Abstract: Mutations in HSPA9 cause CSAs that may be inherited in a recessive or pseudodominant manner. HSPA9 loss-of-function alleles are often inherited in trans with a common coding single nucleotide polymorphism associated with altered gene expression.

Abstract: A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T−B−NK+SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T−B−NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

Abstract: Compared with other SCID entities, patients with RD have an earlier presentation with bacterial rather than opportunistic infections. Myeloablative agents before transplantation support reliable myeloid engraftment and long-term cure in patients with RD.

Abstract: Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease.

Abstract: Introduction: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment (Calzada et al, 2018). In this subgroup, a lack of evidence to support the decision-making behind the choice of therapy has led to a wide diversity in treatments. We evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. Methods: We included patients ≥ 18 years old with MCL from 11 academic centers and defined the deferred subgroup as patients who started therapy ≥ 90 days after diagnosis. Patients who received high dose cytarabine as part of their induction or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy while all other approaches were non-intensive. We identified differences between the baseline characteristics of the two groups using Fisher's exact tests, chi-squared tests, and t-tests as appropriate. We calculated progression-free (PFS) and overall survival (OS) from the date of diagnosis using the Kaplan-Meier method and compared the two groups using the log-rank test. Univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Results: Of 968 identified patients with MCL, 233 did not initiate therapy within 90 days of diagnosis and were considered deferred. Deferred patients had a lower Ann Arbor stage (p 〈 0.001), Ki-67 (p 〈 0.001) and LDH (p=0.007) at diagnosis compared to patients undergoing immediate treatment. Within the deferred group, 80 patients received intensive therapy (including 59 who completed ASCT in first remission), 99 received non-intensive therapy, and the remaining 54 patients did not receive any documented treatment and were excluded from this analysis. The most common intensive regimens included R-HyperCVAD and R-CHOP, and the most common non-intensive regimens included R-bendamustine and R-CHOP without ASCT. There was no difference in time to treatment, ECOG performance status, ethnicity, Ann Arbor stage or presence of B-symptoms between the two groups. However, patients who received non-intensive therapy were older (p 〈 0.001), more likely to have a normal LDH (p=0.03), and more likely to be treated at the reporting academic center (p=0.008). There was no significant difference in OS (Figure 1A, p=0.7) or PFS (Figure 1B, p=0.16) between the deferred patients who subsequently received non-intensive vs. intensive therapy. Univariate analysis of PFS highlighted the significance of: LDH (HR 0.62, p= 0.04), lack of blastoid morphology (HR 0.53, p=0.032), treatment initiation at participating academic center (HR 0.43, p 〈 0.001), post-induction rituximab (HR 0.42, p=0.003), and higher baseline hemoglobin level (HR 0.90, p=0.038) as predictors of improved PFS. Multivariable analysis demonstrated that post-induction rituximab (HR 0.16, p=0.008) and treatment initiation at an academic center (HR= 0.17, p 〈 0.001) predicted improved PFS while pre-existing coronary artery disease (HR=5.28, p=0.015) was associated with decreased PFS. A univariate analysis found that lack of blastoid histology (HR 0.24, p 〈 0.001), normal LDH (HR 0.31, p 〈 0.001), increased baseline hemoglobin (HR 0.83, p=0.005), post-induction rituximab (HR 0.16, p=0.014), and treatment initiation at an academic center (HR 0.34, p=0.003) significantly improved OS. In a multiviariable analysis, lack of blastoid histology (HR 0.11, p 〈 0.001) predicted improved OS while pre-existing diabetes mellitus (HR 5.98, p=0.005) and age (HR 1.08, p=0.001) were significantly associated with inferior OS. Intensity of treatment was not significantly associated with PFS or OS in the univariate or multivariable models. Conclusions: Among this large group of MCL patients who deferred therapy, use of an intensive induction therapy did not improve OS or PFS compared to patients who received non-intensive treatments. Our findings suggest that other patient- and disease-related factors may affect PFS and OS in this patient subgroup. Prospective studies to evaluate tools incorporating these factors will be useful in identifying the optimal therapy approach for patients with MCL who have completed an initial period of observation. Disclosures Calzada: Seattle Genetics: Research Funding. Bachanova:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Gamida Cell: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Danilov:Takeda Oncology: Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astra Zeneca: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding. Grover:Seattle Genetics: Consultancy. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Hill:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Park:Rafael Pharma: Consultancy; BMS: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Speakers Bureau; BMS: Consultancy; Teva: Research Funding; Gilead: Speakers Bureau; Takeda: Research Funding; G1 Therapeutics: Consultancy; Teva: Consultancy. Blum:Novartis: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Morphosys: Research Funding. Hamadani:Cellerant: Consultancy; Celgene Corporation: Consultancy; MedImmune: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; Merck: Research Funding; Janssen: Consultancy. Kahl:Genentech: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Research Funding. Flowers:Denovo Biopharma: Consultancy; Celgene: Research Funding; Spectrum: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Gilead: Research Funding; Pharmacyclics/ Janssen: Consultancy; BeiGene: Research Funding; Bayer: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Abbvie: Research Funding; Gilead: Consultancy; Janssen Pharmaceutical: Research Funding; OptumRx: Consultancy; Genentech/Roche: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Acerta: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: 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; Celgene: 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; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

