Abstract: Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032] ). We now report multicenter results after 〉2 yrs follow-up. Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%] ); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1] , atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle). Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively). Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

Abstract: Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

Abstract: Anti-KEL alloantibodies generated after exposure to paternally derived RBC antigens during pregnancy result in fetal anemia. This is the first animal model of pregnancy associated HDFN, with transfusion and pregnancy resulting in boostable anti-KEL alloantibodies.

Abstract: Background: The indications for treating children with immune thrombocytopenia (ITP) remain controversial. A valid and reliable bleeding assessment tool could assist in objectively quantifying bleeding and influence treatment decisions. Both the ITP Bleeding Score (IBLS) and the ITP-Bleeding Assessment Tool (BAT) have been developed to assess bleeding severity in ITP. The IBLS scores bleeding severity using an 11-item tool with grading from 0 to 2 and the 18-item BAT grades from 0 to 3 or 4. The BAT includes some types of bleeding not represented on the IBLS, such has intramuscular hematomas. To date, no data describe how these two measures compare when measuring bleeding associated with ITP. Objective: To describe and compare bleeding as assessed by both the IBLS and BAT and to correlate bleeding severity with platelet counts in a cohort of children with ITP. Methods: A longitudinal observational cohort of children ages 〉 1 and 〈 18 years with ITP, were enrolled from 2013-2015 in the Pediatric ITP Consortium of North America ICON1 trial. All children were enrolled prior to starting a new second line monotherapy (not IVIG, steroids or anti-D). At enrollment, bleeding was assessed using the IBLS in all children. A subset of children also underwent a BAT assessment. Grades of bleeding were described and compared between tools and agreement in grading was assessed. Severity was correlated with platelet count using Spearman's correlation calculation. Results: 118 children were enrolled from 21 ICON centers. 54% had chronic ITP and the median age was 11.4y (range 1.2-17.8). The mean platelet count was 28 x 109/l (SD 57) and 88% had a baseline platelet count of 〈 30 x 109/l. The burden of skin and oral bleeding was high. Table 1 compares bleeding scores for the 78 patients with both measures. Agreement for grades 0, 1, and 2 between the measures was highest for urinary bleeding (97%), gastrointestinal (95%), subconjunctival (95%), and epistaxis (91%). Agreement between IBLS oral bleeding by historyand BAT gum bleeding was 78% and with BAT oral cavity bleeding was 79%. IBLS oral bleeding by physical examination and BAT gum bleeding was 73% and BAT oral cavity bleeding was 79%. The lowest agreement was seen for skin manifestations. IBLS skin bleeding by history showed only 54% and 62% agreement with the BAT ecchymoses and petechiae items respectively. IBLS skin bleeding by physical examination showed 59% agreement with both the BAT ecchymoses and petechiae items. Grades 3 and 4 scores from the BAT did not provide additional information beyond the IBLS for most sites of bleeding. For sites included on the BAT but not represented on the IBLS, only 1 child had an intramuscular hematoma, 1 suffered an ocular bleed, and none experienced hemarthrosis. Bleeding from minor wounds and bleeding with tooth loss captured additional bleeding symptoms in 9 and 4 children, respectively. There were no episodes of pulmonary or intracranial hemorrhage in the cohort. Table 2 shows the correlation between bleeding severity and platelet count for all items on each measure. Conclusion: The IBLS and BAT were similarly effective at identifying bleeding symptoms, although neither tool showed strong correlation with the platelet count. There were moderate correlations noted between skin bleeding scores and platelet counts for both tools. A major limitation of this comparison is the different definitions of bleeding severity between the two measures. For sites where the items were more detailed, agreement declined (i.e. adding specificity reduced generalizability). While no patients in our cohort exhibited significant grade 3 or 4 bleeding outside of skin findings, we conclude that in the setting of clinical trials, the ability to capture very severe bleeding might be an important distinction that supports using the more complicated BAT, but for clinical practice, a simplified assessment such as the IBLS may suffice. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; BiologicTx: Research Funding. Haley:CSL Behring: Honoraria; Baxalta: Membership on an entity's Board of Directors or advisory committees. Thompson:Celgene: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Mast: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lily: Research Funding; Eli Lily: Research Funding.

Abstract: We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P  〈  .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and β 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon α 2 (rIFNα2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6%v 11.8% [P  〈  .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002] ), and with added HiCy (37.5% v 9.8% [P  〈  .0001]), but not with added rIFNα2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P  〈  .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell rasmutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNα2 to VBMCP, but the numbers were small and improved survival could not be shown.

