bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Flowcytometry-Based Method to Discriminate Malignant From Normal Stem Cells in CML.
Authors: Janssen Jeroen J.W.M. , Deenik Wendy , Smolders Karlijn G.M. , Terwijn Monique , Kelder Angele , Cornelissen J. J. , Schuurhuis Gerrit-Jan , Ossenkoppele Gert J. 
Published: October 2019

Abstract
Abstract 3245
Poster Board III-182
Tyrosine kinase inhibitor (TKI) insensitivity of CML hematopoietic stem cells prevents eradication of the disease by these drugs and is presumably implicated in development of TKI resistance. Probably, improvement of treatment results will involve leukemic stem cell directed therapy. Therefore, more knowledge of stem cell specific targets would be instrumental. Previously, leukemic stem cells could only be identified indirectly by using culture techniques. We developed a new flowcytometric approach that enables to directly distinguish CML stem cells from their normal counterparts within single patient samples. In 24 newly diagnosed CML patients CML CD34+CD38- stem cells could be discriminated from normal stem cells by higher CD34 and CD45 expression and different forward/sideward light scatter properties, reflecting differences in size and granularity. In addition, aberrant expression of CD7, CD11b and CD56 was demonstrated on malignant stem cells, allowing clear discrimination from benign stem cells, that were always negative for these markers. Above all, in all tested CML patients we were able to demonstrate that high CD90 expression is a specific feature of CML stem cells, while CD90 expression is low on their normal counterparts. FISH analysis on FACS sorted cells proved that populations were BCR-ABL positive (in case of high CD34 and CD45 expression and high CD90 expression) or negative (in case of low CD34 and CD45 expression and low CD90 expression), while long term liquid culture assays with subsequent CFU assays and FISH analysis proved their malignant/normal stem cell character. Patients with a large proportion of non-leukemic stem cells had significantly lower clinical risk scores (Sokal, Euro) than patients with few remaining normal stem cells. This new technique will expand our possibilities to identify new CML stem cell specific targets and may improve efficacy assessment of CML treatment as well.

Disclosures
No relevant conflicts of interest to declare.
High Prevalence of Dapsone-Induced Oxidant Hemolysis in North American Stem Cell Transplant Recipients without Glucose-6-Phosphate-Dehydrogenase Deficiency.
Authors: Olteanu Horatiu , Harrington Alexandra , George Ben , Bredeson Christopher , Hari Parameswaran N. , Kroft Steven 
Published: October 2019

Abstract
Abstract 3314
Poster Board III-202

Introduction
Dapsone (4-4'-diaminodiphenylsulfone) is commonly used for Pneumocystis jirovecii pneumonia (PCP) prophylaxis in immunocompromised patients. Oxidant hemolysis is a known complication of dapsone, but its frequency in adult patients who have undergone stem cell transplantation (SCT) for hematologic malignancies is not well established. We report a high prevalence of hemolytic anemia associated with dapsone use in SCT patients in the absence of glucose-6-phosphate dehydrogenase (G6PDH) deficiency.

Patients and Methods
We retrospectively analyzed laboratory data from 30 SCT (29 Caucasian and 1 African-American; 15 male and 15 female) patients receiving dapsone (100 mg orally daily) for PCP prophylaxis to determine the frequency of oxidant hemolysis. All patients had undergone allogeneic (n = 27) or autologous SCT (n = 3) for hematological malignancy or aplastic anemia. Peripheral blood (PB) smears were reviewed in a blinded fashion for the presence of morphologic features of oxidant hemolysis (multiple bite cells in each high power field), with PB smears from the same patient group while not on dapsone serving as controls. Additional demographic and laboratory data, including G6PDH enzyme activity screening test, hemoglobin, reticulocyte count, lactate dehydrogenase and bilirubin levels, were collected from chart review.

Results
29 patients had normal G6PDH activity (results were not available for 1 patient). 38 PB smears were obtained while on dapsone (some patients had more than one bone marrow evaluation). 30 (79%) PB smears from 26 (87%) patients had morphologic evidence of overt oxidant hemolysis. This was significantly higher than in the controls, in which 5/22 (23%) PB smears had morphologic features of oxidant hemolysis (p<0.001, Fisher's exact test). Hemoglobin levels were lower in the dapsone group, compared to the controls (10.0 vs. 12.5 g/dL, p=0.012). Mean LDH (507 IU) and direct bilirubin (1.6 g/dL) were also increased in the patients on dapsone. None of the patients had laboratory signs of hemolysis while not on dapsone.

