ALBERT

Description: Abstract 2060 Poster Board II-37 Introduction: The Flt3-internal tandem duplication can be found in up to 30% of all acute myeloid leukemia (AML) patients and confers a poor risk status characterized by an increased relapse rate and poor overall survival. Moreover, Flt3-ITD-positive AML patients relapsing after allogenic stem cell transplantation (SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor that is approved for the treatment of metastatic renal cell and hepatocellular carcinoma. Besides targeting Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR) it has also significant inhibitory activity against the Flt3 receptor tyrosine kinase, and, specifically the mutated variant of Flt3, Flt3-ITD. It has previously been shown that sorafenib monotherapy may have considerable activity in relapsed Flt3-ITD positive AML. Nevertheless, clinical experience is still limited. Here we report compassionate use experience on 18 relapsed or refractory Flt3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 28 centers in Germany in order to obtain more insight into the clinical efficacy and tolerablilty of sorafenib monotherapy in Flt3-ITD positive AML. Forms were returned from 13 centers, reporting 26 patients. Among them, eight had to be excluded from further analysis. Five of them were Flt3-ITD mutation negative and three received contemporary chemotherapy. Available patient information included age, FAB-classification, karyotype, type and response to prior therapy, sorafenib dosing, tolerability, treatment duration, and response. Results: Of the 18 patients (12 male, 6 female), five were primary refractory to induction chemotherapy and 13 received sorafenib in first (n=11) or second (n=2) relapse. Eight of 18 patients relapsed after SCT and were treated with sorafenib. One patient was treated for steadily increasing Flt3-ITD copy numbers, that is, in molecular relapse after SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 98 days (range, 16-425 days). All patients achieved a hematological response (HR) characterized by complete (n=17) or near complete peripheral blast clearance (n=2). Of the 18 patients the documented best response to sorafenib were: HR in 9 cases, bone marrow response (HR and blast reduction in marrow) in 4 cases, complete remission (normalization of peripheral blood counts and bone marrow blasts 〈 5%) in one case and complete molecular remission (molecular negativity for Flt3-ITD) in 4 patients. After a median treatment duration of 180 days (range, 82-270 days) 7 of the 18 (39%) patients developed clinical sorafenib resistance: two of eight (25%) of the SCT-group and 5 of 10 (50%) of the non-SCT group. Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant side effects, observed in 13 patients. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: Sorafenib monotherapy has significant clinical activity in Flt3-ITD positive relapsed and refractory AML and may be particularly effective in the context of allo-immunotherapy where 3 CMR could be seen. Disclosures: Enghofer: Bayer Schering Pharma: Employment. Off Label Use: sorafenib, used to treat Flt3-ITD positive AML patients.

