Targeted therapies and tumor lysis syndrome

Novel targeted therapies are being approved in clinical trials for many hematologic malignancies. Tumor lysis syndrome (TLS) is being noticed as a novel side effect of many of these agents. A recent review in AJH summarizes the various drugs that have led to TLS as a potential side effect of targeted therapies.

TLS was most common in drug trials dealing with patients with acute leukemias, high grade non Hodgkin’s lymphomas, mantle cell lymphomas, CLL and myeloma. Some of the risk might be tumor related rather than the drug but below are the drugs that could be potential TLS promoting.

Incidence of TLS based on clinical trials for novel targeted therapies

Alvocidib (cyclin dependent kinase inhibitor) – 42% in poor risk AML patients, 13% in CLL patients

Venetoclax( ABT-199)( small molecule B cell lymphoma/leukemia 2 inhibitor)- 2.7-8.9% in CLL

Dinaciclib( cyclin dependent kinase inhibitor)- 15% in patients with AML or ALL and another 15% in CLL

Ibrutinib( Bruton kinase inhibitor)- 6.7% in CLL patients

Dasatinib( BCR-ABL tyrosine kinase inhibitors)- 4.2% in patients with ALL

Lenalidomide( immunomodulatory agent)- 3-4% in CLL patients

Obinutuzumab( anti CD20 agent)- 3-4.8% in CLL patients

Oprozomib( proteasome inhibitor)- 2.4% in various hematologic malignancies

Brentuximab vedotin( anti cd30 antibody)- 1.7% in anaplastic large cell lymphoma patients

Carfilzomib( proteasome inhibitor)- 1% in myeloma patients

Not much found in the two listed below

Idelasib( phosphatidylinositol 3-kinase inhibitor)- No TLS in CLL patients

Ofatumumab( anti CD20 agent)-No TLS in CLL patients

Topic Discussion: Euglycemic Diabetic Ketoacidosis

The first time the term Euglycemic DKA(eDKA) was mentioned was in 1973- in British Medical Journal in patients who were diabetic but didn't have the full blown hyperglyecmic part.  Compared to classic DKA, eDKA presents with mild to moderate hyperglycemia typically <300mg/dl blood glucose levels.  

Why is this more important now?

In 2013, many SGLT2 inhibitors got approved for DM management( the glucoretics).  The FDA performed a FAERS search of adverse effects with these agents and 73 cases were identified of ketoacidosis linked to SGLT-2 inhibitors.  All patients required hospitalization, and 60% had DMII. Blood glucose levels ranged from 90mg/dl - 1300mg/dl( median 211).  Timing of onset was around 43 days or starting or dose change of the agent.  Majority of the cases also had dehydration, infection or change in insulin doses.   No mortality has been reported with this effect.  All patients respond quickly with intravenous hydration and insulin once recognized. The FDA did acknowledge that some of the cases occurred in DMI, where it's an off label use. More detail here. 



Is it a class effect? 
Yes. The initial FDA reporting was done with canagliflozin(invokana). A more recent study found an incidence rate of 0.07% with this agent.  In a large study with dapagliflozin( Farxiga), 0.1% of patients got eDKA.  Empagliflozin(Jardiance) also has been found to cause eDKA. 

What are the risk factors for development of eDKA with SGLT2 inhibitors?

Dehydration
Alcohol use
decrease in insulin use
Infection
Low carbohydrate diet
Reduction in caloric intake
Advance age

Mechanism of action

Ketosis results from restriction of carbohydrate usage with increased reliance on fat oxidation for energy production. The pathogenesis of hyperglyemic DKA is well established. Since SGLT2 are glucoretics as described before, they can lead to volume depletion- like a diuretic and perhaps leading to a "starvation" like ketoacidosis with normal glucose levels. SGLT2 induced glycosuria can happen over 24 hours and this artificial low plasma glucose do not stimulate insulin. In eDKA, insulin deficiency and insulin resistance are milder; therefore, glucose overproduction and under-utilization are quantitatively lesser than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with eDKA than with DKA. Ketoacidosis follows with the same sequence of events in eDKA as in DKA. Insufficient insulin levels will then decrease glucose utilization and promote lipolysis and ketogenesis. In addition, these drugs can increase glucagon levels leading to increase ketone production.

In summary, eDKA is pathophysiologically similar to DKA except for the circumstance—SGLT2-induced glycosuria—that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis.

Prevention and treatment
Blood and urine monitoring of ketones is essential especially when patients get ill or are experiencing one of the risk factors.  Adequate hydration and carbohydrate intake will help and holding the offending agent is indicated.  No data exists on a safe time to restart the agent. 

