ALBERT

Description: Unexplained sudden death is common among patients (pts) with sickle cell diseases (SCD). QTc prolongation is a risk factor for fatal arrhythmias among adults. Cardiovascular autonomic dysfunction has been proposed as a contributing cause for sudden death in SCD but QTc prolongation has only been described in isolated pediatric case reports. Purpose: To investigate the incidence of QTc prolongation among adults with SCD and the relationship between prolonged QTc interval and sudden death. Methods: We reviewed records of 180 consecutive adults with SCD from October 1996 to January of 2007. EKGs and echocardiograms (Echo) were independently reviewed by a cardiologist who was blinded to the patients’ clinical and laboratory data. Bazett’s formula was used to calculate QTc interval. In pts with more than one EKG, the longest QTc data was used for analysis. Results: SCD were divided into 3 groups: homozygous SS = 113 (67%), SC = 34 (20%), Sβthal = 21 (13%). Mean age was 35 years (range 25–45), 66 (58%) were females, 108 (96%) were African American and 4% were Mexican. Other medical problems were prior CVA in 17, congestive heart failure in 11, hypertension in 9, renal insufficiency in 13, and diabetes in 7. Medications included hydroxyurea in 41, methadone in 38, other narcotics in 41, ACE inhibitors in 16 and beta blockers in 16. Twenty five pts were receiving chronic exchange transfusions. EKGs were available in 113 (67%) and Echo in 95 (53%). Serum chemistries and ferritin were available in 110 pts within 24 hours of the EKG and in 3 pts within 48 hours. QTc intervals were prolonged (〉440 msec) in 74 pts (66%). Sixty six pts (47%) pts had more than one EKG with prolonged QTc. QTc intervals increased progressively over 4 years from a mean 434 msec (415–452) to mean 462 msec (446–487), (p=

Description: There is increasing evidence that homeobox (Hox) genes play critical roles in the regulation of hematopoiesis. We found that both forms of the earliest HoxA gene, HoxA1 and its alternatively spliced transcript, HoxA1-T, which lacks the homeobox domain, are expressed in immature populations of hematopoietic stem cells (HSCs) and progenitor cells. In more mature bone marrow cell (BM) populations the levels of HoxA1-T increases relative to HoxA1 with both transcripts absent in mature peripheral blood (PB) cells. Roles for either of these Hox transcripts in hematopoiesis have not yet been described. We overexpressed either HoxA1 or HoxA1-T in BM using a modified GFP-containing MSCV vector (MXIE). Overexpression of either HoxA1 transcript did not affect expression levels of other Hox genes relative to control (empty vector). Overexpression of HoxA1-T significantly reduced the numbers of colony-forming cells (CFCs) produced by 500 GFP+ BM compared to control GFP+ BM (mean±SEM control 73±6.4; HoxA1 57±6.8; HoxA1-T 26.7±5.4; n=6; P

Description: We have previously shown that the human myeloid cell nuclear differentiation antigen (MNDA) is expressed at both the antigen and mRNA levels specifically in human monocytes and granulocytes and earlier stage cells in the myeloid lineage. A 200 amino acid region of the MNDA is strikingly similar to a region in the proteins encoded by a family of interferon-inducible mouse genes, designated Ifi-201, Ifi- 202, Ifi-203, etc, that are not regulated in a cell- or tissue-specific fashion. However, a new member of the Ifi-200 gene family, D3, is induced in mouse mononuclear phagocytes but not in fibroblasts by interferon. The same 200 amino acid region, duplicated in the mouse Ifi- 200 gene family, is also repeated in the recently characterized human IFI 16 gene that is constitutively expressed specifically in lymphoid cells and is induced in myeloid cells by interferon gamma. The 1.8-kb MNDA mRNA, which contains an interferon-stimulated response element in the 5′ untranslated region, was significantly upregulated in human monocytes exposed to interferon alpha. Characterization of the MNDA gene showed that it is a single-copy gene and localized to human chromosome 1q 21–22 within the large linkage group conserved between mouse and human that contains the Ifi-200 gene family. The IFI 16 gene is also located on human chromosome 1q. Our observations are consistent with the proposal that the MNDA is a member of a cluster of related human interferon-regulated genes, similar to the mouse Ifi-200 gene family. In addition, one mouse gene in the Ifi-200 gene family and the human MNDA and IFI 16 genes show expression and/or regulation restricted to cells of the hematopoietic system, suggesting that these genes participate in blood cell-specific responses to interferons.

Description: The results of starch block electrophoresis of normal adult hemoglobin in the various disease states has been reported. The slow-moving fraction, A2, is elevated in all patients so far studied with thalassemia. Some patients with Addisonian pernicious anemia also show an increase in this fraction. Cord blood contains very little A2. The A2 fraction has no correlation with the severity of the disease. The A2 fraction found on starch seems to be identical with the small, fast-moving component noted in the Tiselius apparatus at acid pH. Iron deficiency anemia of the acquired type tends to have a lower amount of A2 than normal, with an increase to average normal values after therapy.