Description: Background The anti-PD1 antibody nivolumab is approved for relapsed or refractory classical Hodgkin lymphoma (cHL) showing high overall response rates (ORR) and a favorable safety profile. However, complete response (CR) is rare in this setting, and most patients develop progressive disease. To evaluate the efficacy of combined nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) as 1st-line treatment for early-stage unfavorable cHL, we conducted the GHSG NIVAHL trial. Methods NIVAHL is a prospective, randomized, investigator-sponsored single-stage phase II trial that enrolled treatment-naïve early-stage unfavorable cHL patients between 18 and 60 years at 35 German centers (NCT03004833). In arm A, patients received 240mg nivolumab and AVD at standard doses on day 1 and 15 of each 28-day cycle for a total of four cycles (4xNivoAVD). In arm B, the same treatment was administered sequentially, starting with 4x nivolumab in 2-weekly intervals, followed by 2xNivoAVD and 2xAVD. Both groups received 30Gy involved-site radiotherapy (IS-RT). Primary endpoint is the centrally reviewed PET/CT-based CR rate after completion of protocol therapy including IS-RT. 55 patients per group were enrolled in order to exclude a CR rate ≤80% with a power of 90% on a one-sided alpha level of 2.5% each. Secondary endpoints will be analyzed descriptively and include treatment-related morbidity (TRMorbidity), progression-free (PFS), overall survival (OS), response at interim and final restaging as well as patient-reported outcomes. Sequential biopsies, blood and microbiome samples were collected for correlative studies. Results Between 04/2017 and 10/2018, a total of 110 patients were enrolled with one patient disqualified due to alteration of HL diagnosis by central pathology review (N=109, group A n=55, group B n=54). The median age of the predominantly female patients (60%) was 27 years. Stage II was present in 95% of cases with ≥3 involved areas as most common risk factor (69%), followed by elevated ESR (48%), large mediastinal mass (20%) and extranodal disease (13%). Mean duration of chemoimmunotherapy was 15 (standard deviation (SD) 3) weeks and 22 (SD 6) weeks with a mean relative dose intensity of 87.4 (SD 15.9)% and 85.8 (SD 24.2)% in groups A and B, respectively. Severe protocol deviations occurred in 4 patients in group A and 5 in group B. Reasons were toxicity (n=5), patient's wish (n=2), incorrect allocation to early-stage unfavorable risk group (n=1) and progressive disease (n=1). Another 2 patients refused to receive IS-RT. Any adverse events (AEs) were reported for 98% of patients. AEs ≥°3 were observed in 73% and 78%, respectively, and serious AEs occurred in 38% and 28% of patients in groups A and B, respectively. TRMorbidity defined as organ toxicity ≥°3 or anemia, thrombocytopenia or infection °4 was documented in 16% and 22% of patients; all of these were organ toxicities predominantly of liver and gastrointestinal tract, with 19/21 events occurring during the first 2 treatment cycles. Data on ongoing or late toxicities is limited by short follow-up. Until 07/2019, 4 cases of persistent hypothyroidism have been reported. At the 1st interim restaging after 2xNivoAVD and 4x nivolumab, the ORR was 100% (54/54) and 96% (49/51), with a CR rate of 85% and 53% in groups A and B, respectively. Interim remission status was not assessed in 1 and 3 patients, respectively, due to treatment discontinuation after incorrect allocation to early-stage unfavorable risk group (n=1) or toxicity (n=3). After completion of systemic therapy, ORR was 100% (54/54) and 98% (50/51) with a CR rate of 81% and 86%, respectively. One patient in group B developed histologically proven primary progressive HL during nivolumab monotherapy while no other case of progressive or relapsed disease or death has been documented so far. The centrally reviewed CR rate at the end of treatment will be reported at the meeting. Additionally, initial data from currently ongoing histopathologic and immunologic studies will also be presented. Conclusion Concomitant and sequential therapy with nivolumab and AVD is feasible with acceptable toxicity. In early-stage unfavorable cHL, concomitant Nivo-AVD induces a high early CR rate. The interim CR rate observed with 4x nivolumab monotherapy is higher than previously reported in relapsed or advanced-stage disease. The primary endpoint and initial PFS data will be reported at the meeting. Disclosures Bröckelmann: Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding. Kerkhoff:EUSA: Honoraria; Hexal: Honoraria; Celgene: Honoraria, Other: Travel Support; Roche: Honoraria; Novartis: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses. von Tresckow:MSD Sharpe & Dohme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria; Amgen: Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. OffLabel Disclosure: Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Description: Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -〉 96.4% and 86.2% -〉 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and 〈 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.

