ALBERT

Description: Hematopoietic Stem cell Transplantation (HSCT) is the definitive treatment for bone marrow failure in diskeratosis congenita (DC). Organ dysfunction (mainly lung and gastrointestinal tract) are often part of the disease and may be a limiting factor for or may affect the final outcome of HSCT. Scarce data or relatively small cohort studies are available in current literature on outcome of HSCT in this disease. We analyzed the outcome of 87 patients diagnosed with DC reported in the data base of the European Society for Blood an Bone Marrow Transplantation (EBMT) who underwent HSCT from 1979 to 2014. In particular we analyzed data on type of HSCT, characteristic of donors, source of cells, incidence of acute and chronic GvHD. Males were 76%. Median age at diagnosis of DC was 5.7 years (0-33 yrs), median age at HSCT was 11.2 years (range 0.56-41 yrs). Median time from diagnosis to HSCT was 19 months (0.62-304 mo). The cell source was bone marrow (BM) in 67%, peripheral blood (PB) in 22% and cord blood (CB) 11%. Twenty six percent of patients were engrafted from a matched related and 53% from a matched unrelated donor. Twenty one percent of subjects were engrafted from a mismatched (both related and unrelated) HSCT. Engraftment was documented in 95% of subjects: 4 % had primary graft failure and 10% lost the graft. Overall 35 patients (40%) died, and 52 were alive (60%) at last follow-up. Causes of death were: infections (43%), multi-organ failure (26%), rejection/oss of graft (14%), GvDH (8.5%) undefined (8.5%). In 32% of cases death was related to transplant. Lung injury was present in 17% of subjects who died. Acute GVDH (mainly grade 2-4) and chronic GvHD occurred in 39% and 30% of cases. Five year OS was 60 %. OS was not significantly different by calendar period (before and after year 2000: 50% vs 67% respectively, p=0.424), by age at transplant (below and above age of 12 years: 64% vs 55% respectively ; p= 0.564) and by source of cells (marrow 60%, cord blood 68%, and peripheral cells 46%; p= 0.687). Conversely, OS in HSCT from mismatched donor was inferior to that of transplants from matched donor (38% vs 65% respectively; p= 0.045). The use of radiotherapy or busulfan (any dose) in the conditioning vs other regimens did not impact on 5 y-OS ( 58% vs 62% respectively; p=0.898). HSCT from HLA matched donor can be considered a treatment option in DC. Transplant related mortality looks rater high. Multi organ failure and lung injury are amongst the main causes of death thus pointing to pre-transplant organ status as important determinant of HSCT outcome. Disclosures Dufour: Pfizer: Consultancy.

