Search

In this retrospective study, we aim to analyze the characteristics, treatments, and overall survival of all patients presenting with isolated myeloid sarcoma (MS) or MS with concomitant acute myeloid leukemia (AML) compared with all patients with AML, treated during the same period. We identified patients with AML with or without MS at diagnosis, presenting to our medical center between the years 1990 and 2005. There was no statistically significant difference between the groups regarding gender, age, cytogenetic risk groups, rate of complete remission, number of cycles of chemotherapy needed to achieve complete remission, and rate of first relapse. The time to death in the MS group was not significantly different (p = 0.60) from the AML group, and radiotherapy did not affect the median time to death. Transplantation prolonged survival in both groups (p = 0.018 and p

We present a case of a 52-year-old male who was evaluated due to anorexia, persistent diarrhea, weight loss, and liver enzyme elevations, with no hematologic laboratory abnormalities. Imaging modalities revealed several tissue lesions involving the pancreas, the right kidney, and an axillary lymph node. Diagnosis of Castleman disease was reached only due to the tissue obtained from the lymph node. Chemotherapy and immunosuppression led to a short remission. The patient underwent autologous stem cell transplantation, and has since been in remission. This case demonstrates the cryptogenic and chameleon-like nature of Castleman disease. Challenges in treating Castleman disease patients reflect current limitations and the need for a greater understanding of disease pathogenesis.

Introduction : A diagnosis of multiple myeloma (MM) has a substantial impact on health-related quality of life (HRQoL) due to associated symptoms, such as bone pain, infection, and fatigue. Furthermore, HRQoL deteriorates with each subsequent line of therapy. The phase 3 OPTIMISMM study (NCT01734928) demonstrated that pomalidomide, bortezomib, and low-dose dexamethasone (PVd) resulted in a significantly longer progression-free survival (PFS) and greater overall response rate (ORR) compared with bortezomib and low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), all of whom had received prior treatment with lenalidomide. Given that HRQoL in RRMM is an important consideration, we conducted this analysis to evaluate the effect of PVd versus Vd on HRQoL in patients enrolled in the OPTIMISMM study. Methods : The OPTIMISMM study was a phase 3, multicenter, randomized, open-label study that enrolled adult RRMM patients who had received 1 to 3 prior anti-myeloma regimens including lenalidomide. Patients (N=559) were randomly assigned to receive PVd (n=281) or Vd (n=278) per 21-day treatment cycle until progression or treatment discontinuation. HRQoL was assessed as an exploratory endpoint using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) questionnaire at Day 1 of each 21-day cycle prior to treatment administration and at the end of treatment. The primary domain of interest was the Global Health Status/QoL domain of the QLQ-C30. Analyses were performed in the HRQoL-evaluable population, which included randomized patients who completed the QLQ-C30 assessment at baseline and at least one post-baseline visit. Key primary analyses of PVd versus Vd on the global QoL domain of the QLQ-C30 included a longitudinal assessment of change from baseline using a mixed-model repeated measure (MMRM) approach; an assessment of the proportion of patients experiencing clinically meaningful deterioration (i.e., ≥10 points worsening from baseline) at pre-selected post-baseline visits; and an analysis of time to first clinically meaningful deterioration. Results : The HRQoL-evaluable population consisted of 240 patients in the PVd group and 209 in the Vd group; baseline characteristics were well-balanced between the treatment groups. HRQoL compliance rates based on the number of patients expected to complete the QLQ-C30 at each given visit exceeded 80% for most visits among both groups. Mean (SD) baseline scores for the global QoL domain of the QLQ-C30 were similar between groups (61.0 [23.2] in the PVd group and 63.5 [21.3] in the Vd group); these scores were maintained over time for both treatment groups, with no clinically meaningful differences observed between the treatment groups at any cycle (Figure 1). The MMRM analyses showed no clinically meaningful difference in global QoL of patients between the PVd group and the Vd group. There was also no significant difference observed in the proportion of patients who experienced clinically meaningful worsening in the global QoL domain between the treatment groups throughout the pre-selected post-baseline visits. The median time to the first clinically meaningful worsening was also similar between treatment groups: 3.0 months for the PVd group and 3.4 months for the Vd group, respectively (hazard ratio: 1.20; 95% confidence interval: 0.9456, 1.5151; p=0.1351; Figure 2 for when death was considered as an event); similar results were observed when death was censored. Conclusions: The results from this analysis of the OPTIMISMM study showed that the triplet regimen of PVd, which consisted of pomalidomide added to the doublet regimen of Vd, did not compromise HRQoL in lenalidomide-treated patients with RRMM. Overall, there were no clinically meaningful differences in the Global Health Status/QoL domain of the QLQ-C30 between treatment groups. These results are meaningful and provide further evidence of the clinical benefits of the addition of pomalidomide to Vd, which include significant improvements in PFS and ORR. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Rodriguez Otero:Clínica Universidad de Navarra: Employment; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hayden:Celgene: Honoraria; Jassen: Honoraria; Amgen: Honoraria. Krauth:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Guo:Celgene Corporation: Consultancy. Purnomo:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Grote:Celgene: Employment. Biyukov:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction Multiple myeloma (MM) can be associated with paraskeletal (PP) or extramedullary (EMP) plasmocytomas (PL). Although PLs are relatively frequent, even at diagnosis, our knowledge on the subject mainly relies on small case series or single center experiences. Remarkably, little is known regarding the role of new drugs on MM with PL. Aim To perform a meta-analysis of 8 EMN-GIMEMA studies focused on the description of PLs characteristics, clinical outcome, and response to new drugs. The trials involved in this meta-analysis have the following identification codes: EUDRACT 2005-00473041, NCT01093196, NCT01063179, NCT01091831, NCT01857115, NCT01190787, NCT00551928, NCT01346787. Patients A total of 2332 newly diagnosed MM patients have been included in the analysis, and 267 (11.4%) had a PL, defined as PP in 243 (10.4%), EMP in 12 (0.5%), and not classified in 12 (0.5%) patients. PLs were evaluated with different techniques as PET, CT, NMR or physical examination accordingly to their site and local guidelines. PP and EMP were single in 195, and multiple in 60 cases, and their median size was 4 cm (range 1-26 cm). Median age at diagnosis was 68 years (range 18-87) in PL, and 69 years (range 25-91) in non-PL patients; male patients were 149 (55.8%) in PL and 1007 (48.8) in non-PL patients. ISS stage in PL and non-PL patients was as follows: stage I in 119 (44.6%) and 682 (33.0%), stage II in 89 (33.3%) and 792 (38.3%), stage III in 38 (14.2%) and 508 (24.6%), unknown in 21 (7.8%) and 83 (4.0%) patients, respectively. Cytogenetics was available in 166 PL, and 1528 non-PL patients, and high risk status, defined as having t(4;14) or t(14;16) or del(17p), was observed in 51 (30.7%) PL, and 446 (21.6%) non-PL patients. PL and non-PL patients received treatment with the following drugs: bortezomib in 65 (24.3%) and 598 (29.0%), lenalidomide in 182 (68.1%) and 1366 (66.1%), and carfilzomib in 20 (7.5%) and 101 (4.9%), respectively. Autologous stem cell transplantation (ASCT) was performed in 112 (41.9%) PL and 782 (37.9) non-PL patients. PL and non-PL patients received maintenance in 108 (40.4%) and 815 (39.5%), continuous treatment in 128 (47.9%) and 1007 (48.7%), and fixed-duration treatment in 31 (11.6%) and 243 (11.7%) cases, respectively. Results With a median follow-up of 62 months (IQ range 34-75) in PL and 65 months (IQ range 40-77) in non-PL patients, 4-years overall survival (OS) was 56% in PL and 67% in non-PL patients (p3 cm PL, 53% ≤3 cm PL vs 67% in non-PL), and a 5 cm threshold (55% >5 cm PL, 57% ≤5 cm PL vs 67% in non-PL), neither by the number of PLs (58% single PL, 50% multiple PLs vs 67% in non-PL), or the onset site (57% PP, 55% EMP vs 67% in non-PL). Four-years OS in PL patients treated with either bortezomib or carfilzomib was 44%; it was 56% in patients treated with lenalidomide; in non-PL patients was 62% when treated with bortezomib or carfilzomib, or 65% when treated with lenalidomide. Four-year progression-free survival (PFS) was 26% in PL and 27% in non-PL patients. In patients that received maintenance, the 4-years PFS from maintenance start was 24% in PL and 30% in non-PL patients. When considering the PFS-2, i.e. the PFS calculated from the treatment start to the time of second relapse/progression, the median time was 42.3 months (95% CI, 36.3 - 51.5) in PL and 46.4 months (95% CI, 44.1 - 48.9) in non-PL patients. Conclusions Our meta-analysis studied the largest number of newly diagnosed MM patients with PL so far reported. We observed that in patients treated with new generation therapies incorporating new drugs, the detrimental effect of PL at diagnosis is limited. The 4-years OS is modestly reduced for PL patients, while we observed that PSF and PFS-2 were similar in PL and non-PL patients, suggesting that effective treatment can overcome the unfavorable prognostic significance of PLs. We also observed that lenalidomide is effective in patients with MM and PL, as are bortezomib and carfilzomib. Disclosures Montefusco: Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Gay:Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. De Paoli:Gilead: Other: Advisory Board; Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Patriarca:Janssen: Other: advisory role; Celgene: Other: advisory role & travel, accommodations, expenses; MSD Italy: Other: advisory role; Medac: Other: travel, accommodations, expenses; Jazz: Other: travel, accommodations, expenses. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ballanti:BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Corradini:Gilead: Honoraria, Other: Advisory Board & Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer. Boccadoro:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

