Economic evaluation of rituximab in addition to standard of care chemotherapy for adult patients with acute lymphoblastic leukemia

<p><b>Aims:</b> Acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia with a poor prognosis in adult patients. The addition of the monoclonal antibody rituximab to standard chemotherapy has been shown to improve survival in adults with ALL. However, it is unknown whether the addition of rituximab is cost-effective. The objective was to determine the economic impact of rituximab in addition to standard of care (SOC) chemotherapy vs SOC alone in newly-diagnosed Philadelphia chromosome-negative, CD20-positive, B-cell precursor ALL.</p> <p><b>Methods:</b> A decision analytic model was constructed, based upon the Canadian healthcare system. It included the following health states over a lifetime horizon (max ≈60 years): event-free survival (EFS), relapsed/resistant disease, cure, and death. SOC was either hyper-CVAD or the Dana Farber Cancer Institute (DFCI) ALL consortium. EFS, overall survival, and serious adverse event (SAE) rates were derived from a large randomized controlled trial. Costs of the model included: first-line treatment and administration, disease management, second-line and third-line treatment and administration, palliative care, and SAE-related treatments. Inputs were sourced from provincial and national public data, the literature, and cancer agency input.</p> <p><b>Results:</b> Quality-adjusted life-years (QALYs) increased by 2.20 QALYs with rituximab in addition to SOC. The resulting mean Incremental Cost-Effectiveness Ratio (ICER) was C$21,828/QALY. At a willingness-to-pay threshold of C$100,000/QALY, the probability of being cost-effective was 98%. Decision outcomes were robust to the probabilistic and deterministic sensitivity analyses, including the SOC backbone as either hyper-CVAD or DFCI.</p> <p><b>Limitations:</b> The results of this analysis are limited by generalizability of the chemotherapy backbone to Canadian practice.</p> <p><b>Conclusions:</b> For adults with ALL, rituximab in addition to SOC was found to be a cost-effective intervention, compared to SOC alone. The addition of rituximab is associated with increased life years and increased QALYs at a reasonable incremental cost.</p

Flow Results Compiled

Compilation of raw data from all flow cytometry experiments including surface staining and phosphoflow. Sheet 1 is all the data for each patient, Sheet 2 is the log2 fold change of the MFI used for the heat map (figure 2), Sheet 3 compares samples collected <30d after diagnosis vs >30d after diagnosis, Sheet 4 examines the effect of freeze-thawing samples on surface staining. Statistical analysis on each sheet

STAT1 and STAT3 phosphorylation in hematological patients with IMI.

<p>(a-d) IFN-γ-induced STAT1 phosphorylation and IL-6-induced STAT3 phosphorylation were measured in peripheral blood mononuclear cells using phospho-flow. (a) On the <i>left</i>, representative dot plots for gating of naïve and memory CD4+ T cells are shown; gating of T cells (CD3+) or monocytes (CD33+, not shown) was done on CD45^high cells in order to avoid interference of the analysis by potential blasts in leukemic patients with residual disease. On the <i>right</i>, representative histograms of the levels of phosphorylated STAT (pSTAT) proteins in non-stimulated (NS) and cytokine-stimulated cells are shown; baseline pSTAT levels are shown in grey, IFN-γ-induced pSTAT1 is shown in purple and IL-6-induced pSTAT3 is shown in orange. (b) Representative histograms of IL-6 induced pSTAT3 (top row) and IFN-γ-induced pSTAT1 (bottom row) in different patient groups. Y axis corresponds to number of events (i.e. number of naïve CD4+ T cells) and X axis corresponds to fluorescence intensity (i.e. pSTAT-Alexa Fluor 488). (c) Percentage of monocytes (CD45^highCD33+ cells), naïve T helper (Th) cells (CD45^highCD3+CD4+CD45RO- cells) and memory Th cells (CD45^highCD3+CD4+CD45RO+ cells) expressing pSTAT3 (top row) and pSTAT1 (bottom row) in response to IL-6 and IFN-γ, respectively, in healthy controls (blue circles; n = 7), hematological patients with IA (red squares; n = 13) or mucormycosis (black inverted triangles; n = 4) and non-IFI hematological controls (green triangles; n = 15). *<i>p</i><0.05, **<i>p</i><0.01 and ***<i>p</i><0.005 using the unpaired two-tailed Student’s <i>t</i>-test. Data are shown as mean ± s.e.m. (d) Heat map for log2 scale of mean fluorescence intensity (MFI) fold change. Fold change was calculated by dividing the MFI of the cytokine-stimulated sample by that of the unstimulated sample. Heat map color scale is showed in the bottom. Each row on the heat map corresponds to an individual patient or control as indicated by the study ID number on the left. Each column on the heat map corresponds to specific cell type/pSTAT as indicated on the top. Note reduced IL-6-induced pSTAT3 in monocytes (<i>p</i> = 0.01 for IA vs. healthy controls and <i>p</i><0.05 for IA vs. non-IFI) and naïve CD4+ T cells (<i>p</i> = 0.006 for IA vs. healthy controls and <i>p</i> = 0.04 for IA vs. non-IFI) from patients with IA, using unpaired two-tailed Student’s <i>t</i>-test.</p

