Publications by authors named "Tara L Lin"

38 Publications

Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.

Blood Adv 2021 Mar;5(6):1719-1728

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.
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http://dx.doi.org/10.1182/bloodadvances.2020003510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993093PMC
March 2021

The important role of intensive induction chemotherapy in the treatment of acute myeloid leukemia.

Expert Rev Hematol 2021 Mar 24:1-11. Epub 2021 Mar 24.

Hematology, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Rome, Italy.

: Intensive induction chemotherapy followed by post-remission consolidation and/or allogeneic hematopoietic transplantation has been a standard-of-care therapy for acute myeloid leukemia (AML) for decades. In recent years, a plethora of new agents have been approved for AML treatment, dramatically changing the AML treatment landscape.: This review provides an overview of the current role of intensive chemotherapy in the changing AML treatment landscape. PubMed-indexed publications (through 2020) and abstracts presented at major national and international conferences were reviewed for inclusion.: While intensive chemotherapy is standard-of-care therapy for younger patients with AML, older patients were historically viewed as universally ineligible for intensive chemotherapy; however, several studies suggest many older patients benefit from intensive chemotherapy with a curative intent, and a more holistic approach to determining eligibility for intensive treatment is recommended. Intensive strategies have also been expanded to include novel chemotherapy designs and chemotherapy in combination with targeted agents for patients with certain disease characteristics, which may permit more personalized treatment decisions. Intensive chemotherapy continues to play a pivotal role for the management of many AML patients and can offer the best chance of long-term remission, especially when followed by transplantation.
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http://dx.doi.org/10.1080/17474086.2021.1886920DOI Listing
March 2021

Preclinical Evaluation of Gilteritinib on NPM1-ALK-Driven Anaplastic Large Cell Lymphoma Cells.

Mol Cancer Res 2021 Jan 29. Epub 2021 Jan 29.

Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the () fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G-G-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies. IMPLICATIONS: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK-driven ALCL cells and pave a path for developing future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/00/0/000/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0738DOI Listing
January 2021

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Nat Med 2020 12 26;26(12):1852-1858. Epub 2020 Oct 26.

The Ohio State University, Columbus, OH, USA.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
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http://dx.doi.org/10.1038/s41591-020-1089-8DOI Listing
December 2020

A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Clin Cancer Res 2020 Dec 30;26(23):6132-6140. Epub 2020 Sep 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.

Patients And Methods: Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m; days 1-10) or decitabine (20 mg/m; days 1-5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.

Results: Forty patients were treated with onvansertib (12-90 mg/m) in combination with LDAC ( = 17) or decitabine ( = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.

Conclusions: The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2586DOI Listing
December 2020

Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of and Expression.

Clin Cancer Res 2020 Nov 20;26(22):5852-5859. Epub 2020 Aug 20.

Winship Cancer Institute of Emory University, Atlanta, Georgia.

Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to and overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML.

Patients And Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.

Results: Fifty-three patients ( = 12, phase Ib and = 41, phase II) with previously untreated ( = 39) or secondary ( = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline and expression higher than the median had improved overall survival compared with patients with below median and expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed.

Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1064DOI Listing
November 2020

High-level MYC expression associates with poor survival in patients with acute myeloid leukemia and collaborates with overexpressed p53 in leukemic transformation in patients with myelodysplastic syndrome.

Int J Lab Hematol 2021 Feb 19;43(1):99-109. Epub 2020 Aug 19.

Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.

Introduction: Patients with mutated and overexpressed p53 have an aggressive course in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Studies on the impact of MYC expression in AML are limited. This is the first study to evaluate MYC expression and p53 status in AML and MDS.

Methods: We identified 214 patients, 101 AML, 79 MDS, and 34 negative control patients. We retrospectively assessed p53 and MYC expression by immunohistochemistry and correlated MYC expression with p53 expression and aberrational status of TP53.

