We are reporting a patient of CML patient developing renal cell carcinoma after one and half years while CML was in CCyR. He was treated with nephrectomy followed by sunitinib administration. Imatinib was continued with dose modification in view of poor tolerability. He developed chronic kidney disease and renal failure requiring haemodialysis. He succumbed after 5 years due to complication of renal failure. Any comments, or suggested variations to the management of this case are welcome…

Clinical Summary:
A 63 year male veterinary doctor diagnosed presented with loss of appetite and weight [not quantified] in February 2006 with splenomegaly [6 cm below the left costal margin]. There was no hepatomegaly or lymphadenopathy. His investigations, including a complete blood picture and a bone marrow aspiration with QRT-PCR for bcr-abl, confirmed a diagnosis of CML in chronic phase. He was started on imatinib 400 mg daily from March 2006.
He attained complete haematological response after 2 months. He tolerated the medication well except for mild nausea, anorexia, facial puffiness and pedal edema. His quantitative BCR ABL at six months of imatinib was 22% [less than one log reduction]. He attained complete cytological response [CCyR] at 12 months. His quantitative BCR ABL after twelve months of Imatinib was 47% [less than one log reduction]. He developed pancytopenia twice during the first year, requiring drug interruption.
Twenty months post diagnosis, he came with a 3-week history of a painless hard swelling [3x5 cm] over the left deltoid region. A fine needle aspiration from the lump revealed clear cell carcinoma. A CECT abdomen revealed a 5x4 cm mass in the lower pole of the left kidney, with hypoechoic lesions in the liver. A CECT of the chest showed bilateral multiple pulmonary nodules. A bone scan was negative for metastasis. The CECT of the brain was normal. He was diagnosed to have CML CP with stage IV renal cell carcinoma.
His CML status at this point showed a quantitative bcr-abl of 25%. He underwent left radical nephrectomy in January 2008. He was started on sunitinib 50 mg, 4 weeks on and 2 weeks off, along with Imatinib.
After 2 cycles of Sunitinib he developed pancytopenia requiring component transfusion and interruption of both drugs. His cytopenia recovered over a week without growth factor support. Both the TKIs were restarted with dose reduction of imatinib to 300 mg. Two weeks later, he developed painful erythematous nodular rash over both soles which resolved in a week with steroids and temporary holding of sunitinib.
After resolution of the rash, sunitinib was restarted. He developed similar rash which progressed to exfoliation even after topical steroids. It subsided in 2 week duration after withholding sunitinib. Sunitinib was restarted at 37.5mg. His Imatinib dose was also adjusted as 200 mg while on sunitinib and to 300 mg without sunitinib as he was requiring multiple blood transfusions for symptomatic anemia.
He developed cough with expectoration, which on a skiagram showed a right lower lobe consolidation which resolved with antibiotics. Since his TSH started rising, he was started on thyroxin supplementation a year after sunitinib therapy. During this period he was found to have normocytic anemia with adequate iron stores requiring blood transfusions thrice. He was started on erythropoietin 3000 units three times a week.
After a year and a half of sunitinib, he developed back ache, limiting his daily activity. A bone scan revealed a D11 vertebral metastasis. His pain resolved with local radiotherapy. As his disease status at other sites was static, sunitinib was continued.
At two and half years of follow up, he presented with breathlessness of a week’s duration with signs of fluid overload, elevated blood pressure [170/100 mm Hg], anemia [Hb 7 g/dl, WBC 6300/cu mm, N75 L20 E4 M1/ Platelets 1.4 lakhs/cu mm], elevated serum creatinine [4.4 mg/dL] without decrease in urine output. He responded to blood transfusion with diuretics. He improved symptomatically and his serum creatinine stabilized at 3 mg/dL. A sonogram showed features of chronic kidney disease. His creatinine gradually increased over 2 months to 6 mg/dL. He was started on maintenance haemodialysis in December 2010. He was on follow up for 4 months after starting dialysis when his CML status was in CHR and stable RCC. He suddenly collapsed at home with bleeding from dialysis catheter and died.

Discussion:
This case illustrates the long disease free survival in CML in the Imatinib era leading to identification of second malignancies, the difficulties in administrating two TKIs and the management of toxicity of TKIs.
Several retrospective analyses show that 4% of CML patients develop a second malignancy [SM]. The median interval from the diagnosis of CML to the diagnosis of SM was 58 months. In our patient, it was 20 months. The SMs seen reported are skin (31%), prostate (15%), melanoma (13%), digestive system (10%), kidney (4%), thyroid (4%), breast (3%), chronic lymphocytic leukemia (3%), hepatobiliary (3%) and other cancers (14%). The median overall survival (OS) of patients treated with TKI developing an SM was shorter than the OS of patients treated with TKI but not suffering from SM.
Our patient had several drug toxicities requiring dose adjustments and drug interruptions. There were no guidelines regarding administrating of both TKIs simultaneously. We tailored the doses of both TKI at maximum tolerable level. Though both diseases were fairly under control our patient unfortunately succumbed to CRF.
Prospective long-term population-based studies in CML patients treated with TKI as first-line therapy are needed to determine the relationship of SM to TKI therapy. There is no evidence at the moment suggesting that exposure to TKIs increases the risk of developing second malignancy.