Description: Objective: Peripheral blood stem cell transplant (PBSCT) can now cure SCD in adults, but may result in a loss of future fertility. Little is documented regarding fertility preservation in women with SCD. The aim of this study was to perform fertility preservation for women with SCD scheduled for PBSCT. Design: Prospective cohort of women with SCD undergoing fertility preservation prior to PBSCT at a large research hospital. Materials and Methods: Patients underwent standard controlled ovarian hyperstimulation (COH) using an antagonist protocol cycle with leuprolide trigger under close multidisciplinary (including reproductive endocrinologists and hematologists) monitoring. All patients were continued on therapeutic or started on prophylactic anticoagulation prior to beginning COH, and maintained on hydroxyurea. Results: Nine reproductive aged women were screened; 1 declined participation, 1 was diagnosed with unrecognized premature ovarian insufficiency, 1 had her fertility preservation cycle canceled due to poor response to fertility medications and 2 patients are scheduled for upcoming cycles. The remaining four women (ages 20, 34, 24, 27) successfully underwent COH, transvaginal oocyte retrieval and cryopreservation of mature eggs (n= 8, 13, 15, 21 oocytes, respectively). The third patient underwent two cycles due to low mature oocyte yield from her initial cycle. Headaches were reported by patients 1 and 2 following gonadotropin injections, with a negative neurologic workup including MRI in patient 2. Patient 3 underwent an exchange transfusion on day 10 of stimulation, which did not adversely impact serum reproductive hormone levels. Patients 3 and 4 reported an acute exacerbation of their chronic pain during COH, which responded well to intravenous fluids, IV and oral pain medications. Therefore, despite severe SCD and co-morbid conditions, the side effects were manageable. There were no venous thrombotic events. Conclusion: These results provide support that fertility preservation can be safely performed in women with SCD under the care of a multidisciplinary team. The safest stimulation protocol (i.e. antagonist cycle with leuprolide trigger for final oocyte maturation) was successful in all patients despite multiple risk factors for failed leuprolide trigger. Fertility preservation is important not only before PBSCT to cure their underlying disease, but also because of high rates of premature ovarian insufficiency in the SCD population post-transplant. Support: Intramural NICHD and NHLBI, NIH. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Multiple myeloma (MM) is more common in men than women but the mechanism(s) driving this are not understood. In our previous study (Myeloma IX) we found sex disparities in the cytogenetic lesions present in myeloma cells at the time of diagnosis and that female sex was associated with reduced overall survival in the context of treatment with traditional chemotherapy (CVAMP/MP) and thalidomide combinations. Here, we evaluate sex differences in almost 4000 patients recruited to the UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Methods: Myeloma XI recruited newly diagnosed patients of all ages, with pathways for transplant eligible (TE) and ineligible (TNE) patients. An induction randomisation compared the triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). Eligible patients underwent autologous stem cell transplant (ASCT) and in both pathways a maintenance randomisation compared lenalidomide (+/-vorinostat) until disease progression versus observation. We compared baseline characteristics of males and females using Fisher's Exact test for categorical characteristics and the Wilcoxon-Mann-Whitney test for continuous characteristics with p1 lesion present. Results: Of 3894 patients enrolled in the trial 2268 (58%) were male and 1626 (42%) were female, in keeping with the known sex disparity in MM. There was no difference in the median age, WHO performance status, ethnicity and most laboratory values of the two groups. Females were more likely to have the molecular risk lesions t(14;16) and del(17p) and had proportionately more HiR and UHiR disease, Table 1. Despite these differences, PFS and OS from induction randomisation did not significantly differ (PFS: Males 25 months, [95% CI 24, 26], Females 24 months, [95% CI 22, 25] and OS: Males 67 months, [95% CI 62, 70], Females 70 months, [95% CI 64, 74]). Molecular lesions that have been associated with outcome remained prognostic in both sexes, with a stepwise reduction in PFS and OS with cumulative risk lesions. PFS: Males SR 29 months, HiR 23 months, UHiR 16 months (p 〈 0.0001), Females SR 27 months, HiR 18 months, UHiR 17 months (p = 0.0007); OS: Males SR 77 months, HiR 59 months, UHiR 34 months (p 〈 0.0001), Females SR 82 months, HiR 54 months, UHiR 41 months (p 〈 0.0001). There was, however, no significant difference in PFS or OS when we compared males and females with a given cytogenetic lesion or cytogenetic risk. There was a significant difference in the proportion of patients of either sex who continued through the trial and underwent ASCT in the TE pathway (Males 72%, Females 67%; p = 0.031), but no significant difference in those that entered the maintenance randomisation (TE: Males 56%, Females 50%, p = 0.107; TNE Males 45%, Females 42%, p = 0.249). There was no significant PFS or OS difference by sex when analysed within each treatment pathway (TE, TNE), induction regimen (CTD, CRD) and maintenance approach (lenalidomide maintenance, observation). Conclusions: Females had a higher proportion of the adverse molecular risk lesions del(17p) and t(14;16) and were more likely to have HiR and UHiR disease. In the context of Myeloma XI trial treatment this did not correspond to a difference in PFS or OS, either overall or within the induction or maintenance randomisation treatment options (even though males were more likely to undergo ASCT). This suggests that in women the treatment delivered may have been able to overcome some of the adverse effect of the risk lesions present or that other factors affecting outcome were more important. on behalf of the NCRI Haematological Oncology Clinical Studies Group. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Abbvie, Janssen: Honoraria; Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Russell:DSI: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. OffLabel Disclosure: CTD/CRD induction therapy for myeloma, Lenalidomide maintenance 10mg 21/28 days

Description: Key Points The outcome of HSCT in this large SCN cohort is acceptable. Given the TRM, a careful selection of HSCT candidates should be undertaken.

