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Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic Leukemia
Bride, Karen L; Hu, Hai; Tikhonova, Anastasia; Fuller, Tori J; Vincent, Tiffaney L; Shraim, Rawan; Li, Marilyn M; Carroll, William L; Raetz, Elizabeth A; Aifantis, Iannis; Teachey, David T
Despite improvements in outcomes for children with B and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKis) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKis, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKis caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKis with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKis and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.
PMID: 34937317
ISSN: 1592-8721
CID: 5108942
Catheter-Directed Thrombolysis for Neonatal IVC and Bilateral Renal Vein Thrombosis: A Case Report
Guichet, Phillip L; Jasinski, Sylwia; Malaga-Dieguez, Laura; De Los Reyes, Francis A; Ahuja, Tania; Bride, Karen L; Patel, Amish
Renal vein thrombosis is the most common non-catheter-associated venous thromboembolism event in neonates, accounting for up to 20% of cases. Although mortality rates are lower than a variety of other forms of pediatric thrombosis, renal vein thrombi are associated with significant short-term and long-term sequelae. This report presents the case of a full-term neonate presenting with bilateral renal vein thrombosis with inferior vena cava involvement treated with catheter-directed thrombolysis. This case report intends to highlight the value of a multidisciplinary approach to pediatric venous thromboembolism and to outline relevant procedural details and current laboratory and imaging monitoring of catheter-directed thrombolysis.
PMID: 32569035
ISSN: 1536-3678
CID: 4492822
Evaluation of phenotype-genotype correlation in two common PIEZO1 mutations P.R2456H and P.L2495-E2495DUP [Meeting Abstract]
Risinger, M; Black, V; Hsieh, L; Prins, R C; Menell, J; Badawi, M; Rutherford, C; Bride, K L; Niss, O; Quinn, C T; Seu, K G; Zhang, W; Kalfa, T A
Hereditary xerocytosis (HX) is a rare autosomal dominant hemolytic anemia caused by mutations in the mechanosensitive cation channel PIEZO1 or, less commonly, in the Ca2+-gated K+ channel KCNN4 (Gardos channel). It is a clinically heterogeneous condition, characterized by erythrocyte dehydration. As erythrocytes traverse narrow capillaries and sinusoids, PIEZO1 is thought to be activated by mechanical stimuli, leading to increased intracellular Ca2+ which then may activate KCNN4, causing K+ efflux and water loss. The P.R2456H and p.L2495-E2496dup PIEZO1 mutations are likely the most common of the PIEZO1 disease-causing mutations and both result in delayed channel inactivation (Glogowska et al., 201 7, Blood 1 30:1 845). The prolonged channel activity in response to mechanical stimulation is likely to contribute to erythrocyte dehydration. Ten patients with PIEZO1-associated HX (5 with P.R2456H and 5 with p.L2495-E2496dup PIEZO1 heterozygous mutations) had their diagnosis established utilizing a Next Generation sequencing panel for hereditary hemolytic and congenital dyserythropoietic anemias (HHA/CDA panel). These patients, along with family members who had similar clinical characteristics (a total of 8 patients with P.R2456H and 6 patients with p.L2495-E2496dup) ranging from 2-63 years of age, were enrolled in an IRB-approved study to explore the phenotype-genotype correlation of the disease. We collected patient and family histories and laboratory data and performed phenotypic testing including ektacytometry and erythrocyte cation determinations by atomic spectroscopy. Most of the patients in our cohort had compensated hemolysis without anemia at the time of evaluation and had not required any transfusions. All of the patients had elevated reticulocyte counts ranging from 5.7 to 1 5.7 %. Reticulocyte counts of individuals with the P.R2456H mutation were significantly higher than those with the p.L2495-E2496dup mutation (Student's t test, p=0.01). Some of the patients had splenomegaly, but it was not a universal finding. Although elevated MCHC is often considered a hallmark of HX, most of the individuals in this cohort had increased MCV and MCH but only high-normal MCHC. Varying percentages of hyper dense cells were detected in blood samples analyzed using an Advia Hematology System and stomatocytes were notable in most peripheral blood smears. Several complications have been associated with HX including hydrops fetalis, hemolytic episodes, thrombosis (especially after splenectomy), gallstones, and iron overload. One patient in our cohort had experienced ascites and a pleural effusion in the perinatal period and one was diagnosed with gallstones at age 11. Nearly all the patients had an increase in total bilirubin. Ferritin levels were increased in the majority of the patients tested after 1 5 years of age. The three patients older than 40 years of age had iron overload verified by T2* MRI imaging of the liver. HX presents several diagnostic challenges due to its heterogeneity. Two of the subjects in our study had been previously diagnosed with hereditary spherocytosis (HS) and one had the diagnosis of congenital dyserythropoietic anemia (CDA) prior to genetic evaluation. Misdiagnosis of individuals with HX as having HS is especially problematic since splenectomy is contraindicated in HX due to a greatly increased incidence of thromboembolic complications. Another diagnostic consideration concerns the use of osmotic fragility tests. Although osmotic fragility tests are frequently used to diagnose HX, ektacytometry provides greater accuracy. In the present study two patients who had ektacytometry results characteristic of HX had reportedly normal osmotic fragility tests in previous work-up. All individuals in our cohort with confirmed disease-causing mutations in PIEZO1 demonstrated the classic left shifted ektacytometry osmoscan indicative of erythrocyte dehydration. In addition, all individuals with these m demonstrated the expected decrease in erythrocyte potassium content not associated with a proportional increase in sodium. This illustrate importance of specialized testing (ektacytometry and/or intracellular cation determinations) and the use of appropriately designed genetic panels to establish an accurate diagnosis in patients with hemolytic anemia of ambiguous phenotype, especially when splenectomy is being contemplated
EMBASE:626414667
ISSN: 0006-4971
CID: 3703472
Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation
Mande, Purvi; Zirak, Bahar; Ko, Wei-Che; Taravati, Keyon; Bride, Karen L; Brodeur, Tia Y; Deng, April; Dresser, Karen; Jiang, Zhaozhao; Ettinger, Rachel; Fitzgerald, Katherine A; Rosenblum, Michael D; Harris, John E; Marshak-Rothstein, Ann
Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.
