ALBERT

Description: Leukocyte extravasation depends on various adhesion receptors at endothelial cell contacts. Here we have analyzed how mouse CD99 and CD99L2 cooperate with PECAM-1. We found that antibodies against mouse CD99 and PECAM-1 trap neutrophils between endothelial cells in in vitro transmigration assays. A sequential function, as has been suggested for human PECAM-1 and CD99, could not be demonstrated. In contrast to these in vitro results, blocking CD99 or CD99L2 or gene disruption of PECAM-1 trapped neutrophils in vivo between endothelial cells and the underlying basement membrane as revealed by electron microscopy and by 3-dimensional confocal fluorescence microscopy in the inflamed cremaster tissue. Leukocyte extravasation was inhibited in interleukin-1β-inflamed peritoneum and in the cremaster by PECAM-1 gene disruption and was further attenuated by blocking antibodies against CD99 and CD99L2. In addition, CD99 and CD99L2 were required for leukocyte extravasation in the cremaster after stimulation with tumor necrosis factor-α, where the need for PECAM-1 is known to be bypassed. We conclude that CD99 and CD99L2 act independently of PECAM-1 in leukocyte extravasation and cooperate in an independent way to help neutrophils overcome the endothelial basement membrane.

Description: Abstract 857 Background: Follicular lymphoma (FL) is an incurable B-cell non-Hodgkin's lymphoma (NHL) representing ∼20% of all NHL. Rituximab (R) is approved for the treatment of CD20+ relapsed/refractory FL, and single-agent bortezomib (Vc; VELCADE®) has shown activity in heavily pretreated patients. Vc and R show additive activity in preclinical models, and the combination was active and well tolerated in a phase 2 study. This randomized, open-label, multi-center, international, phase 3 clinical trial (LYM3001) compared the efficacy and safety of Vc plus R (Vc-R) vs R alone in patients with relapsed or refractory, R-naive or R-sensitive FL. Methods: Patients with grade 1/2 measurable FL who had relapsed/progressed following prior therapy (time to progression [TTP] ≥6 months if prior R-containing therapy), ECOG performance status ≤2, and no peripheral neuropathy grade ≥2 were randomized (1:1) to receive 5-week cycles of Vc-R (Vc 1.6 mg/m2, d 1, 8, 15, 22, cycles 1–5, plus R 375 mg/m2, d 1, 8, 15, 22 in cycle 1 and d 1 only in cycles 2–5) or R alone (administered according to the same schedule as for the Vc-R arm). In both groups, treatment was administered for five cycles or until progression or unacceptable treatment-related toxicity. Randomization was stratified by FLIPI score (0–1 vs 2 vs ≥3), prior R therapy (yes vs no), time since last dose of anti-FL therapy (≤1 vs 〉1 year), and region (US vs EU vs rest of world). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR) rate, TTP, and safety/tolerability. Response and progression were assessed by independent radiology committee (IRC) using the modified International Workshop Response Criteria. Planned sample size was 670 patients to provide 90% power (α=0.05, 2-sided) to detect a 33% improvement in median PFS with Vc-R vs R (i.e. 13.3 vs 10 months). Results: Between April 2006 and August 2008, 676 patients (intent-to-treat [ITT] population) were enrolled from 164 centers in 29 countries across Europe, the Americas, and Asia. Baseline characteristics were well balanced between the two arms; median age was 57 years (range 21–84), 54% were female, 75% were Caucasian and 21% were Asian. The majority of patients (93%) had an ECOG performance status of 0 or 1, 51% and 48% had grade 1 and 2 FL, respectively, and 41%, 35%, and 23% had high, intermediate, and low FLIPI score, respectively; 83% had Ann Arbor Stage III or IV, and 38% had bone marrow involvement at baseline. 33% of patients had received 3 or more prior lines of therapy (range 1–6+); 44% had received prior R therapy. The most common prior regimens were CHOP (38%), CVP (25%), single-agent R (17%), R-CHOP (12%), and R-CVP (11%). At a median follow-up of 33.9 months, a total of 440 PFS events were observed by IRC in the ITT population, 212 in the Vc-R arm and 228 events in the R arm. Median PFS improved from 334 days (95% CI: 278, 365) with R alone to 389 days (95% CI: 351, 456) with Vc-R; the hazard ratio was 0.822 (95% CI: 0.681, 0.991). This improvement is statistically significant with a 2-sided P-value of 0.039. The ORR was 63% with Vc-R vs 49% with R (P6 months) was 50% with Vc-R vs 38% with R (P=0.002). The median time to subsequent antilymphoma treatment was significantly improved in the Vc-R vs R arm (700 vs 537 days, P=0.027). Median OS was not reached in either group. Patients received a median 25 weeks treatment in both the Vc-R and R groups (range 5–40 and 5–35 in the Vc-R and R groups, respectively). Adverse events (AEs) were reported for 95% of Vc-R and 78% of R patients. The most common AEs were diarrhea (52% Vc-R, 8% R), nausea (29% Vc-R, 7% R), and pyrexia (25% Vc-R, 10% R). Most AEs were grade 1 or 2. Grade ≥3 AEs were reported in 46% of Vc-R and 21% of R patients; the most common grade ≥3 AEs were neutropenia (11% vs 4%) and diarrhea (7% vs 0%). Peripheral sensory neuropathy was reported in 17% of patients in the Vc-R arm vs 1% in the R arm; 3% vs 0% grade ≥3. 18% and 11% of Vc-R and R patients, respectively, had serious AEs, only 4% and 1% of patients discontinued due to drug-related AEs, and there were 9 and 4 on-treatment deaths, respectively. Conclusion: The addition of weekly Vc to R therapy in patients with relapsed FL was associated with statistically significant improvements in PFS, response rate, and time to next antilymphoma treatment, with acceptable additional toxicity. Disclosures: Coiffier: Johnson & Johnson: Honoraria. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Mayer:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rule:Johnson & Johnson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermann:Millennium Pharmaceuticals: Research Funding. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. Zhu:Johnson & Johnson: Employment. Enny:Johnson & Johnson: Employment, Equity Ownership. Theocharous:Johnson & Johnson: Employment. van de Velde:Johnson & Johson: Employment, Equity Ownership. Elsayed:Johnson & Johnson: Employment, Equity Ownership.

