifically, 29/30 (97%) received ABVD, 7/30 (23%) escBEACOPP, 20/30 (67%) gemcitabine based regimens, 30/30 (100%) brentuximab vedotin, 8/30 (27%) bendamustine, 3/30 (10%) lenalidomide, 28/30 (93%) other combinations of chemotherapy and 22/30 (73%) radiotherapy. Twenty patients (67%) previously underwent autoHSCT and 4/30 (13%) allogeneic transplantation (alloSCT), two before and two after receiving nivolumab. Median number of nivolumab doses received was 8 (range 1 to 29). Twenty three patients (77%) are still on treatment. Seven patients (23%) discontinued therapy due to disease progression 3/30 (10%), adverse events 2/30 (7%) and referral to alloSCT 2/30 (7%). Overall response rate among 25 evaluable patients was 76%, complete response (CR) - 7/25 (28%), partial response - 12/25 (48%), stable disease - 3/25 (12%) and only 3/25 (12%) progressed, one of them with cHL type of Richter's transformation. Two patients underwent alloSCT in remission following nivolumab treatment. One patient was transplanted from a matched sibling donor and the second patient from a T replete haploidentical donor with post transplantation cyclophosphamide as anti-graft versus host disease prophylaxis. Both patients are in CR, ten and three months post transplantation, respectively. The median overall survival (OS) and progression free survival (PFS) for the cohort were not reached (Figure 1). At 24 weeks the PFS was 74%. Adverse events reported in 9/30 patients (30%) were usually mild. Severe nivolumab related adverse events in 3/30 (10%) included immune related pneumonitis, myelitis and uveitis. No treatment related death occurred. Conclusions: The check point inhibitor nivolumab is a novel therapy for RR cHL patients, previously with unmet need following relapse or refractory to autoHSCT and brentuximab vedotin. Our real life experience confirms and highlights the efficacy and safety of nivolumab in very heavily pretreated young and elderly patients with cHL eligible as well as ineligible for autologous HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Multiple Myeloma is a frequent and usually fatal lymphoproliferative disorder with a median survival of around 30 months.Supportive therapy includes monthly intravenous injections of biphosphonates as prevention, or therapy,of lytic bone disease. We report three cases of Multiple Myeloma patients who developed severe osteomyelitis of the jaws while receiving prolonged biphosphonate therapy.All three patients are very long survivors of Myeloma,being alive 6 to 12 years after diagnosis.They have been treated with biphosphonates for more than 4 years, receiving large doses of Pamidronate(3420 to 4680 mg) and lesser doses of Zoledronate(16 to 72 mg).Jaw infection was unprovoked in wo parients and was cused by dental extraction in the third.Diagnosis of osteomyelitis was confirmed by histology in all three patients, while in two we could demonstrate the presence of Actinomyces.Therapy with hyperbaric oxygen of osteomyelitis refractory to prolonged antibiotherapy, was curative in one patient. To the best of our knowledge, these are the first cases of osteomyelitis of the jaw reported in the literature in Myeloma patients treated with chronic administration of intravenous biphosphonates.Recent reports have alerted physicians of a ’’ growing epidemics’’ of Pamidronate and Zoledronate induced avascular necrosis of the jaw, most of them provoked by teeth removal.Both of these biphosphonates have strong antiosteoclastic activity, and Zoledronate is antiangeogenic, all properties which contribute to the development of bone necrosis.Since the jaws are the only bones in the skeleton exposed to the external environment, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis.Even though it is not possible to prove beyond doubt an etiological link between biphosphonate therapy and the occurrence of osteomyelitis of the jaws, the association of Myeloma with severe immunosupression, the very prolonged biphosphonate therapy in our three patients, and the localization to the jaw, are in favor of a clear relationship between therapy with Zolandronate, Pamidronate and osteomyelitis of the jaws. With the expected life prolongation of Myeloma patients due to recent therapeutic breakthroughs and the increasing use of antiangeogenic agents, it is crucial to be aware of the possibility of a rise in the number of osteomyelitis of the jaws in Myeloma patients.

