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Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy

Bruce D. Cheson, Stephen Ansell, Larry Schwartz, Leo I. Gordon, Ranjana Advani, Heather A. Jacene, Axel Hoos, Sally F. Barrington and Philippe Armand

Article Figures & Data

Figures

  • Figure 1.

    This case illustrates a discrepancy between the revised Lugano Classification (PD) and the immune-related response criteria (PR) given the fact that the immune-related response criteria do not take into consideration PET/CT findings. This type of discrepancy is particularly notable in cases with bone marrow involvement. Oftentimes, lymphomatous involvement of the bone marrow is either not measurable (due to absence of soft tissue component) or imperceptible on CT. Therefore, these findings cannot be integrated in the tumor burden of the immune-related response criteria. Restaging PET-CT is at 12 weeks. Restaging PET/CT 2 at 20 weeks demonstrates new areas of FDG uptake in the left side of T9 vertebral body (arrows) and increasing uptake in the left acetabulum, suggesting increasing extent of marrow disease, whereas this is barely seen on CT. Marked physiologic uptake is also seen in brown fat (asterisks).

  • Figure 2.

    Restaging FDG-PET/CT and contrast-enhanced CT at 19 weeks demonstrates interval resolution of FDG uptake in a liver lesion. Restaging contrast-enhanced CT shows interval decrease in size of the hepatic lesion (arrow). Because the lesion did not disappear, this patient achieved a PR by immune-related response criteria, whereas the absence of FDG uptake on FDG-PET/CT is a CR by the Lugano Classification. There was also a complete metabolic response in the mediastinum and right upper abdomen (asterisks).

  • Figure 3.

    IR(1): Restaging CT 1 at 3 weeks demonstrates overall progression of tumor burden (SPD +124% from baseline) as evidenced interval increase in a right upper lobe lung mass (black arrow), left-sided pleural masses (asterisks), and left retrocrural lymphadenopathy (white arrow), and interval development of a large left-sided pleural effusion. Subsequent follow-up at 7 weeks (restaging CT 2) shows an interval decrease in size of all lesions with resolution of the left pleural effusion (SPD −27% from baseline). Additional follow-up at 13 weeks (restaging CT 3) demonstrates a further interval decrease in tumor burden, and the patient achieved a PR by revised response criteria (SPD −54% from baseline) with clear subsequent clinical benefit from continued treatment.

  • Figure 4.

    IR(2): CT demonstrating pseudo-progression in a patient on nivolumab for Hodgkin lymphoma. May 2015, pretreatment, October and December 2015 shows transient flares in different nodal groups without overall progression in the original target lesions.

  • Figure 5.

    IR(3) showing an increase in FDG uptake in a paracardiac node suggestive of lymphoma without a concomitant increase in size of lesion(s) that meets PD criteria.

Tables

  • Table 1.

    IRC for solid tumors

    Response designationDefinition
    ir complete remissionComplete disappearance of all lesions (whether measureable or not, and no new lesions), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date first documented
    ir partial remissionDecrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation
    ir stable diseaseNot meeting criteria for irCR or irPR, in absence of irPD
    ir progressive diseaseIncrease in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date first documented
    • Adapted from Wolchok et al.31 ir, immune response.

  • Table 2.

    Comparison of RECIST, irRC, and Lugano Classification criteria

    CriteriaCRPRPD
    RECIST 1.1Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mmAt least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diametersAt least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm
    Note: the appearance of one or more new lesions is also considered progression.
    irRCDisappearance of all lesions in two consecutive observations not less than 4 weeks apart≥50% decrease in tumor burden compared with baseline in 2 observations at least 4 weeks apart (as measured bidimensionally)≥25% increase in tumor burden compared with nadir (at any single time point) in 2 consecutive observations at least 4 weeks apart, where Tumor Burden = SPD index lesions + SPD new, measurable lesions
    LuganoPET-CT, score 1, 2, or 3* with or without a residual mass on 5PS OR on CT, target nodes/nodal masses must regress to ≤1.5 cm in LDiPET-CT score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. OR On CT ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sitesPET-CT score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment. OR On CT, an individual node/lesion must be abnormal with: LDi >1.5 cm and increase by ≥50% from PPD nadir and an increase in LDi or SDi from nadir 0.5 cm for lesions ≤2 cm 1.0 cm for lesions >2 cm
    In the setting of splenomegaly, the splenic length must increase by >50% of the extent of its prior increase beyond baseline (eg, a 15-cm spleen must increase to >16 cm). If no prior splenomegaly, must increase by ≥2 cm from baseline. New or recurrent splenomegaly
    New or clear progression of preexisiting nonmeasured lesions
    Regrowth of previously resolved lesions
    A new node >1.5 cm in any axis or a new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma
    Assessable disease of any size unequivocally attributable to lymphoma
    AND/OR new or recurrent involvement of the bone marrow
    LYRICSame as LuganoSame as LuganoAs with Lugano with the following exceptions:
    IR
    IR(1): ≥50% increase in SPD in first 12 weeks
    IR(2): <50% increase in SPD with
    a. New lesion(s), or
    b. ≥50% increase in PPD of a lesion or set of lesions at any time during treatment
    IR(3): Increase in FDG uptake without a concomitant increase in lesion size meeting criteria for PD
    • IR, immune response; LDi, longest diameter; PPD, product of the perpendicular diameters; SDi, short diameter; 5PS, 5-point scale.

    • * A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).

    • PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake greater than liver; 5, uptake markedly higher than liver (2-3 times SUVmax in normal liver) and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.