Description: Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of

Description: Abstract 2724 Background: The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome. Methods: 514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. Results: The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS. Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002). We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866). Conclusions: Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: In addition to breast and colorectal cancers, multiple myeloma has also been associated with vitamin D deficiency. Given the role of vitamin D in calcium absorption and bone metabolism, it is crucial to maintain sufficient levels for multiple myeloma patients because of their high risk of bone-related complications. We hypothesized that there was a high prevalence of vitamin D deficiency and insufficiency among multiple myeloma patients. We also hypothesized that there is inadequate screening of vitamin D levels throughout community oncology clinics nationwide. Methods: This study both evaluated multiple myeloma patients from a single medical practice specializing in this B-cell malignancy who had a 25-OH vitamin D level determined, and separately determined the proportion of oncology sites that screen for this vitamin among their patients. Charts were reviewed from the medical practice specializing in multiple myeloma, and only the first vitamin D determination was analyzed in the study. Demographics and the presence of the following complications at the time or within 1 year from when vitamin D levels were assessed: peripheral neuropathy, skeletal-related events and bone disease. We defined skeletal-related events as pathological fractures, spinal cord compression or requirement for radiation or surgery, and bone disease as having one of the following: osteoporosis, osteopenia or lytic bone disease. Patients were categorized as either having sufficient (〉 30 ng/ml), insufficient (20 to 〈 30 ng/ml) or deficient (

Description: Background: Despite encouraging progress in treatment results, CLL remains incurable and patients (pts) eventually relapse. Currently, the effects of maintenance therapy are unknown for CLL. OFA, a human anti-CD20 monoclonal antibody, has proven efficacy as a monotherapy in refractory CLL. PROLONG is an open-label, two-arm randomized study of OFA versus observation (obs) for pts in remission after induction treatment for relapsed CLL. Here, we report interim analysis results for the key primary and secondary endpoints of the study. Methods: Pts in CR or PR after 2nd or 3rd line treatment for CLL were randomized 1:1 to receive OFA (300 mg followed 1 week later by 1000 mg every 8 weeks for up to 2 years) or observation. Pts on OFA received premedication with acetaminophen, antihistamine and glucocorticoid. Pts were stratified by number and type of prior therapy, and remission status (CR or PR) after induction treatment. The primary endpoint was progression free survival (PFS) from randomization as assessed by investigator. The predefined interim analysis of efficacy occurred at 2/3 study events (minimum 187), with a p

