bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant NFAT2 signaling in chronic lymphocytic leukemia.
Authors: Heitmann Jonas S. , Maerklin Melanie , Poljak Alexandra , Hackl Bettina , Stickel Juliane , Kanz Lothar , Kopp Hans-Georg , Wirths Stefan , Mueller Martin Rudolf 
Published: March 2020

7019 Background: CLL is a malignancy of mature B cells and constiututes the most common leukemia in adults. It is characterized by a progressive accumulation of clonal B cells, which coexpress CD19, CD23 and CD5. NFAT is a family of highly phosphorylated transcription factors residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the significance of NFAT signaling in B-CLL. Methods: NFAT2 expression and aberrant nuclear translocation in CLL cells (n=30) was assessed by Western Blotting and immunofluorescence. In addition, NFAT2 mRNA levels were measured by qRT-PCR and its DNA binding capacity was assessed using an electrophoretic mobility shift assay. Transcriptional activity of NFAT2 proteins in CLL cells was further analyzed by determining the expression of several well characterized NFAT target genes. Results: We detected a profound overexpression of NFAT2 mRNA and protein in all CLL samples. Using qRT-PCR we found that CD19+CD5+ CLL cells exhibited a significant overexpression of NFAT2 as compared to CD19+ B cells isolated from healthy donors (8-200fold). This overexpression of NFAT2 in CLL cells could also be confirmed on the protein level. We could further demonstrate that even under resting conditions significant amounts of NFAT2 protein had translocated to the nucleus in CLL cells, whereas virtually all NFAT2 was in the cytoplasm in non-malignant B cells. Nuclear NFAT2 in CLL cells was able to bind DNA but its transcriptional activity with respect to several apoptosis-regulating genes (i.e. Spp1, Pdcd1) was severely compromised. Conclusions: These results provide strong evidence that the Ca2+/NFAT signalling axis is constitutively activated in CD5+CD19+ CLL cells. Reduced expression of several apoptosis regulators which are known target genes of NFAT2 links deregulation of this signaling cascade to CLL progression. Further investigation is warranted to investigate the therapeutic potential of modulating Ca2+/Calcineurin/ NFAT signaling in CLL.
Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).
Authors: Schub Andrea , Nägele Virginie , Zugmaier Gerhard , Brandl Christian , Hijazi Youssef , Topp Max S. , Kufer Peter , Wolf Andreas , Klinger Matthias 
Published: March 2020

7020 Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+ target cells. Methods: In a phase 2 study, adult patients (N=36) with relapsed/refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ≤5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ≤1 B cell/μL in <1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-γ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean±SD) were 198±61 pg/mL and 694±236 pg/mL at doses of 5 and 15 μg/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.
Efficacy and safety of quizartinib (AC220) in patients age ≥ 70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML).
Authors: Perl Alexander E. , Dohner Hartmut , Rousselot Philippe H. , Marie Jean-Pierre , Martinelli Giovanni , Shah Neil P. , Levis Mark J. , Gammon Guy , Trone Denise , Cortes Jorge E. 
Published: March 2020

7023 Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in AML are each associated with early relapse after standard chemotherapy and poor survival. Quizartinib, an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: We provide detailed analysis from a Ph 2 study (N = 333) of quizartinib monotherapy, focusing on patients (pts) aged ≥ 70 y with AML that relapsed and/or was refractory to prior therapy. Results: A total of 83 pts age ≥70 y included 60 (72%) FLT3-ITD(+) and 23 (28%) FLT3-ITD(-). Median duration of treatment was 14.6 wks for FLT3-ITD(+) pts and 5.9 wks for FLT3-ITD(-) pts. Composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Of 60 FLT3-ITD(+) pts, 32 (53%) had a CRc (1 CR, 3 CRp, 28 CRi). Of 23 FLT3-ITD(-) pts, 10 (43%) had a CRc (2 CR, 1 CRp, 7 CRi). 12/27 FLT3-ITD(+) pts (44%) and 5/10 FLT3-ITD(-) pts (50%) refractory to prior therapy responded to quizartinib, and 12/83 (14%) survived >1 y. The most common (≥10%) Grade 3 or 4 treatment-related adverse events (TRAEs) were febrile neutropenia (22%), anemia (20%), transient QT interval prolongation (17%; no Grade 4), and thrombocytopenia (12%). 15 pts (18%) had TRAEs resulting in discontinuation. Conclusions: Because AML in the elderly, particularly in those aged ≥70 y, is genetically heterogeneous and often follows a myelodysplastic syndrome, there is a wide assumption that it may be less amenable to FLT3-targeted therapy than AML in younger pts. Our data argue against these conclusions and show that pts aged ≥70 y with chemotherapy-resistant AML have preserved high response rates, and promising survival to quizartinib. Clinical trial information: NCT00989261. [Table: see text]
Variations in FLT3 ligand levels during the course of AML treatment.
Authors: Grunwald Michael Richard , Levis Mark J. 
Published: March 2020

