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. 2020 Feb;30(1):71-75.
doi: 10.1097/CMR.0000000000000633.

Absolute lymphocyte count as a prognostic biomarker for overall survival in patients with advanced melanoma treated with ipilimumab

Michael A Postow  1   2 , Scott D Chasalow  3 , Deborah Kuk  1 , Katherine S Panageas  1 , Michael L Cheng  1 , Jianda Yuan  1 , Jedd D Wolchok  1   2
Affiliations

Absolute lymphocyte count as a prognostic biomarker for overall survival in patients with advanced melanoma treated with ipilimumab

Michael A Postow et al. Melanoma Res. 2020 Feb.

Abstract

Biomarkers are needed to estimate which patients benefit most from combination ipilimumab and nivolumab immunotherapy. Rigorous biomarker analyses from prior ipilimumab randomized studies without nivolumab are likely to inform which biomarker analyses should be prioritized when examining patients treated with the combination. For the first time, the current analyses investigate absolute lymphocyte count (ALC) in randomized, controlled trials of ipilimumab without nivolumab to assess whether ALC is prognostic or predictive of ipilimumab treatment benefit. Data included patients (n = 1136) treated in the two randomized, controlled phase III studies MDX010-20 and CA184-024. ALC was measured at pretreatment baseline and every 3 weeks for up to 12 weeks, before each dose of ipilimumab. Cox proportional hazards models were used to estimate and test associations between ALC measures and overall survival (OS). In both randomized studies, baseline ALC and ALC halfway through induction (at week 6) were associated with OS not only in ipilimumab-treated patients but also in patients treated with non-ipilimumab control treatments. ALC increased in patients receiving ipilimumab, but this degree of change was not predictive of ipilimumab treatment benefit. Using data from randomized, controlled studies, we were able to conclude for the first time that baseline ALC, ALC halfway through induction (week 6) and the degree of ALC change from baseline to week 6 are prognostic biomarkers in melanoma patients, and do not appear to be predictive of ipilimumab treatment benefit. This more comprehensive understanding of ALC as a biomarker from ipilimumab trials will inform subsequent biomarker investigations in ongoing ipilimumab combination studies such as ipilimumab in combination with nivolumab.

