Citations

Calcification and ossification are uncommon in schwannomas; however, when present these findings may cause diagnostic confusion with other mesenchymal tumors which more frequently harbor these features. We sought to better characterize the type and rate of calcification and ossification in schwannomas. Cases of schwannoma diagnosed at our institution from 2005 to 2019 were reviewed to determine the type and amount of calcification and ossification present. Of 2116 total cases of schwannoma reported during the study period, 38 cases harbored calcification or ossification per the pathology report. Thirty‐two of the 38 cases had slides available for review, of which 27 (84.3%) showed calcification, nine showed ossification (28.1%), and four (12.5%) cases demonstrated both. Foci of ossification typically occurred adjacent to large vessels. Of the 27 cases showing calcification, coarse dystrophic calcification was seen in 22 cases, psammomatous calcification in nine cases, and combined dystrophic and psammomatous calcification was seen in four cases. Cases with psammomatous calcification predominantly occurred in spinal roots and cerebellopontine angle of a younger age group with almost equal gender distribution. All four cases tested for protein kinase cyclic adenosine monophosphate‐dependent type I regulatory subunit alpha immunohistochemical stain demonstrated retained expression. We confirm that calcification and ossification are rare findings in schwannoma. Awareness that these features may be present in these tumors will prevent misdiagnosis and ensure appropriate clinical management.

Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic muscle wasting and weakness, also known as sarcopenia, can compound deficits associated with cancer cachexia in older adults and makes studying this condition more complex in this population. Multiple measurement options are available to assess the older patient with cancer and cachexia and/or sarcopenia including anthropometric measures, imaging modalities such as Dual X-ray absorptiometry (DEXA) and Computed Tomography (CT), muscular strength and physical performance testing, and patient-reported outcomes (PROs). A geriatric assessment (GA) is a useful tool when studying the older patient with cachexia given its comprehensive ability to capture aging-sensitive PROs. Interventions focused on nutrition and increasing physical activity may improve outcomes in older adults with cachexia. Efforts to develop targeted pharmacologic therapies with cachexia have not been successful thus far. Formal treatment guidelines, an updated consensus definition for cancer cachexia and the development of a widely adapted assessment tool, much like the GA utilized in geriatric oncology, could help advance the field of cancer cachexia over the next decade.

Key Points A mixed methods study of surveys, interviews, and focus groups raises concerns about the state of the adult hematology workforce. Hematology/oncology fellowship program directors, fellows, and practicing clinicians offer different strategies to address these problems.

Members of the Translational Breast Cancer Research Consortium conducted an expert‐driven literature review to identify a list of domains and to evaluate potential measures of these domains for inclusion in a list of preferred measures. Measures were included if they were easily available, free of charge, and had acceptable psychometrics based on published peer‐reviewed analyses. A total of 22 domains and 52 measures were identified during the selection process. Taken together, these measures form a reliable and validated list of measurement tools that are easily available and used in multiple cancer trials to assess patient‐reported outcomes in relevant patients.