7026 Background: FLT3 ligand (FL) is a hematopoietic growth factor expressed in many tissues. AML patients who are administered myeloablative therapy exhibit a marked and transient rise in plasma FL concentrations. Furthermore, the presence of high concentrations (1000 pg/mL) of FL impedes the efficacy of FLT3 tyrosine kinase inhibitors in vitro. However, the behavior of FL concentrations throughout the course of AML treatment remains unknown. This pilot study was undertaken to track the relationship between AML therapy and FL levels over time. Methods: Ten AML patients were enrolled in an IRB-approved procurement protocol. Blood samples were collected at weekly intervals for one year, and plasma was isolated by centrifugation. Plasma FL and stem cell factor (SCF) concentrations were measured by ELISA. Results: We observed four distinct patterns in FL fluctuations. First, in all cases where induction or consolidation chemotherapy resulted in an aplastic bone marrow (nine patients), FL concentrations rose markedly and consistently to levels >1000 pg/mL following the administration of chemotherapy. Second, in three of four patients whose leukemia was refractory to induction chemotherapy, FL concentrations remained below 500 pg/mL during induction. Third, in two patients receiving the FLT3 TKI sorafenib, FL concentrations did not rise above 500 pg/mL while on this medication. Fourth, in one patient receiving the hypomethylating agent 5-azacitidine, FL concentrations remained below 100 pg/mL throughout the course of therapy. SCF concentrations did not vary throughout the course of chemotherapy. Conclusions: An “FL surge” was seen when cytotoxic chemotherapy resulted in aplasia. This FL surge was not seen with sorafenib or 5-azacitidine. In addition, the FL surge was attenuated in three patients whose leukemia was refractory to chemotherapy. These observations give rise to two new hypotheses regarding FL: 1) It is possible to maintain lower FL levels with targeted agents than with chemotherapy; and 2) Residual leukemia appears to inhibit the FL surge, providing indirect evidence of cross-talk between leukemia and the stromal microenvironment. This inhibition may be the explanation for why AML patients develop pancytopenia early in relapse.
Outcomes of hematopoietic stem cell transplant recipients admitted to the medical intensive care unit.
Authors: Tran Duc Quang , Langston Amelia A. , Waller Edmund K. , Simon Melanie , Gleason Charise , Casbourne Daniela , Fisher Micah , Kaufman Jonathan L. , Flowers Christopher , Lonial Sagar , Nooka Ajay K. 
Published: March 2020

7035 Background: Outcome results for hematopoietic stem cell transplant (HSCT) patients admitted to intensive care unit (ICU) and prognosis is infrequently reported during recent years, especially in view of increasing use of unrelated donors, increasing use of transplant maneuver in older patients using reduced intensity conditioning regimens and improvement in supportive care. We assessed our institutional survival outcomes and evaluated predictors of mortality in HSCT recipients admitted to ICU. Methods: Among the 390 HSCTs performed from March 2011 until July 2012, we retrospectively evaluated 34 HSCT patients admitted to ICU. 22 patients received mechanical ventilation (MV) or vasopressor support and were analyzed separately. All previously defined predictors of mortality were evaluated. SPSS version 20 was used for statistical analysis. Results: 9% of all HSCT patients were admitted to ICU. 65% of patients received allogeneic transplants. Major underlying hematological malignancies were AML/MDS (29%) and myeloma (24%). 41% were admitted for respiratory failure and 23.5% for sepsis. Median age was 55.5 (range: 27-76). Median length of ICU stay was 7 days (0-42) and median APACHE II score was 20 (9-39). 30 day and 60 day mortality rates are 47% and 62% among all patients; 54% and 68% among MV patients or receiving vasopressors. Predictors for day 30 mortality on univariate analysis among all patients were APACHE II score ≥26 (p=0.05). Predictors for day 60 mortality were APACHE II score ≥31 (p=0.001) and multiorgan failure (p=0.009). Among patients receiving MV or vasopressors, APACHE II score ≥31 is the only significant predictor of mortality (p=0.011). On multivariate analysis, APACHE II score ≥31 at day 30 hazards ratio (HR) 3.777 (95%CI 1.041-13.69; p=0.043) and at day 60 HR 3.789 (95%CI 1.07-13.45; p=0.039) are significant predictors of mortality. Conclusions: Significant predictors identified on multivariate analyses were APACHE II score ≥31 at day 30 and day 60. Interestingly, type of transplant is not a significant predictor of mortality. Future studies with larger patient samples and longer follow up are required for further understanding of prognosis in these patients.
Day 100 peripheral blood absolute monocyte/lymphocyte count prognostic score and survival in diffuse large B-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.
Authors: Velazquez Ana I. , Markovic Svetomir , Inwards David James , Micallef Ivana N. M. , Johnston Patrick B. , Hogan William J. , Ansell Stephen Maxted , Porrata Luis F. 
Published: March 2020