Description: Key Points ECM is associated with an early marked increase in plasma VWF levels and accumulation of UL-VWF multimers. Following P berghei infection, VWF−/− mice survive significantly longer compared with WT controls.

Description: Key Points Bone marrow-specific deletion of Pak2 is associated with macrothrombocytopenia and abnormal megakaryocyte morphology and function. Pak2 deletion is associated with defects in megakaryocyte endomitosis and the activation of Aurora-A and LIM kinase.

Description: Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Description: Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS

Description: Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) occurs primarily in older patients (pts) who often have increased comorbidities and cannot tolerate aggressive treatments, which leads to poorer outcomes (Balducci, Cancer Control 2015; Thurmes, Leuk Lymphoma 2008). Alkylating agents, such as chlorambucil (clb), have been commonly used to treat these pts (Eichhorst, Blood 2009). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. RESONATE-2 (PCYC-1115) is a randomized phase 3 trial designed to compare the efficacy and safety of ibr vs clb in pts with treatment-naïve (TN) CLL/SLL (Tedeschi, ASH 2015). Primary results, as assessed by an independent review committee (IRC), demonstrated with a median follow-up of 18.4 mo that ibr significantly reduced the risk of progression or death by 84% (P

Description: Background Transplant non-eligible (TNE) myeloma patients are a very heterogeneous group that is not well-defined on the basis of age alone, but rather by the interplay of age, physical function, cognitive function and comorbidity better defined as 'frailty'. The International Myeloma Working Group (IMWG) has published a scoring system for myeloma patient frailty that predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). It has been proposed to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but has not been validated prospectively. We hypothesize that by defining subgroups of patients based on the IMWG frailty score, and guiding up-front dose adjustments we can personalize therapy to improve treatment tolerability and therefore short-term outcomes, along with quality of life. In addition we plan to compare the use of single agent immunomodulatory (IMiD) based maintenance therapy with an IMiD and proteasome inhibitor maintenance doublet to try and improve long-term outcomes for patients. Study Design and Methods Myeloma XIV (NCT03720041) is a phase III, multi-center, randomized controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRd), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (IR) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. The trial outline is shown in Figure 1. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomized (R1) on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomization (R2) on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians are blinded to maintenance allocation. The primary objectives of the study are to determine: Early treatment cessation (within 60 days of randomization) for standard versus frailty-adjusted up-front dosingProgression-free survival (PFS, from maintenance randomization) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (IR) The secondary objectives of the study include determining: progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, overall survival (OS), overall response rate (ORR), treatment compliance and total amount of therapy delivered, toxicity & safety including the incidence of Second Primary Malignancies (SPMs), Quality of Life (QoL), cost-effectiveness of standard versus frailty-adjusted up-front dosing of IRd and cost-effectiveness of IR versus R. Exploratory analyses include the association of molecular subgroups with response, PFS and OS. Seven hundred and forty participants will be enrolled into the trial at R1 to give 80% power to demonstrate a difference in early cessation and ensure that at least 478 participants remain and are randomized at R2 (based on attrition rates in our previous study Myeloma XI). At R2 478 patients will give us 80% power to detect an eight month difference in PFS between R and IR. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Best:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Bowcock:Takeda: Honoraria, Research Funding. Boyd:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Drayson:Abingdon Health: Consultancy, Equity Ownership. Henderson:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty adjusted dosing. Ixazomib and lenalidomide combination as maintenance.