Renal Toxicity of High-Dose Methotrexate (HD-MTX)nephro-necker.org/fr/pdf/2018/19.pdf ·...
Transcript of Renal Toxicity of High-Dose Methotrexate (HD-MTX)nephro-necker.org/fr/pdf/2018/19.pdf ·...
Renal Toxicity of High-Dose Methotrexate (HD-MTX)
Actualités Néphrologiques Jean Hamburger 2018 Hugo GARCIA MD. PhD Student.
Summary
I. Introduction
① HD-MTX History & Main Indications
② Mechanism of Action
③ Elimination Routes
④ Renal Toxicity
⑤ Extrarenal Toxicities
⑥ Toxicity Risk Factors
⑦ Prevention of HD-MTX Toxicities
⑧ Efficacy of RRT
⑨ Enzymatic Treatment
II. Results
① Inclusion Criteria & AKI Incidence
② Cohort Characteristics
③ Acute Renal Toxicity
④ Late Renal Sequelae
⑤ Extrarenal Toxicities
⑥ Impact on Survival
⑦ Glucarpidase Impact
⑧ Conclusion
⑨ Perspectives
① HD-MTX History & main Indications
1947
ALL NHL 1980s :,Head & Neck, Breast, Bladder cancers …
Low-Dose Intermediate-Dose HD-MTX (≥ 1 g/m2)
Rheumatoid Arthritis Psoriasis Juvenile Idiopathic Arthritis
BMT (GVH Prevention) Solid Malignancies (Breast, H&N, …) Choriocarcinoma Hydatiform Mole Ectopic Pregnancy
ALL NHL Osteosarcoma
② Mechanism of Action
MTX is an Antimetabolite
Dihydrofolate Reductase Inhibitor
> Tetrahydrofolate deficit
> DNA Synthesis Defect
> S-Phase arrest
Affects proliferative tissues
Rescue with Leucovorin (Folinic-Acid)
③ Elimination Routes
Glomerulus
Glomerular Filtration 50-60%
Proximal Tubule
Tubular Secretion 25-30%
RFC1 OAT1 OAT3
OAT4 MRP2 MRP4 BCRP
Hepatocyte
Biliary Secretion 8-20%
OAT4 OATP1B1 OATP1B3
MRP2 MRP4 BCRP
Aldehyde Oxydase
Hepatic Hydroxylation>10%
④ Renal Toxicity
Variable incidence depending on: treated malignancy AKI classification used
OS ALL NHL
2% 20% >30%
Several mechanisms involved: Intratubular Precipitation of MTX and 7-OH MTX Direct Tubular Toxicity (ATN) Acute Interstitial Nephritis?
Garneau et al. 2015. Acute Methotrexate-Induced Crystal Nephropathy. N. Engl. J. Med. 373, 2691–2693. Mulay et al. 2014. Molecular mechanisms of crystal-related kidney inflammation and injury. Nephrology Dialysis Transplantation 29, 507– 514.
⑤ Extrarenal Toxicities Myelosuppression: Unavoidable without Leucovorin Rescue More common in cas of Polychemotherapy (NHL) Anemia less common (partly by Hemodilution)
Hepatotoxicity: Reversible, dose-dependent Cytolysis (ALT>AST) Acute Hepatic Failure uncommon (unless chronic HBV infection)
Mucositis: Common complication, including hyperalgic forms Gastrointestinal Bleedings, Potential Portal of Entry
Cutaneous Toxicity: Palmar Erythema or Erythroderma (Lobster Syndrome) infrequent
Encephalopathy: Mostly asymptomatic. More common in children. Reversible after a few days Posterior Leukoencephalopathy (MRI)
Reddick et al. 2005. Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate. American Journal of Neuroradiology 26, 1263–1269.
Cheng et al. 1998. Systemic chemotherapy alone for patients with non-acquired immunodeficiency syndrome- related central nervous system lymphoma. Cancer 82, 1946–1951
⑥ Toxicity Risk Factors Patient-related: Age Commorbidities (HTN, DM, HF, …) Third Space Fuid Collections At-risk Genetic Polymorphisms
Drug-related : Dose and Infusion Time At-risk Comedication
RFC1 OAT1 OAT3
OAT4 MRP2 MRP4 BCRP
OAT4 OATP1B1 OATP1B3
MRP2 MRP4 BCRP
Nephrotoxic Drugs
NSAID, ACEi/ARB Aminoglycoside, Vancomycin Iodinated Contrast
Urinary Acidifiers
Loop & Thazide Diuretics Cola Beverage
Drug-drug Interactions
PPI, NSAID, Gemfibrozil β-lactam Antibiotic, Pristinamycin,Probenecid
NSAID NSAID PPI PPI
NSAID β-lactam PPI Probenecid
Gemfibrozil Pristinamycin
⑦ Prevention of HD-MTX Toxicities
Kidney function assessment (SCr): Relative Contraindication when eGFR <50 ml/min/1,73m2 +/- Dose Adjustment when Age >70 Y.O. or subnormal eGFR Hyperhydratation and Urinary Alcalinization: Fluid Inpout of 3l/m2
Alcaline pH ≥ 7 required prior to HD-MTX Infusion Additional IV-Bicarbonate as needed
Clinical and Biological Monitoring: Urinary pH, Diuresis, Weight Daily SCr and Serum Methotrexate Measurements
Intracellular Leucovorin Rescue: 24-36 Hrs after starting MTX Infusion Dose Adjustement according to MTX Levels
Bleyer, W.A., 1989. New vistas for leucovorin in cancer chemotherapy. Cancer 63, 995–1007.
