ALBERT

Beschreibung: Initial therapy with novel combinations including bortezomib, lenalidomide or thalidomide show a superior overall response rate (80–90% range) and high CR/nCR rate (20–30% range). Although a number of studies demonstrated that achieving CR/nCR after ASCT prolongs survival, it is not clear whether improved quality of response after initial cytoreduction impacts on overall outcome of treatment of myeloma. Recently, we completed accrual to a phase II trial of initial therapy with VDD for patients with active myeloma. The primary objective was to determine the rate of CR/nCR in response to VDD. Secondary objectives included overall response, safety, and feasibility of collection of peripheral blood stem cells. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg per on days 1, 2, 4, 5, 8, 9, 11, 12 (same total dose of 160 mg dexamethasone per cycle). The study opened in July 2005 and enrolled 30 patients. Presently, 28 of 30 patients are evaluable for response of which 18 completed 6 cycles. The characteristics of the evaluable patients included: median age 61 (range 39–83), stage III disease in 26 patients (stage II in 2), chromosome 13 deletion in 12, t(4;14) in 2, median beta2-microglobulin 4.4. CR/nCR was observed in 9 patients (32%), very good partial response (VGPR) in 6 (21%), partial response (PR) in 10 (36%) and minor response (MR) in 1 (4%) for an overall response (≥ PR) of 89%, and ≥ VGPR of 53%. The change of dexamethasone schedule did not appear to affect response rates. There was no grade 4 hematological toxicity and grade 3 was limited, with thrombocytopenia in 2 patients and neutropenia in 1. There were no episodes of neutropenic fevers. Grade 3–4 non-hematological toxicities included 4 patients with fatigue, 3 patients with pneumonia, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with partial small bowel obstruction, and 1 with diarrhea secondary to Cryptosporidium sp. Fatigue was significantly reduced after the change of dexamethasone schedule. Peripheral neuropathy was limited to grade 1–2 and observed in 9 patients. All patients are alive. To date, 18/18 patients had successful harvesting of peripheral blood stem cells (median 8.2 x 106 CD34+ cell/kg, range 3.2 to 41.2) and 17 completed at least a single autologous stem cell transplant using melphalan 200 mg/m2 as the preparative regimen (12 single, 5 tandem). Responses were further improved in 11 of these 17 patients bringing overall response rate (≥ PR) to 96%, with 79% of patients achieving ≥ VGPR and 54% achieving CR/nCR. These results indicate that initial treatment with VDD is very effective and well tolerated and does not adversely affect stem cell harvest. Moreover, it appears to improve probability of achieving CR/nCR and VGPR after transplant compared to results from randomized studies with single or tandem transplantation. Considering that achieving CR/nCR or VGPR after ASCT has been associated with improved survival, VDD appears promising as an initial treatment strategy to improve survival.

Beschreibung: This phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd—carfilzomib (20, 27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly dexamethasone (40/20 mg cycles 1-4/5+)—in 28-day cycles. After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum planned dose level (carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. This study is registered at http://www.clinicaltrials.gov as NCT01029054.