We found that Livin, an Inhibitor of Apoptosis Protein, is specifically cleaved to produce a truncated Livin protein (tLivin) and demonstrated the paradoxical pro-apoptotic activity of tLivin. mini-tLivin (mtLivin) is a 70 aa derivative of tLivin that remarkably, exhibits a pro-apoptotic activity as potent as tLivin. Our findings regarding tLivin and mtLivin suggest unique therapeutic avenue against cancer. To improve the delivery and efficacy of mtLivin for treatment we conjugated mtLivin-to nanoparticles (NPs) of poly (lactide-co-glycolide) (PLGA) and targeted the nano-delivery system to diffuse large B-cell lymphoma (DLBCL) using CD40L. Delivery of mtLivin with nanoparticles should enhance stability, provide prolonged bioavailability, intracellular uptake and efficacy. We generated bifunctional mtLivin-CD40L-NPs to target mtLivin-NPs to DLBCL cells. Various cell lines were used to evaluate the biological activity of free and conjugated (targeted or not) mtLivin including 293T, 721.221 B cells, L428 Hodgkin's lymphoma, OCI-LY19 DLBCL cells and OCI-LY19- GLuc cells that constitutively express a gaussia luciferase reporter. Targeted, bifunctional mtLivin-CD40L-NPs elicited significant cell death of DLBCL cells while monofunctional mtLivin-NPs had a lower effect. mtLivin-NPs may induce cell death of some cell lines without targeting (e.g. 293T) yet targeting is required to induce marked cell death of DLBCL cells. To best mimic lymphoma disease in humans, a disseminated lymphoma model was used to evaluate the antitumor effect of targeted mtLivin treatment. NOD/SCID mice were injected with OCI-LY19- GLuc cells or into the tail vein. Gaussia luciferase reporter allows IVIS imaging to monitor tumor size and location in mice. Mice were treated approximately once a week with various mtLivin-NPs formulations. Luciferase signal was observed as early as day 2 after tumor cells injection. Immunohistochemistry for anti-CD20, a human B-cell marker, showed infiltration of OCI-ly19-Gluc cells in spleen and brain close to tumor cells injection (Day 2). With time, lymphoma infiltrations were detected in brain, bone marrow, lungs, spleen and liver. All control mice exhibited paralysis and did not survive beyond 28 days. In contrast, 37.5% of animals receiving mtLivin-NPs and 71.4 % of animals receiving mtLivin-CD40L-NPs achieved complete pathological tumor response and survived significantly longer. All treatments in this study were well-tolerated. In terms of mechanism, we show high caspase-3 activity in tumors from mice that were treated with mtLivin-CD40L-NPs demonstrating the ability of the nanoparticles to target the tumors and to induce apoptotic tumor cell death. The resistance of tumor cells to drug-induced apoptosis is a major cause of cancer treatment failure. We designed mtLitvin targeted nanoparticles constituting novel personalized therapeutic approach for resistant cancer. Disclosures No relevant conflicts of interest to declare.