Abstract: For the past decade, survival (S) for adults with ALL has remained at 30–40% despite achieving high complete remission (CR) rates of 70–90%. CALGB 19802 was designed to test the hypothesis that dose intensification of daunorubicin (D) and cytarabine (Ara-C) could improve disease-free survival (DFS) and that aggressive high dose intravenous (IV), oral (PO) and intrathecal (IT) methotrexate (MTX) could replace cranial irradiation (RT) for central nervous system (CNS) prophylaxis. Treatment consisted of 6 monthly courses of intensive therapy followed by 18 mos of maintenance. In pts & lt; 60 yrs, the D dose during induction and in post-remission therapy was increased in cohorts from 45 mg/m2 on days 1–3 (used in prior CALGB ALL studies) to 60 and then to 80 mg/m2/day X 3. In pts ≥ 60 yrs, D was increased from 30 to 60 mg/m2/day X 3. High-dose Ara-C and CNS prophylaxis with IV, PO, and IT MTX were given in post-remission modules for all pts with a goal of targeting serum methotrexate levels to be 1–2 μM at 30 hours following the IV MTX infusion. No cranial RT was given. From 1/99–1/01, 163 adults with untreated ALL were enrolled. Median age was 40 yrs (range, 16–82) and 33 (20%) were ≥ 60 yrs old; 61% were male. Of 127 centrally reviewed cases, 100 (79%) were precusor B-cell; 19 (15%) precursor T-cell; and 8 (7%) were bilineal or biphenotypic. A large proportion, 46 (46%) of 100 centrally reviewed and evaluable cases, had poor risk cytogenetics as defined in prior CALGB studies: 31 with t(9;22), 7 with t(4;11), 6 with −7 and 2 with +8. With a median follow-up of 4.4 years, the S and, especially DFS, for pts & lt; 60 yrs was improved for those who received D at 80 mg/m2 vs 60 mg/m2. The outcome of all 163 evaluable pts is summarized below: CR (%) 3 yr DFS [95% CI] 3 yr S [95% CI] OVERALL 128 (78.5) 32% [24–41] 36% [29–44]     AGE/ D DOSE      & lt; 60/ 60 mg/m2 36 (92%) 24% [11–39] 35% [20–50]      & lt;60/ 80 mg/m2 72 (79%) 43% [31–54] 46% [35–56]     60+/ 60 mg/m2 20 (61%) 10% [2–27] 8% [2–21] Disease progression during treatment occurred in 43 (26%) and 20 (12%) were removed for alternative therapies including 16 pts who received allo-SCT in CR1. Relapses have occurred in 84 (66%) pts; of these, 10 (8%) were isolated CNS relapses. CNS relapses tended to occur more frequently in pts with hour 30 serum MTX levels of & lt; 1μM during CNS prophylaxis. Age ≥ 60 was significantly associated with worse DFS and S. DFS was longer for precursor T-ALL (median S at 3 years not reached). Interestingly, neither WBC & gt; 30,000/μl nor adverse cytogenetics were significantly associated with worse outcomes. Higher levels of minimal residual disease (MRD) using quantitative clone specific PCR following induction therapy was predictive of inferior DFS (p = .02). In conclusion, omission of CNS irradiation did not result in higher CNS relapse rates than what has been reported in prior CALGB studies; furthermore, adjustment of MTX dosing to achieve targeted serum MTX levels may reduce the risk of CNS relapse. Younger pts who received 80 mg/m2 D had improved DFS and S. However, in contrast to other reports, the differences were not statistically significant. Thus, risk-adapted approaches to eradication of MRD using new agents and/or biologically targeted therapies should be incorporated into front-line treatment of ALL.