⑧ Efficacy of RRT
Peritoneal Dialysis: not efficient Conventional HD: low efficiency (Rebound of MTX levels +++) Improved Clearance when adding Charcoal Hemofiltration High-Flux Hemodialysis: better Results Continuous RRT (CVVHF/CVVHDF): best Clearances
+
Hydrophilic Small MW
-
Protein Binding Large Volume of Distribution
Widemann et al. 2004. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma: Incidence, treatment, and outcome. Cancer 100, 2222– 2232.
⑨ Enzymatic Treatment 1971:
Carboxypeptidase G1 Discovery 1985:
Recombinant Carboxypeptidase G2 Production (Glucarpidase)
2007: EMA Marketing Validation
Withdrawal
2012 : FDA Approval
($113,400 in a 70 kg patient)
1992: In vivo studies
(HD-MTX treated monkeys)
1995: First treated patient
One single IV dose, well tolerated, dramatic Decrease of Serum MTX Levels. No controlled Trial!
Widemann et al. 2010. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction. J. Clin. Oncol. 28, 3979–3986.
Objectives of the Study
Identify Risk Factors for Severe AKI (Stage 3 KDIGO) and Extrarenal Toxicities
Describe Clinical Features of HD-MTX associated AKI in adult patients
Analyse Clinical Impact of Glucarpidase compared to Conservative Management
Analyse the Effects of Different Hydration Strategies
① Inclusion Criteria & AKI Incidence R
ésu
lta
ts
Versailles (1)
IGR (6)
Cochin (22) Pitié (13)
Curie (1) Necker (6)
Saint-Louis (26)
Robert Debré (1) AKI KDIGO ≥ 1 (SCr Elevation ≥ 50%) Or Delayed MTX Elimination (DME) ( MTX ≥ 3 µmol/l at 42 Hrs or later)
Center Treated Malignancies Incidence (KDIGO ≥ 1 or DME)
1 OS & Breast (≥ 6 g/m2) 18% (7 patients /39)
2 NHL (≥ 3 g/m2) 15% (13 patients /87)
② Baseline Population
Malignancy
Age
eGFR (ml/min/1.73m2)
② Baseline Population
Pharmacology %
First MTX Course 55
MTX dose- g/m2 4,6
Polychemotherapy 66
At-Risk Medications 76
PPIs 47
Diuretics 41
ACEi/ARBs 14
β-lactam 13
Co-Trimoxazole 11
NSAIDs 0
Comorbidities %
None 59
High Blood Pressure 29
Diabetes Mellitus 9
Heart Failure 9
CKD 5
Obesity 8
Malnutrition 15
③ Acute Renal Toxicity
AKI Stage (KDIGO)
Stage 3 AKI (%) Yes No Odds Ratio P
Comedication 43.9 11.1 6.25 .012
PPI Use 52.9 20.5 4.3 .004
Obesity 83.3 31.4 10.9 .011
Molar Bicarbonate Use 14.3 44.0 0.21 .042
Serum MTX (H36) .041
Events %
Mean Peak SCr - µmol/l 205
Oliguria 16.6
Anuria 1.3
Fluid Overload 29.2
RRT 5.3
③ AKI: Evolution
④ Late Renal Sequelae Baseline Month 3 Last follow-up
No CKD
Stage 2
Stage 3A
Stage 3B
Stage 4
Late Renal Sequelae (%) Yes No Odds Ratio P
Female Sex 25.0 6.7 4.7 .047
Comorbidity 24.0 2.8 11.0 .010
Baseline eGFR .005
Obesity 66.7 5.4 34.6 <.001
Stage 3 AKI 26.3 4.8 7.1 .014
⑤ Extrarenal Toxicities
Myelotoxicity %
Grade 3 Anemia 62.7
RBCs Transfusion 59.2
Grade 3 Thrombopenia 48.0
Platelet Transfusion 40.8
Grade 3 Neutropenia 54.8
G-CSF Use 67.6
Sepsis 51.3
Undetermined (41.0)
Pneumonia (28.2)
Central Line (12.8)
Urinary (7.7)
Others (10.3)
Other Toxicities %
Rash 11.8
Mucositis 41.1
Encephalopathy 17.1
Grade 3 Liver Injury 21.9
⑥ Impact on Survival
Overall %
In-patient Mortality 10.5
3-month Mortality 17.3
Mean Length of Stay - d 18.4
HD-MTX Reintroduction 70.6
In-patient Mortality (%) Yes No Odds Ratio P
Hematological Malignancy 12.7 0 ND 0.17
Cerebral Involvement 27.8 5.2 7.1 .006