8026Background: Multiple myeloma (MM) remains mostly incurable despite advances in treatments in the last decade. Major clinical challenges include: capturing inter- and intra- patient heterogeneit...

Patients with advanced melanoma usually do not benefit from conventional chemotherapy treatment. There is therefore a true need for a new kind of therapy for melanoma. One factor responsible for the poor prognosis of melanoma is the inhibitor of apoptosis protein (IAP) family member Livin. In this study, we applied a novel approach for the treatment of melanoma, using a unique strain of the oncolytic Newcastle disease virus (NDV-HUJ). We found that, unlike chemotherapeutic drugs, NDV-HUJ, a one-cycle replicating virus, overcomes the resistance to apoptosis of melanoma primary cultures that over express the Livin protein. In contrast, melanoma tumor cells that do not express Livin are relatively resistant to NDV-HUJ treatment. Furthermore, we show that NDV-HUJ-induced oncolysis is attributed to the dual function of Livin: although Livin inhibits apoptosis through the inhibition of caspases, under the robust apoptotic stimulation of NDV-HUJ, caspases can cleave Livin to create a truncated protein with a paradoxical proapoptotic activity. Thus, NDV-HUJ is a potent inducer of apoptosis that can overcome the antiapoptotic effect of Livin and allow cleavage of Livin into the proapoptotic tLivin protein. Moreover, the results indicate that the interferon system, which is functional in melanoma, is not involved in NDV-induced oncolysis. Taken together, our data offer the possibility of a new viral oncolytic treatment for chemoresistant melanoma.

BACKGROUND: Storing ovarian tissue for fertility preservation in cancer patients carries the risk of the presence of malignant cells that could lead to recurrence of cancer after reimplantation. Methods to exclude presence of cancer cells were used to improve the safety of cryopreservation-reimplantation procedures. METHODS: Fifty-eight patients with hematological malignancies were referred for the storage of ovarian tissue for fertility preservation. Investigation included preoperative imaging and histological evaluation of fresh ovarian tissue. After thawing markers to detect minimal residual disease (MRD) were used and compared with patient's disease used as positive control (five patients). RESULTS: Preoperative imaging detected disease in the ovaries (two patients). Conventional histology post-tissue harvesting did not disclose malignant cells (56 patients). MRD results post-thawing were negative in Hodgkin's disease (CD30 immunohistochemical staining), in T- and B-cell lymphoma (PCR for T-cell receptor and Ig clones, respectively) and in two chronic myelogenous leukemia patients (RT-PCR for BCR-ABL gene expression). However, highly sensitive real-time RT-PCR was positive in one CML patient and, this alarming result avoided tissue transplantation. CONCLUSIONS: Preoperative imaging prevented operations and storage of tissue with cancer. Evaluation of stored ovarian tissue for MRD using sensitive markers is essential to increase safety and to prevent reimplantation of tissue with malignant cells.

Monoclonal antibodies (mAbs) are a recent addition to multiple myeloma (MM) therapies and a number of mAbs directed at myeloma cell surface molecules are in development. Daratumumab is a CD38 mAb that has demonstrated substantial activity and good tolerability in four phase I, phase I/II and phase II studies as monotherapy, as well as in combination with current standard treatments in MM. The positive results obtained in the relapsed/refractory setting in patients with advanced-stage disease and in a small number of patients with newly diagnosed disease provide the rationale for the investigation of the agent in a number of ongoing phase III trials. mAbs are generally better tolerated than conventional chemotherapy; however, their use requires other special considerations. Such factors include those common to all mAbs, namely infusion-related reactions, but also factors that are observed with mAbs used in myeloma, such as interference with response assessment, or factors that are related to CD38 mAbs such as daratumumab, for instance blood typing interference. Our review provides an overview of the results from the daratumumab clinical trials conducted to date, as well as practical management considerations for the use of daratumumab based on our experience with the agent.

Natural killer (NK) cells are part of the innate immune system, capable of killing tumor and virally infected cells. NK cells induce apoptosis in the target cell by either granule- or receptor-mediated pathways. A set of inhibitory and activation ligands governs NK cell activation. As transformed cells often attempt to evade NK cell killing, up-regulation of a potential anti-apoptotic factor should provide a survival advantage. The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We have previously described a new IAP family member, termed Livin, which has two splice variants (alpha and beta) with differential anti-apoptotic activities. In this study, we explore the ability of Livin to inhibit NK cell-induced killing. We demonstrate that Livin beta moderately protects against NK cell killing whereas Livin alpha augments killing. We show that Livin beta inhibition in Jurkat cells is apparent upon concomitant activation of an inhibitory signal, suggesting that Livin augments an extrinsic inhibitory signal rather than functioning as an independent inhibitory mechanism. Finally, we demonstrate that detection of both Livin isoforms in melanoma cells correlates with a low killing rate. To date, this is the first evidence that directly demonstrates the ability of IAP to protect against NK cell-induced apoptosis.

Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

BACKGROUND Menorrhagia is a serious complication in young female oncology patients who suffer from severe thrombocytopenia during myelosuppressive treatment. To the authors' knowledge, little is known regarding the incidence of this complication or the effectiveness of possible therapies for its prevention. METHODS In this retrospective clinical study, after a thorough gynecologic evaluation, young female oncology patients with regular menstrual cycles undergoing myelosuppressive treatments received either depo-medroxyprogesterone acetate (DMPA), or D-tryptophan-6-luteinizing hormone-releasing hormone depot treatment (gonadotropin-releasing hormone agonist [GnRH-a]), or no treatment before the administration of myelosuppresive chemotherapy. Only patients who later developed severe thrombocytopenia (

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.

Objective: To evaluate the diagnostic efficacy of image-guided cutting-edge-needle biopsy of peripheral lymph nodes and superficial masses for the diagnosis of lymphoma, for which many still advocate open surgical resection. Methods: A retrospective analysis was performed of the medical records of 114 lymphoma patients who presented with peripheral lymphadenopathy and superficial masses and who underwent diagnostic image-guided biopsy. There were 69 non-Hodgkin lymphoma patients, 38 Hodgkin lymphoma patients, and 7 patients who were evaluated for histologic transformation of CLL or high grade lymphoma. Results: Image-guided needle biopsy was diagnostic in 96/114 (84.2%) patients. The procedure was diagnostic in 59/69 (85.5%) of NHL patients and in 30/38 of Hodgkin disease patients (79%). Diagnoses were achieved for all 7 cases where histologic transformation was suspected. Conclusion: Percutaneous image-guided needle biopsy is a safe and reliable procedure with a high diagnostic yield. It can be used as a first step in patients suspected of having lymphoma presenting with enlarged peripheral lymph nodes and superficial masses.