Description: Introduction The therapeutic options for diffuse large cell B cell lymphoma (DLBCL) patients (pts) that fail to respond/relapse after≥2 treatment regimens are limited. The SCHOLAR-1 study reported an overall response/ complete remission (ORR/CR) rates of 26%/ 7% with a median overall survival (OS) of 6.3 months in chemorefractory and early relapsing DLBCL pts. Polatuzumab vedotin (Pola) is a conjugated antibody that delivers the microtubule inhibitor MMAE to CD79b-expressing cells. Polatuzumab administered in combination with Bendamustine-Rituximab (P-BR) has been recently approved by the FDA for pts with relapsed/refractory (R/R) DLBCL that failed to respond≥2 prior therapies. The current study investigated the tolerability and efficacy of Pola mainly with BR, in DLBCL pts, treated through a compassionate program after failing ≥2 prior regimens. Methods Data of all pts with consecutive R/R DLBCL, treated with Pola-BR or Pola-R (2-8 cycles) in 11 Israeli centers between 6/2018 and -5/2019 were analyzed. Inclusion criteria for this study were: R/R DLBCL (denovo and transformed follicular lymphoma [t-FL]), age ≥ 18 years, ≥ 2 prior treatments. We evaluated pt characteristics, treatment details and toxicities, overall response and CR rates, progression free survival (PFS) and OS. Cox regression model was used to define factors affecting outcomes. Results 34 patients- (denovo DLBCL, n=24 and t-FL, n=10 ⌈50% -non CGB and 50% - GCB type⌉) were included. Median age at Pola administration was 65.5 (range 60-72) years. Stage ≥3 disease was recorded in 88% and IPI ≥3 in 73.5%. Median prior lines was 3 (range 3-5); including anthracyclines and rituximab in 100% and cisplatin-based regimens in 91%. 32% relapsed after ASCT and 9% after CART infusion. 53% had primary refractory disease, 29% had refractory relapse and 18% had prior sensitive relapse. 22 pts received Pola-B, mostly with Rituximab (n=19), and 12 received Pola-R. In 5 pts, Pola-based regimen was used as a bridge for Allo SCT (all responded CR, n=4 and PR, n=1) and in 6 as a bridge to CARTs (all responded CR n=1, PR n=2, SD n=3). Median number of Pola B cycles was 3 (3-5) and median Pola-R cycles was 4 (3-6). Median B dose per cycle was 90 mg/m2 (45-90). GCSF was used in 47%. Early treatment discontinuation due to progressive disease (PD) occurred in 8 (23%) of the entire cohort: 23% of Pola-B pts and 25% of Pola-R pts. Safety: Hematological AEs grade 3-4, reported with Pola- B vs Pola-R were: neutropenia (45.5.% vs 33%), thrombocytopenia (25% vs 8%) and anemia (23% vs 17%). Infections were recorded in 41% and 36% of Pola-B pts and Pola-R respectively. Neutropenic fever was reported in 36% in Pola-B pts and none in Pola-R. Pulmonary infections were recorded in 33.3% and 27.3% of Pola-B and Pola-R pts respectively, resulting in death in one pt. Peripheral neuropathy occurred in 18% of Pola- B pts (grade ≤2) vs 8% with Pola -R. Hospitalization due to AEs was recorded in 41% of Pola-B vs 25% of Pola-R. Pola dose reduction due to AE was reported in 1 pt (8%) in the Pola-R. Efficacy: ORR for the entire cohort was 65%, including 38% CRs and 27% PRs. 12% pts attained SD and 23% experienced PD. ORR was higher in non-GCB than in GCB pts 80% vs 43% (p=0.036). Median follow up of the entire cohort from Pola administration was 4.4 months (range 0.6-11.4). 6 months projected OS and PFS were 83% and 63%, respectively. Post Pola treatment in pts that failed to respond/Relapsed post pola: 8 patients had PD; 3 died from progression, 1-CART, 1-Allo SCT, 2-paliative care and 1-unknown. Additional 5 pts progressed during follow up; 4-CART and 1-palliative care. 1 patient continues Pola treatment after achieving SD. Univariate analysis for factors predicting PFS and OS GCB type (HR-1.816, P=0.055), Primary refractory vs relapsed disease (HR-1.507, p=0.049) and a higher number of prior lines since diagnosis (HR-1.35, p=0.079) tended to be associated with shorter time to progression. T-FL vs denovo DLBCL was associated with decreased OS (p=0.008). Data of 60 patients, including pts treated recently, therefore, not evaluable at the time of abstract submission, would be presented at ASH. Conclusions The toxicity of Pola-based regimen was relatively low. Pola based treatment provided an encouraging PFS and OS in pts with R/R DLBCL that failed to respond ≥2 prior therapies, treated in a real-life setting. Primary refractory disease, higher number prior lines and t-FL vs denovo DLBCL were associated with inferior outcome. Figure Disclosures Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

