Onconephrology: B cell Malignancies and the KidneyKenar D. Jhaveri, MDAssociate Professor of MedicineRenal Division, Hofstra NSLIJ School of Medicine, NY

The Diseases The Chemotherapy

Ganguli et al Nat Neph 2015

61 year-old man with a history of B cell chronic lymphocytic leukemia not on chemotherapy presented with a rise in serum creatinine from 0.8 mg/dL to 4.1 mg/dL over the last 2 weeks and a WBC count of 103,000. A kidney sonogram reveals large kidneys.

CD20

A common but under-recognized complication of hematologic malignancies

696 patients with malignant lymphoma:◦ 33.5% with lymphomatous infiltration of kidneys◦ 26% unilateral, 74% bilateral involvement◦ Only 14% diagnosed before death

Common imaging findings:◦ Bilateral symmetrical enlargement of the kidneys◦ Localized mass or masses in an otherwise normal kidney

Richmond J et al. Am J Med. 1962 Feb;32:184-207

Lam AQ and Humphreys BD. Clin J Am Soc Nephrol. 2012 Oct;7(10):1692-700.

Management: treatment of primary malignancy

Lymphomatous Infiltration

Other renal complications to consider in lymphoma patients:◦ Ureteral obstruction◦ Urate nephropathy◦ Hypercalcemia◦ Paraproteinemia( cast nephropathy and other paraprotein

diseases can be seen with B cell disease as well and not just plasma cell diseases)

◦ Drug toxicities

Richmond J et al. Am J Med. 1962 Feb;32:184-207

A 67-year-old Caucasian male was referred for evaluation of proteinuria, edema and elevated serum creatinine level.

Pt. had intermittent history of LE swelling (for nearly 1.5 years) that worsened over the last 3-4 months.

Three months prior to this evaluation, pt. received a 3-month course of Sulindac for “colonic polyps”.

Sulindac was discontinued as patient developed worsening LE edema.

ROS was significant for fatigue, worsening LE edema, and recent onset arthralgias. No history of gross hematuria or rash.

No history of recent travel or sick contacts. No history of DM Medication on initial evaluation included Aspirin,

Levothyroxine and Simvastatin

Pt. had a normal serum creatinine (1.0) approximately 6 months ago at PMD’s office.

Lab work done during initial evaluation revealed an elevated serum creatinine level of 2.6 mg/dL.

He had CLL ( WC baseline 25-30 since 3 years not needed to be treated)

Month Serum Creatinine

Serum Albumin

2010 1.0mg/dl 4.72011 1.0mg/dl 4.3

Jan 2014 1.0mg/dl 3.9March 2014 1.4mg/dl 3.8April 2014 1.7mg/dl 2.5May 2014 1.8mg/dl 1.5July 2014 2.6mg/dl 1.4

First Bone Marrow BiopsyFirst Bone Marrow BiopsyDone 1.3 years ago (April 2013): •Concurrent chronic lymphocytic leukemia and MGUS- extensive marrow involvement (70%) of B-CLL (kappa restricted) in nodular and interstitial patterns. •In addition there is 10% lambda monoclonal plasma cells are c/w early evolving myeloma. •The CLL and myeloma clones appear unrelated as they have different kappa/lambda clonality. •Features of osteopenia noted as well.

Diff: •23% N•73% L•10% M

• WBC: 32.4 ( 70%L)• Hgb: 12.4• Hct: 38.1• Plt: 324

Free light chains:Kappa: 1.67Lambda: 7.48Ratio: 0.22

• Protein /crt trend in the urine

• 3 months ago: 1• 2 months ago: 4• 2 weeks ago: 15• Current: 25

• SIFE: IgG kappa migrating protein identified

• M spike 0.1g/dl

• Na 136, K 4.1, Cl 106, Co2 16, BUN 40, Creat 2.6

• Glucose 153, Ca 9.8, Phos 4.8, Mg 2.0

• CLL (65%) • Lambda light chain plasma cell (5%) and moderately

hypercellular marrow (negative for amyloid)• Flow: 53% clonal B lymphocytes with CLL - kappa