Beschreibung: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder with protean clinical manifestations caused by the overproduction of T-cell derived cytokines. Cytokine-dependent activation of the Janus family kinases (JAK) is a hallmark of the final common pathway in HLH pathogenesis. Therefore, we initiated a single center, open-label, investigator-initiated trial to assess the efficacy and safety of ruxolitinib in adult patients with secondary HLH. Methods: Adult patients (≥18 years) who fulfilled 5 of 8 diagnostic criteria were eligible. Patients with CNS involvement or an active malignancy were ineligible. Patients who had received any prior systemic therapy (excluding corticosteroids) within 7 days of treatment were ineligible. Patients with normal renal function received oral ruxolitinib 15 mg twice daily on a continuous, 28-day cycle. Dose reductions for renal insufficiency and toxicity are permitted. Treatment was continued indefinitely until disease progression, unacceptable toxicity, or any other conditions for treatment discontinuation were met. The first patient was enrolled in February, 2016 and enrollment is ongoing. The primary endpoint is overall survival at 2 months. Secondary endpoints include the response rate, duration of response, progression-free and overall survival. Adverse events were graded and attributed in accordance with the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program. Disease parameters evaluable for response included all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for HLH. A complete response (CR) required normalization of all signs and laboratory abnormalities. At least 25% improvement in two or more signs/laboratory abnormalities was required for a partial response (PR). At least a 50% worsening in two or more signs/laboratory abnormalities was considered progressive disease (PD), while failure to fulfill any of these criteria was considered stable disease (SD). Results: A total of 4 patient have been enrolled, all of whom fulfilled at least 5 of 8 diagnostic criteria for HLH. Hemophagocytosis, a pathologic hallmark of HLH, was observed in every patient. At the time of treatment initiation, all patients were anemic [median hemoglobin 7.1 g/dL (range: 6.2-7.5 g/dL)] and thrombocytopenic [median platelet count 47 K/uL (range: 14-107 K/uL)]. Three patients were neutropenic [median ANC 0.95 K/uL (range: 0-1.9 K/uL)]. HLH was secondary to an autoimmune disorder (n=3), infection (n=1), and a homozygous mutation in the STXBP2 gene, recently identified as a causative defect in primary HLH, was observed in one patient. Cytopenias significantly improved within the first week of treatment in all patients. On day +7, the mean increase in hemoglobin was 1.88 g/dL (0.2-3 g/dL), in ANC was 1.53 K/uL (range 0.1-5.3 K/uL) and platelet count was 74 K/uL (range 17-116 K/uL). Neutropenia resolved by day +40 and thrombocytopenia resolved by day +47 in all patients. Three of four patients became transfusion independent within 2 days of treatment initiation. Three of four patients received corticosteroids prior to and after initiation of ruxolitinib. The mean corticosteroid (prednisone equivalent) dose prior to treatment initiation was 225 mg/day (range: 60-391 mg/day) and was 38 mg/day (range: 0-75 mg/day) on day +30. Within 47 days of treatment initiation, corticosteroids were discontinued in 2 patients, and were discontinued in all patients by day +54. Significant improvements in ferritin and sIL-2R were also observed with a median 92.6% decrease in ferritin by day +30 (range 86.4-92.6%) and 86% median decrease in sIL-2R by day +30 (range 66.6-92.7%). All patients achieved at least a PR, and 2 patients remain on treatment (〉2 months, 〉8 months). Two patients discontinued treatment, one for progressive disease (due to recurrent symptoms), and another for drug intolerance (neuropathic foot pain). No severe adverse events have been observed. In addition to the patients enrolled in this study, two additional patients who met eligibility criteria were similarly treated (off study) at another institution. Both of these patients achieved at least a PR and remain on treatment (〉8 months, 〉14 months). Conclusions: Ruxolitinib led to rapid and durable responses and was well tolerated in adult patients with secondary HLH. Disclosures Devata: Affimed: Research Funding. Phillips:Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Sood:Bayer: Research Funding. Wilcox:Incyte, Corp: Research Funding.

Beschreibung: Understanding hematologic cell types, their characteristics, and how they function physiologically and pathologically can be challenging to master, especially for first- or second-year medical students. The current mainstays of undergraduate medical education include lectures, PowerPoint, and supplemental textbook readings. Many learners retain information better when they feel connected to the content. Accordingly, we developed a hematology personality quiz as an innovative, fun, and memorable learning tool. Given that our intention was to focus on foundational hematology, we included thirteen common hematologic cell types as "results" for the quiz. These included erythrocyte, reticulocyte, platelet, neutrophil, eosinophil, basophil, mast cell, monocyte, natural killer cell, CD8+ T-cell, CD4+ T-cell, mature B-lymphocyte, and plasma cell. We generated personality traits that were complementary to each cell's form and function. Platelets, for example, are very sticky cells that rely on adhesion, activation, and aggregation to achieve primary hemostasis. We translated this function into a personality type that is outgoing/communicative, touchy-feely, and always trying to connect with others, noting that platelet personalities may get "stuck" on what others think. Erythrocytes, which deliver oxygen to tissues as they squeeze into and out of vessels, were matched with energetic and flexible personality types. Working backwards from the 13 cells/personality types, we generated 20 quiz questions whose results correlated with the cells' scientific properties and personality traits. Questions included "How long would you last in a zombie apocalypse?" as well as asking quiz takers whether they rely on "gut-feelings" or are more data driven when making decisions. The former corresponded to the average life span of the cell, the latter to the innate vs adaptive immune system. The number of questions was later reduced to 13 to eliminate redundancy. Our content was then integrated on a commercially available online quiz platform, using a frequency algorithm to generate results. Each answer corresponded to specific cell types. After answering the quiz questions, participants are paired with a single personality type that correlates with the majority of their selected responses. In addition to generating a complementary personality type, each result is coupled with information about the cell, an image of the cell under electron microscopy, as well as high yield clinical correlations. Faculty reviewed material for appropriate content. While the quiz generates one result, students have access to all thirteen results after completion. As part of our pilot phase, the quiz and a corresponding survey were sent to all first-year medical students during the hematology learning sequence as well as second-year medical students rotating on the internal medicine clerkship. Using a Likert scale, the participants were asked to rate their enjoyment of the quiz, how well their result matched their personality, whether it facilitated learning, whether they would use the comprehensive guide to study, and if it increased their interest in hematology. Our preliminary findings (tables 1 and 2) indicate that a hematology-based personality quiz can be a fun tool to promote learning. Disclosures Ahmed: Immunovant: Other: Institutional PI on industry initiated trial; Cadence: Other: Institutional PI on industry initiated trial.