Results: The level of both p53 and MYC expression was significantly higher in AML (mean: 9.7%; 12.1%) and MDS (mean: 5.2%; 5.5%) patients compared with control cases (mean: 0.18%; 2.3%; P = .001-0.02). p53 and MYC expression levels were even more elevated in AML when compared to MDS patients (P < .001). MYC expression was significantly associated with p53 expression and TP53 aberration in AML patients but not in MDS patients (P < .001). p53 expression and >20% MYC expression showed an adverse impact on overall survival (OS) (P < .05) in AML patients while p53 but not MYC expression showed an adverse impact on OS in MDS patients. MYC and p53 dual expression, as well as combined MYC expression and TP53 aberration, showed negative impact on OS in AML patients. MDS patients with leukemic transformation revealed an interval increase in expression of both p53 and MYC.

Conclusion: High-level MYC expression associates with p53 abnormality and poor survival in AML. MYC may provide proliferative advantage for leukemic progression in p53 dependent and independent manner.
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http://dx.doi.org/10.1111/ijlh.13316DOI Listing
February 2021

Safety of gemtuzumab ozogamicin as monotherapy or combination therapy in an expanded-access protocol for patients with relapsed or refractory acute myeloid leukemia.

Leuk Lymphoma 2020 08 20;61(8):1965-1973. Epub 2020 May 20.

Washington University Medical School, St. Louis, MO, USA.

Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML ( 139), combination therapy for R/R AML ( 183), or treatment for R/R APL ( 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease ( 4) and drug-induced liver injury ( 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs. NCT02312037.
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http://dx.doi.org/10.1080/10428194.2020.1742897DOI Listing
August 2020

Final safety and efficacy results from the CPX-351 early access program for older patients with high-risk or secondary acute myeloid leukemia.

Leuk Lymphoma 2020 05 26;61(5):1188-1194. Epub 2020 Feb 26.

University of Kansas Medical Center, Kansas City, KS, USA.

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar drug ratio, achieved superior efficacy compared with conventional chemotherapy in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML) in phase 2 and 3 studies. Prior to CPX-351 commercialization, an expanded access program (EAP) provided CPX-351 access for this population in the United States. In this phase 4, single-arm, open-label study (NCT02533115), 52 patients were treated with CPX-351 for 1-2 induction cycles and ≤4 consolidation cycles. The primary endpoint was safety. The most common serious adverse events were febrile neutropenia (19%), pneumonia (10%), and infection (8%). The 30- and 60-d mortality rates were 0% and 6%, respectively. Remission was achieved by 44% of patients; 90% of patients were alive at study completion. Overall, these results support outcomes from prior studies and the use of CPX-351 in older adults with newly diagnosed, high-risk/secondary AML.
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http://dx.doi.org/10.1080/10428194.2020.1725503DOI Listing
May 2020

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

JCO Oncol Pract 2020 06 27;16(6):e464-e475. Epub 2020 Jan 27.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT.

Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1.

Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% 35%, respectively [ = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months).

Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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http://dx.doi.org/10.1200/JOP.19.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291544PMC
June 2020

A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Cancers (Basel) 2019 Dec 26;12(1). Epub 2019 Dec 26.

Department of Medicine, Division of Hematology/Oncology Miller School of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.

Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia ( = 2), pneumonia/acute respiratory failure ( = 1), and hypotension ( = 1). 9.76 mg/m was defined as the MTD of OXi4503 when administered in combination with 1 g/m ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434-NA), which was significantly longer than the median OS time of 113 days (95% CI: 77-172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, -value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study.
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http://dx.doi.org/10.3390/cancers12010074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016810PMC
December 2019

Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 3;25(9):1713-1719. Epub 2019 Jun 3.

Division of Hematologic Malignancies and Cellular Therapy, Internal Medicine Department, University of Kansas Medical Center, Kansas city, KS; Division of Hematology and Bone Marrow Transplantation Program, University of Rochester Medical Center, Rochester, NY. Electronic address:

Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia. Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34 cell engraftment by reducing erythropoietin levels. A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery. In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls. Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen. Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery. All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days. A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (n = 19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, P = .002). HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted. © 2019 American Society for Blood and Marrow Transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.028DOI Listing
September 2019

A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias.