restricted• Phenotype and <0.5% lambda monoclonal plasma cells

Kappa lc

Lambda lc

• Amyloidosis, AL lambda type• Acute Tubular Injury• Rare Tubular Casts suggestive of Cast Nephropathy• Severe Glomerulosclerosis with Moderate to Severe IFTA• Cortical and Perirenal Mononuclear Infiltrate with features suggestive of Small Lymphocytic Lymphoma/CLL

AL Amyloidosis (lambda) Leukemic Infiltration Cast Nephropathy

Bortezomib based chemo

Bendamustine and Rituximab based chemo

Idelalisib based chemo

CLL

CLL and the Kidney- Single Center- Mayo Clinic Experience

Existing Renal Disease at the time of CLL diagnosis

At a single center, 7.5% had AKI ( crt greater than 1.5mg/dl)and 0.7% had a crt >3.0mg/dl

Patients with AKI were statistically hadCLL advanced stage ( Rai III-IV 20.2%, Rai I-II 6.4%, Rai 0 7.0%)Men > WomenOlder ageCD49d positive

Kari G. Rabe et al. Blood 2013;122:5302

Acquired Renal Disease at the time of CLL diagnosis

16.1% acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. Older ageMalesCD49d IGHV UM , unfavorable FISH (del17p- or 11q), AP-70+ ,CD38+ Shorter time to first treatment (TTT)(p<0.001) and overall survival(OS) (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency.On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001).

Kari G. Rabe et al. Blood 2013;122:5302

MPGN CLL infiltration

TMA MCD

Strati et al. Haematologica 2015

Other less commonly observed findings were AIN, AL lambda amyloidosis, light chain cast nephropathy, membranous GN and mesangial proliferative GN.

Strati P et al. Haematologica 2015

33 patients at Mayo Clinic with Amyloidosis and CLL 61% had AL Amyloidosis and 39% had non-AL Amyloidosis Of the AL Amyloidosis cohort, 4 had the same clone of

light chain as found in the CLL and another 6 had different clones

Treatment was aimed at either plasma cells, B cells or both.

Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

Of all the lymphoid malignancies, MCD has been classically associated with Hodgkin’s lymphoma

Lien, Y.-H. H. & Lai, L.-W. Nat. Rev. Nephrol. 2010

The association between Hodgkin’s disease and albuminuria was described by Galloway in 1922 Since then, several solid tumors & hematological malignancies have been associated with various glomerular pathology & diseases

Ganguli et al Nat Neph 2015

A 42-year-old man presented with 3 months of lethargy, malaise, intermittent low-grade fevers, and a 10-kg weight loss. On examination, his temperature was 38.7 ◦, heart rate 92 bpm, and blood pressure 96/62 mmHg. His conjunctivae were pale and mucous membranes dry. He had tender lymphadenopathy in both axillae, in the groin, and on neck exam in the posterior cervical chain. On abdominal examination, his liver span was slightly increased and tender, and a spleen tip was palpable at the level of the umbilicus. Extremities revealed 2+ dependent edema, scattered petechiae, and 2+ distal pulses. Laboratory testing identified potassium 6.6 mEq/L, bicarbonate 16 mEq/L, anion gap 22, creatinine 5.8 mg/dL, albumin 3.1 mg/dL, calcium 5.9 mg/dL, phosphate 18.7 mg/dL, and uric acid 21.3 mg/dL. Blood counts showed a white blood count (WBC) of 125 K with abundant blasts, hemoglobin 7.2 mg/dL, and platelets 17 K. Urinalysis demonstrated a specific gravity of 1.012, pH 5.5, 1+ protein and 2+ blood, and sediment with degenerating tubular cells and amorphous phosphate crystals. Because of progressive kidney failure, hyperkalemia, and dropping urine output in the setting of TLS, urgent dialysis was initiated.