Description: We have previously shown that the human myeloid cell nuclear differentiation antigen (MNDA) is expressed at both the antigen and mRNA levels specifically in human monocytes and granulocytes and earlier stage cells in the myeloid lineage. A 200 amino acid region of the MNDA is strikingly similar to a region in the proteins encoded by a family of interferon-inducible mouse genes, designated Ifi-201, Ifi- 202, Ifi-203, etc, that are not regulated in a cell- or tissue-specific fashion. However, a new member of the Ifi-200 gene family, D3, is induced in mouse mononuclear phagocytes but not in fibroblasts by interferon. The same 200 amino acid region, duplicated in the mouse Ifi- 200 gene family, is also repeated in the recently characterized human IFI 16 gene that is constitutively expressed specifically in lymphoid cells and is induced in myeloid cells by interferon gamma. The 1.8-kb MNDA mRNA, which contains an interferon-stimulated response element in the 5′ untranslated region, was significantly upregulated in human monocytes exposed to interferon alpha. Characterization of the MNDA gene showed that it is a single-copy gene and localized to human chromosome 1q 21–22 within the large linkage group conserved between mouse and human that contains the Ifi-200 gene family. The IFI 16 gene is also located on human chromosome 1q. Our observations are consistent with the proposal that the MNDA is a member of a cluster of related human interferon-regulated genes, similar to the mouse Ifi-200 gene family. In addition, one mouse gene in the Ifi-200 gene family and the human MNDA and IFI 16 genes show expression and/or regulation restricted to cells of the hematopoietic system, suggesting that these genes participate in blood cell-specific responses to interferons.

Description: Background: The CALGB 10403 protocol (10403) is an intensive pediatric regimen that has demonstrated a median event-free survival (EFS) of 78.1 months and an estimated 3-year overall survival (OS) of 73% in adolescents and young adults (18-39 yrs) (AYA) with ALL (Stock et al, Blood 2019). The backbone of this regimen includes pegylated asparaginase (PEG-ASP) and steroids, both of which have significant toxicities that increase with age and co-morbidities including obesity. These toxicities have traditionally precluded extending pediatric-inspired regimens to older pts. We have previously demonstrated that adequate asparaginase activity levels and less toxicity were achieved with reduced PEG-ASP dosing (Derman et al, Leukemia & Lymphoma 2020). Therefore, we performed a single-institution retrospective analysis of AYAs and adults up to age 60 yrs with ALL treated using a modified 10403 regimen with reduced dose PEG-ASP and glucocorticoids to evaluate treatment response. Modifications to PEG-ASP/steroid dosing in patients on a reduced-dose (RD) regimen are summarized in Figure 1. We evaluated characteristics and outcomes of these patients (pts). Methods: Retrospective cohort analysis identified pts with ALL who received RD 10403. RD was defined as receiving ≤ 1000IU/m2 of PEG-ASP along with dexamethasone 10mg/m2 on Days 1-7 and Days 15-21 during induction. Dose reduction for PEG-ASP was made for all pts ≥ 50 years old, body mass index (BMI) ≥ 30, diabetes mellitus and/or underlying liver dysfunction (including cirrhosis, non-alcoholic fatty liver disease; liver chemistry cut-off was not used). In patients with severe metabolic syndromes steroids were further reduced to administration on days 1-7 alone. Patients with CD20+ disease received rituximab during Course I, II, and III. Survival curves (EFS and OS) were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 30 consecutive pts with Ph negative B-cell or T-cell ALL and treated with RD from 8/2014-4/2019 were identified. Pt characteristics are outlined in Table 1. Median age in RD cohort was 46 years old. 53% of RD patients were identified as having high-risk disease (Ph-like ALL, MLL-rearranged, TP53-mutated, and/or early T-cell precursor (ETP) ALL). Median PEG-ASP dose during induction was 1000IU/m2 and 83% of patients achieved therapeutic asparaginase levels at Day 11 of induction (≥0.1IU/mL). 13 patients received 1000IU/m2, 12 patients received 500IU/m2, 4 patients received 250IU/m2, and 1 patient had PEG-ASP held during induction. Median total dexamethasone dose during induction was 140mg/m2; 22 patients received 140mg/m2, 7 received 70mg/m2, and 1 received 113mg/m2. At least one Grade 3+ toxicity was seen in 40% of patients during induction (hepatotoxicity in 8 pts, thrombosis in 4 patients, pancreatitis in 2 patients). Treatment related mortality (TRM) during induction was 3%; overall TRM attributable to 10403 was 10%. The morphologic complete remission (CR) rate was 77% (n=23) at 28 days. Measurable residual disease (MRD) was assessed by multicolor flow cytometry (sensitivity 10-4) and 18 patients (78% of all patients in a CR) achieved MRD-negativity by Day 28. 8 patients underwent allogeneic stem cell transplant (allo-SCT); 4 in first complete remission (3 with MLL-rearrangement and 1 with persistent MRD positivity) and 4 in a second complete remission (CR2) or later. Of the patients that did not go onto transplant, 6 have completed maintenance therapy per 10403 and 5 are still being treated per 10403. Median EFS of the entire cohort of patients was 54.5 months; estimated 3-year OS was 55% and estimated 3-year EFS was 54% (Figure 2A, 2B). For the 16 high-risk patients, the CR rate was 69% at 28 days and estimated 3-year OS was 61% (Figure 3). Conclusions: Our retrospective analysis demonstrates that a modified 10403 regimen with dose reduction of PEG-ASP and dexamethasone in older adults up to 60 years old or younger patients with comorbid conditions is feasible. We found that the RD 10403 regimen mitigates toxicity while still achieving high post-induction CR and MRD negativity rates. Our preliminary analysis demonstrates encouraging 3-year EFS and OS in this high-risk cohort. Prospective evaluation of RD 10403 for older adults can be recommended. Disclosures Gurbuxani: UpToDate: Honoraria. Liu:BMS: Research Funding; Agios: Honoraria, Other: Regional Advisory board meeting; Karyopharm: Research Funding. Thirman:AstraZeneca: 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; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding. Godley:Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees; UptoDate, Inc.: Honoraria. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: 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, Research Funding. Larson:Novartis, Takeda, CVS/Caremark, Celgene, Amgen, Epizyme: Consultancy; Astellas, Celgene, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals, Cellectis, Forty Seven: Research Funding. Stock:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Research Funding; Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Honoraria; Research to Practice: Honoraria; American Society of Hematology: Honoraria.