ELISA Data (PTX3 IL17 and IFN)

Data from PTX3, IL-17 and IFN-gamma ELISAs

Effect of IL-6 on <i>Aspergillus</i>-induced IL-17 production.

<p>(<b>a</b>) Levels IL-17 (pg/mL) measured by immunoassay on culture supernatants are shown. <i>Left</i> panels show the levels of IL-17 in supernatant of peripheral blood mononuclear cells (PBMCs) incubated in media alone (NS) or in the presence of <i>Aspergillus fumigatus</i> lysate (50 mg/mL) for 72hr. <i>Right</i> panels correspond to levels of IL-17 in supernatant of PBMCs incubated with <i>Aspergillus fumigatus</i> alone or in the presence of recombinant human IL-6 (100ng/mL). Detectable <i>Aspergillus</i>-induced cytokine production was defined as >2.5 fold change from baseline. Each line corresponds to an individual patient or control as indicated by the study ID number on the right. *<i>p</i><0.05 using the paired two-tailed Student’s <i>t</i>-test. (<b>b</b>) Heat map for log2 scale of IL-17 levels fold change. Each row on the heat map corresponds to an individual patient or control as indicated by the study ID number on the left. Fold change was calculated by dividing the IL-17 levels produced in response to Phorbol 12-Myristate 13-Acetate and ionomycin (50 ng/mL and 1 mg/mL, respectively; depicted as PMA/Io) or <i>Aspergillus fumigatus</i> (50 mg/mL; depicted as <i>Aspergillus</i>) stimulation by those of non-stimulated cells; and by dividing IL-17 levels in response to <i>Aspergillus</i> (50 mg/mL) plus IL-6 (100ng/mL) by those of cells stimulated with <i>Aspergillus</i> lysate alone (depicted as <i>Asp</i> + IL-6). Heat map color scale is showed in the bottom.</p

Pattern recognition receptors in hematological patients with IMI.

<p>(a) Serum levels of PTX3 (ng/mL) measured by immunoassay in healthy controls (blue circles; n = 6), hematological patients with IA (red squares; n = 12) or mucormycosis (black inverted triangles; n = 4) and non-IFI hematological controls (green triangles; n = 16) are shown. *<i>p<</i>0.05, **p<0.01, and ***p<0.005 using the unpaired two-tailed Student’s <i>t</i>-test. (b-d) Surface expression of dectin-1 (b), TLR2 (c) and TLR4 (d) on monocytes was measured by flow cytometry. Gating on CD45^highCD14+ cells was performed in order to avoid interference of the analysis by potential blasts in leukemic patients with residual disease. Dot plots represent the percentage of monocytes (CD45^highCD14+ cells) expressing dectin-1, TLR2 or TLR4 in peripheral blood samples from healthy controls (blue circles; n = 7), hematological patients with IA (red squares; n = 12) or mucormycosis (black triangles; n = 4) and non-IFI hematological controls (green triangles; n = 13). *<i>p</i><0.05, **<i>p</i><0.01 using the unpaired two-tailed Student’s <i>t</i>-test. All data are shown as mean ± s.e.m.</p