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

CONSULT ROUNDS: Tumor lysis syndrome 2

What dialysis modality is the best for TLS?

On one hand you can have severe hyperkalemia that might require urgent hemodialysis and on other hand there is constant catabolic turnover that might require a continuous modality.

1. Treat the life threatening electrolyte disorder first namely hyperkalemia and might need few hours of HD followed by continuous form of dialysis (CVVH, CVVHD, CVVHDF) to prevent rebound hyperkalemia and combat the catabolic breakdown.

2. The phosphate clearance might be best achieved via a continuous modality in such cases.  High dialysate flows might be necessary.

3. Peritoneal dialysis is usually not recommended mainly because it cannot clear uric acid well.

CONSULT ROUNDS: Tumor Lysis Syndrome 1

Tumor lysis syndrome(TLS) is a frequent clinical syndrome nephrologists encounter.
The Cairo Bishop classification allows for the diagnosis of TLS
Those are

1. Uric acid >= 8.0
2. K >= 6.0
3. Phos >= 4.6
4. Calcium <7.0
5. AKI
6. Cardiac arrhythmia
7. Seizure or symptomatic hypocalcemia

Two of the four lab criteria have to be met within 24 hours period and 3 days before to 7 days after receiving chemotherapy and no other cause of AKI has to be found.  Interestingly, LDH is not a criteria to help diagnose TLS but is usually the most useful clinically.  If one looks at risk factors, LDH is included along with WBC count, tumor burden, renal function at baseline and baseline uric acid levels.

Consult Rounds: High Uric Acid

Uric acid elevations are frequently noted in patients with renal insufficiency as a clearance related problem.
We also note seriously high uric acid levels in patients with tumor lysis syndromes or large tumor burdens.
HCTZ can also do it.


What about tissue hypxia? Changes in oxygen tension has been associated with modulation of purine turnover.  
Rat and human studies have shown that uric acid levels in hypoxia are much higher than normoxia and hyperoxia.  There is a correlation that hypoxia results in greater purine catabolism and leading to increased production of uric acid. Hence we often see lactate levels correlating well with uric acid levels in sepsis.

Few ref:
http://www.ncbi.nlm.nih.gov/pubmed/8470901
http://www.ncbi.nlm.nih.gov/pubmed/20730463
http://www.ncbi.nlm.nih.gov/pubmed/17067515
http://www.ncbi.nlm.nih.gov/pubmed/17269363

Tumor Lysis Syndrome

 From the NEJM Blog: Tumor Lysis Syndrome