Description: Neurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It occurred as the initial manifestation of malignancy in 26% of cases. The affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%) with multiple site involvement in 58%. Imaging studies often suggested the diagnosis with 77% positive magnetic resonance imaging, and 84% (16 of 19) positive computed tomography-positron emission tomography studies. Cerebrospinal fluid cytology was positive in 40%, and nerve biopsy confirmed the diagnosis in 23 of 26 (88%). Treatment in 47 patients included systemic chemotherapy (70%), intra-cerebrospinal fluid chemotherapy (49%), and radiotherapy (34%). Response to treatment was observed in 46%. The median overall survival was 10 months, with 12- and 36-month survival proportions of 46% and 24%, respectively. NL is a challenging diagnosis, but contemporary imaging techniques frequently detect the relevant neural invasion. An aggressive multimodality therapy can prevent neurologic deterioration and is associated with a prolonged survival in a subset of patients.

Description: Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P

Description: Background Patients (Pts) with induction resistant Myeloma, either primary refractory or those relapsing early after completing induction, have dismal prognosis. To elucidate clinical and molecular pathways of refractoriness, we designed a clinical trial to evaluate the safety and efficacy of a quadruple salvage regimen of Carfilzomib (CFZ)/ lenalidomide (LEN)/dexamethasone (DEX) / daratumumab (DARA) (KRD-D) in newly diagnosed MM (NDMM) Pts with primary or secondary induction resistance (KYDAR trial) . Using a high resolution molecular tool of massively-parallel single-cell RNA-sequencing (MARS-seq) calibrated for this trial, we aimed to identify gene expression signatures associated with clinical response and resistance. Methods Population included forty NDMM Pts treated with a bortezomib-containing induction regimen, who either: i) Failed to achieve a minimal response after 2 cycles or a partial response after 4 cycles (Group A), ii) Had early relapse within 18 months from starting of therapy (group B) AND were not candidates (at screening) for autologous transplant. Following informed consent, all Pts were enrolled to receive KRD-D treatment in eighteen 28-day (d) cycles (Cy) or until disease progression/unacceptable toxicity. CFZ: 56 mg/m2 IV days 1,8,15 (Cy 1-9), d 1,15 (Cy 10-18). LEN: 25 mg (Frail: 15mg) d1-21; Dex 40mg (Frail: 20mg) weekly; DARA: IV 16mg/Kg weekly (Cy 1-2), q14d (Cy 3-6), q28d. After 18 cycles, Pts continued to receive DARA/Len. We applied longitudinally our calibrated protocol for scRNA-seq of MM PC (Ledergor et al 2018) to 31 KYDAR Pts at different time points, and compared them to NDMM and to healthy age and sex matched controls. Pts with partial response or better (IMWG criteria) after 3 cycles were defined as "responders". Primary efficacy endpoints were safety and tolerability. Secondary endpoints included overall response rate (ORR); progression free survival (PFS), and overall survival (OS). Results Forty Pts were enrolled across 13 medical centers in Israel. Data on 36 Pts with a cutoff date of June 2nd 2019 are presented and will be further updated at the meeting. Patients had highly aggressive MM characteristics (Table): 78% had intermediate/high risk FISH abnormalities, 39% had extramedullary disease, and 38% were frail. At a current median follow-up of 4 months (range 1-12m), 20 Pts are still under active therapy. Of the 16 Pts that discontinued therapy: 9 had progressed, 2 had an adverse event (AE), 1 died, and 3 discontinued due to other causes. All Pts had at least 1 AE, most were grade 1-2; There were 90 treatment emergent AE (TEAEs) and 18 regimen related grade 3-4 AEs. TEAEs occurring in ≥2 Pts included neutropenia (38%), thrombocytopenia (26%), infections (21%), anemia (18%), pneumonia (15%), diarrhea (9%) and rash (9%). Durable and deep responses were achieved (Fig. A). ORR was 91% (30/34): near CR-stringent CR 24% / very good partial response 47% / partial response 21% / stable disease 3% / progressive disease 6%. At median follow-up PFS is 85% and OS is 97%. Applying MARS-seq, we profiled a total of 39,492 PC sampled from 11 control subjects, 12 newly diagnosed MM patients and 31 KYDAR Pts at different time points. We classified the different cell groups based on expression levels of the most variable genes and used the differentially expressed genes to annotate malignant PC types (Fig. C). We identified multiple genes and pathways that are differentially expressed between healthy controls, NDMM and induction-refractory KYDAR Pts (Fig D). Importantly comparing the responder and non-responder Pts, in the KYDAR trial we identify statistically significant genes for responding and non-responding group, including critical immune checkpoints and regulatory genes in the proteasome, and apoptotic pathways (Figure E). Conclusions KRD-D quadruple regimen was safe and well tolerated, and provided an effective salvage in a cohort of induction resistant MM Pts, with an ORR of 91%, with deep responses achieved in 71%, equivalent to 2nd line triplet regimens in non-selected MM. Single cell analysis showed a dramatic change in the PC transcriptome following therapy. Furthermore, differences in gene expression patterns between responders and non-responders unveil potentially druggable escape mechanisms used by the highly resistant tumors including immune checkpoints that may serve as perspective biomarkers and therapeutic targets. Disclosures Cohen: Janssen Â: Consultancy; Amgen Â: Consultancy, Research Funding; Neopharm Â: Consultancy; Takeda Â: Consultancy; Madison Â: Consultancy; VBL Therapeutics Â: Employment. Ledergor:Immunai: Consultancy.

Description: Biphosphonates (zoledronate, pamidronate and clodronate) are frequently used for bone disease prevention and treatment in patients with multiple myeloma. Monthly biphosphonate therapy improves quality of life and in some reports survival. However, biphosponates are associated with adverse effects such as renal impairment and osteonecrosis of the jaws. We have recently described 3 myeloma patients who developed oseomyelitis of the jaw during chronic biphosphonate therapy. In a national survey we found 11 patients from 6 centers in Israel with osteomyelitis of the jaws probably due to prolonged therapy with intravenous biphosphonates. Nine were female. Median age at the time of diagnosis of myeloma was 67 years (range 59–86). nine patients suffered from IgG myeloma, and 2 had light chain disease. In five patients MGUS was known during 4 to 9 years before development of overt myeloma. All patients had received chemotherapy, and 2 underwent ABMT. Median time from diagnosis of myeloma to diagnosis of osteomyelitis of the jaw was 30 months (range 15–48). In six cases osteomyelitis was provoked by dental procedure. In all cases the diagnosis of osteomyelitis was confirmed by bone biopsy and in 7 colonies of Actinomyces Israeli were demonstrated. In one patient Pseudomonas Aeruginosa was also found. All patients had been treated with biphosphonates before diagnosis of osteomyelitis (13 to 48 months): eight with pamidronate, and 3 with zoledronate. The mean total dose of pamidronate was 3190 mg (range 1690–4680), and zoledronate- 72mg (range 16–96). Therapy for osteomyelitis included prolonged antibacterial treatment, surgical debridment, and hyperbaric oxygenation. Acute, and chronic, osteomyelitis of the jaws secondary to biphosphonate therapy, is frequently encountered among myeloma patients and should be reported separately from another complication of biphosphonates, osteonecrosis of the jaws.

Description: Thrombosis is the major complication of Polycythemia Vera (PV) and the main cause of morbidity and mortality. Hypercoagulability is principally secondary to hypervisosity of the whole blood. Blood viscosity is an exponential function of the hematocrit, and red cell aggregation increases in high hematocrit level, creating the potential for vascular stasis. PV is also associated with endothelial dysfunction that can predispose to arterial disease. Reduction of the red cell mass to a safe level by phlebotomy is the first principle of therapy in PV. Such an effective therapy may have some effect on the arterial compliance in PV patients; nevertheless, to the best of or knowledge, the influence of phlebotomies on arterial hemodynamic parameters has not be studied in PV patients. In this study we estimated the influence of phlebotomies on large arteries (C1) and small arteries compliance (C2) in PV patients by non invasive method. Hemodynamic parameters were studied by Pulse Wave Analysis using the HDI-Pulse Wave CR2000 (Minneapolis MN, USA) immediatly before and after venesection (300–500cc of blood) (short effect of phlebotomy) and repeated within 3 months, after the hematocrit has been reduced to below 45% in male and 42% in female (long effect). Seventen PV (10 males) patients diagnosed according to the PVSG criterias have been included. 37 phlebotomies were performed with analysis of short effect (for 3 patients phlebotomy was performed 5 times, for one patient- 4 times, for five-twice, and for eight- once). There were 10 mesurements of long time effect of the phlebotomy. The median age of the patients was 66 years (range 48–82). The median hematocrit level was 49.3% (range 46.5–62) before phlebotomy. 47 measurements of the arterial compliance were performed (two patients visited 6 times, one- five times, one-4 times, three- 3 times, seven- twicely, and 3 patients once). The mean large artery compliance (C1) before phlebotomy was 12.0 ml/mmHg x 10 (range 4.5–28.6), in 36 measurements these parameters were normal for gender and age adjustment, and in 11 they were borderline. Immediately after phlebotomy the mean large artery compliance was 12.6 ml/mmHg x 10 (range 5.2–20.1). The mean small artery compliance (C2) before and immediately after phlebotomy were 4.4 mg/mmHg x 10(range 1.2–14.3) and 5.5 mg/mmHg x 10 (range 1.2 – 15.6) respectively (delta C2 1.1- not statistically significant). In 47 measurements of C2 before phlebotomy, 22 were within normal range, 6 borderline, and 19 pathological.. In 37, C2 measurements after phlebotomy, 21 were within normal range, 4 borderline and 12 pathological. The long term effect analysis demonstrates that the mean C1 after hematocrit normalization was13.8 mg/mmHg x 10 (delta 1.8- not statistically significant). The mean C2 after hematocrit normalization was 4.76 mg/mmHg x 10 (delta 0.36- not significant). In conclusion, phlebotomy has no significantly short or long term influence on large and small artery compliance in PV patients.

Description: Arterial compliance disturbances are frequently observed among patients with chronic anemia. Few non-invasive studies were performed to determine hemodynamic changes in anemic patient. In this work we studied parameters of large arteries (C1) and small arteries (C2) compliance before and after blood transfusion (one packed cells unit(400cc)) by CR 2000 Hypertension Diagnostics Inc/Pulse Wave (Minneapolis MN, USA). We included 20 patients with chronic transfusion dependent anemia. The median age was 74±6 years. Twelve patients had MDS, 1 CML, 2 myelofibrosis, 2 NHL, one CLL, one thalassemia, and one patient with anemia of chronic disease. Hemoglobin range before transfusion was 7.5–9.0 g/dl. 14 patients also suffered from arterial hypertension, 5 from diabetes mellitus and received oral treatment; eight patients were smokers. Large arterial compliance before hemotransfusion was 9.8±3.8 ml/mmHgx10, and 9.2±2.9 after hemotransfusion (p