Since the first internationally accepted response criteria, the Lugano Classification Response Criteria, were published in 1999, advances in immunomodulatory therapies that affect imaging interpretation have resulted in the need for revised criteria for staging and response. To redefine response outcomes with use of immunomodulatory drugs, Bruce D. Cheson, MD, from the Georgetown University Hospital Lombardi Comprehensive Cancer Center in Washington, DC, and authors coined the term “Indeterminate Response (IR),” which they reviewed in an article published in Blood.1
“We are encountering an increasing number of drugs, other than traditional cytotoxic chemotherapy, with which response assessment may be complicated by the development of a flare reaction, also called pseudoprogression,” Dr. Cheson told ASH Clinical News. “This follows several potential patterns: an increase in the size of lesions, the development of new lesions despite regression of the initial lesions, or increased F-fluorodeoxyglucose (FDG)-avidity despite no change in lesion size. Unless this phenomenon is recognized, patients may be taken off a drug that is actually effective. Thus, we have introduced IR, which is assigned to patients until a subsequent scan distinguishes response from progressive disease.”
The report from Dr. Cheson and authors evolved from a workshop on response guidelines in the setting of immunomodulatory agents convened by the Lymphoma Research Foundation and Cancer Research Institute, which included clinical research investigators and representatives from the pharmaceutical industry and U.S. Food and Drug Administration.
The proposed provisional modification, the LYmphoma Response to Immunomodulatory Therapy Criteria (LYRIC), introduced IR as a more flexible classification than those provided in the Lugano Classification. “The term ‘IR’ does not make a direct reference to the underlying mechanism, recognizing that a delayed response and an immune-mediated flare can both occur in the early treatment period and may be difficult to distinguish from progression by physical exam or imaging alone,” Dr. Cheson and authors wrote. “Moreover, the term provides the flexibility to allow patients to continue treatment past IR in some circumstances with a mandatory subsequent evaluation within 12 weeks to confirm or refute true progressive disease.”
IR is defined as one or more of the following:
- an increase in overall tumor burden of ≥50% of up to six measurable lesions in the first 12 weeks of therapy, without clinical deterioration
- appearance of new lesions or growth of one or more existing lesions ≥50% at any time during treatment occurring in the context of lack of overall progression of overall tumor burden
- an increase in FDG uptake of one or more lesions without a concomitant increase in lesion size or number
If patients are categorized as IR, a mandatory repeat imaging is required after 12 weeks and response should be re-evaluated with the following considerations:
- The comparison should be between the first IR and the current overall tumor burden, with an increase of ≥10% constituting progressive disease. An increase of ≥5 mm of at least one lesion for lesions ≤2 cm and 10 mm for lesions >2 cm should also be considered.
- The new or growing lesions should be added to the target lesions, up to a total of more than six lesions.
- Since inflammatory response may result in an increase in the standardized uptake value of a lesion, the patient will not be considered to have progressive disease unless there is evidence of progressive disease by an increase in lesion size or the development of a new lesion.
“We propose that the modified response criteria be incorporated as secondary endpoints in upcoming clinical trials of immunomodulatory therapy,” the authors concluded. “This will allow patients to continue what may be beneficial therapy and the generation of data that can be analyzed to determine whether this strategy of treatment past IR does indeed confer a clinical benefit.”
“Physicians need to be aware of this possibility when using drugs with the potential for a flare,” Dr. Cheson told ASH Clinical News. “If pseudoprogression is suspected, the patient should be left on the medication if he or she appears to be otherwise responding and there is no evidence of clinical deterioration until a repeat scan clarifies whether the observation was a flare or actual progression.”
The study is limited by the subjective nature of certain measures included in the IR definition, such as “clinical deterioration.”
In an editorial accompanying the report, Joseph M. Connors, MD, from the British Columbia Cancer Agency Centre for Lymphoid Cancers in Canada, discussed the challenges of implementing these new LYRIC criteria. “What will be particularly challenging is the necessity to avoid the mistake of considering a new agent ineffective, while at the same time protecting patients from continuing to be exposed to worsening toxicity because off-target tissue injury is erroneously considered non-specific. It is imperative that we remember the provisional nature of these proposed changes and actively participate in their refinement.”2
- Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano classification response criteria for lymphoma in the era of immunomodulatory therapy: The LYmphoma response to immunomodulatory therapy criteria (LYRIC). Blood. 2016 August 29. [Epub ahead of print]
- Connors JM. Is the lymphoma better? Not easy to determine. Blood. 2016;128:2481-82.