7041 Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) at day 100 post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) have not been evaluated. We previously reported that absolute monocyte (AMC)/lymphocyte count (ALC) prognostic score (AMLCPS) at diagnosis of DLBCL patients is a prognostic factor of survival, stratifying patients into three risk groups: low- (AMC<630/μL and ALC>1000/μL), intermediate- (AMC ≥ 630/μL or ALC ≤ 1000/μL) and high-risk (AMC ≥ 630/μL and ALC ≤ 1000/μL) (Leukemia 25: 1502-9, 2011). Therefore, we evaluated day 100 AMLCPS as a prognostic factor of survival by landmark analysis from day 100 post-APBHSCT in DLBCL patients. Methods: DLBCL patients that achieved complete response by day 100 post-APBHSCT qualified for the study. From 2000 to 2007, 134 consecutive DLBCL patients were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier analysis. Results: The median follow up from day 100 for the cohort was 5.5 years (range: 0.17-12.17 years) and for living patients (N=93) was 6.9 years (range: 2.5-12.17 years). Day 100 AMLCPS was able to stratify patients into three risk groups low-, intermediate-, and high-risk for OS [low: median OS = not reached, 5-year survival rate = 94% (95%CI 83.3%-98.1%); intermediate: median OS = not reached, 5-year survival rate = 70% (95%CI 58.0%-79.8%); high: median OS = 2.2 years, 5-year survival rate = 13% (95%CI 3.4%-40.5%); p<0.0001] and PFS [low: median PFS = not reached, 5-year progression free rate = 87% (95%CI 74.5%-94.3%); intermediate: median PFS = 10.9 years, 5-year progression free rate = 67% (95%CI 55.4%-77.5%); high: median PFS = 1 year, 5-year progression free rate = 13% (95%CI 3.4%-40.5%); p<0.0001]. The day 100 AMLCPS was balanced in relation to the International Prognostic Index (IPI; p=0.22), infused CD34+ stem cells (p=0.92), and disease status pre-APBHSCT (complete remission versus partial response; p=0.11). Conclusions: The day 100 AMLCPS is a simple biomarker that can help identify DLBCL patients post-APBHSCT with poor clinical outcomes.
Incidence of engraftment fever post autologous transplant for lymphomas and analysis of risk factors.
Authors: Pandey Avinash , Mittal Sushant S. , Thippeswamy Ravi , Rajamanickam K. Deepan , Gokarn Anant , Bhosale Bharatsinha Baburao , Mathew Libin , Kannan Sadhna , Bagal Bhausaheb Pandurang , Gawande Jayant Shankar , Khattry Navin 
Published: March 2020

