Use of drug pharmacokinetics in conditioning regimen

Transcription

1 Use of drug pharmacokinetics in conditioning regimen Jayr Schmidt Filho, MD A.C.Camargo Cancer Center Oncohematology team UCTC HC-FMUSP/ ICESP Medical Coordinator

2 Disclosures No disclosures for this lecture!

3 Rationale for High Dose Therapy Thomas ED et al. J Clin Invest :

4 Conditioning Regimen Effects Adapted from Gyurcokza B et al. Blood (3):

5 Partial Spectrum of Conditioning Regimen of Various Intensities, their impact on toxicity, and the Dependence of Transplant Success Upon GVT Effects a TBI at 1200 cgy b 200 cgy c 3,2 16 mg/kg d mg/m2 AraC: Cytarabine ; BU: Busulfan ; Cy: Cyclophosphamide ; Flu: Fludarabine ; GVT: graft versus tumor Mel: Melphalan ; TBI: total body irradiation ; THY: Thymoglobulin Deeg HJ, et al. Leukemia 2006;20:

6 Defining Conditioning Intensity RIC regimens do not fit criteria for MA or NMA regimens 1.Bacigalupo A et al. Biol Blood Marrow Transplant : Giralt SA et al. Biol Blood Marrow Transplant :

7 MAC versus RIC 1.Martino R et al. Blood : Aoudjhane M et al. Leukemia :

8 Relapse Post-HSCT: Two Populations Clift RA et al. Blood. 1998;92:

9 How can we improve the outcomes? Clift RA et al. Blood. 1998;92: Giralt S. ASH 2016 Educ Book

10 Pharmacokinetic Dosing Variability and Conditioning Regimen-Related Toxicity Pharmacokinetic-guided dosing procedures Higher event-free survival rates; Less relapse; Less graft failure; Lower toxicity. Choice of preparative regimen: MAC, NMA, RIC. Pharmacodynamics of BU depends on: Age; Underlying disease; Components of conditioning regimen. Jenke A et al. Bone Marrow Transplant. 2005:35:

11 Importance of Therapeutic Drug Monitoring Pharmacokinetic-guided dosing is necessary with: Busulfan, cyclophosphamide, and melphalan; Because all these drugs use glutathione for their metabolism; Busulfan is a drug that uses up glutathione and specifically affects glutathione S-transferase in the liver. Cyclophosphamide requires glutathione S-transferase for its metabolism; BU/Cy x Cy/BU. Oral vs IV Busulfan; Oral BU without drug monitoring is associated with higher graft failure rates and higher toxicities. Order of administration. Bartelink H et al. Biol Blood Marrow Transplant. 2008; 14:88-98 McCune J et al. Bone Marrow Transplant. 2007;13:

12 Importance of Pharmacokinetic Guided Dosing The dose-limiting toxicity of BU/Cy is well documented; Cardiotoxicity; Hemorrhagic cystitis; Mucositis; Instersticial pneumonia; VOD/ SOS. Important to determine the toxicities of BU in combination with Cy/ Flu/ Mel; BU as a single agent: less toxic to the liver! Challenging population to treat: Obese and underweight patients, children and infants <12 months, patients with hepatic alterations/ disease. Hassan M et al.bone Marrow Transplant. 2000; 25: Jenke A et al. Bone Marrow Transplant. 2005:35:

13 Toxicity of Busulfan Exposure With or Without Melphalan Melphalan may be a substrate for glutathione and ultimately when used in combination with busulfan can certainly cause some issues without PK-guided dosing, both either with busulfan or with melphalan or in combination. Bartelink IH et al. Biol Blood Marrow Transplant: 2009:15:

14 Cy metabolism and PK variations MacDonald GB et al. Blood 2003:101: McCune J et al. Bone Marrow Transplant. 2007;13:

15 Cy metabolism and PK variations Cy (and also Melphalan) metabolism is highly variable; The metabolite CEPM is a useful reporter molecule for: Liver toxicity; Nonrelapse mortality; Overall survival. MacDonald GB et al. Blood 2003:101:

16 The Impact of Switching from Oral to IV BU Nguyen L et al. EJHP. 2006:58-59

17 Maden T et al. Biol Blood Marrow Transplantation :56-64

18 LaMaistre et al. Journal of Oncology Pharmacy Practice. 2010

19 PK-Dose Guidance of IV BU with FLU with allo HCST Improves PFS in Patients with AML and MDS: Results of a Randomized Phase III Study The dose-adjusted group will have an average escalation of 20% and a consistent AUC at that level. Andersson BS et al. Blood 2011;118(21) 892

20 EFS Curves Andersson BS et al. Blood 2011;118(21) 892

21 Interpatient variability in the pharmacological biomarkers was high Circulating CD8+cells were more sensitive to fludarabine administration. Chimerism 87% No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T-cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). Cancer Chemother Pharmacol July; 76(1):85-96

22 HLA-identical allo 107 donors and patients with leukemia. Candidate genes were: P450 cytochrome family (CYP2B6) glutathione-stransferase family (GST), multidrug-resistance methylenetetrahydrofola te reductase (MTHFR) Vitamin-D receptor (VDR) genes.

23 ATG on conditioning regimen: prevention of GVHD Immune reconstitution issues (may impair) ATG half-life (5-14 days) may prolong if lymphopenia Previous data on children: High exposure after HSCT: deficiente imune reconstitution High exposure pre HSCT: less GVHD and graft failure Retrospective study. PK/PD ALL, AML, MDSLLA, LMA, SMD N=146 ( ) NMA (Flu-90 + TBI-200) ATG dose: 8 mg/kg for 4 days start on D-8 Weekly sérum ATG dosing Admiraal R et al. Lancet Haematol 2017

24 Admiraal R et al. Lancet Haematol 2017

25 Optimal Bellow optimal Above optimal Optimal Exposure:: AU per day/ml Bellow: higher risk of NRM Bellow AND Above: higher risk of RRM Admiraal R et al. Lancet Haematol 2017

26 Cumulative dose Calculus= x lymphocyte count (10 9 /L) Starting on D-9 Admiraal R et al. Lancet Haematol 2017

27 Conclusion IV BU is safe however PK dose adjustment is recommended when available to improve efficacy and reduce toxicity; Fludarabine, Melphalan and Cyclophosphamide PK is highly variable; Drug metabolism genes polymorphisms are correlated with clinical outcomes; ATG PK and PD adjusted doses correlates with better OS, EFS, NRM, RRM, and perhaps lower agvhd and cgvhd.

28 Acknowledgements UCTC Medical Team: Professor Vanderson Rocha (for making this dream come true) Jayr Schmidt Filho Livia Mariano Marina Nascimento Erick Xavier Marina Fonseca Thales Dalessandro Marcelo Atanázio Madson Farias Aliana Menezes Luciana Tucunduva Giancarlo Fatobene Residents and fellows Nursing team: Priscila Cosenza (outpatient clinic) Tania Alves/ Aline Ramos (inpatient clinic) And many others. Data Manager: Renata Rossetti Pharmacist: Carolina Ferreira Outpatient Secretary: Kelly Dias BMT Office: Denise Macknavicius