Description: Background: The addition of sorafenib to standard induction and consolidation therapy in newly diagnosed patients (pts) ≤60 years (yrs) with acute myeloid leukemia (AML) led to significant prolongation of event-free survival (EFS) and relapse-free survival (RFS) in the randomized placebo-controlled SORAML trial (NCT00893373). After a median follow-up of 3 yrs, a benefit for sorafenib treated pts was observed also in overall survival (OS), but this difference was not significant. Here, we present updated survival data and information on relapse treatment and outcome. Methods: In the SORAML trial, 267 newly diagnosed untreated fit AML pts up to 60 yrs of age and irrespective of FLT3 mutation status received two cycles of induction chemotherapy with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk pts in first complete remission (CR) with a sibling donor and for all high-risk pts with a matched related or unrelated donor. At study inclusion, pts were randomized to receive either sorafenib (2x400 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months (mos) after the end of consolidation. The primary endpoint of the trial was EFS. The results after follow-up of 3 yrs were presented at ASH 2014 (Röllig et al., Blood 2014; 124: 6) and fully published (Röllig et al., Lancet Oncol 2015; 16: 1691-9). Here, we present the results after prolonged follow-up. For this analysis, information on remission and survival status, mode and outcome of relapse treatment including SCT were collected for all randomized pts and analyzed by standard statistical methods. Results: Of 267 treated pts, 134 were randomized in the sorafenib arm and 133 in the placebo arm with a resulting CR rate of 60% and 59%, respectively. After a median observation time of 78 mos, the primary study endpoint EFS in the placebo vs sorafenib arm was 9 mos vs 26 mos (HR 0.68, p=0.01) in univariate Kaplan Meier analysis. The beneficial effect of sorafenib on EFS was confirmed in multivariate Cox regression analysis with a HR of 0.61 (p=0.005). Median RFS in the placebo vs sorafenib arms was 22 vs 63 mos, corresponding to a HR of 0.64 (p=0.033). Exploratory analyses were performed in the 70 relapsing pts (40 after placebo vs 30 after sorafenib treatment). Among relapsing pts, 82% vs 73% achieved a second CR. In these two groups, 88% and 87% of pts received a SCT as part of salvage treatment. A lower proportion of pts in the placebo arm received a second SCT as salvage treatment (5% vs 13%). In the context of salvage SCT, the proportion of haploident donors in the placebo and sorafenib group was 3% vs 15% and the incidence of Grade 3/4 GVDH was 17% vs 0%. SCT-related non-relapse mortality (NRM) was similar in both groups, but the cumulative incidence of second relapse (CIR) was higher in the sorafenib group (35% vs 54% after 48 mos). Therefore, median OS from relapse in the placebo vs sorafenib groups were 27 mos vs 10 mos, corresponding to a HR of 1.68 (p=0.098). The projected median OS from randomization is 83 mos in the placebo arm and was not reached for the sorafenib arm, corresponding to a 5-year OS of 52% vs 61% (HR 0.81, p=0.263). Conclusion: Mature follow-up data confirms the antileukemic efficacy of sorafenib in younger AML pts with and without FLT3 mutation. The addition of sorafenib to standard chemotherapy resulted in a significantly longer EFS and clinically relevant 36% risk reduction for relapse or death. Five pts need to be treated (NNT) to prevent one relapse or death at 3 years and six pts at 5 yrs. Exploratory analyses in relapsing pts show that survival after relapse is shorter after sorafenib which might be due to i) a higher rate of second SCTs and a higher incidence of haploidentical SCT despite the lower frequency of severe GVHD, most likely by chance and not explainable by systematic reasons and ii) a lower response to salvage treatment after sorafenib therapy. Despite these observations, primary sorafenib treatment led to an OS benefit with a 19% risk reduction for death which was not statistically significant since this phase II trial was not adequately powered to detect OS differences. Figure Figure. Disclosures Rollig: Bayer: Research Funding; Janssen: Research Funding. Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis: Acceleron: Consultancy; Celgene: Consultancy. Mackensen: AMGEN: Research Funding. Hänel: Roche: Honoraria; Novartis: Honoraria. Thiede: Roche: Consultancy; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Agendix: Employment. Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria.

Description: Cell adhesion in the multiple myeloma (MM) microenvironment is a mechanism by which MM plasma cells escape the effects of therapy and survive. To improve clinical strategies and overcome drug resistance, approaches directed to both MMPCs and bone marrow microenvironment are under investigation. Here, we examined the cell membrane protein Junctional adhesion molecule-A (JAM-A) as a clinical biomarker and novel therapeutic target for MM. We evaluated JAM-A expression by real time PCR (RT-PCR), flow cytometry and immunofluorescence microscopy in 132 MM patients at different stages and various MM cell lines. Next, we measured the concentrations of soluble JAM-A from MM and healthy subjects sera by enzyme linked immune assay (ELISA). We investigated JAM-A functionally in vitro and in vivo by transient gene silencing (siRNA) and with blocking antibodies. Patient-derived plasma cells (MMPCs) expressed increased JAM-A expression levels when compared to control PC from healthy individuals. Elevated JAM-A expression correlated with poor prognosis (Figure 1A,B). Furthermore, soluble JAM-A was significantly increased in MM patient sera when compared to healthy subjects. Additionally, MM cell lines showed high expression of both membrane and cytoplasmic JAM-A. Consequently, inhibition of JAM-A using specific siRNA treatment resulted in diminished tumorigenic potential, including decreased colony formation, chemotaxis and migration. Importantly, treatment of luciferase+RPMI-8226 MM bearing NSG with a JAM-A blocking monoclonal antibody reduced significantly MM progression and dissemination in vivo when compared to MM bearing mice that received an non-specific isotype control antibody (Figure 1C). Conclusively, our data suggest that JAM-A can serve as a biomarker of malignancy in MM patients. Soluble plasma JAM-A could contribute to serum-based clinical stratification. Furthermore, therapeutic targeting of JAM-A appears attractive for clinical translation. Figure 1 Figure 1. Disclosures Einsele: Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria.