PMCID:6025993
PMID: 29889098
ISSN: 1558-8238
CID: 3166972
Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL)
Bride, Karen L; Vincent, Tiffaney L; Im, Soo-Yeon; Aplenc, Richard; Barrett, David M; Carroll, William L; Carson, Robin; Dai, Yunfeng; Devidas, Meenakshi; Dunsmore, Kimberly P; Fuller, Tori; Glisovic-Aplenc, Tina; Horton, Terzah M; Hunger, Stephen P; Loh, Mignon L; Maude, Shannon L; Raetz, Elizabeth A; Winter, Stuart S; Grupp, Stephan A; Hermiston, Michelle L; Wood, Brent L; Teachey, David T
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.
PMCID:5833263
PMID: 29305553
ISSN: 1528-0020
CID: 2927142
Utility of the immature platelet fraction in pediatric immune thrombocytopenia: Differentiating from bone marrow failure and predicting bleeding risk
McDonnell, Alicia; Bride, Karen L; Lim, Derick; Paessler, Michele; Witmer, Char M; Lambert, Michele P
BACKGROUND:Differentiating childhood immune thrombocytopenia (ITP) from other cause of thrombocytopenia remains a diagnosis of exclusion. Additionally factors that predict bleeding risk for those patients with ITP are currently not well understood. Previous small studies have suggested that immature platelet fraction (IPF) may differentiate ITP from other causes of thrombocytopenia and in combination with other factors may predict bleeding risk. METHODS:/l. Each patient chart was reviewed for final diagnosis and bleeding symptoms. A bleeding severity score was retrospectively assigned. RESULTS:/l in patients with ITP. CONCLUSIONS:IPF measurement alone has utility in both the diagnosis of ITP and identifying patients at increased risk of hemorrhage. Further study is required to understand the pathophysiological differences of ITP patients with lower IPF/AIPN.
PMID: 28921855
ISSN: 1545-5017
CID: 3144772
Hematopoietic Stem Cell Transplantation (HSCT) for Acute Lymphoblastic Leukemia (ALL) in First Remission (CR1): A Single-Institution Retrospective Cohort Study Demonstrating Excellent Event-Free (EFS) and Overall Survival (OS) [Meeting Abstract]
Bride, Karen L.; Freedman, Jason L.; Bunin, Nancy J.; Hunger, Stephen P.; Rheingold, Susan R.; Seif, Alix E.
ISI:000370910300337
ISSN: 1083-8791
CID: 3144762
Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial
Bride, Karen L; Vincent, Tiffaney; Smith-Whitley, Kim; Lambert, Michele P; Bleesing, Jack J; Seif, Alix E; Manno, Catherine S; Casper, James; Grupp, Stephan A; Teachey, David T
Patients with autoimmune multi-lineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N=12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response, including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1-3 months of starting sirolimus. Double negative T (DNT) cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multi-lineage cytopenias secondary to common variable immune deficiency (CVID), Evans syndrome (ES) or systemic lupus erythematosus (SLE), and most achieved a CR (N= 8), although the time to CR was often slower than was seen in ALPS. Six children with single lineage autoimmune cytopenias were treated and only two responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over one year (median 2 years, range 1-4.5 years). In summary, sirolimus led to complete and durable responses in a majority of children with refractory multi-lineage autoimmune cytopenias. The responses seen in ALPS patients were profound suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment for patients needing chronic therapy. The results in other multi-lineage autoimmune cytopenia cohorts were encouraging and sirolimus should be considered in children with SLE, ES, and CVID.
PMCID:4705607
PMID: 26504182
ISSN: 1528-0020
CID: 1817482