OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Duvelisib – Copiktra®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Duvelisib	1201438-56-3	C22-H17-Cl-N6-O

ANNOTATED BIBLIOGRAPHY

References updated: 12 July 2022

Abbreviations: CLL, chronic lymphocytic leukemia; PI3K, phosphatidylinositol 3-kinase; SLL, small cell lymphocytic lymphoma.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; does not discuss duvelisib or other PI3K inhibitors).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2018/211155Orig1Orig2s000MultidisciplineR.pdf.

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; mentions that duvelisib has serious hepatotoxicity and that review of laboratory test results found 8 cases of concomitant elevations in ALT or AST with bilirubin that was twice normal; ALT elevations arose in 43% of treated patients and to above 5 times ULN in 8% although there were no deaths from hepatic failure).
• Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007. [PMC free article: PMC4161365] [PubMed: 24450857]

  (Among 220 patients with relapsed CLL treated in a placebo controlled trial, progression free survival improved with idelalisib and rituximab compared to rituximab alone, but side effects were more common with the combination including ALT or AST elevations [35% vs 19%] which were above 5 times ULN in 5% vs 1% and led to drug discontinuations in some patients, but there were no clinically apparent cases of liver injury).
• Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, Fisher DC, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–203. [PMC free article: PMC4946200] [PubMed: 27247136]

  (Among 24 patients with relapsed or refractory CLL treated with idelalisib, 19 [79%] developed ALT elevations which were above 5 times ULN in 13 [54%], usually within 28 days of starting therapy and sometimes worsening despite drug discontinuation leading to corticosteroid therapy in 16 subjects; rechallenge with idelalisib led to recurrence within a few days, but abnormalities were mild and tolerable in those on corticosteroids).
• Brown JR. The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia. Semin Oncol. 2016;43:260–4. [PubMed: 27040704]

  (Review of the role of aberrant PI3K signaling in cancer with delta and lambda isoenzymes predominantly expressed in hematopoietic cells making them candidates for targeted therapy in B cell related leukemias and lymphomas).
• Flinn IW, Patel M, Oki Y, Horwitz S, Foss FF, Allen K, Douglas M, et al. Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. Am J Hematol. 2018;93:1311–7. [PMC free article: PMC6220789] [PubMed: 30033575]

  (Among 31 patients with refractory, indolent non-Hodgkin lymphoma treated with 8 different doses of duvelisib, the overall response rate was 58% and dose limiting toxicities were rash and ALT or AST elevations, which arose in 57% of patients, and to above 5 times ULN in 43% with 11 dose modifications and 4 discontinuations but no instance of enzyme elevations with jaundice).
• Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132:2446–55. [PMC free article: PMC6284216] [PubMed: 30287523]

  (Among 159 patients with relapsed or refractory CLL or SLL treated with duvelisib [25 mg twice daily] or ofatumumab [iv every 3 weeks], progression-free survival was greater with duvelisib [13.3 vs 9.9 months] and adverse reactions included diarrhea [51%], neutropenia [33%], fever [29%], nausea [23%], cough [21%], fatigue [13%], rash [10%] and ALT elevations above 5 times ULN [3%]).
• O'Brien S, Patel M, Kahl BS, Horwitz SM, Foss FM, Porcu P, Jones J, et al. Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study. Am J Hematol. 2018;93:1318–26. [PMC free article: PMC8260004] [PubMed: 30094870]

  (Among 79 patients with CLL treated with duvelisib in multiple dose levels [8 to 75 mg twice daily] given in 28-day cycles, the overall response rate was 56% [in relapsed or refractory patients] and 83% [in treatment-naïve], and adverse events were common including ALT elevations in 31% which were above 5 times ULN in 11%).
• Blair HA. Duvelisib: first global approval. Drugs. 2018;78:1847–53. [PubMed: 30430368]

  (Review of the mechanism of action, history of development, pharmacology, clinical efficacy and safety of duvelisib shortly after its approval as monotherapy for CLL and SLL; mentions that it has “manageable tolerability” and increased ALT and AST levels occur in 3% of patients).
• Flinn IW, Cherry MA, Maris MB, Matous JV, Berdeja JG, Patel M. Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia. Am J Hematol. 2019;94:1325–1334. [PubMed: 31490009]

  (Among 46 patients with relapsed or refractory non-Hodgkin lymphoma or CLL treated with duvelisib and rituximab alone or with bendamustine, the overall response rate was 72% and common adverse events were neutropenia, fatigue and rash; ALT elevations arose in 22% which were above 5 times ULN in 6.5% but there were no cases of clinically apparent liver injury with jaundice or deaths from liver disease).
• Flinn IW, Miller CB, Ardeshna KM, Tetreault S, Assouline SE, Mayer J, Merli M, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37:912–922. [PubMed: 30742566]

  (Among 129 patients with refractory or relapsing non-Hodgkin lymphoma treated with duvelisib [25 mg twice daily in 28 day cycles], the overall response rate was 47% and adverse events included diarrhea [49%], nausea [30%], neutropenia [29%], fatigue [28%], cough [27%] and ALT elevations above 5 times ULN [5.4%] but without clinically apparent liver injury).
• Davids MS, Kuss BJ, Hillmen P, Montillo M, Moreno C, Essell J, Lamanna N, et al. Efficacy and safety of duvelisib following disease progression on ofatumumab in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study. Clin Cancer Res. 2020;26:2096–2103. [PubMed: 31964785]

  (Among 90 patients who received ofatumumab in the phase III DUO trial [Flinn 2018] who were switched to duvelisib [25 mg twice daily], 69 [77%] had an objective response while common adverse events were diarrhea [47%], neutropenia [26%], fever [24%], rash [23%] and thrombocytopenia [10%]; ALT elevations above 5 times ULN occurred in 2-3% and resulted in drug discontinuation in 1% of patients).
• Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38:2849–2861. [PubMed: 32459600]

  (Among 310 patients with relapsed or refractory CLL treated with acalabrutinib vs idelalisib and rituximab with or without bendamustine, the 12 month predicted progression-free survival was 88% vs 68% and serious adverse event rates were 29% vs 56% and ALT elevations above 5 times ULN arose in 1% vs 6%).
• Lampson BL, Brown JR. The evolving use of phosphatidylinositol 3-kinase inhibitors for the treatment of chronic lymphocytic leukemia. Hematol Oncol Clin North Am. 2021;35:807–826. [PMC free article: PMC8239250] [PubMed: 34174987]

  (Review of the mechanisms of action, clinical efficacy and safety of three PI3K inhibitors [idelalisib, duvelisib and umbralisib] as therapy of CLL, all of which were promising in early studies among refractory patients, but when used as front line therapy they had higher rates of adverse events including infections and immune mediated colitis, pneumonitis and hepatitis that were often corticosteroid responsive).
• Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, Francoeur K, et al. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021;35:1064–1072. [PMC free article: PMC7895867] [PubMed: 32820271]

  (Among 32 patients treated with duvelisib [25 mg once or twice daily] for 1 week and then with standard chemotherapy for 6 cycles, followed by duvelisib alone for up to 2 years, adverse events were frequent [94%], including thrombocytopenia [81%], neutropenia [78%], lymphopenia [77%], nausea, fatigue, fever and ALT or AST elevations above 5 times ULN in 28).