Description: The advent of imatinib has considerably changed treatment in chronic myeloid leukemia (CML). Although response rate and duration of response with imatinib monotherapy continue to be impressive, the majority of patients (pts) in complete cytogenetic remission (CCR) retain BCR-ABL transcripts as markers of residual disease and potential cause of relapse. In addition rapid evolvement of blast crises from CCR has been reported. Therefore, we designed an investigator-initiated phase IV prospective trial aiming to address the role of imatinib in combination with interferon alpha (IFN) or Ara-C and treatment intensification with high dose imatinib. In July 2002, the German CML-Study Group has activated the four-armed randomized controlled trial comparing imatinib 400 mg/d with imatinib+IFN, imatinib+Ara-C and imatinib after IFN failure in newly diagnosed pts with chronic phase CML. Randomization is stratified according to prognostic risk groups and not biased by consecutive allogeneic stem cell transplantation (SCT). High risk pts are randomly assigned to primary imatinib-based therapies including a 4th treatment arm with imatinib 800 mg/d. The treatment arm imatinib after IFN failure retains the chance of an IFN-induced CCR with 10 year-survival rates of 70–80%. In case of IFN failure pts are crossed over to imatinib. Allogeneic SCT is recommended for all pts with high risk, imatinib failure and EBMT-score 0–1. By August 2004, 429 pts were randomized: imatinib 400 mg/d (n=103), imatinib+IFN (n=130), imatinib+Ara-C (n=108), imatinib after IFN failure (n=84), and imatinib 800 mg/d (n=4). According to the New CML score, 34% of patients were low risk, 56% intermediate risk, and 10% high risk. At baseline, median WBC count was 63/nl (3.5–513), median platelet count was 385/nl (49–2,799) and median hemoglobin was 12.7 g/dl (6.1–16.6). We sought to evaluate results of the first cohort of pts (n=217) with a 〉12 months follow-up, recruited between 7/2002 and 5/2003 (imatinib 400 mg/d, n=52; imatinib+IFN, n=70; imatinib+Ara-C, n=49; imatinib after IFN failure, n=46). Median age was 56 yrs (16–82), 62% of pts were male. Cytogenetic data are available from 117 pts (68%) randomized to primary imatinib-based therapies. At 12 months, 104 pts (89%) achieved a major cytogenetic remission (Ph+

Description: Multiple myeloma (MM) plasma cell (MMPC) interactions with the microenvironment control MMPC growth, survival, drug-resistance and intra- and extramedullary dissemination. Dissemination of MMPCs through bone marrow niches and in extra-medullary sites is an active process of invasion involving bone marrow endothelial cells, multiple adhesion molecules and chemokine receptors. Since enhanced angiogenesis characterizes MM, we investigated whether junctional adhesion molecule-A (JAM-A) mediated interactions between MM bone marrow endothelial cells (MMECs) and MMPCs impact disease progression. To this end, we analyzed JAM-A expression levels in MMECs of 312 MM patients in two independent cohorts with flow cytometry, namely 111 newly diagnosed (NDMM) and 201 relapsed/refractory (RRMM) and compared them to 36 monoclonal gammopathy of undetermined significance (MGUS) and healthy subjects. To corroborate our data and investigate at a gene-expression level the prognostic value of deregulated genes (FDR