Conclusions
Dapsone-induced oxidant hemolysis in SCT patients is 20-fold higher than the reported rate in HIV-infected patients receiving this agent. This high prevalence in patients without G6PDH deficiency suggests the coexistence of other sources of oxidant stress specific to this patient cohort.

Disclosures
Bredeson: Esai: Honoraria.
Incidence and Risk Factors for Lower Alimentary Tract Mucositis (neutropenic enterocolitis) Following 1528 Courses of Chemotherapy in a Homogenous Population of Myeloma Patients: Clinical and Research Implications.
Authors: Krishna Somashekar G , Weizhi Zhao , Krishna Kavya , Grazziutti Monica , Barlogie Bart , Anaissie Elias 
Published: October 2019

Abstract
Abstract 3343
Poster Board III-231

Background:
lower alimentary tract mucositis (L-ATM), also known as neutropenic enterocolitis, is a complication of chemotherapy with high mortality rates. The incidence, risk factors and mortality of L-ATM remain unknown.

Purpose:
To determine the incidence, risk factors and mortality of L-ATM in a homogeneous population of patients with multiple myeloma.

Patients and Methods:
303 newly diagnosed myeloma patients (2004 - 2007) were enrolled in a protocol consisting of induction chemotherapy, tandem melphalan-based autologous stem-cell transplantation (ASCT) and consolidation. Lower -ATM was defined as grade II-IV enteritis/colitis occurring during neutropenia. All data were collected prospectively. The analysis of risk factors included body surface area (BSA), creatinine clearance (CrCl), serum albumin and other pretreatment variables. Multiple logistic regression model was used to compute adjusted odds ratio (OR) and 95% confidence intervals (CI).

Results:
47 patients (15.5%) developed L-ATM during 1528 chemotherapy cycles (including 536 ASCT). BSA < 2 m2 (OR 2.853; 95% CI 1.232, 6.607; p = 0.0144) and CrCl <60ml/min (OR 3.089; 95% CI 1.176, 8.114; p = 0.0221) increased the risk for L-ATM while higher serum albumin was protective (OR 0.695; 95% CI 0.517, 0.936; p = 0.0167). No L-ATM-related death was observed.

Conclusions:
Lower-ATM is not uncommon among myeloma patients undergoing multiple cycles of chemotherapy but does not contribute to mortality. The risk for L-ATM is determined by lower values of BSA, renal function and serum albumin. These findings have significant implications for the study and management of L-ATM in patients undergoing chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.
Long Term Follow-up of Recipients of Combined HLA-Matched Nonmyeloablative Bone Marrow and Kidney Transplantation for Multiple Myeloma with End-Stage Renal Disease.
Authors: Spitzer Thomas R , Sykes Megan , Tolkoff Rubin Nina , Kawai Tatsuo , McAfee Steven L , Dey Bimalangshu , Ballen Karen , Delmonico Francis , Saidman Susan , Sachs David H , Cosimi Benedict 
Published: October 2019

Abstract
Abstract 3368
Poster Board III-256
Specific tolerance following combined kidney and bone marrow transplantation (Kd/BMT)for patients with end stage renal disease (ESRD) with or without an underlying malignancy has been accomplished, as evidenced by prolonged normal renal function without ongoing immunosuppression (IS)and the demonstration of in vitro donor specific hyporesponsiveness (N Engl J Med 2008; 358:353-361; Am J Transplant 2006;6:2121-2133). In order to achieve potent anti-myeloma responses and induce tolerance through the induction of mixed chimerism (MC) for the renal allograft, 7 patients (median age 48 (34-55) yrs with multiple myeloma (MM) and ESRD received a combined HLA-matched Kd/BMT, with longest follow-up time of almost 11 years. An eighth pt developed cyclophosphamide (CY) cardiotoxicity on day -5 and did not receive a transplant. Preparative therapy for the transplants consisted of CY 60 mg/kg (days -5, -4) with hemodialysis 14 hrs after each CY dose, equine anti-thymocyte globulin, 15-20 mg/kg on days -1, +1, +3, and +5 and thymic irradiation (700 cGy) on day -1. Cyclosporine (CSP) was begun on day -1, with combined Kd/BMT on day 0. Nine additional donor lymphocyte infusions were given to 5 pts (5 for chimerism conversion, 4 for persistent/progressive disease (PD)). Acute (A) and chronic (C) GVHD developed in one patient following DLI for early PD, while chronic GVHD developed in two pts (one after a second stem cell transplant). Characteristics and outcomes of the 7 combined Kd/BMT recipients are as follows:

# after 2nd transplant (myeloablative) from the same donor ; FDC: full donor chimerism In summary, 5 of 7 pts are alive, 4 without evidence of MM from 2.7 to 10.9 yrs post-Kd /BMT. Three pts have normal renal function without IS, while two pts have normal renal function on IS for chronic GVHD. Sustained renal allograft tolerance and prolonged anti-myeloma responses are achievable following nonmyeloablative HLA-matched kidney and BMT and the induction of mixed chimerism. This study was supported by the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases.

