Novel immunotherapies for leukemia could raise life-threatening syndrome

Novel chimeric antigen receptor (CAR) T-cell infusion immunotherapies and blinatumomab show promise against acute lymphoblastic leukemia (ALL), but these agents entail a potentially life-threatening treatment-related toxicity, cytokine release syndrome (CRS), according to Noelle Frey, MD, MS, of the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia.

FreyFrey spoke at a December 3 session on ALL management at the 58th American Society of Hematology (ASH) Annual Meeting in San Diego.

“Incidence of CRS will expand as immunotherapy expands,” Frey warned.

More research is still needed to optimize the risk-to-benefit ratio, she noted.

Novel immunotherapies are in clinical testing for patients with ALL. CART-cell treatments involve engineering a patient’s own immune cells, while blinatumomab is a bispecific CD19-directed CD3 T-cell engager that activates endogenous T cells when bound to the CD19-expressing target cell.

“It’s important to remember that these are living drugs; their capability to proliferate and live in-vivo is critical,” Frey noted.

CART-cell therapies and blinatumomab have distinct mechanisms of action but similar toxicities. T-cell engagers like blinatumomab are associated with neurotoxicities, as well, including encephalopathy, seizure, aphasia, and hallucinations.

“The mechanism of toxicity is unclear,” Frey said. But CART cells are found in patients’ cerebrospinal fluid, and neurotoxicity may therefore be T cell or cytokine mediated. Neurotoxicity seems to be associated with high disease burden and elevated levels of interleukin 6 (IL-6) on day 1 of treatment; neurotoxicity does not appear to respond to anti-cytokine treatment.

CRS Risk

Bispecific T-cell engagers and CART-cell therapies also frequently induce CRS, a systemic and potentially life-threatening reaction.

Clinical CRS onset is characterized by fever, hemodynamic instability, and capillary leak, she said. But CRS can evolve into a cascading, life-threatening “cytokine storm” (hypercytokinemia).

“Fever often starts low but it can get very high-104 or 105 degrees Fahrenheit,” Frey said. “Unfortunately, this syndrome can progress beyond high fever and become associated with life-threatening symptoms [such as] hypoxic respiratory failure.”

Because it is so new, relatively little is known about novel immunotherapy-associated CRS. CRS after CART-cell infusion seems to be associated with ALL disease burden, infusional dose, concurrent infection, and possibly, variation in CARTs (“product variance”), Frey said.

Frey and colleagues are studying whether baseline patient cytokine profiles can predict CRS or CRS severity. Such a predictive biomarker might allow infusional dose modifications or closer monitoring.

But the optimal time to intervene when CRS occurs is unknown. “That’s a key topic of ongoing studies,” Frey said.

Next: Need to 'harmonize' CRS definitions

Need to 'harmonize' CRS definitions

It has been difficult to compare CRS findings across immunotherapy studies because of varying descriptions, criteria and definitions.

Various grading schemes and reporting systems intended to guide anti-cytokine treatment decisions yield different grades for a given case. For example, a 32-year-old patient with ALL “who develops hypotension requiring low-dose pressors after CART-19” might be deemed to have Grade 2 CRS using the 2014 Consensus Scale, Grade 3 on the PENN/CHOP scale, or Grade 4 on the Common Terminology Criteria for Adverse Events (CTCAE) scale, she noted.

The U.S. National Institutes of Health’s Office of Biotechnology Activities convened a meeting in June 2015 to discuss T-cell immunotherapy CRS and to harmonize definitions of CRS.

With mild-to-moderate CRS, blinatumomab can be withheld until symptoms resolve and then restarted at a lower dose and escalated if toxicity doesn’t recur. Patients can be premedicated with dexamethasone before restarting treatment.

“We have the luxury of being able to stop and restart treatment with this drug,” Frey said.

Tocilizumab can also be used to reverse blinatumomab-associated CRS “but the optimal timing is not clear,” Frey said.

Prevention of CRS during blinatumomab therapy involves cytoreduction, prophylactic dexamethasone, and drug dose escalation, Frey said. “The luxury here is that you can hold ore restart the drug,” she noted.

Optimizing the risk-to-benefit ratio for patients administered CART-cell therapies for ALL will involve the timing of tocilizumab in relation to CART infusion and the clinical signs of CRS, she said. Fractionated dosing schedules and real-time dose modification when CRS symptoms appear will help. In the future, CARTs can be engineered with “targets for destruction” or molecular “switches,” she said, for more precise management of their activity.

Frey disclosed research funding and consultancy payments from Novartis and Amgen, respectively.