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Figures

Fig. 1
Fig. 1
Hazard ratio (HR) estimates from Cox PH models, for each treatment group in each trial. HR estimates compare OS hazards for (A) ALC1 at the 75th and 25th percentiles; (B) ALC1 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; (C) ALC3 at the 75th and 25th percentiles; (D) ALC3 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; and (E) Slope3 at the 75th and 25th percentiles. Diamonds show point estimates. Horizontal bars show 95% confidence intervals (CI), based on Wald statistics. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab; N = number of patients included in the analysis per treatment group. All patients with a baseline (no more than 28 days prior to confirmed treatment initiation) and at least one post-baseline ALC evaluation were included in the ALC1 analyses. Of those patients, all with ≥ 1 ALC evaluation at least 7 days after dose 2 and prior to dose 3 were included in the ALC3 and Slope3 analyses. Percentiles are from the ALC1, ALC3, or Slope3 distributions over both trials combined. For ALC1, 25th percentile = 1.01 × 109 cells/L; 75th percentile = 1.80 × 109 cells/L; interquartile range = 0.79 cells/L. For ALC3, 25th percentile = 1.15 × 109 cells/L; 75th percentile = 2.08 × 109 cells/L; interquartile range = 0.93 cells/L. For Slope3, 25th percentile = −0.021 × 109 cells/L/week; 75th percentile = 0.070 × 109 cells/L/week; interquartile range = 0.091 cells/L/week. For each patient, Slope3 was estimated by simple linear regression, using all ALC assessments in the period from ALC1 to ALC3, and actual assessment dates. Examination of scaled Schoenfeld residuals suggested that the PH assumption was reasonable for all Cox PH models.
Fig. 1
Fig. 1
Hazard ratio (HR) estimates from Cox PH models, for each treatment group in each trial. HR estimates compare OS hazards for (A) ALC1 at the 75th and 25th percentiles; (B) ALC1 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; (C) ALC3 at the 75th and 25th percentiles; (D) ALC3 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; and (E) Slope3 at the 75th and 25th percentiles. Diamonds show point estimates. Horizontal bars show 95% confidence intervals (CI), based on Wald statistics. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab; N = number of patients included in the analysis per treatment group. All patients with a baseline (no more than 28 days prior to confirmed treatment initiation) and at least one post-baseline ALC evaluation were included in the ALC1 analyses. Of those patients, all with ≥ 1 ALC evaluation at least 7 days after dose 2 and prior to dose 3 were included in the ALC3 and Slope3 analyses. Percentiles are from the ALC1, ALC3, or Slope3 distributions over both trials combined. For ALC1, 25th percentile = 1.01 × 109 cells/L; 75th percentile = 1.80 × 109 cells/L; interquartile range = 0.79 cells/L. For ALC3, 25th percentile = 1.15 × 109 cells/L; 75th percentile = 2.08 × 109 cells/L; interquartile range = 0.93 cells/L. For Slope3, 25th percentile = −0.021 × 109 cells/L/week; 75th percentile = 0.070 × 109 cells/L/week; interquartile range = 0.091 cells/L/week. For each patient, Slope3 was estimated by simple linear regression, using all ALC assessments in the period from ALC1 to ALC3, and actual assessment dates. Examination of scaled Schoenfeld residuals suggested that the PH assumption was reasonable for all Cox PH models.
Fig. 1
Fig. 1
Hazard ratio (HR) estimates from Cox PH models, for each treatment group in each trial. HR estimates compare OS hazards for (A) ALC1 at the 75th and 25th percentiles; (B) ALC1 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; (C) ALC3 at the 75th and 25th percentiles; (D) ALC3 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; and (E) Slope3 at the 75th and 25th percentiles. Diamonds show point estimates. Horizontal bars show 95% confidence intervals (CI), based on Wald statistics. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab; N = number of patients included in the analysis per treatment group. All patients with a baseline (no more than 28 days prior to confirmed treatment initiation) and at least one post-baseline ALC evaluation were included in the ALC1 analyses. Of those patients, all with ≥ 1 ALC evaluation at least 7 days after dose 2 and prior to dose 3 were included in the ALC3 and Slope3 analyses. Percentiles are from the ALC1, ALC3, or Slope3 distributions over both trials combined. For ALC1, 25th percentile = 1.01 × 109 cells/L; 75th percentile = 1.80 × 109 cells/L; interquartile range = 0.79 cells/L. For ALC3, 25th percentile = 1.15 × 109 cells/L; 75th percentile = 2.08 × 109 cells/L; interquartile range = 0.93 cells/L. For Slope3, 25th percentile = −0.021 × 109 cells/L/week; 75th percentile = 0.070 × 109 cells/L/week; interquartile range = 0.091 cells/L/week. For each patient, Slope3 was estimated by simple linear regression, using all ALC assessments in the period from ALC1 to ALC3, and actual assessment dates. Examination of scaled Schoenfeld residuals suggested that the PH assumption was reasonable for all Cox PH models.
Fig. 1
Fig. 1