Cancer Chemother Pharmacol 2019 07 16;84(1):163-173. Epub 2019 May 16.

Celator/Jazz Pharmaceuticals, Palo Alto, CA, USA.

Purpose: Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.

Methods: Twenty-six adults with acute leukemia were treated with CPX-351 for 1-2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline.

Results: Mean QTcF changes were < 10 ms at all time points. No clinically meaningful effects on heart rate, QRS interval, PR interval, or QTcB were observed. Estimated mean half-lives for total cytarabine and daunorubicin were > 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea.

Conclusions: The cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin.

Trial Registration: Clinicaltrials.gov identifier: NCT02238925.
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http://dx.doi.org/10.1007/s00280-019-03856-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562048PMC
July 2019

Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.

J Clin Oncol 2019 05 20;37(15):1277-1284. Epub 2019 Mar 20.

10 Weill Cornell Medical College, New York, NY.

Purpose: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.

Patients And Methods: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).

Results: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).

Conclusion: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.
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http://dx.doi.org/10.1200/JCO.18.01600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524989PMC
May 2019

Long-term results of a pilot study evaluating hyperbaric oxygen therapy to improve umbilical cord blood engraftment.

Ann Hematol 2019 Feb 31;98(2):481-489. Epub 2018 Oct 31.

Hemagology/Oncology and Bone Marrow Transplantation Program, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA.

Umbilical cord blood (UCB) transplantation is a promising option for hematopoietic stem cell transplantation in patients with hematologic malignancies who lack an HLA-matched sibling or well-matched unrelated donor; however, it has a higher incidence of delayed or failed engraftment because cell doses are low and bone marrow homing is inefficient. We have demonstrated that pre-treating irradiated immune-deficient mice with hyperbaric oxygen (HBO) prior to UCB CD34+ cell transplantation lowered host systemic erythropoietin (EPO) and improved UCB CD34+ cell homing and engraftment. These findings suggested that EPO-EPO-R signaling plays a role in UCB CD34+ homing and engraftment. In a pilot clinical trial, we showed that recipients of HBO therapy prior to UCB cell infusion had reduced systemic EPO, which was associated with improved kinetics of blood count recovery. Although early clinical outcomes at day 100 were encouraging, with improved overall survival, the long-term effects of HBO therapy on UCB-transplanted patients were not evaluated. In this study, we examined the long-term outcome of patients in our pilot study, compared with a historic control group, and correlated their clinical outcomes to serum EPO response to HBO. While 50% of HBO-treated patients received single UCB units, ~ 90% of the control patients received double UCB units. Although HBO patients had much better rates of survival at 6 months, their 1-year survival did not significantly differ from the control group. HBO-treated patients had on average lower relapse and non-relapse mortality rates, and less chronic graft versus host disease (GVHD), but had increased acute GVHD. However, these differences were not statistically significant, probably because of the small sample size. In the HBO-treated cohort, immune reconstitution analysis showed significant improvement in early B cell recovery, with a trend toward improvement in early NK cell recovery. When we evaluated the ratio of 8 h to baseline EPO levels, we found a non-significant trend toward lower EPO values in those who neither relapsed nor died by 1 year, compared to those who died or relapsed. This result suggests that EPO response to HBO may be associated with better outcomes. Disease progression-free survival was also improved in those who had more than 80% reduction in EPO levels in response to HBO. Our study highlights the long-term safety of HBO therapy when used prior to UCB transplantation. Future UCB transplant patients who receive HBO should have their serum EPO response measured, as it may be a marker of relapse/mortality.
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http://dx.doi.org/10.1007/s00277-018-3532-1DOI Listing
February 2019

Functional genomic landscape of acute myeloid leukaemia.

Nature 2018 10 17;562(7728):526-531. Epub 2018 Oct 17.

Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
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http://dx.doi.org/10.1038/s41586-018-0623-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280667PMC
October 2018

A novel extracellular matrix-based leukemia model supports leukemia cells with stem cell-like characteristics.

Leuk Res 2018 09 16;72:105-112. Epub 2018 Aug 16.

Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States; Division of Hematology/Oncology and Blood and Marrow Transplantation Program, 2330 Shawnee Mission Parkway, University of Kansas Medical Center, Kansas City, KS, United States; Department of Medicine, Hematology/Oncology and Bone Marrow Transplant Program, University of Rochester Medical Center, Rochester, NY, 14642, United States. Electronic address:

Acute myeloid leukemia (AML) relapse results from the survival of chemotherapy-resistant and quiescent leukemia stem cells (LSC). These LSCs reside in the bone marrow microenvironment, comprised of other cells and extracellular matrix (ECM), which facilitates LSC quiescence through expression of cell adhesion molecules. We used decellularized Wharton's jelly matrix (DWJM), the gelatinous material in the umbilical cord, as a scaffolding material to culture leukemia cells, because it contains many components of the bone marrow extracellular matrix, including collagen, fibronectin, lumican, and hyaluronic acid (HA). Leukemia cells cultured in DWJM demonstrated decreased proliferation without undergoing significant differentiation. After culture in DWJM, these cells also exhibited changes in morphology, acquiring a spindle-shaped appearance, and an increase in the ALDH cell population. When treated with a high-dose of doxorubicin, leukemia cells in DWJM demonstrated less apoptosis compared with cells in suspension. Serial colony forming unit (CFU) assays indicated that leukemia cells cultured in DWJM showed increased colony-forming ability after both primary and secondary plating. Leukemia cell culture in DWJM was associated with increased N-cadherin expression by flow cytometry. Our data suggest that DWJM could serve as an ECM-based model to study AML stem cell-like cell behavior and chemotherapy sensitivity.
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http://dx.doi.org/10.1016/j.leukres.2018.08.012DOI Listing
September 2018

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia.

J Clin Oncol 2018 09 19;36(26):2684-2692. Epub 2018 Jul 19.

Jeffrey E. Lancet, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Geoffrey L. Uy, Washington University School of Medicine, St Louis, MO; Jorge E. Cortes, The University of Texas MD Anderson Cancer Center, Houston, TX; Laura F. Newell, Oregon Health & Science University, Portland, OR; Tara L. Lin, University of Kansas Medical Center, Kansas City, KS; Ellen K. Ritchie, Weill Cornell Medical College, New York; Jonathan E. Kolitz, Northwell Health System, Lake Success; Daniel H. Ryan, University of Rochester, Rochester, NY; Robert K. Stuart, Medical University of South Carolina, Charleston, SC; Stephen A. Strickland, Vanderbilt-Ingram Cancer Center, Nashville, TN; Donna Hogge, Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver, British Columbia, Canada; Scott R. Solomon, The Leukemia Program at Northside Hospital Cancer Center Institute, Atlanta, GA; Richard M. Stone, Dana-Farber Cancer Institute, Boston, MA; Dale L. Bixby, University of Michigan, Grass Lake, MI; Gary J. Schiller, University of California-Los Angeles, Los Angeles; Matthew J. Wieduwilt, University of California-San Diego, La Jolla; Kamalika Banerjee, Michael Chiarella, Arthur C. Louie, Jazz Pharmaceuticals, Palo Alto; Bruno C. Medeiros, Stanford University School of Medicine, Stanford, CA; and Antje Hoering, Cancer Research and Biostatistics, Seattle, WA.

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.
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http://dx.doi.org/10.1200/JCO.2017.77.6112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127025PMC
September 2018

Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Oct 8;23(10):1641-1645. Epub 2017 Jun 8.

Division of Hematologic Malignancy and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas. Electronic address:

Although outpatient autologous stem cell transplantation (ASCT) is safe and feasible in most instances, some patients undergoing planned outpatient transplantation for multiple myeloma (MM) will need inpatient admission for transplantation-related complications. We aim to evaluate the difference, if any, between outpatient and inpatient ASCT cohorts of MM patients in terms of admission rate, transplantation outcome, and overall survival. We also plan to assess whether the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and Karnofsky Performance Status (KPS) can predict unplanned admissions after adjusting for confounding factors. Patients with MM (n = 448) who underwent transplantation at our institution between 2009 and 2014 were included in this retrospective analysis. Patients were grouped into 3 cohorts: cohort A, planned inpatient ASCT (n = 216); cohort B, unplanned inpatient admissions (n = 57); and cohort C, planned outpatient SCT (n = 175). The statistical approach included descriptive, bivariate, and survival analyses. There were no differences among the 3 cohorts in terms of type of myeloma, stage at diagnosis, time from diagnosis to transplantation, CD34 cell dose, engraftment kinetics, and 100-day response rates. Serum creatinine was higher and patients were relatively older in both the planned inpatient (median age, 62 years; range, 33 to 80 years) and unplanned (median age, 59 years; range, 44 to 69 years) admission cohorts compared with the outpatient-only cohort (median age, 57 years; range, 40 to 70 years) (P < .05). Performance status (cohort A: median, 90%; range, 60% to 100%; cohort B: 80%, 50% to 100%; cohort C: 80%, 60% to 100%) was lower (P < .05) and HCT-CI score (cohort A: median, 1.78; range, 0 to 8; cohort B: 2.67, 0 to 9; cohort C: 2.16, 0 to 7) was higher (P < .004) in both inpatient groups compared with the planned outpatient cohort. With a median follow up of 5 years, poor performance status (KPS <70%) appeared to be associated with worse survival (P < .002). HCT-CI >2 also appeared to be associated with worse outcomes compared with HCT-CI 0 to 1, the the difference did not reach statistical significance (hazard ratio, 1.41l 95% confidence interval, 0.72 to 2.76). Only 1 patient out of 448 died from a transplantation-related cause. Outpatient transplantation for myeloma is safe and feasible. In our experience, one-third of the patients undergoing outpatient transplantation needed to be admitted for transplantation-related toxicities. Patients in this group had lower preexisting KPS and higher HCT-CI scores. Whether planned admission for this group would have prevented unplanned admissions and undue stress on patients and the healthcare system should be tested in a prospective manner.
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http://dx.doi.org/10.1016/j.bbmt.2017.06.001DOI Listing
October 2017

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.

Blood 2016 12 19;128(25):3000-3010. Epub 2016 Oct 19.

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34 cells. A significant population of UCB CD34 HSPC expresses cell surface EPOR. Exposure of UCB CD34 HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34 HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34 cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).
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http://dx.doi.org/10.1182/blood-2016-05-715292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179334PMC
December 2016

Outcomes for newly diagnosed patients with acute myeloid leukemia dosed on actual or adjusted body weight.

Cancer Chemother Pharmacol 2015 Oct 1;76(4):691-7. Epub 2015 Aug 1.

University of Kansas School of Medicine, The University of Kansas Cancer Center, 2330 Shawnee Mission Parkway, Mail Stop 5003, Westwood, KS, 66205, USA.

Purpose: Data from solid tumor malignancies suggest that actual body weight (ABW) dosing improves overall outcomes. There is the potential to compromise efficacy when chemotherapy dosages are reduced, but the impact of dose adjustment on clinical response and toxicity in hematologic malignancies is unknown. The purpose of this study was to evaluate the outcomes of utilizing a percent of ABW for acute myeloid leukemia (AML) induction chemotherapy dosing.

Methods: This retrospective, single-center study included 146 patients who received 7 + 3 induction (cytarabine and anthracycline) for treatment of AML. Study design evaluated the relationship between percentage of ABW dosing and complete response (CR) rates in patients newly diagnosed with AML.

Results: Percentage of ABW dosing did not influence CR rates in patients undergoing induction chemotherapy for AML (p = 0.83); nor did it influence rate of death at 30 days or relapse at 6 months (p = 0.94). When comparing patients dosed at 90-100 % of ABW compared to <90 % ABW, CR rates were not significantly different in patients classified as poor risk (p = 0.907). All favorable risk category patients obtained CR.

Conclusions: Preemptive dose reductions for obesity did not influence CR rates for patients with AML undergoing induction chemotherapy and did not influence the composite endpoint of death at 30 days or disease relapse at 6 months.
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http://dx.doi.org/10.1007/s00280-015-2829-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725583PMC
October 2015

Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation.

J Clin Apher 2016 Aug 29;31(4):347-52. Epub 2015 May 29.

Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas.

Extracorporeal photopheresis (ECP) is a commonly used treatment for severe graft-versus-host-disease (GVHD). We sought to evaluate the effects of ECP over a prolonged period on forced expiratory volume in 1 s (FEV1) in patients with pulmonary GVHD. We identified eight patients who developed new airflow obstruction following allogeneic stem cell transplantation and a substantial decline in FEV1 despite receiving corticosteroids and standard therapy for pulmonary GVHD. Those eight patients were treated with ECP for a period of 1 year, with a primary endpoint of FEV1 change during this treatment period. Over the first 3 months of ECP, there was no further decline in FEV1 in seven of the eight patients. However, over the 1 year period, only two of the eight patients had stability in FEV1. The rate of FEV1 decline was substantially less once ECP was initiated, though the median FEV1 continued to decline over 1 year of therapy. All patients survived through the first year of ECP therapy. There was a significant decrease in the median dose of prednisone per patient throughout the 12 months of ECP treatment. ECP shows promise in slowing rate of decline of FEV1 in pulmonary GVHD, though the effects may not be long lived. J. Clin. Apheresis 31:347-352, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jca.21404DOI Listing
August 2016

High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA.

Case Rep Hematol 2015 26;2015:343854. Epub 2015 Jan 26.

Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, KS 66210, USA.

Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-trans retinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.
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http://dx.doi.org/10.1155/2015/343854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321077PMC
February 2015

Rates of complete diagnostic testing for patients with acute myeloid leukemia.

Cancer Med 2015 Apr 26;4(4):519-22. Epub 2015 Jan 26.

Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas School of Medicine, 3901 Rainbow Blvd., Kansas City, Kansas, 66210.

In addition to cytogenetics, additional molecular markers of prognosis have been identified and incorporated into the management of patients with acute myeloid leukemia (AML). We hypothesized that rates of molecular testing would be higher in an academic center versus community sites. A retrospective chart review included all de novo AML patients (excluding M3) at Kansas University Medical Center (KUMC) from January 2008 through April 2013. Records were evaluated for completeness of molecular testing as indicated by karyotype (FLT3, CEBPα, NPM1 in normal cytogenetics AML and c-KIT in core binding factor [CBF] AML). 271 charts were reviewed: 98 with CN-AML and 29 with CBF AML. Seventy were diagnosed at KUMC, 57 at a community site. Molecular testing was sent in 76/98 (77%) patients with CN-AML. Patients diagnosed at KUMC had a significantly higher rate of molecular testing (51/55, 93%) as compared to those diagnosed at outside centers (18/43, 41%) (P < 0.001). Of 29 patients with CBF AML, c-kit mutational analysis was performed more frequently at KUMC (14/15, 93%) than in community sites (8/14, 57%) (P = 0.035). There was a trend towards increased testing at both KUMC and community sites in later years. Rates of molecular testing in AML were higher in an academic center versus community sites in the 5 years following the World Health Organization revised classification of AML. All physicians who diagnose and treat AML must remain up to date on the latest recommendations and controversies in molecular testing in order to appropriately risk stratify patients and determine optimal therapy.
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http://dx.doi.org/10.1002/cam4.406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402066PMC
April 2015

IgG kappa monoclonal gammopathy of undetermined significance presenting as acquired type III Von Willebrand syndrome.

Blood Coagul Fibrinolysis 2014 Sep;25(6):631-3

aDepartment of Internal Medicine, Division of Hematology/Oncology bDepartment of Pathology, Division of Pathology, University of Kansas Medical Center, Kansas City, Kansas, USA.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia and cardiovascular disorders that often present a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand disease (VWD). Here, we present the case of a patient with a 32-year history of type III VWD that was ultimately found to be AVWS related to an IgG MGUS. In this case report, we highlight the diagnostic challenges of AVWS to ensure proper identification and potentially lifesaving treatment of this rare disorder.
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http://dx.doi.org/10.1097/MBC.0000000000000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119490PMC
September 2014

Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation.

Ann Hematol 2014 May 18;93(5):847-54. Epub 2013 Dec 18.

Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA,

Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment. We sought to determine the incidence and characterize the pulmonary manifestations of PES. A retrospective review of patients who underwent UCBT at the University of Kansas Medical Center over a 5-year period was performed. Data collected included patient baseline characteristics, presence of PES, pulmonary findings, treatments, and survival. Forty-four patients underwent UCBT with 22 of those patients developing PES. Full-intensity myeloablative conditioning regimen was found to be a risk factor for development of PES. Of those 22 patients, 13 had resting hypoxemia. The most common radiographic findings included diffuse ground glass opacities with pleural effusions. Fifteen patients with PES received corticosteroids, of which 12 had improvement in fevers and rash. These patients had a trend toward worse mortality than those not receiving corticosteroids. There was a nonsignificant trend toward worse survival in patients with PES and hypoxemia compared to those without hypoxemia. PES is a common complication following cord blood transplantation, with hypoxemia being present in over half of patients with PES. Hypoxemia with PES and treatment with corticosteroids may portend a worse prognosis.
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http://dx.doi.org/10.1007/s00277-013-1981-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109706PMC
May 2014

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34⁺ cells in a murine model of umbilical cord blood transplantation.

Blood Cells Mol Dis 2014 Jan 14;52(1):59-67. Epub 2013 Aug 14.

Division of Hematology/Oncology and Blood and Marrow Transplantation Program, 2330 Shawnee Mission Parkway, University of Kansas Medical Center, Kansas City, KS 66205, USA. Electronic address:

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six- to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34⁺ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received 2 hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34⁺ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood, and spleen retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34⁺ cell infusion significantly improves engraftment.
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http://dx.doi.org/10.1016/j.bcmd.2013.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075130PMC
January 2014

A novel three-dimensional stromal-based model for in vitro chemotherapy sensitivity testing of leukemia cells.

Leuk Lymphoma 2014 Feb 15;55(2):378-91. Epub 2013 May 15.

Hematology/Oncology, Blood and Marrow Transplant Program.

The disparate response of leukemia cells to chemotherapy in vivo, compared to in vitro, is partly related to the interaction of leukemic cells and the three-dimensional bone marrow stromal microenvironment. We investigated the effects of chemotherapy agents on leukemic cell lines co-cultured with human bone marrow mesenchymal stem cells (hu-BM-MSCs) in a three-dimensional model (3D). Comparison was made to leukemic cells treated in suspension, or grown on a hu-BM-MSC monolayer (2D conditions). We demonstrated that leukemic cells cultured in 3D were more resistant to drug-induced apoptosis compared to cells cultured in 2D or in suspension. We also demonstrated significant differences in leukemic cell response to chemotherapy using different leukemic cell lines cultured in 3D. We suggest that the differential responses to chemotherapy in 3D may be related to the expression of N-cadherin in the co-culture system. This unique model provides an opportunity to study leukemic cell responses to chemotherapy in 3D.
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http://dx.doi.org/10.3109/10428194.2013.793323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090917PMC
February 2014

Bendamustine associated with irreversible ascending paralysis.

Case Rep Hematol 2013 27;2013:931519. Epub 2013 Feb 27.

Internal Medicine Department, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Bendamustine is an alkylating agent currently used in the treatment of lymphoproliferative disorders. Many adverse effects, including a rare case of reversible neurotoxicity, have been reported in association with bendamustine. Herein, we report the first case of irreversible ascending paralysis related to bendamustine.
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http://dx.doi.org/10.1155/2013/931519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600208PMC
March 2013