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Background: Outcomes of patients with AML have remained poor despite the availability of cytotoxic chemotherapy, hypomethylating agents (HMAs) and targeted therapies. HMAs, such as azacitidine, in combination with Bcl-2 inhibitors like venetoclax have demonstrated response rates of 67% in newly diagnosed AML and 21% in relapsed/refractory (RR) AML (DiNardo et al. Blood 2019 and Am J Hematol 2018). While the combination of azacitidine and venetoclax is efficacious in AML, preclinical studies indicate potential mechanisms of drug resistance including overexpression of MCL-1, an anti-apoptotic protein (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that has demonstrated activity against AML (Swords RT et al. Blood. 2010). Pevonedistat induces NOXA, a pro-apoptotic protein leading to neutralization of MCL-1 inducing apoptosis (Wang et al. Biochem Biophys Res Commun. 2017). Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated synergistic effect (Knoor KL et al. Cell Death Differ. 2015). Hence, we hypothesize that the addition of pevonedistat to the combination of azacitidine and venetoclax would enhance the therapeutic efficacy by overcoming resistance to apoptosis. Study design and methods: This is an investigator-initiated phase Ib study evaluating the safety of pevonedistat, azacitidine and venetoclax. Patients aged 18 years or above with morphologically documented AML (de novo, secondary or therapy-related), ECOG performance status 0-2 and adequate organ function are eligible for the study. Major exclusion criteria are patients with isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, active acute GVHD, veno-occlusive disease, acute promyelocytic leukemia, liver cirrhosis and severe liver impairment. While the dose escalation phase is available only for patients with RR-AML, the dose expansion phase can also include newly diagnosed AML patients who are ineligible for intensive induction. The study is planned to be conducted at Medical College of Wisconsin, Mayo Clinic and University of Pennsylvania. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. The study will follow 3+3 design with dose escalation (Arms A and B), de-escalation in case of dose limiting toxicity (DLT) (arms Z and Y) and dose expansion phase (figure 1). Patients will be entered sequentially to each dose level, starting with dose level 0. The DLT observation period for dose-escalation will be 1 cycle. The maximal tolerated dose (MTD) will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experiences a DLT. A minimum of 9 and a maximum of 24 patients will be needed for the dose escalation phase and 6 patients for the dose expansion phase. Response rate, duration of response and exploratory endpoints will be analyzed using descriptive statistics. Kaplan-Meier method will be used to determine survival. Disclosures Guru Murthy: Cardinal Health Inc.: Honoraria. Michaelis:Incyte: Consultancy, Research Funding; Pfizer: Equity Ownership, Research Funding; Novartis: Consultancy; Macrogeneics: Research Funding; Millenium: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Research Funding; ASTEX: Research Funding; Bioline: Research Funding. Abedin:Jazz Pharmaceuticals: Honoraria; Agios: Honoraria; Helsinn Healthcare: Research Funding; Pfizer Inc: Research Funding; Actinium Pharmaceuticals: Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Helsinn: Consultancy.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received <4 cycles (p <0.0001) and median OS of 20.4 m compared to 15.2 m respectively (HR 0.78, 95% CI 0.45-1.3, p 0.36). Those who received at least 6 cycles (44 patients) had an OR rate of 82% compared to 26% in 43 patients who received < 6 cycles (p<0.0001), and median OS of 23.8 m vs 13.6 m respectively (HR 0.51, 95% CI 0.3-0.85, p 0.009). Results were consistent when r/r MDS/CMML and HMA-naïve MDS/CMML were analyzed separately. Landmark OS analysis also favored those who received guadecitabine for at least 4 or 6 cycles compared to those who received <4 and < 6 cycles even in the absence of objective response (OS HR of 0.82 and 0.42 respectively) but the sample size was small to show statistical significance (p 0.58 and 0.10 respectively) Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit. Disclosures Savona: Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Griffiths:Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Persimmune: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Podoltsev:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Samus Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Other: Grant funding, Research Funding; Arog Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AI Therapeutics: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