Abstract: Abstract 230 The prognosis for patients (pts) with acute myeloid leukemia (AML) who are aged 60 years or older at the time of initial diagnosis is poor. Even for pts achieving a first complete remission (CR1), prospects for long-term survival are poor due to the very high risk of relapse. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with conventional chemotherapy when performed in younger pts with AML in CR1. However, the toxicity of this approach in older pts is prohibitive. A reduced intensity conditioning (RIC) regimen may mitigate the risk of early toxicity and while early results in older AML pts have been encouraging and suggest disease free survival (DFS) rates above 30% at 3 yrs (Farag et al, Biol Blood Marrow Transplant 2011), most data are retrospective and pts have not been treated uniformly. We therefore sought to determine the effectiveness of a uniform RIC regimen given to older pts with AML in CR1 on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The study, activated in 2004, was initially limited to recipients of a matched related donor (MRD) graft but was amended in 2006 to include matched unrelated donor grafts (URD). The primary endpoint of the study was 2-year DFS. We hypothesized that DFS at 2-years would exceed 20% and powered the study to detect a 2-year DFS probability of 35% for URD recipients. We focused the primary analysis on URD recipients since the majority of older pts require an URD graft. Eligible pts were from 60–74 years old inclusive, had AML in CR1 following induction chemotherapy, availability of a 6/6 MRD or 8/8 URD, and absence of significant end-organ damage prior to transplantation. Adverse events (AE) were initially recorded according to NCI-CTCAE v3.0, amended to v4.0 in 10/2010. Accrual was completed in 12/2011. 132 pts were registered at 21 centers and 123 transplanted (MRD (47%); URD (53%). All donor grafts were mobilized and collected following G-CSF (PBSC). The median age of pts was 65 (range 60–74) and 76 pts (62%) were male. At diagnosis, 67% had an intermediate risk karyotype, 20% adverse risk, 〈 1% favorable, and in 11% data were missing. More than 90% achieved CR following standard “7+3” based induction. CR1 was achieved after 1 (59%) or 2 (41%) induction cycles. Consolidation therapy was administered for one (50%) or two (24%) cycles and 17% received no consolidation with data missing in 9%. All but the initial 8 MRD recipients (who received fludarabine and busulfan alone) were conditioned with the same regimen containing fludarabine (30mg/m2/day × 5), busulfan (6.4mg/kg IV total dose), and antithymocyte globulin (ATG; thymoglobulin) (7.5mg/kg total dose). Only one case of primary graft failure was reported. With a median follow-up of 3.3 yrs, the results in the 123 transplanted pts are depicted below: Event Cumulative incidence at 100 days* or 2yrs† 95% CI Acute GVHD 2-4 9.4%* 4.1–15% Acute GVHD 3-4 3.4%* 1.2–6.7% Chronic GVHD 26%† 17–34% Relapse 47%† 37–57% Treatment related mortality (TRM) 14%† 7.2–21% Event Probability at 2 yrs 95% CI DFS 39% 30–50% DFS URD only 38% 26–55% Overall survival (all pts) 46% 36–57% The rates of both acute and chronic GVHD as well as TRM were relatively low. There were 81 grade 3–5 non-hematologic AE recorded, including 7 grade 5 (4 infections, 1 each cardiac, pulmonary, and second malignancy). Relapse was the most common cause of death. In conclusion, the results of this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in CR1 demonstrate the feasibility and effectiveness of RIC allografting using MRD or URD PBSC grafts. DFS appears better following a RIC allograft compared to results achieved historically after conventional therapies, warranting prospective comparison in pts with contemporary cytogenetic and molecular disease characterization. Future research should also focus on preventing disease relapse after RIC allografting in this population. Disclosures: Devine: Sanofi: Honoraria, Research Funding. Off Label Use: Antithymocyte globulin for GVHD prophylaxis is included in the abstract. Vij:Millennium: Speakers Bureau. Shea:Otsuka: Research Funding.

Abstract: Background: Decision-making in selecting second-line therapies for pediatric patients with immune thrombocytopenia (ITP) has not been studied. Using data collected from physicians experienced in treating ITP, we developed a conceptual model of factors that informed treatment choice. This study was a component of ICON1, a prospective, observational, longitudinal cohort study of second line treatments for childhood ITP performed by the Pediatric ITP Consortium of North America (ICON). Methods: Physicians who enrolled patients in ICON1 were asked to rank the top three reasons they chose a specific treatment so as to weight each factor. Those choices that were ranked 1, 2, or 3 were weighted to develop a propensity scored decisional model. In other questions, physicians were asked about all factors that may have influenced decisions to begin a particular second line therapy and this data was then used to examine additional factors that influenced therapy choices and to compare between therapies. Results: ICON1 enrolled 118 patients; 101 had primary ITP and 53 were receiving their first second line therapy. The majority of physicians in the study saw eleven or more patients per year, and the time since completion of fellowship ranged from 1 to 44 years (mean 12.5 (SD 11)). The most important factors guiding treatment decisions in propensity weighted modeling were "patient preference factors": patient/parental preference (40%), and treatment-related factors: possibility of remission (38%), side effect profile (36%), efficacy (27%), long-term toxicity (33%), and ease of administration (30%). Physician factors, such as experience and adhering to published guidelines, rarely influenced decision-making with only 2% of physicians giving published guidelines as a reason for choice of therapy, and there being no difference in choice based on years since fellowship or experience in treating ITP patients. However, 28% of physicians stated their comfort level with a treatment strongly influenced their choice. Additionally, 38% of physicians did not endorse any patient clinical factors (e.g. frequency of bleeding, expected compliance, response to other therapies, age, comorbidities) as key in their decision-making. Health system factors, such as insurance approval or distance from the closest medical center, rarely influenced treatment choice. Treatments could be categorized into five groups: oral immunosuppressive agents, rituximab, romiplostim, eltrombopag or splenectomy. A significant determinant of choosing splenectomy or rituximab was the "possibility of long-term remission" (p 〈 0.001). A high percentage of treatment factors impacted the decision to prescribe: for rituximab 92% of physicians endorsed at least one treatment factor; for oral immunosuppressants, and romiplostim and eltrombopag, 100% of physicians endorsed at least one treatment factor. Among the top 3 choices for each medication, treatment related factors were major determinants (Table). Oral agents, were significantly more likely to be chosen for ease of administration and expected adherence (p 〈 0.001). When examining the reasons physicians chose particular therapies, physicians indicated "this agent is most efficacious" most frequently for romiplostim, but not for eltrombopag (p 〈 0.001) and were more likely to choose rituximab in patients in whom there was lower expected compliance (p=0.017). Conclusions: This first analysis of physician decision making regarding second line therapies shows that patient preference and physician perception of treatment characteristics (efficacy, side effects, possibility of long term remission) are primary drivers of physician choice in contrast to guidelines, clinical characteristics and health system factors. Future comparative effectiveness studies are necessary to better inform patient and physician choice. Disclosures Lambert: Novartis: Consultancy. Grace:Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Bussel:Cangene: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; BiologicTx: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Speakers Bureau; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haley:Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria. Neufeld:Novartis: Consultancy.