BACKGROUND Central nervous system involvement is a well recognized complication of systemic non-Hodgkin lymphoma. Most central nervous system recurrences occur within the first 2 years after the initial diagnosis and are considered to represent clonally related recurrence of systemic disease. The authors attempted to investigate the clonal relation between the late-delayed central nervous system involvement and the original systemic tumor. METHODS The authors studied archival, formalin fixed, paraffin embedded tissue samples from 8 patients with isolated cerebral involvement diagnosed > 3 years after their initial presentation with aggressive, systemic, B-cell non-Hodgkin lymphoma. The rearranged immunoglobulin heavy-chain variable region genes (VH) from both sites were amplified by polymerase chain reaction and were sequenced when necessary. RESULTS In three of five patients who had interpretable results, a distinct, monoclonal, VH family-specific band profile was obtained from the cerebral and systemic lymphoma. In the other two patients, a similar VH band pattern was observed and also was compared using direct sequencing, which demonstrated sequence differences between tumors from the two sites. CONCLUSIONS Clonal variance between the cerebral and systemic lymphoma in these patients suggested the possibility that some instances of late-delayed recurrence in the central nervous system represent a second, new B-cell lymphoma rather than a true recurrence of the original systemic tumor, a finding that may have significant clinical and biologic implications. Cancer 2004. © 2004 American Cancer Society.

Apoptosis is a crucial biological process that prevents uncontrolled cell proliferation and eliminates harmful cells. Resistance to apoptotic stimuli is a hallmark feature of various cancers. One of the mechanisms through which tumor cells are believed to acquire resistance to apoptosis is by overexpression of inhibitor of apoptosis proteins (IAPs). IAPs are a group of structurally related proteins that were initially identified in baculoviruses. Mammalian IAPs block apoptosis either by binding and inhibiting caspases or through caspase-independent mechanisms. This family of proteins has become increasingly prominent in the field of cancer biology. To date, overexpression of several IAPs has been detected in various cancers. This paper reviews the recent advances in the research of IAPs. The differential expression and the biological significance of each IAP in various cancer types will be discussed. Finally, we review the most recent advances in the research efforts aimed at using IAPs as potential targets for cancer therapy.

Mammalian heparanase (endo-beta-glucuronidase) degrades heparan sulfate proteoglycans and is an important modulator of the extracellular matrix and associated factors. The enzyme is preferentially expressed in neoplastic tissues and contributes to tumour metastasis and angiogenesis. To investigate the epigenetic regulation of the heparanase locus, methylation-specific and bisulfite PCR were performed on a panel of 22 human cancer cell lines. Cytosine methylation of the heparanase promoter was associated with inactivation of the affected allele. Despite lack of sequence homology, extensively methylated CpG islands were found both in human choriocarcinoma (JAR) and rat glioma (C-6) cells which lack heparanase activity. Treatment of these cells with demethylating agents (5-azacytidine, 5-aza-2'-deoxycytidine) resulted in stable dose- and time-dependant promoter hypomethylation accompanied by reappearance of heparanase mRNA, protein and enzymatic activity. An inhibitor of histone deacetylase, Trichostatin A, failed to induce either of these effects. Upregulation of heparanase expression and activity by demethylating drugs was associated with a marked increase in lung colonization by pretreated C-6 rat glioma cells. The increased metastatic potential in vivo was inhibited in mice treated with laminaran sulfate, a potent inhibitor of heparanase activity. We propose a model wherein expression of mammalian heparanase gene is modulated by the interplay between trans-activating genetic and cis-inhibitory epigenetic elements in its promoter.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection. Keywords: Listeria monocytogenes meningitis, Hydrocephalus