Description: BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p

Description: Abstract 778 Background: Combination chemo-immunotherapy regimens are used in the majority of patients with advanced stage indolent lymphoma who require treatment. Despite high overall response rates following frontline therapy, nearly all patients relapse and many die of their disease. Bendamustine in combination with anti-CD20 monoclonal antibody therapy has been shown to be highly active and well tolerated. Ofatumumab is a fully humanized (IgG1) monoclonal antibody that binds specifically to a unique epitope on CD20, and is active in indolent B-cell non-Hodgkin's lymphoma (NHL). The efficacy and safety of both agents in combination has not been described. The purpose of this phase 2, multicenter study was to determine the efficacy and safety of bendamustine in combination with ofatumumab in first-line treatment of patients with indolent B-cell NHL. Methods: Untreated patients with follicular lymphoma (FL) (grade 1–3a), marginal zone lymphoma (MZL), or lymphoplasmacytic lymphoma (LPL) who met predefined need-for-treatment criteria and had adequate hematologic function, ≥ stage 2 disease, and measurable disease (〉 1.5cm) were eligible for study entry. Patients were scheduled to receive 6–8 28 day cycles of bendamustine (90 mg/m2 on days 1 and 2) and ofatumumab (300 mg on day 1 of cycle 1, 1000 mg on day 8 of cycle 1, and 1000 mg on day 1 of subsequent cycles). The primary objective of the study was to determine the overall response rate (ORR) based on 2007 International Working Group criteria. The secondary objectives were safety and complete response (CR) rate following treatment. Results: Fifty patients were enrolled and 49 received treatment between May and December 2010. Forty-five patients were eligible for efficacy analysis (4 pts withdrew prior to first post-baseline response assessment). Thirty-six patients had FL; 13 had MZL or LPL. Fifty-five percent had bone marrow involvement, and 94% had stage III/IV disease. In general, the combination of bendamustine and ofatumumab was well-tolerated. Forty-one of the 49 patients received at least 6 cycles of bendamustine/ofatumumab (4 received 7–8 cycles; median = 6). Seven patients withdrew from the study due to adverse events. Ongoing safety analysis showed the most commonly observed treatment-emergent adverse events (≥25% patients) were constipation (35%), diarrhea (27%), nausea (61%), fatigue (51%), and infusion related reaction (47%). Nausea and fatigue were more often attributed to bendamustine. Infusion-related reaction was more often attributed to ofatumumab. The most common (≥ 3 patients) grade 3/4 adverse events were neutropenia and fatigue. Serious adverse events (SAEs) occurred in 13 (27%) patients. The most common SAEs were sepsis (3 patients), dehydration (3), febrile neutropenia (2), fever (2), and infusion reaction (2). One patient died following a diagnosis with non-small cell lung cancer, which was deemed unrelated to study treatment. An objective response was attained in 98% (60% CR) of patients, 1 patient (2%) had stable disease. To date, no patients have progressed through 3 months of post-treatment follow-up. Further analysis on the safety of the combination is ongoing. Conclusions: Bendamustine and ofatumumab was well tolerated and active in patients with previously untreated indolent NHL. The ORR of 98% and CR of 60% in the evaluable population compare favorably with previously reported response rates observed in patients with indolent lymphoma. Phase II studies in other histologies are underway and the results of this study support further evaluation of the combination in randomized trials. Acknowledgments: This study was sponsored by Cephalon. Ofatumumab was provided by GlaxoSmithKline. Disclosures: Fowler: Cephalon, Inc.: Research Funding, Scientific advisory board. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Forero:Cephalon, Inc.: Research Funding. Munteanu:Cephalon, Inc.: Employment. Davis:Cephalon, Inc.: Employment. Brown:Cephalon, Inc.: Employment. Czuczman:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 480 Introduction: Vorinostat (VOR), an oral inhibitor of histone deacetylase (HDAC) class I and class II proteins, affects pathways regulating cell proliferation and apoptosis in a diverse array of tumor types. Phase 1/2 trials in multiple myeloma (MM) have indicated clinical activity of vorinostat, as both a single agent and in combination with bortezomib (BTZ) and immunomodulatory drugs (IMiDs). Materials and methods: The present study (MK-0683 PN095) was an open-label, single-arm phase 2b trial of VOR plus BTZ in BTZ-refractory patients (defined as 〈 25% response on therapy, or progression during or 〈 60 days after completion of therapy) and patients considered to be refractory, intolerant, or ineligible for IMiD-based therapy regimens. Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received ≥ 2 prior anti-myeloma regimens, and relapsed or progressed following prior systemic therapy. Patients received 21-day cycles of BTZ (1.3 mg/m2 intravenously [IV]; days 1, 4, 8, and 11) plus oral VOR 400 mg/d on days 1 to 14. If patient had no change as the best response after 4 cycles of treatment or progressive disease after 2 cycles of treatment, oral dexamethasone 20 mg on the day of and day after each dose of BTZ could be added to the treatment regimen. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint was overall response rate (ORR; ≥ partial response). Secondary and exploratory endpoints included clinical benefit response (ORR + minimal response), overall survival (OS), time to progression (TTP), progression-free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group criteria and the European Bone and Marrow Transplantation Group criteria. All efficacy data will be confirmed by an Independent Adjudication Committee. Results: Between January 2009 and October 2010, 143 patients were enrolled from 41 centers in 12 countries across Asia-Pacific, Europe, and North America. Median duration of MM for the entire study population was 4.6 years, including 31% whose disease had progressed on or within 60 days of last therapy and 66% whose disease had achieved 〈 25% response to the regimen immediately preceding study entry. The study population was heavily pretreated, having received a median of 4 prior lines of therapy (range 2–17, ≥ 4 prior regimens: 69%). Prior anti-myeloma agents included 100% BTZ (median 2 prior regimens containing BTZ), 100% IMiDs (thalidomide [85%], lenalidomide [71%], or pomalidomide [4%]), and 74% stem cell transplant. As of July 2011, 142 of the enrolled patients received study medication, with a median exposure of 4 cycles (mean 6.2 cycles; range 1–26 cycles). The most common treatment-emergent adverse events regardless of relationship to study drug were predominantly hematologic and gastrointestinal disorders. Of interest, peripheral neuropathy was infrequent and grade ≥ 3 PN occurred in 2 patients (1.6%). The final efficacy evaluation of the IAC will occur in September 2011. Conclusions: Final data for all primary and secondary endpoints, including response assessment and time-to-event data for PFS/TTP, OS, and duration of response will be available at the annual ASH meeting. Disclosures: Siegel: Millenium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Dimopoulos:Celgene, Ortho-Biotech: Consultancy, Honoraria. Yoon:NK Bio: Consultancy; Celgene: Consultancy. Kaufman:Merck; Celgene: Research Funding; Millenium; Onxy; Novartis; Keryx: Consultancy. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Leleu:Janssen Cilag, Celgene, Novartis-Amgen, Leo Pharma, Chugai, Roche: Honoraria, Research Funding. Cavo:Millennium: 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, Speakers Bureau. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Graef:Merck: Employment. Houp:Merck: Employment. Sun:Merck & Co., Inc.: Employment. Howe:Merck: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: .