As I tell my new patients with CML, the therapies available are so good that I can keep them alive long enough to die from something else or get a second malignancy. If I recall, MD Anderson published a look a few years ago at secondary malignancies in their CML population. It wasn't much different from the general population. In our own experience with over 700 CML patients, we do see the usual malignancies associated with aging and lifestyle - breast, lung, bladder, lymphoma, colon, prostate, skin, etc including at least two cases of renal cell diagnosed simultaneously with the CML diagnosis and after several years of therapy.
The main learning point here is that our patients do well and get these other cancers, and because they have CML, we and the primary care physicians cannot ignore usual screening and work-up of symptoms as they can get other treatable and curable diseases including malignancies, diabetes, cardiac disease and the list goes on.
The second main learning point here is that most patients can undergo therapy of their second malignancy with surgery, radiotherapy and even chemotherapy without having to stop their CML therapy. For the most part, the drugs we use do not touch normal stem cells and hence do not enhance the untoward effects of the other treatments.

Very informative case report and discussion. That the patient finally passed away due to chronic renal disease and not either of the malignancy is pertinent. The question is whether either of the TKIs contributed to the deteriorating renal function? As has been pointed out no guidelines exist on the simultaneous administration of Imatinib and Sunitinib. Such instances of use of multiple biologic agents or targeted therapy will only increase in the future. Hence careful attention to their drug interaction as well as such reporting to create larger awareness is vita. I congratulate Raghu for taking this initiative and sharing this with us

Thank you very much for the informative report and discussion. I agree with Purvish's point that drug related renal dysfunction needs to be kept in mind, because it is not routine for us to carefully monitor renal functions or their deterioration while the patient is on a TKI.
We had recently reviewed data on renal dysfunction in patients with CML and those on TKIs

CML related Renal dysfunction can be attributed to the following;
A. Most commonly in Blast Crisis via. acute tubular insufficiency or necrosis, and hypercalcemic nephropathy
B. Minimal change in a nephritic syndrome
C. Proliferative glomerulonephritis
D. Renal manifestation or Renal involvement: Infiltration: Tubulo-Interstitial space infiltration
E. Myeloproliferative disorders can cause glomerulopathy. This appears to be a late complication of myeloproliferative neoplasms [particularly primary myelofibrosis] with guarded prognosis

Imatinib related Renal dysfunction are possibly due to the following,
A. Tumor lysis syndrome, with precipitation and deposition of uric acid in the renal tubules, and toxic tubular damage.
B. Tubular Dysfunction -Tubular cells are susceptible to the toxic effects of drugs, as they have a role in concentrating and reabsorbing the glomerular filtrate, what exposes them to high levels of circulating toxins.
a. In the case of imatinib, the toxic effect may be related to platelet-derived growth factor receptor (PDGFR) inhibition. PDGF-β expression has been reported in proximal tubules and mesangial and interstitial cells. It has been shown in animal models that PDGF-β/PDGFR axis plays an important role in renal tubular cell regeneration after acute tubular necrosis. So, by inhibiting PDGFR, imatinib may interfere in tubular repair mechanisms.
b. Acute renal injury, is most often irreversible.
c. Long-term treatment with Imatinib is related to a clinically relevant decrease in the estimated GFR that may lead to chronic renal failure
d. Important to monitor renal function of CML patients under imatinib therapy by measuring the creatinine levels and estimating GFR. Attention must be paid to concomitant administration of other potentially nephrotoxic agents.
e. Imatinib can also induce partial Fanconi syndrome with massive aminoaciduria & through proximal tubular dysfunction - hypophosphatemia

[Dasatinib & Nilotinib related acute renal failure have also been reported]

Sunitinib:
Reported renal adverse effects of sunitinib are hypertension, proteinuria, renal insufficiency, and thrombotic microangiopathy. Among patients receiving sunitinib, the incidence of all grade increased creatinine levels is 12 to 65%, with the highest incidence in patients with mRCC. (Metanalyses: Acta Oncol 2009)
Renal function deteriorates in 57% of the patients with preexisting RI at the start of TKI therapy (Ann Oncol 2010)
Causes of Sunitinib induced renal infury:
a. uncontrolled hypertension
b. anti-VEGF activity (and down-regulation of nitric oxide production and up-regulation of hypoxia-induced oxidative stress) leading to direct toxicity to Glomeruli and tubules.
c. nephrotic range proteinuria

We are thankful to Prof. Raghu for bringing this case to iCML forum. It was an interesting case to diagnose and manage. We did not think of RCC at the time clinical examination of subcutaneous swellings. Our clinical diagnosis was EMCT ? blast crisis. Surprisingly pathologist informed us it was clear cell malignancy and advised us to look for primary in kidney. Then imaging was done to confirm the diagnosis. After confirming the diagnosis we searched for literature and decided to start him on both TKIs. But he could not tolerate both TKIs and required dose interruptions and adjustments.
We realized that frequent monitoring of S Creatinine could have prevented the renal failure.
Recently we have seen two elderly patents with raised S Creatinine with Imatinib and dose interruptions normalized the S Creatinine. So in elderly and high risk patients frequent monitoring of GFR can prevent renal failure.
Thanks to Dr Vevek Radhakrishnan for posting his views and reasons for kidney damage in the era of TKIs.
We require guidelines on dose adjustment of Imatinib according to GFR to prevent morbidity and mortality of CML patients.