Disclosures:
Off Label Use: Equine anti-thymocyte globulin: in vivo T cell depletion Cyclophosphamide:conditioning therapy for transplantation.
Long-Term Complete Responses to Combination Therapies in Sézary Patients.
Authors: Daulat Seema , Talpur Rakhshandra , Hosing Chitra , Duvic Madeleine 
Published: October 2019

Abstract
Abstract 3369
Poster Board III-257

Introduction:
Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL), is defined as erythroderma and >1000 abnormal T-cells per mm3 in the peripheral blood, and is currently incurable. A recent study of erythrodermic CTCL conducted at our center reported a median overall survival of 5.1 years which is twice that in the literature [Vidulich K, et al. Int. J of Dermatol. 2009; 48: 243-252]. Although complete remissions (CR) may be achieved in earlier stages of CTCL, they are rarely achieved in SS patients.

Patients and Methods:
A retrospective analysis of a prospective database of 1550 CTCL patients seen at the MD Anderson Cancer Center since 1984 identified a subset of 145 SS patients (9%) whose long-term complete responses (>2 years) to various therapies is reported. The most commonly used combination therapies were topical steroids, psoralen with ultraviolet A (PUVA), oral retinoids (isotretinoin, acetretin, or bexarotene), alpha-interferon, and extracorporeal photopheresis (ECP). A combination of total skin electron beam radiation (TSEB) followed by induction chemotherapy and allogeneic stem-cell transplant was given to 23 CTCL patients. Chronic Staphylococcus aureus carriers identified by cultures were treated with antibiotics and preventive skin care.

Results:
Of the 145 Sézary Syndrome patients, 13 (8.96%) achieved CRs, including 6 females and 7 males. Their median age was 48 (20 to 85 years) at diagnosis. Nine were Caucasian, 3 were African American, and 1 was Hispanic. At initial diagnosis their stages were IB (n=1), stage III (n=3), stage IVA (n=4), and stage IVB (n=5). Six achieved a CR on front-line combination immunomodulatory therapy consisting of ECP with alpha-interferon and/or oral retinoids, antibiotics, and topical steroids. Seven SS patients failed therapy but were able to obtain CRs after TSEB and allogeneic peripheral blood stem cell transplantation (SCT) from matched related donors (n=6) or unrelated (n=1) donors. The conditioning regimen for SCT was fludarabine and melphalan. The median time between diagnosis and CR was 4.07 years (range 1 to 20 years). The median duration of CR is 5 years (mean 5.15 years, range 2 to 13 years).

Conclusion:
Sézary Syndrome is extremely symptomatic and usually refractory to current therapies. CRs may be achieved using immunomodulatory therapy with biological response modifiers and photopheresis or with total skin electron beam followed by non-ablative allogeneic stem cell transplant in appropriate patients and may have an impact on overall survival.

Disclosures:
No relevant conflicts of interest to declare.
Long Term Results of Allogeneic Hematopoietic Cell Transplantation in Elderly Patients.
Authors: Stadler Michael , Dammann Elke , Buchholz Stefanie , Hertenstein Bernd , Krauter Juergen , Eder Matthias , Ganser Arnold 
Published: October 2019

Abstract
Abstract 3388
Poster Board III-276

BACKGROUND:
Allogeneic hematopoietic cell transplantation (alloHCT) has curative potential in many hematologic malignancies; however, substantial treatment related toxicities have restricted its use to younger patients, mostly below 55 years of age. With the development of reduced intensity conditioning regimens, alloHSCT is being applied more widely in elderly patients, too.

PATIENTS:
Here we report long term results of all consecutive alloHCT recipients above the age of 55 years at our institution between October 1996 and April 2009. Among a total of 649 patients allotransplanted, 172 were more than 55 years old: 86 patients in the age group over 55 to 60 years, 61 patients in the cohort over 60 to 65 years, and 25 patients older than 65 years.