Abstract: Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P  〈  .001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P  〈  .001).

Abstract: Abstract 957 Background: For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), standard-of-care second-line therapy in patients eligible for consolidative high-dose therapy with autologous stem cell rescue (HDT/ASCR) is rituximab (R) combined with a platinum-containing regimen such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP). In patients with early relapse or refractory disease following first-line treatment, the efficacy of second-line rituximab combined with salvage chemotherapy is lower in patients previously treated with rituximab combined with chemotherapy compared to patients treated with chemotherapy alone (Gisselbrecht et al. J Clin Oncol 2010). Ofatumumab (OFA), a fully human monoclonal antibody against CD20, uses an alternate binding site from that of rituximab, and demonstrates more potent complement-dependent cytotoxicity in vitro than does rituximab (Teeling et al. J Immunol 2006). We hypothesize that the inclusion of ofatumumab in second-line therapy could improve response rates for aggressive B-cell non-Hodgkin's lymphoma (NHL) relapsing after, or refractory to, rituximab-containing initial therapy. Methods: Between May 2009 and April 2011, 61 patients (pts) were enrolled with relapsed or refractory CD20 positive aggressive B-cell NHL (DLBCL, transformed low grade lymphoma or grade 3B follicular lymphoma). Pts were transplant eligible with either pathologically confirmed relapse after first-line therapy or primary refractory disease. Initial therapy must have included rituximab combined with anthracycline/anthracenedione chemotherapy. Sites elected to treat all of their pts with either ICE or DHAP. Chemotherapy was dosed every 21 days for 3 cycles. OFA was dosed on D1 and D8 of cycle 1, then D1 of cycles 2 and 3. Initially, the first dose of OFA was 300mg, but the study was amended to increase the first dose to 1000mg. All other doses of OFA were 1000mg. Response was assessed after cycles 2 (CT) and 3 (CT + PET). The primary endpoint was overall response rate (ORR) using modified RRCML criteria (Cheson et al. J Clin Oncol 2007). Results: 61 pts were enrolled; 35 pts were treated with ICE and 26 pts with DHAP. 21 pts received an initial OFA dose of 300mg and 40 pts received 1000mg. High risk disease was well represented, with 80% having disease that was either primary refractory (47%), relapsed within 12 months of diagnosis (30%), or progressed from unknown response within 12 months of diagnosis (3%); 48% of pts had a second-line age-adjusted IPI (sAAIPI) of 2 (41%) or 3 (7%) risk factors. 9 (15%) pts were prematurely withdrawn from treatment due to investigator decision (n=5, usually due to stable disease deemed an inadequate response), AEs (n=3) or pt decision (n=1). 2 pts were CD20 negative and excluded from the efficacy analysis. The ORR in the 59 evaluable pts was 61% (95% CI: 47%–74%), with CR in 37% (95% CI: 25%–51%). For OFA+DHAP, the ORR was 69% (95% CI: 48%–86%), with CR in 42% (95% CI: 23%–63%), and for OFA+ICE, was 55% (95% CI: 36%–72%), with CR in 33% (95% CI: 18%–52%). For patients with sAAIPI of 2 or 3 (29 pts), the ORR was 59% (95% CI: 39%–77%), with CR in 31% (95% CI: 15%–51%). For pts with primary refractory or early relapsing disease, the ORR was 55% (95% CI: 40%–70%), with CR in 30% (95% CI: 17%–45%). 