Renal Toxicity of High-Dose Methotrexate (HD-MTX)

Actualités Néphrologiques Jean Hamburger 2018 Hugo GARCIA MD. PhD Student.

hugo.garcia@aphp.fr

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?

?

vs

Thank you for your Attention!

Participating Centers COCHIN : service d’hématologie clinique (Pr BOUSCARY) service de cancérologie (Pr GOLDWASSER, Mme BELLANGER) INSTITUT CURIE : service d’oncologie pédiatrique (Dr MICHON, Dr PACQUEMENT) IGR : unité adolescents et jeunes adultes (Dr BRUGIERES, Dr GASPAR) laboratoire de pharmacologie (Dr BROUTIN, Dr PACI) NECKER : service d’hématologie adultes (Pr HERMINE, Pr SUAREZ) pharmacie (Dr BOURGET, Dr MAGNARD) PITIÉ-SALPÉTRIÈRE : service d’hématologie clinique (Dr ALGRAIN, Pr LEBLOND) ROBERT DEBRÉ : service d’hématologie-immunologie (Pr BRETHON) SAINT-LOUIS : service clinique des maladies du sang (Pr DOMBRET, Dr RAFFOUX) service d’immunopathologie clinique (Dr GALICIER, Pr OKSENHENDLER) service d’onco-hématologie (Pr THIEBLEMONT) service d’hématologie adolescents et jeunes adultes (Pr BOISSEL) VERSAILLES : service d’hématologie-oncologie (Pr ROUSSELOT)