Encephalopathy 38.5 4.8 12.5 .0003
Mucositis 16.7 2.3 8.4 .028
Sepsis 18.0 2.7 7.9 .03
Fluid Overload 23.8 3.9 7.7 .001
⑦ Glucarpidase Impact
Glucarpidase ATU Eligibility? (76 patients) - MTX H48 ≥ 10 µmol/l - MTX H48 ≥ 3 µmol/l & ↗ SCr ≥ 50%
Eligible (29 patients)
Not-Eligible (27 patients)
Conservative (22 patients)
Stage 3 AKI: 13,6% Oliguria : 15,0% Fluid Overload: 23,8% RRT : 4,5%
Anemia: 45,5% Thrombopenia: 31,8% Neutropenia: 47,6% Sepsis: 31,8%
Liver Injury: 4,8% Mucositis 19,0% Rash: 0% Encephalopathy: 13,6%
Length of Stay: 12 j (7) Mortality: 4,5%
Glucarpidase (5 patients)
Stage 3 AKI: 40,0% Oliguria : 20,0% Fluid Overload: 40,0% RRT : 0%
Anemia: 40,0% Thrombopenia: 40,0% Neutropenia: 40,0% Sepsis: 60,0%
Liver Injury: 20,0% Mucositis 20,0% Rash: 40,0% Encephalopathy: 20,0%
Length of Stay: 12 j (12) Mortality: 20,0%
Conservative (8 patients)
Stage 3 AKI: 25,0% Oliguria : 25,0% Fluid Overload: 37,5% RRT : 0%
Anemia: 71,4% Thrombopenia: 71,4% Neutropenia: 71,4% Sepsis: 50,%
Liver Injury: 57,1% Mucositis 50,0% Rash: 12,5% Encephalopathy: 25,0%
Length of Stay: 20 j (20) Mortality: 0%
Glucarpidase (21 patients)
Anemia: 71,4% Thrombopenia : 52,4% Neutropenia: 60,0% Sepsis: 57,1%
Liver Injury: 23,8% Mucositis 47,6% Rash: 19,0% Encephalopathy: 19,0%
Length of Stay: 22 j (15) Mortality: 14,3%
Stage 3 AKI: 42,9% Oliguria: 9,5% Fluid Overload: 30,0% RRT: 4,8%
Stage 3 AKI: 58,8% Oliguria : 23,5% Fluid Overload: 31,3% RRT : 11,8%
Anemia: 70,6% Thrombopenia: 47,1% Neutropenia: 52,9% Sepsis: 64,7%
Liver Injury: 31,3% Mucositis 60,0% Rash: 11,8% Encephalopathy: 17,6%
Length of Stay: 23 j (18) Mortality: 17,6%
⑦ Glucarpidase Impact: Stratification
Early Glucarpidase
Treatment <H48 (17 patients)
⑦ Glucarpidase Impact: Eligible Patients
Glucarpidase Use(%) Yes No Odds Ratio P
Mean Length of Stay - d 21.7 20.3 ND .8
In-patient Mortality 14.3 0 ND
Sepsis 57.1 50.0 1.3 .73
Stage 3 AKI 42.9 25.0 2.25 .38
Grade 3 Thrombopenia 52.4 71.4 0.44 .38
Grade 3 Neutropenia 60.0 71.4 0.6 .09
Grade 3 Liver Injury 23.8 57.1 0.23 .1
⑦ Glucarpidase Impact: SCr Kinetics
⑧ Conclusion
HD-MTX nephrotoxicity is still observed in adult patients. Non-anuric AKI that may induce late Renal Sequelae in at-risk Patients. Extrarenal Toxicities and Underlying Malignancy are the Main Predictors of Mortality Glucarpidase is a costly & frequently used Antidote in France
-No controlled study published concerning clinical endpoints -Difficulties to analyze retrospective data (Indication Bias) -No clear renal or clinical Benefit -Non-significant trends towards reduced Myelotoxicity (without effects on Sepsis Incidence) and Hepatotoxicity (always reversible)
⑨ Perspectives Optimize AKI & DME Prevention Identify at-risk Patients (Pharmacogenomics, Urinary Metabolome) Quickly screen AKI (Biomarkers?) Molar 8,4% Sodium Bicarbonate Use? Avoid at-risk Comedications Prefer Acetazolamide when Diuretic needed
Assess Glucarpidase Impact in a RCT
Optimize AKI Care Avoid Hyperhydratation when SCr rises prevent Fluid Overload and Anemia Specifically target innate Inflammation in renal Interstitium?
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Thank you for your Attention!
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