Abstract: We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P  〈  .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and β 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon α 2 (rIFNα2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6%v 11.8% [P  〈  .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002] ), and with added HiCy (37.5% v 9.8% [P  〈  .0001]), but not with added rIFNα2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P  〈  .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell rasmutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNα2 to VBMCP, but the numbers were small and improved survival could not be shown.

Abstract: Background: Children with ITP who are prescribedsecond line treatments vary in terms of their clinical phenotype, prior treatments, and health related quality of life (HRQoL). Objective: To describe the clinical characteristics and HRQoL of North American pediatric patients with ITP initiating second line treatments. Methods: A longitudinal observational cohort of 118 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, steroids or anti-D) as monotherapy. Baseline demographic and clinical characteristics were recorded, including response to prior treatments, worst bleeding scores, and baseline platelet counts. Fisher's exact test was used to compare treatment with phase of ITP, age cohort, and gender. HRQoL was measured by patient/caregiver report using the Kids ITP Tool (KIT) where 0 is worst and 100 is best, while physicians assessed the perceived effect of ITP on patient HRQoL using a 5-point scale. Spearman correlations were used to test for association between bleeding, HRQoL, and duration of ITP. ANOVA was used to compare the mean KIT scores of the treatment groups. Results: The clinical characteristics of the cohort are shown in the Table. Median age at enrollment was 11.4 y and 15% had newly diagnosed ITP, 31% had persistent ITP, and 54% had chronic ITP. The median number of prior treatments was 3 (range: 1-9). The prior response rate (platelet 〉 30 x 109/µL and no bleeding) to prednisone was 59% and IVIG 66%. Fifty-five (47%) patients had received at least one prior second line treatment. At enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 44%, moderately in 38%, and almost not at all in 3%. The mean score of the child KIT report was 71.4 (SD 17.2), the parent proxy KIT was 64.7 (SD 16.4), and the parent impact KIT was 36.1 (SD 19.2). The physician's assessment of the patient's HRQoL significantly correlated with the child report (p 〈 .001) and parent proxy report (p 〈 .001). The number of prior treatments and the worst bleeding score did not significantly correlate with the child or parent proxy KIT scores with the exception of gynecologic bleeding on the parent proxy report (p=.002). The duration of ITP significantly correlated with child (p=0.001) and parent proxy KIT scores (p=0.005) where a longer duration was associated with better HRQoL. The number of prior treatments, worst bleeding, and phase of ITP did not correlate with the parent impact KIT score. Treatments selected for second line treatment included: rituximab (n=42), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=16), splenectomy (n=4), and dapsone (n=3). The selected treatment was not significantly different by age, gender, baseline child KIT score, or duration of ITP. Baseline parent proxy KIT scores varied significantly between selected treatments (p=0.03) and were significantly lower in children starting on eltrombopag in comparison to romiplostim (56.4 (SD 15.1) vs. 70.3 (SD 15.1), respectively; p=0.03). Conclusions: Children with ITP starting on new second line treatments often have received multiple prior treatments and nearly half start these treatments prior to being diagnosed with chronic ITP, including 15% who were in the newly diagnosed phase. Physician assessment of patient HRQoL correlates well with child and parent proxy report of HRQoL. The number of prior treatments and worst bleeding score did not correlate with HRQoL. Longer duration of ITP was associated with a better HRQoL, suggesting that the level of concern related to ITP may lessen over time. Baseline KIT scores were significantly different in children starting on specific treatments. Future analysis will compare the change from baseline in HRQoL in children treated with second line therapies. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Cangene: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Genzyme: Research Funding; BiologicTx: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haley:Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria. Thompson:Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Mast: Research Funding; Mast: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Eli Lily: Research Funding; Eli Lily: Research Funding.