Here is a nice review on this topic
http://onlinelibrary.wiley.com/doi/10.1111/jdi.12401/pdf

Detective Nephron: the next case

Check out the next venture of Detective Nephron in the August issue of Kidney News 2016

http://www.kidneynews.org/kidney-news/features/detective-nephron-world-renowned-for-expert-analytical-skills-trains-budding-physician-detectives-on

TOPIC DISCUSSION: New anti retrovirals and the kidney

As HIV becomes a chronic illness, novel agents to combat this virus have been out in the last decade. We are familiar with the renal toxicities of tenofivir for many years. Tenofivir is the cisplatin of the ID world.  But what about the new novel agents?
Here is a table that summarizes the new agents and their known or unknown renal toxicities

Drug name( trade)	Mechanism of Action	Renal effect	Excretion	Reference
Rilpivirine(Edurant)	Non nucleoside reverse transcriptase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2 , appear after 1-2 weeks after treatment and can then plateau	Renal	https://www.ncbi.nlm.nih.gov/pubmed/23211772 https://www.ncbi.nlm.nih.gov/pubmed/21763936
Dolutegravir(Tivicay)	Integrase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2, appear 1-2 weeks after treatment and then plateau	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22905856
Cobicistat(Tybost)	Inhibitor liver enzymes so other HIV drugs effect gets enhanced	Decreases in secretion of creatinine  in the apical side of proximal tubule as it inhibits MATE 1 transporter, can be as early as day 7 of start.	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22732469

Tenofivir dispoxil fumarate( TDF) is the classic nephrotoxic agent.  It actively taken up by the proximal tubular cell via OAT1 and 3 and released in urinary space by secretion of MDRP-2 and 4. There is a novel tenofivir formulation called tenofivir alafenamide fumrate( TAF) which is used in lower dosage combinations and lower level of parent drug is noted. In addition, TAF does not bind to these organic transporters and hence less renal tubular trafficking. Once out in clinical use, we might see less tenofivir related renal toxicities. 

A lot of combination agents are being used to combat the virus. The list below from FDA approved AIDS website compiles them with their trade names. The most nephrotoxic ones are the ones that contain TDF as expected or one of the above mentioned agents that block creatinine secretion.

abacavir and lamivudine (abacavir sulfate / lamivudine, ABC / 3TC)	Epzicom	No renal concerns
abacavir, dolutegravir, and lamivudine (abacavir sulfate / dolutegravir sodium / lamivudine, ABC / DTG / 3TC)	Triumeq	Slight increase in creatinine
abacavir, lamivudine, and zidovudine (abacavir sulfate / lamivudine / zidovudine, ABC / 3TC / ZDV)	Trizivir	No renal concerns
atazanavir and cobicistat (atazanavir sulfate / cobicistat, ATV / COBI)	Evotaz	Slight increase in creatinine
darunavir and cobicistat (darunavir ethanolate / cobicistat, DRV / COBI)	Prezcobix	Slight increase in creatinine
efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir DF, EFV / FTC / TDF)	Atripla	Contains tenofivir- renal toxicity can be present
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide, EVG / COBI / FTC / TAF)	Genvoya	Contains tenofivir
elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (QUAD, EVG / COBI / FTC / TDF)	Stribild	Contains tenofivir
emtricitabine, rilpivirine, and tenofovir alafenamide (emtricitabine / rilpivirine / tenofovir AF, emtricitabine / rilpivirine / tenofovir alafenamide fumarate, emtricitabine / rilpivirine hydrochloride / tenofovir AF, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide fumarate, FTC / RPV / TAF)	Odefsey	Tenofvir alafenamide does not bind to the proximal tubule transporters and is potentially less nephrotoxic
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (emtricitabine / rilpivirine hydrochloride / tenofovir disoproxil fumarate, emtricitabine / rilpivirine / tenofovir, FTC / RPV / TDF)	Complera	Contains tenofivir- hence renal failure can occur and rilpivirine can increase crt as well
emtricitabine and tenofovir alafenamide (emtricitabine / tenofovir AF, emtricitabine / tenofovir alafenamide fumarate, FTC / TAF)	Descovy	Novel tenovifir- hence less likely
emtricitabine and tenofovir disoproxil fumarate (emtricitabine / tenofovir, FTC / TDF)	Truvada	Can cause AKI given tenofivir presence
lamivudine and zidovudine (3TC / ZDV)	Combivir	No renal issues
lopinavir and ritonavir (ritonavir-boosted lopinavir, LPV/r, LPV / RTV)	Kaletra	No renal issues