Incidence of Tumor Lysis Syndrome Varies with Type of Hematologic Malignancy

Reprinted from Adv. Chronic Kidney Dis. 21, 18–26, Wilson, F. P. & Berns, J. S. Tumor lysis syndrome: new challenges and recent advances. Copyright © 2014, with permission from Elsevier

Wilson FP and Berns JS. Adv Chronic Kidney Dis 21:18-28, 2014

Metabolic pathways involved in uric acid metabolism and tumor lysis syndrome

Wilson FP and Berns JS. Adv Chronic Kidney Dis 21:18-28, 2014

Volume expansionForced diuresis?( when and why?)AllopurinolRasburicaseDialysis ( hemodialysis vs CRRT)

Allopurinol Rasburicase Hydration

Fludarabine Pentostatin Alkylating agents( chlorambucil, cyclophosphamide,

bendamustine, ifosfamide) MTX Anthracyclines

Hemorrhagic cystitis No tubular injury SIADH( resolves after 24 hours of discontinuation)

Lymphoid malignancies Neurotoxicity and Nephrotoxicity -- TMA classically

seen with this agent 4mg/m2 per week renal injury

Margolis et al Sem Oncology 2000Grever MR et al Blood 1983

Shirali A, Perazella M, ACKD Jan 2014

Mr. Fos is a 68 Y old male with refractory non Hodgkin’s lymphoma. The patient has a baseline SCr. of 1.3mg/dL and bland urine now presents with AKI getting RICE protocol. Post-treatment patient developed rising SCr; glucosuria, proteinuria, hypokalemia, metabolic acidosis and hypophosphatemia. Despite d/c of chemotherapy, the patient’s renal insufficiency progressed and he required dialysis 10 months after last dose of chemotherapy.

WHAT IS THE NEPHROTOXIC drug in RICE?

H L

0.0

2.5

5.0

7.5

10.0

12.5

Jan 2009 Apr Jul Oct

Creatin ine

mg

/d

l

FERATOVIC, SABAN

Creatinine (mg/dl)

Alkylating agent Proximal dysfunction-Fanconi Syndrome Most Data in children

◦ Tubulopathy-30% ◦ Clinically significant Fanconi syndrome-5%

Glucosuria with normal blood glucose levels Hypophosphatemia, hypokalemia, metabolic acidosis,

hypouricemia, aminoaciduria AKI-usually resolves prior to next course Chronic renal disease

◦ Up to 50% suffer some degree of impairment◦ Average decline in GFR 35ml/min/1.73m2 (51Cr-EDTA)◦ Progressive even after IFOS stopped

Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645

Cumulative dose >60-100gm/2 (*)

Age at treatment 3-5yrs (?)

Prior or concurrent treatment with cisplatin/carboplatin

H/o nephrectomy

Renal irradiation

Hydronephrosis

Jones D., et al. Pediatr Blood Cancer (2008); 51(6):724-731

Retrospective review 259 patient

▫Pts who received cisplatin were excluded

Decline in GFR correlated with ▫ Age (p<0.001)▫ Carboplatin exposure (p<0.001)

No Correlation with

▫ Ifosfamide dose-(?low overall dose)▫Aminoglycoside exposure▫Auto BMT

Latcha S., Flombaum CD. Personal communication, MSKCCLatcha S., Flombaum CD. Personal communication, MSKCC

Shirali A, Perazella M. ACKD Jan 2014

Mr. Kohl Farabean is a 48 year old with AML who presented to the hospital with fever and headaches for one week. His neutropenic fever was treated with intravenous vancomycin, cefepime and voriconazole and oral acyclovir. There was no prior kidney disease and on admission the serum creatinine was 1.15 mg/dL with good urine output. On hospital day 9 re-induction therapy with “Drug Z” 30 mg/m2 intravenous(IV) daily days 1 to 5 (his first exposure to this drug) and “Drug Y “(he had previously been treated with this agent) 2 g/m2 IV daily days 1 to 5 two hours after “Drug Z” was initiated. On hospital day 11, AKI was detected with rise in serum creatinine from 0.97 mg/dL prior to initiation of chemotherapy on day 9 to 2.14 mg/dL on day 11. Urine output decreased and he became anuric on day 11. There was no laboratory evidence of tumor lysis syndrome. Later on hospital day 11 the serum creatinine increased to 3.56 mg/dL. Hemodialysis was started on hospital day 12 due to worsening azotemia and anuria.

