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PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

BACKGROUND: MF is characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib is an oral JAK2 inhibitor approved in the United States for treatment (Tx) of adult patients (pts) with intermediate (INT)-2 or high-risk MF. The randomized, placebo (PBO)-controlled, phase III JAKARTA trial evaluated clinical outcomes with fedratinib in pts with JAK-inhibitor-naïve MF. Initial findings from the JAKARTA study have been reported (Pardanani, JAMA Oncol, 2015). JAKARTA data were recently reanalyzed in preparation for regulatory review. OBJECTIVE: Evaluate the clinical efficacy and safety with fedratinib 400 mg/day in updated analyses of the JAKARTA study. METHODS: JAKARTA was an international, randomized, double-blind, PBO-controlled study that enrolled pts aged ≥ 18 years with INT-2 or high-risk primary, post-PV, or post-ET MF. Pts were randomly assigned 1:1:1 to fedratinib 400 mg, fedratinib 500 mg, or PBO, administered orally once-daily for ≥ 6 consecutive 4-week cycles ("randomized Tx period"). After completing 6 Tx cycles (or earlier in the case of disease progression), pts randomized to PBO could crossover to fedratinib. The primary endpoint was the spleen volume response rate (SVRR), the proportion of pts who achieved a ≥ 35% spleen volume reduction from baseline (BL) confirmed by MRI/CT at end of cycle 6 (EOC6), confirmed by follow-up scan 4 weeks later. Secondary endpoints included SVRR without 4-week confirmation, durability of spleen response, and symptom response rate (proportion of pts with a ≥ 50% reduction from BL in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) at EOC6. An exploratory analysis evaluated proportions of pts with ≥ 50% reductions from BL at EOC6 in individual MFSAF symptom scores: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. These analyses are limited to pts randomized to fedratinib 400 mg (the approved starting dose of fedratinib) or to PBO. Efficacy analyses were performed for the intention-to-treat (ITT) population and safety was assessed in all pts who received ≥ 1 dose of study drug. RESULTS: 96 pts were randomized to fedratinib 400 mg and 96 pts to PBO. In the fedratinib and PBO arms, median ages at BL were 63 (range 39-86) and 66 (27-85) years, respectively, 65% and 60% of pts had primary MF, 76% and 73% had constitutional symptoms, median spleen volumes were 2652 (316-6430) and 2660 (662-7911) mL, and median TSS were 15.3 (0-57) and 12.4 (0-53). Median durations of exposure were 15.5 months in the fedratinib 400 mg arm and 6 months in the PBO arm. With a confirmation scan 4 weeks after EOC6, SVRR was significantly higher in the fedratinib arm (37% [95%CI 27%, 46%]) vs. the PBO arm (1% [0%, 3%]) (P < 0.0001). Without the confirmation scan, SVRR at EOC6 was 47% (95%CI 37%, 57%) in the fedratinib 400 mg arm and 1% (0%, 3%) in the PBO arm (P < 0.0001; Figure). Estimated median duration of spleen response with fedratinib was 18.2 months. Symptom response rate at EOC6 for evaluable pts (ie, with TSS data available at BL and EOC6) was 40% (36/89) with fedratinib and 9% (7/81) with PBO (P < 0.0001). Fedratinib was associated with higher response rates vs. PBO in all 6 MFSAF symptoms: abdominal discomfort (41% vs. 15%, respectively), night sweats (58% vs. 22%), bone or muscle pain (33% vs. 14%), early satiety (51% vs. 18%), pruritus (39% vs. 20%), and pain under the ribs on the left side (42% vs. 24%). The most common Tx-emergent adverse events (TEAEs) during the randomized Tx period were grade 1-2 gastrointestinal events (Table). New or worsening grade 3 anemia and grade ≥ 3 thrombocytopenia laboratory abnormalities were reported in 34% and 12% of fedratinib-treated pts, most (75%) occurring within 3-4 months of Tx initiation. Compared with PBO, fedratinib-treated pts more frequently experienced increased serum creatinine, amylase, and lipase; these were mainly grade 1-2 in severity. TEAEs led to Tx discontinuation for 14% of fedratinib pts and 8% of PBO pts. CONCLUSIONS: Fedratinib 400 mg/day significantly reduced splenomegaly and symptom burden in pts with JAK-inhibitor-naïve MF. Relatively few pts discontinued fedratinib therapy due to TEAEs, suggesting these events are manageable. These data corroborate results initially reported for the JAKARTA trial, and further support the efficacy and safety of fedratinib in this pt population. Disclosures Masszi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Drummond:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jourdan:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Ribrag:AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding; argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; gustave roussy comprehensive cancer center: Current Employment. Rambaldi:Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria; MSD: Honoraria. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Zhang:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Harrison:Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau.

AbstractBackground and ObjectivesDescribe patient‐reported functional outcomes for hand and foot sarcoma survivors treated with limb‐sparing surgery and radiation therapy (LSS + RT).MethodsFifty‐four patients with hand/wrist and foot/ankle sarcomas treated with LSS + RT from 1991 to 2015 were identified. Survivors ≥18 years old without subsequent amputation completed self‐assessed functional surveys: Toronto upper extremity salvage score (TESS‐UE) and Michigan hand outcomes (MHQ) surveys for hand; TESS lower extremity (TESS‐LE) and Foot and Ankle Outcomes (FAOS) surveys for foot. Scoring scales: 0–100, MHQ and TESS; ‐26 to 56 and 25‐59, FAOS core and shoe comfort, respectively. Higher scores denote superior function.ResultsFive‐year local tumor control was 88%. Fourteen of 24 hand (58%) and 14/18 foot (78%) survivors completed surveys. Mean TESS‐UE and MHQ scores were 89.4 and 72.8, respectively. Mean TESS‐LE, core FAOS, and shoe comfort scores were 92.4, 46.19, and 53.1, respectively. No factors correlated with outcomes. TESS‐UE and MHQ scores strongly correlated (r = .87). TESS‐LE and FAOS scores were associated with a poor correlation (r = .02 and r = .69).ConclusionsThe largest patient‐reported functional outcomes analysis for hand and foot sarcoma survivors treated with LSS + RT demonstrates excellent local tumor control and acceptable functional outcomes. Further exploration of optimal functional assessment tools is needed given the potential scope differences.