RESULTS:
73 elderly patients were female and 99 male. Diagnoses included acute lymphoblastic leukemia (14 patients), acute myelogenous leukemia (AML, 57), myelodysplastic syndromes or secondary AML (71), chronic myelogenous leukemia (7), myelofibrosis (6), lymphoma (11), and multiple myeloma (6). Advanced disease was present in 131 patients (76%) at the time of transplant. 164 patients (95%) had a WHO performance score of 0 to 1. According to the HCT comorbidity index (HCTCI), 67 patients (39%) had no comorbid conditions, whereas 58 patients (34%) had 1 to 2, and 47 (27%) had 3 or more comorbidities (not significant). Conditioning regimens were of reduced intensity in 147 patients (85%, in the majority FLAMSA-based) and myeloablative in 25 patients (15%). 56 patients (33%) received a graft from a related donor and 116 (67%) from an unrelated donor. With a median follow-up of 11 months (range: less than 1 to 127), 55 patients have relapsed (32%). Non-relapse mortality was 27% (46 of 172 patients). At last follow-up, 80 of 172 patients (47%) were alive and 77 (45%) in complete remission. Probabilities of overall (OS) and disease-free survival (DFS) at four years were 40 and 35%, respectively. Interestingly, long term OS and DFS were similar among the patients aged 55 to 65 years when compared to the 477 patients below 55 years allotransplanted during the same period at our institution. Only the age cohort over 65 years had a significantly reduced outcome with 22% DFS at four years (p = 0.006). Comorbidities were distributed comparably in all three elderly age groups, but remained without statistical effect on survival, likely due to the overriding influence of high risk status.

CONCLUSIONS:
In our experience, alloHSCT was feasible in elderly patients of sufficient performance status, with acceptable toxicity and relapse rates, and with insignificant impact from comorbid conditions. Up to the age of 65 years, outcome was not inferior to that of patients below 55 years of age.

Disclosures:
No relevant conflicts of interest to declare.
Targeting the Leukemia Initiating Cells in a Mouse T-ALL Model.
Authors: Tatarek Jessica , Cullion Kathleen , Kelliher Michelle 
Published: October 2019

Abstract
Abstract 3474
Poster Board III-411
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is largely caused by aberrant activation of the TAL1/SCL, LMO1/2 and NOTCH1 oncogenic pathways. Although most patients respond to cytotoxic therapy, 20-30% relapse and currently we cannot distinguish children likely to relapse from those who will respond to therapy. Evidence is emerging that some malignancies are driven by a rare initiating population that is capable of extensive self-renewal and is resistant to conventional chemotherapy. Although the leukemia-initiating cells (L-ICs) have been well documented in AML and CML, it is unclear whether T-ALL is driven by a rare L-IC and whether relapse reflects an inability to eliminate L-ICs. To determine whether T-ALL is driven by a rare L-IC, we utilized a murine model of T-ALL in which expression of the Tal1 and Lmo2 oncogenes arrests thymocyte development via E47/HEB inhibition and 75% of tumors develop spontaneous gain of function mutations in Notch1. We have shown that treatment with γ-secretase inhibitors (GSIs) to inhibit Notch1 activity induces apoptosis of mouse T-ALL cells in vitro and when administered in vivo extends the survival of leukemic mice. We demonstrate that clonal mouse T-ALL tumors are phenotypically heterogeneous, containing immature CD4- and CD8-negative, double negative (DN) 3 and 4 thymic progenitors and differentiated double positive (DP) and/or single positive (SP) leukemic blasts. Importantly, the DN3 or DN4 progenitors are maintained upon serial transplantation of the tumor into syngeneic recipient mice. Injection of serial dilutions of murine T-ALL cells reveal that the tumors are also functionally heterogeneous; with 1/5000-1/50,000 tumor cells exhibiting leukemia initiating activity. We found the CD44-, CD25+ DN3 progenitors enriched in disease potential, whereas mice injected with DP leukemic blasts failed to develop leukemia. Consistently, our preleukemic studies reveal a 3.5-fold increase in the percentage of Notch1 active, DN3/4 thymic progenitors, raising the possibility that Notch1 drives L-IC growth. Collectively, these studies suggest that activation of the Notch1-c-Myc pathway may confer self-renewal capabilities on committed thymic progenitors. The effects of Notch inhibitors on mouse L-IC survival and activity will be discussed.