Description: Background Chronic myeloid leukemia (CML) stem cells are inherently insensitive to tyrosine-kinase inhibitors (TKI). However, an important minority of CML patients was shown to discontinue TKI without experiencing molecular relapse. Underlying mechanisms are currently unknown. Plasmacytoid dendritic cells (pDCs) are critical regulators of immune responses. Following activation, pDC upregulate MHC-class II and other DC activation markers such as CD86 (also known as B7.2). CD86 is a co-stimulatory molecule during T-cell activation, but also ligand of the inhibitory immune checkpoint receptor CTLA-4, which counteracts T-cell activation. The origin and function of pDC in CML biology is unknown. Within a sub-study of the EUROSKI TKI discontinuation trial we prospectively tested the hypothesis that pDC counts and CD86 expression status govern relapse risk following TKI discontinuation. Methods: Using flow cytometry, cell sorting and fluorescence in situ hybridization (FISH), CD86 expression and BCR-ABL status were analyzed in PDCA-2+/CD123+ peripheral blood (pB) pDC of untreated CML patients (CML pDC), normal donors and 123 patients, who had stopped TKI therapy in deep molecular remission within the international EUROSKI study (EUDRACT 2011-000440-22). All 123 EUROSKI patients had given written informed consent to participate in the immunological sub-study of the EUROSKI trial. Fresh samples from 19 EUROSKI centers in Germany were centrally analyzed prior, as well as 1, 2, 3 and 6 months after TKI discontinuation. PB CD86+ pDC counts were calculated per 105 cells in the lymphocyte gate. Decision trees and 10-fold cross validation were employed to establish relapse prediction accuracy for this value. Results CML pDC were BCR-ABL-FISH positive (median: 81%; range, 57 to 100%). In contrast, the proportion of CD86+ CML pDC varied substantially (median: 25.9%, range 3.2% to 82.4%), suggesting that CD86 expression on CML pDC was not a direct consequence of oncogenic BCR-ABL signaling. This was confirmed experimentally in a murine CML model. In contrast to CML pDC, remission pDC were always BCR-ABL FISH negative (n=10), but still displayed a comparable high proportion of CD86 positive pDC (median: 21%; range, 2.2% to 62%). In contrast, normal donor pDC were rarely CD86 positive (median: 6.8%; range, 4.2% to 17%), reinforcing the aberrant, and BCR-ABL-independent nature of CD86 expression on CML and remission pDC. As a result, healthy donors displayed only between 26 to 84 CD86+ pDC per 105 lymphocytes, whereas EUROSKI remission patients exhibited between 6 to 309 CD86+ pDC per 105 lymphocytes. Based on the important role of CD86 as a high affinity ligand of the inhibitory immune checkpoint receptor CTLA-4, we next asked, whether CD86+ pDC counts are associated with relapse risk after TKI discontinuation. Strikingly, statistical models suggested that a CD86+ pDC count below or above 95 CD86+ pDC/105 lymphocytes optimally separated two relapse categories of EUROSKI patients. Whereas relapse free survival (RFS) (loss of MMR) for patients with more than 95 CD86+ pDC/105 lymphocytes was 30% (n=32), RFS was 69% for patients (n=91) with less than 95 CD86+ pDC/105 lymphocytes (p

Description: Recently, it was shown that interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, has a potential role in chronic myeloid leukemia (CML). Deletion of ICSBP gene in mice leads to a CML-like syndrome and samples from CML patients exhibited impaired ICSBP expression. The present study found that ICSBP expression correlated with risk features determined by Sokal score in untreated CML (P = .007 for high versus low risk). In addition, analyzing ICSBP expression during interferon-α (IFN-α) therapy in “good” (n = 27) versus “poor” (n = 15) cytogenetic responders, high ICSBP levels were only observed in “good” responders (P = .0002). Together, these data suggest that ICSBP levels are related to initial presentation of CML and the therapeutic response of CML to IFN-α, indicating an important role of ICSBP in CML.

Description: Background. Combined modality treatment (CMT) consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy of involved-field radiotherapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity. Aims. We assessed whether omitting consolidating radiotherapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT. Methods. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. PET-2 was centrally assessed by a panel blinded towards the randomization result, with FDG uptake not higher than the mediastinal blood pool (i.e., Deauville score 1-2) defined as negative. The trial was designed to exclude inferiority of 10% or more in 5-year PFS of ABVD only compared with CMT in a per-protocol analysis among PET-negative patients, corresponding to a non-inferiority margin of 3.01 for the hazard ratio, and to detect a 5-year PFS difference of 5% or more between PET-2-positive and -negative patients receiving CMT, each with 80% power. Results. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4-96.5) with CMT and 86.1% (81.4-90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%-13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5-99.8) with CMT and 98.4% (96.5-100.0) with ABVD. 693 patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2-96.2) among PET-2-negative and 88.1% (83.8-92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference was more pronounced (5-year PFS 93.1% [90.7%-95.5%] vs. 80.1% [71.2%-88.9%], p=0.0004). Conclusion. In early-stage favorable HL, radiotherapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity. Disclosures Greil: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Sandoz: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Tresckow:MSD: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.