Introduction Several trials have shown that maintenance therapy prolongs progression-free survival (PFS) in multiple myeloma (MM) patients, eligible and ineligible for autologous stem cell transplantation (ASCT); conflicting data exist about its impact on overall survival (OS). The role of maintenance in patients with a sensitive disease is still unclear. We conducted a retrospective pooled analysis to clarify the impact of continuous treatment in patients achieving a complete response (CR). Methods Data from newly diagnosed MM patientsenrolled in 4 phase III trials were analysed. Two trials included ASCT-eligible patients: RV-MM-209 [melphalan-prednisone-lenalidomide (MPR) vs melphalan 200 mg/m2 (Mel200), followed by lenalidomide maintenance vs no maintenance), RV-MM-EMN-441 (cyclophosphamide-lenalidomide-dexamethasone vs Mel200, followed by lenalidomide vs lenalidomide-prednisone maintenance). Two studies enrolled elderly, ASCT-ineligible patients: GIMEMA-MM0305 (bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide vs bortezomib-melphalan-prednisone) and EMN01 (MPR vs cyclophosphamide-prednisone-lenalidomide vs lenalidomide-dexamethasone, followed by lenalidomide vs lenalidomide-prednisone maintenance). The primary endpoint of the study was to evaluate the impact of maintenance on PFS and OS in patients who achieved CR. Univariate analyses of OS and PFS were performed. Response was considered as a time-dependent variable with a landmark point at 12 months. Lastly, a multivariate analysis was performed to evaluate the impact of maintenance and ASCT as independent variables. Results A total of 1964 patients were retrospectively analysed. Of 1503 patients who received maintenance therapy, 254 achieved a CR and 931 a very good partial response (VGPR) or partial response (PR). After a median follow-up of 41 months, a significant 5-year OS (80% vs 54%; HR 0.55, p=0.02; Figure 1) and 5-year PFS (52% vs 19%; HR 0.47, p The same analysis was conducted in patients achieving a suboptimal response (VGPR or PR): the 5-year PFS advantage was confirmed in patients who received maintenance vs patients who did not (30% vs 13% HR 0.65, p A subgroup analysis was conducted in CR patients according to the treatment received [ASCT vs conventional chemotherapy (CC)]; the PFS benefit among patients treated with maintenance was confirmed across both the subgroups (ASCT group: HR 0.45, p=0.02; CC group: HR 0.45 P In multivariate analysis, maintenance therapy and treatment with ASCT confirmed the favourable impact on PFS and OS in patients achieving CR. Conclusion In CR patients,maintenance therapy significantly prolongs PFS and OS. In order to optimize treatment efficacy and to prolong survival in patients with a sensitive disease, the intensification with maintenance is strongly recommended. Disclosures Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaidano:Novartis: Honoraria, Other: Advisory boards; Celgene: Research Funding; Karyopharm: Honoraria, Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Morphosys: Honoraria, Other: Advisory boards; GlaxoSmithKline: Honoraria, Other: Advisory boards; Amgen: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Background: Preclinical studies have demonstrated synergistic antitumor activity when immune checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1)/PD ligand-1 (PD-L1) axis were combined with the Bruton's tyrosine kinase inhibitor ibrutinib. To test this hypothesis, we conducted a phase 1/2a study evaluating the safety and efficacy of ibrutinib in combination with nivolumab in patients (pts) with relapsed or refractory (R/R) high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse-large B-cell lymphoma (DLBCL), and Richter's transformation (RT). Methods : The study was initiated with Part A to establish the safety of oral (po) ibrutinib administered at the approved doses of 420 mg (CLL, FL, DLBCL) and 560 mg (FL, DLBCL) per day (qd) in combination with standard, intravenous (IV) nivolumab dosing of 3 mg/kg every 2 weeks. A modified toxicity probability interval design was used; approximately 18 pts would be enrolled. In Part B, we examined the efficacy of this combination in 4 expansion cohorts: pts with R/R, ibrutinib and PD-1 inhibitor naïve CLL and SLL (including deletion 17p and 11q), FL, DLBCL (GCB and ABC/non-GCB), and pts with RT. Approximately 35 pts would be enrolled in each cohort. In Part B, pts received 420 mg ibrutinib (CLL, SLL) or 560 mg ibrutinib (FL, DLBCL, RT) with nivolumab. Results: As of June 8, 2017, 141 pts were treated. Median time on study for CLL, SLL, FL, DLBCL, and RT was 71.4, 78.1, 65.5, 19.9, and 12.8 weeks, respectively. In Part A, 14 pts were enrolled, and 1 dose-limiting toxicity of hyperbilirubinemia grade 3 (by CTCAE) was observed, which resolved after 5 days. Thus, the combination of oral ibrutinib (420 mg or 560 mg qd) and IV nivolumab (every 14 days) displayed an acceptable safety profile. In Part B, an additional 127 pts were enrolled: 35 pts (CLL and SLL), 35 pts (FL), 37 pts (DLBCL), and 20 pts (RT). Median age was 65 years (range, 20-89 years), and 61.7% of pts were men. Median number of prior therapies was 3 (range, 1-12). Most common adverse events (AEs) for all pts were grade 1-2 and included diarrhea (31%), pyrexia, and fatigue (each 23%). The incidence of grade 3-4 neutropenia was 24% (DLBCL) to 56.7% (CLL), with febrile neutropenia reported in 2%, 5%, and 13% of pts with CLL, RT, and DLBCL, respectively. Grade 3-4 anemia was observed in 20% (FL, RT) to 24% (DLBCL) of pts. Immune-related AEs (IRAEs) occurred in 46.8% of all pts and were generally grade 1-2. Grade ≥3 IRAEs were reported in 13.5% of all pts; most common were rash and alanine aminotransferase increased. AEs leading to treatment discontinuation or death were reported in 27.0% or 6.4% of treated pts, respectively. Reported deaths were considered unrelated to study drugs. The overall response rate (ORR, complete response [CR] + partial response [PR]) was 83.3% for CLL (including PR with lymphocytosis), 66.7% for SLL, 30.0% for FL, 35.6% for DLBCL, and 60% for RT (Table). Preliminary data indicated that median progression-free survival (PFS) was immature and subject to maturation with longer follow-up for CLL, not estimable (NE) due to lack of events for SLL, 5.5 months (95% confidence interval [CI]: 2.9, 12.7) for FL, 3.2 months (95% CI: 2.0, 4.7) for overall DLBCL (4.1 months [95% CI: 2.1-7.6] for non-transformed DLBCL and 1.9 months [95% CI: 0.7-4.7] for transformed DLBCL), and 3.6 months (95% CI: 1.4, NE) for RT. Median duration of follow-up for CLL, SLL, FL, DLBCL, and RT was 15.90 (range 1.7, 25.5), 17.02 (1.9, 17.7), 13.34 (0.7, 21.3), 14.75 (0.4, 19.2), and 4.60 (1.4, 11.1) months, respectively. There was a trend toward increased CR and PFS in DLBCL pts with elevated PD-L1 protein staining (≥5% of tumor cells) by central immunohistochemistry analysis. In RT, 2/8 responders (PR or better) had elevated PD-L1 staining. PD-L1 staining was not elevated for all other cohorts. Conclusions : The combination of ibrutinib and nivolumab at full doses displayed an acceptable safety profile in pts in R/R non-Hodgkin lymphoma. The ORR was comparable to those observed with single-agent ibrutinib in CLL, SLL, FL, and DLBCL. Historical results demonstrate poor outcomes in pts with RT treated with single-agent ibrutinib or with chemotherapy. In this study, the rate of clinical response observed in pts with RT exceeded expectation and may support further clinical evaluation. Biomarker analysis is ongoing to identify pts who may benefit most from this novel therapy. Disclosures Younes: Incyte: Honoraria; Curis: Research Funding; Johnson & Johnson: Research Funding; Sanofi: Honoraria; Merck: Honoraria; Bayer: Honoraria; Bristol-Myers Squibb: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Janssen: Honoraria; Seattle Genetics: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Novartis: Research Funding. Lopez-Guillermo: Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Roche: Consultancy, Other: Research grant. Bosch Albareda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masood: Bristol-Myers Squibb: Employment, Equity Ownership. Streit: Janssen Research & Development: Employment, Equity Ownership. Alvarez: Janssen Research & Development: Employment, Equity Ownership. Ceulemans: Janssen Research & Development: Consultancy. Kharabi Masouleh: Janssen Research & Development: Employment. Balasubramanian: Janssen Research & Development: Employment, Equity Ownership. Schaffer: Janssen Research & Development: Employment, Equity Ownership. Wang: Janssen Research & Development: Employment. Fourneau: Janssen Research & Development: Employment. Jurczak: Gilead: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Pfizer: Research Funding; Celtrion: Research Funding; Janssen: Research Funding; Acerta Pharma: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jagiellonian University: Employment; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding.