45 pts underwent peripheral blood stem cell mobilization, and 43 (96%) mobilized ≥2×106 CD34+ cells/kg (median, 5.8×106 CD34+ cells/kg). Grade ≥3 AEs occurred in 47 pts (77%); the most common were thrombocytopenia (59% pts), anemia (36%), neutropenia (26%), lymphopenia (23%), leukopenia (18%), febrile neutropenia (13%), and hypokalemia (13%). 3 pts (12%) treated with OFA+DHAP had grade ≥3 nephrotoxicity. 3 pts discontinued treatment due to chemotherapy related AEs: mental status change (2 pts), respiratory distress (1 pt), and elevated creatinine (1 pt). No treatment related deaths were reported. Conclusions: OFA combined with salvage ICE or DHAP showed promising activity with an ORR of 61%. Treatment was adequately tolerated, with no unexpected toxicity, and stem cell mobilization was not adversely affected. Furthermore, the results are particularly promising in patients with primary refractory or early-relapsing disease, a group that has been reported to have extremely adverse outcomes. In order to compare rituximab to OFA in the salvage setting, a phase III randomized trial of OFA+DHAP and R+DHAP is ongoing. Disclosures: Matasar: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma), as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Czuczman:Ortho Biotech: Research Funding; Centocor: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Abbott: Research Funding; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rodriguez:Genentech: Research Funding; Pfizer Pharmaceuticals: Research Funding; Ortho Biotech: Research Funding. Fennessy:Glaxo Smith-Kline: Employment, Equity Ownership. Shea:Otsuka: Research Funding; Millenium: Research Funding; Genzyme: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Bristol-Myers Squibb: Research Funding. Spitzer:Amgen: Equity Ownership; Celgene: Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau; Merck: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau. Fayad:GSK: Research Funding. Liao:GlaxoSmithKline: Employment. Edvardsen:GlaxoSmithKline: Employment. Lisby:Genmab: Employment.

Abstract: The effect of the putative iron regulatory peptide hepcidin on iron absorption was investigated in mice. Hepcidin peptide was synthesized and injected into mice for up to 3 days, and in vivo iron absorption was measured with tied-off segments of duodenum. Liver hepcidin expression was measured by reverse transcriptase–polymerase chain reaction. Hepcidin significantly reduced mucosal iron uptake and transfer to the carcass at doses of at least 10 μg/mouse per day, the reduction in transfer to the carcass being proportional to the reduction in iron uptake. Synthetic hepcidin injections down-regulated endogenous liver hepcidin expression excluding the possibility that synthetic hepcidin was functioning by a secondary induction of endogenous hepcidin. The effect of hepcidin was significant at least 24 hours after injection of hepcidin. Liver iron stores and hemoglobin levels were unaffected by hepcidin injection. Similar effects of hepcidin on iron absorption were seen in iron-deficient and Hfe knockout mice. Hepcidin inhibited the uptake step of duodenal iron absorption but did not affect the proportion of iron transferred to the circulation. The effect was independent of iron status of mice and did not require Hfe gene product. The data support a key role for hepcidin in the regulation of intestinal iron uptake.