Vincristine-Induced Toxicities Secondary to Azole Antifungal Therapy in Patients with Hematologic Malignancies

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1 Vincristine-Induced Toxicities Secondary to Azole Antifungal Therapy in Patients with Hematologic Malignancies Kara E. Loth, PharmD PGY2 Oncology Resident Wake Forest University Baptist Medical Center Winston-Salem, NC

2 Disclosure Disclosure statement: these individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation. Resident: Kara Loth (nothing to disclose) Project Director, Advisor(s), & Co-Investigators: Brandy Strickland, Gregory Russell, Kevin Buckley, LeAnne Kennedy (nothing to disclose)

3 Wake Forest University Baptist Medical Center Winston-Salem, NC Academic teaching facility 872 acute care beds NCI-designated Comprehensive Cancer Center

4 Vincristine (Oncovin ) Vinca alkaloid used in treating many hematologic malignancies Acute Lymphoblastic Leukemia (ALL) Non-Hodgkin s Lymphoma (NHL) Common Toxicities Peripheral neuropathy Seizure Constipation Ileus Hyperbilirubinemia 1 Harnicar S, Adel N, Jurcic J. J Oncol Pharm Practice. 2009;00:1-8.

5 Antifungal Prophylaxis National Comprehensive Cancer Network Guidelines Antifungal prophylaxis during induction and consolidation therapy for adult leukemia patients WFUBMC Practice Leukemia and lymphoma patients Fluconazole prophylaxis Brahm HS, Lindsey RB, Corey C, et al. Prevention and treatment of cancer related infections. NCCN Clinical Practice Guidelines in Oncology. physician_gls/ PDF/infections.pdf. Accessed November 10, 2009.

6 Potential Drug Interaction Vincristine (VCR) is metabolized by cytochrome P450 enzymes Azole antifungals are cytochrome P450 substrates and inhibitors Azole antifungals may inhibit the metabolism of vincristine Gubbins PO. Current Opinion in Infectious Diseases. 2007;20:

7 Purpose Evaluate the incidence of toxicity and dosage modifications in patients receiving vincristine and azole antifungal therapy compared to vincristine therapy alone

8 Study Objectives Primary Incidence of vincristine toxicity Nervous system disorders Gastrointestinal disorders Hyperbilirubinemia Secondary Incidence of vincristine dosage modifications Dosage reductions Dose held or omitted

9 Methods Retrospective, cohort study Patients identified from a computer-generated list IRB-approved Inclusion Criteria Adult and pediatric patients with ALL and NHL Vincristine ± concurrent fluconazole or voriconazole Treatment between July 2005 and June 2009 Exclusion Criteria Concurrent therapy with a strong cytochrome P450 inhibitor other than an azole antifungal

10 Data Collection Patient demographics Azole antifungal administered Potential causes of peripheral neuropathy Opioid use Iron supplementation Bowel regimen Total bilirubin Vincristine dosage reductions Vincristine toxicities

11 Toxicity Grading of toxicity was based on Common Toxicity Criteria v4.0 Grades 1 4 Chart notes documenting an occurrence Constipation Ileus Peripheral neuropathy Seizure Hyperbilirubinemia

12 Common Toxicity Criteria v4.0 Gastrointestinal Grade 1 Grade 2 Grade 3 Grade 4 Constipation Occasional or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enema Persistent symptoms with regular use of laxatives or enemas indicated Ileus - Symptomatic; altered GI function; bowel rest indicated Obstipation with manual evacuation indicated; limiting self care ADL Severely altered GI function; TPN indicated Lifethreatening consequences (obstruction, toxic megacolon) Lifethreatening consequences; urgent intervention indicated Laboratory Value Grade 1 Grade 2 Grade 3 Grade 4 Hyperbilirubinemia >ULN x ULN > x ULN > x ULN >10.0 x ULN Update October Accessed April 13, 2010.

13 Common Toxicity Criteria v4.0 Neuropathy Grade 1 Grade 2 Grade 3 Grade 4 Peripheral Neuropathy Asymptomatic; loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function Sensory alteration or paresthesia (including tingling), interfering with function, but not interfering with ADL Sensory alteration or paresthesia interfering with ADL Lifethreatening consequences; urgent intervention indicated Seizure Brief partial seizure; no loss of consciousness Brief generalized seizure Multiple seizures despite medical intervention Lifethreatening; prolonged repetitive seizures Update October Accessed April 13, 2010.

14 Statistical Analysis Sample size 10% difference 89 patients in each group 80% power 5% two-sided alpha Descriptive statistical analysis Student s t-test Chi-squared test Fisher s exact test

15 241 Patients Identified 63 Excluded 178 Analyzed 89 Vincristine Alone 89 Vincristine + Azole Antifungal 80 Fluconazole 9 Voriconazole

16 Patient Demographics VCR + Antifungal N=89 VCR Alone N=89 p-value Age in years, Mean ± SD 44.4 ± ± NS Male Gender, n (%) 55 (62) 50 (56) NS Diagnosis NHL, n (%) 26 (29) 59 (66) < ALL, n (%) 63 (71) 30 (34) <0.0001

17 % of Patients Risks of Toxicity p= p=ns Bowel Regimen Iron Opioid VCR + Azole VCR only

18 Risks of Peripheral Neuropathy VCR + Antifungal N = 89 VCR alone N = 89 p-value Platinum, n (%) 0 (0) 4 (4) NS Taxane, n (%) 2 (2) 0 (0) NS Previous Vincristine, n (%) 16 (18) 31 (35) Diabetes Mellitus, n (%) 16 (18) 11 (12) NS

19 % of Patients Toxicity Outcomes p = Constipation Peripheral Neuropathy Hyperbilirubinemia VCR + Azole VCR alone

20 % of Patients Grading Toxicity Constipation Peripheral Neuropathy Hyperbilirubinemia p=ns p=ns p = 0.02 VCR + Azole VCR alone

21 Dose Modifications Secondary Outcomes VCR + Azole N = 89 VCR Alone N = 89 p-value Dosage Reductions, n (%) 15 (17) 4 (4) Therapy Held, n (%) 7 (8) 0 (0) 0.014

22 Limitations Study design Reliance on accurate chart documentation Pediatric and adult patients were included

23 Conclusions There is a greater incidence of constipation and hyperbilirubinemia in patients treated with vincristine plus an azole antifungal There is a greater incidence of dosage modifications in patients treated with vincristine plus an azole antifungal Consider holding the azole antifungal or changing to an alternative therapy during vincristine administration

24 Acknowledgements Brandy Strickland, PharmD Gregory Russell, MS Kevin Buckley, MD LeAnne Kennedy, PharmD, BCOP

25 Vincristine Induced Toxicities Secondary to Azole Antifungal Therapy in Patients with Hematological Malignancies Kara E. Loth, PharmD PGY1 Pharmacy Practice Resident Wake Forest University Baptist Medical Center Winston-Salem, NC