8041 Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m2]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m2] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]

Summary Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m2 intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1–9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0–4) and four prior systemic therapies (range 1–9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.

Livin is a member of the Inhibitor of Apoptosis (IAP) protein family that inhibits apoptosis triggered by a variety of stimuli. We previously demonstrated that while Livin inhibits caspase activity, caspases can cleave Livin to produce a truncated protein, tLivin and that this newly formed tLivin paradoxically induces cell death. However to date, the mechanism of tLivin-induced cell death is not fully understood. In this study, we set out to characterize the form of cell death mediated by tLivin. Here we demonstrate that, unlike most death-promoting proteins, tLivin is a flexible inducer of cell death capable of promoting necrosis or apoptosis in different cell lines. The unusual flexibility of tLivin is displayed by its ability to activate an alternative form of cell death when apoptosis is inhibited. Thus, tLivin can promote more than one form of cell death in the same cell type. Interestingly, in cells where tLivin induces necrosis, deletion of the caspase binding BIR domain results in tLivin-induced apoptosis, suggesting the BIR domain can potentially hamper the ability of tLivin to induce apoptosis. We further elucidate that tLivin activates the JNK pathway and both tLivin-induced apoptosis and necrosis are partially mediated by JNK activity. Acquired resistance to apoptosis, common in many tumors, impinges on the efficiency of conventional anti-cancer agents that function primarily by inducing apoptosis. The ability of tLivin to induce death of apoptosis-compromised cells makes it an attractive candidate for targeted cancer therapy.

PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immunoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48.

The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (or400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.

Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non-Hodgkin's lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986-95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy-proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.

In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Ph-positive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation.

The advent of radiologic guidance techniques for percutaneous biopsy has changed the approach to the routine diagnosis of mediastinal lymphoma. The aim of the present study was to evaluate the diagnostic accuracy of CT-guided percutaneous core-needle biopsy (PCNB) in the clinical management of patients with mediastinal lymphoma. The results of 49 CT-guided PCNB of mediastinal lymphoma performed under local anesthesia in 42 ambulatory patients were analyzed. A positive diagnosis of lymphoma was obtained in 30 of 42 patients, with an overall success rate of 71.5 %. The technique was equally successful in the diagnosis of Hodgkin's and non-Hodgkin's lymphoma. There were no major complications. Percutaneous CT-guided CNB of mediastinal lymphoma is a quick, safe, accurate, and efficient alternative to open biopsy in the evaluation of mediastinal lymphoma, mainly at presentation. It should become the preferred initial diagnostic procedure for obtaining histologic samples in patients with suspected mediastinal lymphoma.

Thirteen chronic myeloid leukemia (CML) patients, 10 with variant Philadelphia (Ph) translocations and 3 Ph negative cases, were analyzed by fluorescence in situ hybridization (FISH) with the use of BCR and ABL cosmid probes and a chromosome 22 painting probe. In the variant Ph translocations, the BCR-ABL fusion gene was located on the Ph chromosome; in 1 CML Ph-negative patient, the BCR-ABL fusion gene was located on the Ph chromosome; and, in 2 patients, it was located on chromosome 9. The chromosome 22 painting probe was detected on the third-party chromosome of the variant translocation, and in none of the variant translocations was there any detectable signal on chromosome 9. In CML patients with clonal evolution of a simple Ph, a signal of the chromosome 22 painting probe was detected on the der(9) of the Ph translocation. It was concluded that the variant Ph translocations evolved simultaneously in a three-way rearrangement. The clinical parameters of the 13 patients were similar to those of a large group of CML patients with a simple Ph translocation. It is suggested that, to determine the prognosis of CML patients with a complex karyotype, FISH analysis with a chromosome 22 painting probe be performed.

We have assessed the outcome of 66 refractory and relapsed acute leukemia patients treated with high dose mitoxantrone and cytarabine. Therapy consisted of a total dose of 40–60 mg/m2 mitoxantrone and 3 g/m2 of cytarabine daily on 5 consecutive days. A total of 28 patients were treated for primary resistant and 38 patients for early or late relapsed leukemia. A total of 35 patients achieved CR. Four patients died during the induction course. Toxicity was acceptable and comparable to other salvage regimens. The median disease-free and overall survivals were 4 and 6 months, respectively. Although this regimen is effective in achieving remission in refractory leukemia, its duration is short.

Cutaneous T-cell lymphomas (CTCL) are diseases characterized by cutaneous infiltrates of malignant clonally expanded T cells. CTCL cells exhibit a cytokine profile consistent with T helper-2 type (TH2) cells. Eosinophilic pneumonias are individual syndromes characterized by eosinophilic pulmonary infiltrates and commonly peripheral blood eosinophilia. CTCL and chronic eosinophilic pneumonia are rare clinical entities. We report a patient with the association of CTCL and chronic eosinophilic pneumonia. To understand the mechanism leading to the eosinophilia, we examined the patient's cytokine profile. This was consistent with a high TH2 activity. Her interleukin (IL) 5, 6, and 10 levels were extremely high, while her IL-2 and interferon-gamma (IFN-gamma) levels (TH1 profile) were low. We believe that eosinophilic pneumonia in this patient is probably secondary to high TH2 cytokine levels induced by tumor cells. We suggest that eosinophilic pneumonia should be considered as a possible diagnosis in patients with CTCL who have respiratory complaints.

BACKGROUND The past decade has witnessed a growing frequency of therapy-related secondary tumors. The authors studied nine children with secondary malignancies. The primary tumors were bilateral retinoblastoma, neuroblastoma, brain tumor, Wilms' tumor, colon adenocarcinoma, and Hodgkin's disease. The secondary tumors were osteosarcoma at the site of previous radiotherapy, myelodysplastic syndrome, acute myelocytic leukemia, glioblastoma, thyroid carcinoma, and B-cell lymphoma. METHODS DNA was extracted from the primary and secondary tumors and analyzed for genetic alterations in the p53 gene and in 7 separate microsatellites. RESULTS The authors found p53 mutations in 7 patients, loss of heterozygosity in 1 patient, and both mutation and loss of heterozygosity in 1 patient. Mutations were demonstrated in the primary tumors only in two patients and in the secondary tumors only in three patients. Two patients had a mutation in both the primary and the secondary tumor; in both patients the two mutations were in different exons. Microsatellite instability (MIN) was identified in five to seven loci in the secondary tumors of all patients. CONCLUSIONS The observed MIN is compatible with the presence of a mutator phenotype that predisposes these children to the development of secondary malignancies. Cancer 1999;85:504–10. © 1999 American Cancer Society.