7043 Background: Engraftment fever (EF) is a phenomenon observed in some patients undergoing autologous transplant (ASCT). We analyzed our data to evaluate the incidence and risk factors associated with EF. Methods: Seventy-nine patients underwent ASCT (53-Hodgkin’s and 26- Non Hodgkin’s) from August 2007 – January 2013. All except 5 received LACE (Lomustine, Ara-C, Cyclophosphamide and Etoposide) conditioning regimen. EF was defined as onset of fever with rising white cell count for which no infectious cause was ascertained. Patients of EF and non-EF groups were compared for the following variables to determine risk factors. These included histology, number of lines of chemotherapy regimens pre-transplant, complete remission (CR) at transplant, peripheral blood CD 34 count on day 1 of collection (PBCD34-D1), CD 34 cell dose collected and infused and number of days of stem cell collection. Results: The median age at transplant was 23.5 years with 57 males and 22 females. Time to neutrophil and platelet engraftment was 10 and 13 days respectively. EF was seen in 35 patients (44 %) at a median of 9 days. Short course of methylprednisolone (n=28) or hydrocortisone (n=3) was given to which all responded. On univariate analysis, PBCD34-D1 > 50/uL (P = 0.037), CD 34 cell dose infused >5.9x106/kg (P=0.012),CD34 cell dose collected > 7.2 x 10 6 /kg (P=0.032) , those receiving ≤ 2 lines of chemotherapy regimens before transplant (P=0.04), those who had ≤ 2 days of stem cell collection (P=0.002) and patients in CR at transplant (P = 0.015) were associated with risk of developing EF. On multivariate analysis, patients in CR at transplant and those who had ≤ 2 days of collection had higher risk of EF. Conclusions: The incidence of EF is high. Patients with lesser days of stem collection and those in CR at transplant have significant risk of developing EF.
Rapid identification of drug-resistant BCR-ABL(+) leukemia.
Authors: Rieder Ronald J. , Zhao Zhihui , Chalmers Alex , Stone Richard M. , Galinski Ilene 
Published: March 2020

7050 Background: Approximately 20% of patients with chronic myeloid leukemia and most patients with BCR-ABL-positive acute leukemia demonstrate resistance to imatinib mesylate resulting in treatment failure or suboptimal patient outcomes. We hypothesize that monitoring the development of cellular stress in BCR-ABL cells incubated with tyrosine kinase inhibitors (TKI) can be used as an early marker for determining the effects of the drugs on the cancer cells enabling rapid identification of drug-resistance and facilitating change to more effective therapies. Methods: The dielectric permittivities of non-leukemic peripheral blood mononuclear cells (PBMCs) and BCR-ABL cell lines known to be resistant (K562R and BaF3/T315I) or sensitive (K562 and HL60/BCR-ABL) to different TKIs were measured in the presence of imatinib (IMT), dasatinib (DAS), nilotinib (NIL), or ponatinib (PON) using the Z-Sense differential impedance sensing platform to record any changes in cellular stress. We also performed similar measurements on PBMCs from newly diagnosed CML patients exposed in vitro to the same TKIs. Results: Non-leukemic PBMCs showed no significant background levels when incubated with the following TKI concentrations: IMT (5 mg/mL), DAS (5 mg/mL), NIL (2.5 mg/mL), and PON (5 ng/mL). Normalized dielectric responses for all drug-resistant cell lines showed no change in value similar to control runs where no drugs were added. In contrast, all responses obtained for cell lines sensitive to these same TKIs were immediate and continuously decreased in value over time compared with resistant cell lines (p<0.01). All sensitivities were confirmed by MTT assay. Notably, the response of BaF3/T315I cells to PON was easily distinguished from the responses to IMT, DAS, and NIL. Of significance, all responses of BCR-ABL(+) patient blood to the four TKIs measured prior to commencing therapy were qualitatively similar to sensitive cell line measurements and subsequently confirmed to respond to IMT therapy. Conclusions: Drug-sensitive BCR-ABL(+) cells can be readily distinguished from drug-resistant cells without cell culturing in less than 60 minutes by monitoring the development of cellular stress in response to TKI drugs using differential impedance sensing.
Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update.
Authors: Larson Richard A. , Hochhaus Andreas , Saglio Giuseppe , Kim Dong-Wook , Jootar Saengsuree , Le Coutre Philipp D. , Reiffers Josy , Pasquini Ricardo , Goldberg Stuart L. , Clark Richard E. , Kemp Charisse N. , Fan Xiaolin , Menssen Hans D. , Hughes Timothy P. , Kantarjian Hagop M. 
Published: March 2020

7052^ Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS), MR4 (≤ 0.01%IS), and MR4.5 (≤ 0.0032%IS) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n = 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n = 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n = 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497. [Table: see text]
Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.
Authors: Spector Nelson , Leber Brian , Lipton Jeffrey Howard , De Souza Carmino , Moiraghi Beatriz , Steegmann Juan Luis , Schwarer Anthony P. , Cervantes Francisco , Hughes Timothy P. , Purkayastha Das , Collins LaTonya R , Szczudlo Tomasz K. , Rea Delphine 
Published: March 2020

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]