Drug Z = clofarabine Drug Y = cytarabine

Jhaveri KD, Chidella S, Allen S, Fishbane S. Clofarabine induced kidney disease. J Onco Pharm Pract 2013

Type study % patients with renal insult

Renal injury grade Other

Case report – 1 patient 1 Proteinuria, Aki No biopsy ( reversible)

Phase trials( AML)-112 adults patients

36% rise in creatinine Grade 3( 6%) No biopsy

Phase trials(AML)- 106 adults patients

14-16% Grade 4 No biopsy

FAERS database ( our review)

29 patients reported No grade reported No biopsy

Kintzel PE, Visser JA, Campbell AD. Clofarabine-associated acute kidney injury and proteinuria. Pharmacotherapy. 2011 Sep;31(9):923. Kantarjian H et al;. J Clin Oncol. 2010 Feb 1;28(4):549-55Burnett AK et al. J Clin Oncol, 2010 May 10;28(14):2389-95http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm accessed January 23, 2013

Rituximab Ofatumumab Obinutuzumab

AIN: Acute interstitial nephritisHTN: HypertensionTMA: Thrombotic microangiopathy

Ibrutinib( Bruton’s tyrosine kinase inhibitor)- no published cases of acute renal disease

Cases of severe TLS has been reported Initial trial– 35% of patients had increases in crt from

baseline. 5% had Grade >=3 renal failure( one had

hydronephrosis, others had hypotension, and disease progression)

Wang M Blood 2015

ABT-199/venetoclax– Tumor lysis syndrome( severe variant)

Idelalisib( Phosphoinositide 3-kinase delta inhibitor)- no renal toxicity noted

Lenolidomide ( immunomodulator)- AIN, fanconi syndrome

Anti CTLA4 therapy- AIN, lupus like nephritis Pd-1 inhibitor agents ( for lymphoma)- AIN

Antibodies against CTLA-4 Acute granulomatous interstitial nephritis(5 cases) Nephrotic syndrome like lupus nephritis(2 cases) Cell mediated immunity related Steroids might be useful

Izzedine H et al Investig New Drugs 2014Fadel F et al. NEJM 2012

In one trial, there was an increased incidence of elevated creatinine in the nivolumab-treated group as compared to the chemotherapy-treated group (13% vs. 9%).

Steroids help resolve the renal dysfunction in 50% of the cases. It is presumed to be AIN from an immune mediated process.

The FDA label has guidelines to start steroids as the creatinine rises rapidly.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf

Nephritis occurred in 3 (0.7%) patients- 1 was autoimmune nephritis and 2 were AIN

The time to onset of autoimmune nephritis was 12 months after the first dose of pembrolizumab(5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy.

Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal failure.

All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf

Agent CKD Dialysis

Bendamustine 40-80 GFR on changes,<40 data limited– recommend not use

No data

Cyclophosphamide 10-90- no changes<10%- reduce dose by 25%

Reduce dose by 50% and after HD

Ifosfamide 45-60, reduce by 20%30-45, reduce by 25%<30, reduce by 30%

No data

Fludarabine Reduced dose of 20mg/m2 Administer after HD

Rituximab No dose adjustment No dose adjustment

Idelalisib No data No data

Clofarabine 50% reduced dose No data

Ibrutinib No dose adjustment No data

The Diseases The Chemotherapy

Both are toxic to thekidney