AbstractIntroductionThe proximal humerus is a common site of primary and metastatic disease in the upper extremity. Historically, the goal of a hemiarthroplasty reconstruction was to provide a stable platform for hand and elbow function, with limited shoulder function. Techniques utilizing a reverse endoprosthesis (endoprosthetic replacement [EPR]) and allograft‐prosthetic composite (APC) have been developed; however, there is a paucity of comparative studies.MethodsA total of 83 (42 females, 41 males) patients undergoing an intraarticular resection of the humerus were reviewed. Reconstructions included 30 reverse and 53 hemiarthroplasty; including hemiarthroplasty EPR (n = 36) and APC (n = 17), and reverse EPR (n = 20) and APC (n = 10).ResultsReverse reconstructions had improved forward elevation (85° vs. 44°, p < .001) and external rotation (30° vs. 21°; p < .001) versus a hemiarthroplasty. Reverse reconstructions had improved American Shoulder and Elbow Surgeons scores (65 vs. 57; p = .01) and Musculoskeletal Tumor Society 93 scores (72 vs. 63; p < .001) versus hemiarthroplasty. Subluxation of the reconstruction was a common (n = 23, 27%), only occurring in hemiarthroplasty patients (EPR [n = 13, 36%] and APC [n = 10, 59%]).ConclusionThe current series highlights the improved functional outcome in patients undergoing reconstruction with a reverse arthroplasty compared to the traditional hemiarthroplasty. Currently reverse shoulder arthroplasty (APC or EPR) is our preferred methods of reconstruction in this patient population.

AbstractBackgroundNonuterine leiomyosarcomas (LMS) are common extremity soft‐tissue sarcomas. Deep LMS are at an increased risk for recurrence; however, few studies have focused on superficial LMS.MethodsWe reviewed the clinicopathological features of 82 patients with a primary superficial LMS. The mean age and follow‐up were 57 ± 15 and 7 ± 5 years. Depth was classified as dermal (based in the skin; n = 35, 43%) and subcutaneous (based below the dermis, above the fascia; n = 47, 57%) on the final resection specimen. Dermal cases were treated with negative margin resection, while subcutaneous tumors were evaluated by a multidisciplinary team for consideration of possible adjuvant therapy.ResultsThe 10‐year disease‐specific survival (DSS) for superficial LMS was 90% with no difference (p = .18) in the 10‐year DSS between patients with dermal (100%) and subcutaneous (86%) LMS. All disease recurrences occurred in subcutaneous LMS (17% vs. 0%, p = .02) and subcutaneous tumors had a worse10‐year metastatic free survival (81% vs. 100%, p = .03).ConclusionsThe results of this study suggest that dermal LMS can be managed with a negative margin resection alone. Although the prognosis for patients with subcutaneous LMS is quite favorable, there is some risk for local and distant recurrence, and such patients will benefit from multidisciplinary care.

AbstractCancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Background: Sacral tumor resections require a multidisciplinary approach to achieve a cure and a functional outcome. Currently, there is no accepted classification system that provides a means to communicate among the multidisciplinary teams in terms of approach, osseous resection, reconstruction, and acceptable functional outcome. The purpose of this study was to report the outcome of sacral tumor resection based on our classification system. Methods: In this study, 196 patients (71 female and 125 male) undergoing an oncologic en bloc sacrectomy were reviewed. The mean age (and standard deviation) was 49 ± 16 years, and the mean body mass index was 27.2 ± 6.4 kg/m 2 . The resections included 130 sarcomas (66%). The mean follow-up was 7 ± 5 years. Results: Resections included total sacrectomy (Type 1A: 20 patients [10%]) requiring reconstruction, subtotal sacrectomy (Type 1B: 5 patients [3%]) requiring reconstruction, subtotal sacrectomy (Type 1C: 104 patients [53%]) not requiring reconstruction, hemisacrectomy (Type 2: 29 patients [15%]), external hemipelvectomy and hemisacrectomy (Type 3: 32 patients [16%]), total sacrectomy and external hemipelvectomy (Type 4: 5 patients [3%]), and hemicorporectomy (Type 5: 1 patient [1%]). The disease-specific survival was 66% at 5 years and 52% at 10 years. Based on the classification, the 5-year disease-specific survival was 34% for Type 1A, 100% for Type 1B, 71% for Type 1C, 65% for Type 2, 57% for Type 3, 100% for Type 4, and 100% for Type 5 (p < 0.001). Tumor recurrence occurred in 67 patients, including isolated local recurrence (14 patients), isolated metastatic disease (31 patients), and combined local and metastatic disease (22 patients). At 5 years, the local recurrence-free survival was 77% and the metastasis-free survival was 68%. Complications occurred in 153 patients (78%), most commonly wound complications (95 patients [48%]). Following the procedure, 154 patients (79%) were ambulatory, and the mean Musculoskeletal Tumor Society (MSTS93) score was 60% ± 23%. Conclusions: Although resections of sacral malignancies are associated with complications, they can be curative in a majority of patients, with a majority of patients ambulatory with an acceptable functional outcome considering the extent of the resection. At our institution, this classification allows for communication between surgical teams and implies a surgical approach, staging, reconstruction, and potential functional outcomes. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.