Lawsone (2-hydroxy-1,4-naphthoquinone) is the active ingredient of Lawsonia alba, whose crushed leaves are known as henna, used as a hair and skin dye in many parts of the world. Accidental or deliberate ingestion of Lawsone has a high mortality rate (up to 31%) owing to rhabdomyolysis and renal failure. The authors report the first successful use of plasmapheresis as an adjunct to the treatment of these symptoms in a 69-year-old man who suffered severe symptoms of Lawsone poisoning due to inadvertent ingestion. Although most cases reported in the literature have been treated using supportive techniques, including hemodialysis, the high mortality despite these measures suggests that prompt plasma exchange may be a lifesaving technique for this syndrome.

Chronic myelocytic leukemia (CML) is a common neoplasm of hematopoietic pluripotent stem cells. Although the evolution from chronic phase to blast crisis (BC) in CML patients is an inevitable clinical feature, little is understood about the mechanisms responsible for the transformation. We have previously performed allelotype analysis in CML BC and have detected frequent loss of heterozygosity (LOH) on the short arm of chromosome 1. To know the common region of LOH where a putative tumor suppressor gene may reside, deletional mapping was performed using 33 microsatellite markers spanning chromosome 1 in 30 patients with CML BC (21 myeloid and 9 lymphoid). DNA was extracted from slides of bone marrow smears or from bone marrow mononuclear cells. In each patient, DNA from chronic phase was analyzed alongside DNA from either their BC or accelerated phase. Allelic loss on 1p was observed in 14 of the 30 individuals (47%): 10 of the 21 myeloid and 4 of the 9 lymphoid BC cases. Serial cytogenetic information was available in 10 cases with LOH on 1p; interestingly, deletions in this region were not detected. Two samples showed LOH at all informative loci on 1p, whereas the other 12 samples showed LOH on at least one but not all loci on 1p. The common region of LOH resided proximal to D1S508 and distal to D1S507 (1p36). Our results suggest that a tumor suppressor gene that frequently plays an important role in the evolution to BC resides on 1p36 in CML. © 1998 by The American Society of Hematology.

We describe a previously healthy male patient, with severe immune thrombocytopenic purpura (ITP) following CMV infection which was refractory to steroids and intravenous immunoglobulin, who developed massive intracranial bleeding. Despite an extremely low platelet count (2×109/liter) which was refractory to platelet transfusions, successful emergency splenectomy was performed, with rapid resolution of the thrombocytopenia. Bleeding complications are extremely rare in viral-associated ITP. Emergency splenectomy should be considered in the presence of life-threatening bleeding when other modalities fail to produce a rise in the platelet count. Infection with CMV should be ruled out in cases of severe, treatment-resistant ITP.

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma.

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon α (IFNα) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNα-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNα therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNα therapy far better than the cytogenetic response.

Immune hemolytic anemia (IHA) may complicate the course of chronic lymphocytic leukemia (CLL), especially in patients with advanced disease, and as a complication of treatment with chlorambucil or fludarabine. Bendamustine, a novel agent with both alkylating and purine-analog properties, was approved in the USA for use in CLL in 2008. Since then, clinical data on its adverse events are accumulating. IHA related to bendamustine was seldom described and is thus reported and reviewed. We assessed five cases of CLL patients complicated by IHA, out of 31 treated with bendamustine for a relapse of their disease. Also reviewed are previous case reports in the literature. Bendamustine-related IHA is more common than suspected (16 %). No such cases were found in non-CLL patients. Personal history of fludarabine-triggered AIHA may be a risk factor for this complication (recorded in 4/5 patients, 80 %). The mechanism is thought to be related to the loss of T cell regulatory control as described for other agents. Physicians using bendamustine for the treatment for CLL should be aware of this complication.

As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.

Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

During the last decade the frequency of therapy-related acute leukemia (t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly observed. Over the past 15 years, we treated 56 patients with t-leuk who had received prior chemotherapy (39%), radiotherapy (11%), or both (45%). The drugs received included alkylating agents and topoisomerase II inhibitors. The primary tumors included hematological malignancies (49%) and solid tumors such as breast or ovarian cancer. The median age at diagnosis of the primary tumor was relatively young (43 years +/- 18). Twelve patients had more than one primary tumor and 31 patients had a family history of malignancy. Karyotypic abnormalities were found in 91% of the patients. Prognosis was uniformly poor, with an overall median survival of 10 months. Twelve of the 18 patients examined (67%) had a multidrug resistance phenotype. P53 genes of the leukemic cells, as well as the original tumors, were analyzed in 21 patients using polymerase chain reaction (PCR) with single-stranded conformation polymorphism analysis followed by sequencing. P53 mutations were identified in 38% of these patients, a relatively high prevalence compared with other forms of MDS or de novo acute myeloid leukemia. Mutations were nongermline and restricted to the leukemic cells. We identified different p53 mutations in the various primary tumors of individual patients. The presence of a mutator phenotype was assessed by PCR analysis of microsatellites in eight loci (one trinucleotide repeat sequence, four dinucleotide, and three mononuclear repeat sequences). Microsatellite instability in two to seven loci were found in 15 of 16 (94%) of the patients. This instability is compatible with a mutator phenotype, which predisposes the patients to the development of malignancies including t-leuk.

Splenectomy is an effective treatment for immune thrombocytopenic purpura (ITP). The recent advances in laparoscopic technique and technology have made laparoscopic splenectomy a viable option. Over 36 months we performed a total of 17 laparoscopic splenectomies, 15 of them for ITP and 2 for familial spherocytosis. We present our initial experience with laparoscopic splenectomy in 15 patients (age 16-71 years) with ITP. Operations were performed 2-24 months after the establishment of the diagnosis and initiation of appropriate therapy. Technically, the splenic artery was clipped first; the lower pole of the spleen and its posterolateral attachments were dissected using endoclips and electrocautery; the hilum and short gastric vessels were separated using an endostapler; the spleen was placed in a plastic bag, its opening pulled out through the umbilical incision, and the spleen fragmented and aspirated out of the bag. Operations lasted 100-300 min (mean 170 min). No patient required blood transfusion. The postoperative course was uneventful in all patients with minimal requirement of analgesia and early return to normal activity. Platelet counts returned to normal in all patients in a follow-up period of 2-36 months. Laparoscopic splenectomy is safe and effective for patients with ITP because of reduced operative trauma, less postoperative pain, cosmetic advantage, and possibly less postoperative complications.