Purpose: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that presents with a wide spectrum of clinical diseases, ranging from single-organ lesions to systemic disease. Although previously thought of as an immune disorder, LCH was reclassified as an inflammatory myeloid neoplasm in the 2016 Histocyte Society classification after discovery of BRAF V600E or MAP2K1 gain-of-function mutations and evidence of clonality in most LCH patients. In this revised classification, LCH was divided into single-system LCH, pulmonary LCH, or multisystem LCH. However, there is a lack of data on clinical features and outcomes in the subgroup of "unifocal" non-pulmonary LCH in adults. In this study, we sought to address the gaps in knowledge for unifocal adult LCH utilizing our institution's experience over 20 years. Methods: We retrospectively reviewed the medical records of 189 adult patients (defined as >18 years old at diagnosis) with histopathologically confirmed LCH who were seen at our tertiary referral center between 1997 and 2018. Of these, 44 met criteria for unifocal LCH at diagnosis after careful exclusion of other sites of disease involvement. Results: We included 44 adult patients with unifocal LCH at diagnosis, with median age 42 years (range 19 to 88) and 55% males. 84% were Caucasians and 50% were smokers. Most commonly involved disease sites included bone (43%), skin (25%), pituitary (14%), and gastrointestinal (11%), with common presenting symptoms of head pain/swelling (25%), skin rash (20%), abdominal pain/diarrhea (11%), and diabetes insipidus (9%). Resection/excision was the most common first line therapy in 24 patients (63%); none had local recurrence and 3 patients developed recurrence at a new site. Radiation was the second most common therapy in 6 patients, with an overall response rate of 83%; none had local recurrence and 1 patient had recurrence at a new site. Other less common first-line treatments included resection followed by radiation (2), topical immunosuppression (2), dexamethasone (1), cladribine (1), smoking cessation (1), and observation (1) (Table 1). Cladribine used as first-line therapy for pituitary LCH resulted in progressive disease, but cladribine used as second-line therapy in 2 cases (including one who had progressed to multisystem disease) resulted in partial remission with no further recurrence in both cases. Patients were followed for a median of 3.8 years (range 0.1 to 18.8), with 5 patients lost to follow-up. By time of last follow-up, 11 (28%) had developed recurrence: 1 had local recurrence, 5 developed disease at a new site within the same system (skin or bone), and 5 developed multisystem disease (Figure 1). Median time to recurrence was 2 years (range 0.2 to 6.6). 2 out of 5 patients tested for BRAF had a V600E mutation, both of whom had isolated unifocal bone disease and remained in complete remission following resection at time of last follow-up. Median overall survival (OS) from time of diagnosis was not reached and overall 5-year OS was 94%. 3 patients died, only 1 of progressive LCH. Conclusion: In our study, most patients with unifocal adult LCH achieved a complete remission with surgical resection or local radiation. None of the patients treated with resection or radiation developed local recurrence, but around 1 in 5 developed distant recurrence within 5 years. However, the overall prognosis was very good, and none of the patients in the cohort progressed to "high-risk" organ (liver, spleen, or bone marrow) involvement or pulmonary involvement. Further studies are warranted to assess the role of MAPK-ERK mutations in the prognosis of unifocal LCH. Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding. Vassallo:Sun Pharmaceuticals: Research Funding; Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 206 AML patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response (CR, CRi, or CRp based on 2003 IWG criteria, grouped together as composite CR or CRc), and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 206 AML patients: 103 patients (50%) for each of Treatment Naïve (TN) unfit for intensive chemotherapy, and relapsed/refractory (r/r) AML. Median age was 68.5y (range 22-92y), ECOG PS ≥2 in 26%, poor risk cytogenetics in 41%, secondary AML in 26%, and median baseline BM blasts % was 40% in the total AML population. 108 patients (52.4%), and 155 patients (75%) received <4 and <6 cycles respectively. The primary reasons for treatment discontinuation before 4 and 6 cycles respectively (% from the total population of 206 patients) were early progression (20.4, and 30.6%), and early death (12.6%, and 17%). However, 9.7% and 14% discontinued treatment before 4 or 6 cycles respectively as a result other less objective reasons such as patient decision, investigator decision, or adverse events which might have been manageable without treatment discontinuation. The landmark analysis population included 161 patients for 4-cycle analysis, and 133 for the 6-cycle analysis. In those patients, there were no major differences in baseline characteristics between those who received at least 4 or 6 cycles and those who did not. In the landmark analysis comparing those who received at least 4 cycles (97 patients) and those who did not (64 patients), CRc rate was 62% vs 25% (p < 0.0001) and median OS was 13.7 m vs 6.1 respectively (HR 0.53, 95% CI 0.37-0.75, p 0.0003). In the landmark analysis comparing those who received at least 6 cycles (51 patients) and those who did not (82 patients) the CRc rate was 82.4% vs 35.4% (p < 0.0001), and median OS of 19.9 m vs 8.8 m respectively (HR 0.42, 95% CI 0.27-0.64, p <0.0001). The results were consistent when TN and r/r AML patients were analyzed separately. More interestingly the landmark OS benefit in patients who received at least 4 or 6 cycles was also evident in patients who did not have an objective CRc. Patients with no CRc who received at least 4 cycles had a median OS of 8 m vs 5.4 m in those who did not (HR 0.63, 95% CI 0.40-0.98,p 0.04). Patients with no CRc who received at least 6 cycles had a median OS of 12.9 vs 8 m in those who did not (HR 0.40, 95% CI 0.17-0.94, p 0.03). Summary/Conclusions: In a prospective phase 2 study of 206 TN and r/r AML patients treated with the HMA guadecitabine, patients who were alive at or beyond 3 and 5 months who continued treatment for at least 4 or 6 cycles respectively achieved a highly significant response and survival benefit compared to those who discontinued treatment before cycle 4 or 6. The survival benefit was evident even in patients who did not have an objective response. Reasons for treatment discontinuation should be weighed carefully before stopping HMA treatment with guadecitabine before 4 or 6 cycles in AML patients to maximize response and survival benefit. Failure to achieve an objective response after 4 cycles should not be a reason for treatment discontinuation as long as patient can still benefit. Disclosures Yee: MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: 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; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Griffiths:Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; New Link Genetics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Genentech, Inc.: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Daver:Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Glycomimetics: Research Funding; NOHLA: Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding.