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2. Cost effectiveness of therapeutic drug monitoring for imatinib administration in chronic myeloid leukemia.

Author

Kibum Kim, Gwendolyn A McMillin, Philip S Bernard, Srinivas Tantravahi, Brandon S Walker, and Robert L Schmidt

Subjects
Medicine, Science
Abstract

BackgroundImatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy.MethodsWe developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed.ResultsThe lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY.ConclusionsAlthough the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

Published
2019
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3. Supplementary Figure 4 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Figure 4

Published
2023

4. Supplementary Methods, Legends from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Methods, Legends

Published
2023

5. Supplementary Table 1 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Table 1

Published
2023

6. Supplementary Figure 1 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Figure 1

Published
2023

7. Supplementary Figure 3 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Figure 3

Published
2023

8. Supplementary Figure 2 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Figure 2

Published
2023

9. Data from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Purpose:Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.Experimental Design:A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear–cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).Results:JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo.Conclusions:Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.

Published
2023

10. Supplementary Figure 5 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Figure 5

Published
2023

11. Supplementary Table 2 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Table 2

Published
2023

12. Supplementary Table 3-8 from Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis

Author

Michael W. Deininger, Thomas O'Hare, Josef T. Prchal, Kenneth M. Boucher, Rodney R. Miles, Mohamed E. Salama, Todd W. Kelley, Jamshid S. Khorashad, Sharon Shacham, Erkan Baloglu, Brayden J. Halverson, Sabina I. Swierczek, Hannah M. Redwine, Kevin C. Gantz, Phillip M. Clair, Anna M. Eiring, William L. Heaton, Ami B. Patel, Hein Than, Qiang Wang, Jonathan M. Ahmann, Anna V. Senina, Clinton C. Mason, Srinivas Tantravahi, Anthony D. Pomicter, and Dongqing Yan

Abstract

Supplementary Table 3-8

Published
2023

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