Hazard ratio (HR) estimates from Cox PH models, for each treatment group in each trial. HR estimates compare OS hazards for (A) ALC1 at the 75th and 25th percentiles; (B) ALC1 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; (C) ALC3 at the 75th and 25th percentiles; (D) ALC3 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; and (E) Slope3 at the 75th and 25th percentiles. Diamonds show point estimates. Horizontal bars show 95% confidence intervals (CI), based on Wald statistics. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab; N = number of patients included in the analysis per treatment group. All patients with a baseline (no more than 28 days prior to confirmed treatment initiation) and at least one post-baseline ALC evaluation were included in the ALC1 analyses. Of those patients, all with ≥ 1 ALC evaluation at least 7 days after dose 2 and prior to dose 3 were included in the ALC3 and Slope3 analyses. Percentiles are from the ALC1, ALC3, or Slope3 distributions over both trials combined. For ALC1, 25th percentile = 1.01 × 109 cells/L; 75th percentile = 1.80 × 109 cells/L; interquartile range = 0.79 cells/L. For ALC3, 25th percentile = 1.15 × 109 cells/L; 75th percentile = 2.08 × 109 cells/L; interquartile range = 0.93 cells/L. For Slope3, 25th percentile = −0.021 × 109 cells/L/week; 75th percentile = 0.070 × 109 cells/L/week; interquartile range = 0.091 cells/L/week. For each patient, Slope3 was estimated by simple linear regression, using all ALC assessments in the period from ALC1 to ALC3, and actual assessment dates. Examination of scaled Schoenfeld residuals suggested that the PH assumption was reasonable for all Cox PH models.
Fig. 1
Fig. 1
Hazard ratio (HR) estimates from Cox PH models, for each treatment group in each trial. HR estimates compare OS hazards for (A) ALC1 at the 75th and 25th percentiles; (B) ALC1 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; (C) ALC3 at the 75th and 25th percentiles; (D) ALC3 dichotomized as ≥ 1 vs. < 1 × 109 cells/L; and (E) Slope3 at the 75th and 25th percentiles. Diamonds show point estimates. Horizontal bars show 95% confidence intervals (CI), based on Wald statistics. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab; N = number of patients included in the analysis per treatment group. All patients with a baseline (no more than 28 days prior to confirmed treatment initiation) and at least one post-baseline ALC evaluation were included in the ALC1 analyses. Of those patients, all with ≥ 1 ALC evaluation at least 7 days after dose 2 and prior to dose 3 were included in the ALC3 and Slope3 analyses. Percentiles are from the ALC1, ALC3, or Slope3 distributions over both trials combined. For ALC1, 25th percentile = 1.01 × 109 cells/L; 75th percentile = 1.80 × 109 cells/L; interquartile range = 0.79 cells/L. For ALC3, 25th percentile = 1.15 × 109 cells/L; 75th percentile = 2.08 × 109 cells/L; interquartile range = 0.93 cells/L. For Slope3, 25th percentile = −0.021 × 109 cells/L/week; 75th percentile = 0.070 × 109 cells/L/week; interquartile range = 0.091 cells/L/week. For each patient, Slope3 was estimated by simple linear regression, using all ALC assessments in the period from ALC1 to ALC3, and actual assessment dates. Examination of scaled Schoenfeld residuals suggested that the PH assumption was reasonable for all Cox PH models.
Fig. 2
Fig. 2
Fitted mean ALC vs. weeks since first ipilimumab or placebo dose, by treatment group for (A) MDX010–20; and (B) CA184–024. Thick curves show fitted means and thin curves show pointwise two-sided 95% confidence intervals for the means. Vertical lines show nominal dosing days. Inverted triangles in (B) indicate ipilimumab doses, in contrast to placebo doses. Patients included in the analyses — 639 of 643 (MDX010–20) and 497 of 498 (CA184–024) — had ≥ 1 ALC assessment in the period from 28 days prior to a confirmed date of treatment initiation to 28 days after dose 4 of study drug. For each study, estimated means and confidence intervals are from an extended linear model, fit by restricted maximum likelihood. The model had fixed effects of treatment group and days since first dose (DSFD). The effect of DSFD was modeled by linear regression splines with, for each patient, a knot at the actual day of each dose, and interaction between treatment group and the splines. Within-patient correlations were modeled by a spatial exponential structure with Euclidean distance, and within-patient variances were inversely proportional to the number of ALC measurements on a given day. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab.
Fig. 2
Fig. 2
Fitted mean ALC vs. weeks since first ipilimumab or placebo dose, by treatment group for (A) MDX010–20; and (B) CA184–024. Thick curves show fitted means and thin curves show pointwise two-sided 95% confidence intervals for the means. Vertical lines show nominal dosing days. Inverted triangles in (B) indicate ipilimumab doses, in contrast to placebo doses. Patients included in the analyses — 639 of 643 (MDX010–20) and 497 of 498 (CA184–024) — had ≥ 1 ALC assessment in the period from 28 days prior to a confirmed date of treatment initiation to 28 days after dose 4 of study drug. For each study, estimated means and confidence intervals are from an extended linear model, fit by restricted maximum likelihood. The model had fixed effects of treatment group and days since first dose (DSFD). The effect of DSFD was modeled by linear regression splines with, for each patient, a knot at the actual day of each dose, and interaction between treatment group and the splines. Within-patient correlations were modeled by a spatial exponential structure with Euclidean distance, and within-patient variances were inversely proportional to the number of ALC measurements on a given day. DTIC = dacarbazine; gp100 = glycoprotein 100 peptide vaccine; ipi = ipilimumab.
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