Disclosures:
No relevant conflicts of interest to declare.
MYBL2 Is a Candidate Tumor Suppressor Gene In MDS
Authors: Heinrichs Stefan , Conover Lily , Bueso-Ramos Carlos E. , Kilpivaara Outi , Levine Ross , Stevenson Kristen , Neuberg Donna , Bejar Rafael , Ebert Benjamin L. , Garcia-Manero Guillermo , Kantarjian Hagop M. , Look A. Thomas 
Published: October 2019

Abstract
Abstract 1865
Cytogenetic changes, mainly deletions, can be found in about 30–50% of patients with Myelodysplastic Syndromes (MDS). To identify a tumor suppressor candidate within a commonly deleted region on chromosome 20q, we performed gene expression analysis on CD34+ bone marrow cells obtained from 8 patients with a 20q aberration and 18 with a normal karyotype. However, we were unable to identify genes that were significantly differentially expressed in aberrant 20q karyotype as compared to normal karyotype MDS patients. In contrast, a comparison of CD34+ cells from all MDS cases analyzed (n=26) with CD34+ cells obtained from normal bone marrow (n=4) revealed 108 genes that were differentially expressed. Interestingly, one of the top-scoring genes was MYBL2, which is located on chromosome 20q. MYBL2 levels were downregulated more than two-fold in 18 out of 26 cases. RNAi-mediated knockdown of MYBL2 in CD34+ normal bone marrow cells revealed a signature of genes functionally associated with the G2/M cell cycle phase confirming the well-documented role of MYBL2 as key transcription factor governing the onset of cell division. We hypothesize that in a subset of MDS cases the control of cell division may be impaired by low levels of MYBL2 such that altered cell fates established during cell division in early hematopoietic stem and progenitor cells will lead to clonal expansion with imbalanced or impaired differentiation. Indeed, gene set enrichment analysis revealed a strong enrichment of MYBL2 signature genes in MDS CD34+ cells. In support of a potential role as tumor suppressor, resequencing of MYBL2 (144 patients) identified 2 somatic mutations, pinpointing an additional mechanism to reduce expression of normal levels of wild-type MYBL2.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Impact of Chromosomal Abnormalities In Elderly Patients with Multiple Myeloma Treated with High-Dose Melphalan (MEL140) and Autologous Stem Cell Transplantation
Authors: Liebisch Peter , Straka Christian , Einsele Hermann , Hinke Axel , Sandermann Andreas , Dohner Hartmut , Langer Christian 
Published: October 2019

Abstract
Abstract 1914

Background:
Although chromosomal aberrations (CA) have emerged as important outcome predictors in multiple myeloma (MM), the prognostic significance of many recurring genomic changes is still unknown. Moreover, there is only scarce data on the implication of CA in elderly patients (pts.) receiving high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT).

Aims:
To evaluate the prognostic relevance of recurring CA as detected by cIg-FISH for elderly pts. with MM receiving HD-CTX and ASCT.

Patients and Methods:
Between 05/2001 and 08/2006, 549 pts. 60–70 yrs. of age with newly diagnosed symptomatic MM entered the DSMM II trial of the Deutsche Studiengruppe Multiples Myelom to receive two cycles of HD-CTX (melphalan 140 mg/sqm) followed by ASCT after 3–4 cycles of dexamethason-based induction chemotherapy (IC; arm A1) or no IC (arm A2). cIg-FISH and DNA probes mapping to chromosome bands 1p22, 1q21.2, 6q21, 8p11.2, 9q34, 11q25, 13q14, 14q32, 17p13, and 22q11 were applied to all pts. with sufficient bone marrow specimen at diagnosis. 289 pts. with a median age of 64 yrs. were included in the present analysis.

Results:
After a median follow-up of 82 weeks (w) the following CA were associated with a significantly shorter event-free survival (EFS): 17p13 deletion (17p–; 55 vs. 93 w, p<.0001); translocation t(4;14) (t(4;14); 65 vs. 95 w, p<.001), 1q21.2 gains (+1q21.2; 79 vs. 99 w, p=.0002); 13q14 deletion (13q–; 82 vs. 99 w, p=.03); and 8p11.2 deletion (8p–; 80 vs. 95 w, p=.04). Overall survival (OS) was significantly shorter in pts. with +1q21.2 (148 vs. 231 w, p<.0001); 17p– (118 vs. 219 w, p=.001); and t(4;14) (t(4;14); 195 vs. 223 w, p=.017). In a multivariable analysis t(4;14) (p<.001); 17p– (p=.0089); +1q21.2 (p=.031); and beta-2-microglobulin (p=.033) independently predicted outcome.

Conclusion:
In this large cohort of uniformly treated elderly pts. with newly diagnosed MM, CA – in particular 17p–, t(4;14), and +1q21.2 – remain strong predictive markers for outcome.
Supported by a grant from the Else Kröner-Fresenius-Stiftung to P.L. and H.D.

Disclosures:
No relevant conflicts of interest to declare.