A marker chromosome was identified in leukemic cells on an AML patient. The G-banding pattern resembled on i(10q), but its centromeric position was not clear; in some cells it had a telocentric shape, in others a metacentric or acentric shape. The origin of the marker chromosome was confirmed by FISH, using chromosome-10-specific painting. To determine the centromeric position, C-banding and alpha-satellite probes were applied in FISH, and none of them gave a positive signal. Despite the absence of the centromeric alpha-satellite sequences and the constricted feature of the centromere, the essential centromeric activity was retained in this chromosome, namely, the separation of sister chromatids in anaphase.

Background: Patients (pts) aged >65 years (yrs) with AML have a median overall survival (OS) of ~3 months (mos), with worsening OS as age increases: median OS for pts ages 66-75 yrs is ~6 mos, but is only ~2.5 mos for pts ages 76-89 yrs (Walter, Leukemia, 2015). Treatment (Tx) options are limited for these pts, who often have disease features associated with Tx resistance, such as prior hematologic disorders, and a greater risk of Tx-related mortality. With current Tx options, in this setting many physicians or pts do not pursue active AML Tx. The phase 3, randomized AZA-AML-001 study compared AZA and CCR in older pts with AML (Dombret, Blood, 2015). Aims: Assess outcomes with AZA vs CCR in elderly pts (age ≥75 yrs) with AML in the AZA-AML-001 study overall and in the subset of pts with myelodysplasia-related changes (AML-MRC), and descriptively compare them with outcomes for pts aged 65-74 yrs. Methods: Pts aged ≥65 yrs with newly diagnosed AML (>30% bone marrow blasts), ECOG performance status ≤2, intermediate- or poor-risk cytogenetics, and WBC counts ≤15x109/L were eligible. Pts were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: low-dose ara-C (20mg SC BID x10d/28d), intensive chemotherapy (7+3), or best supportive care only. These analyses evaluated outcomes in pts aged 65-74 yrs (" Results: In all, 223 pts were aged 85 yrs (AZA n=14; CCR n=13). Median age in the Conclusions: As expected, OS and response rates were lower in elderly pts in both Tx arms than in younger pts. Median OS was meaningfully prolonged with AZA (+4.6 mos) vs CCR in pts aged 65-74 yrs. Higher proportions of AZA-treated pts remained alive at each 3-month landmark than CCR-treated pts, mainly in the younger age group, although 1-year survival was also higher in pts aged ≥75 yrs. Given the higher IR of infections, prophylactic use of antimicrobials or growth factors might be considered for elderly pts treated with AZA. Pts with AML-MRC retained the relative OS benefits of AZA vs CCR. While OS for AML-MRC pts aged ≥75 yrs was longer with AZA (+2.1 mos) vs CCR, pts with AML-MRC aged ≥75 yrs in both treatment groups had decreased OS compared with the median OS for all pts aged ≥75 yrs, consistent with reports that AML-MRC is more difficult to treat than AML not otherwise specified (Weinberg, Blood, 2009). Disclosures Seymour: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Buckstein:Celgene: Honoraria, Research Funding; Novartis: Honoraria. Santini:Astex: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Seattle Genetics: Consultancy; Jansen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; ONO: Consultancy; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Xenetic Biosciences: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Celator: Consultancy. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Sunesis: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Menarini: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

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.

Introduction: Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of 20% and/or 2X109/L plasma cells (PCs) in the peripheral blood (PB) of the patient. Data regarding this entity are scarce and based on case reports and few retrospective case series. Most of the reports are dated prior to the incorporation of novel agents into MM treatment. The aim of this multicenter retrospective study was to evaluate the response and survival of PPCL patients in the era of the novel agents. Methods: We searched for the diagnosis of PPCL, during the years 2002-2016, in the medical summaries of 16 medical centers in Israel which routinely treat patients with MM. Patients with the presence of plasma cells in the blood during the course of MM (secondary plasma cell leukemia) were excluded. Results: 40 PPCL patients were identified in 11 of the 16 medical centers. It is probable that several patients were recorded as MM and thus not identified as PPCL. The characteristics of the patients and their disease are available for 35 patients and are summarized in table 1. One third of the patients presented with light chain disease and over two thirds had hypercalcemia at diagnosis. The median age was 60 and 3 patients were aged less than 35 years at diagnosis. The median number of treatments was 2. 83% of the patients received at least one IMiD or proteosome inhibitor (PI), 51% received both IMiD and PI. 17% of the patients received more than one line of IMiDs and a similar number of patients received more than one line of PIs (Fig. 1). The type of novel agents that were used are shown in figure 2. 45.7% of the patients underwent hematopoietic stem cell transplant (HSCT), of those, 4 patients (11%) have undergone tandem auto-allo HSCT and 1 (3%) - tandem auto-auto HSCT. 29% of the patients did not responded to induction therapy and 57% achieved PR or better response. 13 out of 35 patients (37%) are still alive and one is lost to follow-up. The median overall survival (OS) was 11 months.7 patients (20%) survived less than 2 months while 13 (37%) survived more than 24 months, including 7 who survived more than 48 months. Among the 16 patients who underwent HSCT, all the 4 who underwent tandem auto-allo-transplant survived more than 32 months. Conclusions: Despite the modest size of this patient cohort, several inferences may be made. Patients with PPCL have unique characteristics compared to MM patients; lower median age, more frequent light chain disease and hypercalcemia at presentation. Extreme leukocytosis or leukopenia are rare. Despite intensive use of novel agents, the median OS of this cohort remains poor - 11 months. The best results were seen in patients who received tandem auto-allo HSCT, suggesting that the immunotherapeutic graft-versus-myeloma effect may offer the best hope for long-term survival to patients with PPCL. Table 1 Patient and disease characteristics Table 1. Patient and disease characteristics Figure 1 Combinations of novel agents Figure 1. Combinations of novel agents Figure 2 Types of novel agents Figure 2. Types of novel agents Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.