Description: Background Mutations in NOTCH1 (NOTCH1mut ) have been found in CLL with an incidence of about 10% and have been associated with unmutated IGHV, +12q, and poor outcome in previous studies. In the CLL8 trial (1st line FCR vs. FC), NOTCH1mut was identified as an independent unfavorable prognostic factor for progression free survival (PFS) and a predictive factor for reduced benefit from the addition of Rituximab to FC. Methods We assessed the incidence and impact of NOTCH1mut in the OMB110911 trial (1st line Chl vs. O-Chl) in patients considered inappropriate for fludarabine-based therapy. Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative for the full trial population. The mutation hotspot fragment (chr9:139,390,619-139,390,840) of exon 34 of NOTCH1 was analyzed by Sanger sequencing and by NGS using Illumina MiSeq. NGS was used to evaluate the sensitivity of Sanger sequencing to detect c.7541_7542delCT mutation and to determine the exact variant frequency of the mutant allele. Results The c.7541_7542delCT mutation was found by Sanger sequencing and by NGS in 45 (12.0%) of 376 patients (24 in O-Chl and 21 in Chl). When comparing baseline characteristics, there were significant associations of NOTCH1mut with +12q (p=0.01), absence of 13q- (p=0.006) and unmutated IGHV (p=0.009), but not with gender, age , Binet stage, ECOG, CIRS, B symptoms, WBC, ß2-MG, 6q-, 11q-, and 17p-. Regarding response to treatment, there was no association between NOTCH1mut and ORR or CR, neither in the whole group nor when analyzing the treatment arms separately. At a median follow-up of 29.0 months for PFS there were 249 events, at the medium follow-up of 31.7 months for OS 63 events in the 376 patient cohort. Similar to the full trial cohort, also in our cohort, O-Chl as compared to Chl resulted into significant improved PFS (median 22.4 vs. 13.1 months, HR=0.54, p20%. For this subgroup, the effect of NOTCH1mut on PFS in the O-Chl treatment arm was even more pronounced (O-Chl: HR 2.459, p