Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia

Abstract

As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

CD38 is expressed on T-ALL and ETP T-ALL blasts with stable expression following induction chemotherapy and at relapse. (A) Averages of MFI measured by flow cytometry of 21 patients with T-ALL enrolled on the Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma (AALL1231) study. The gating strategy is described in the supplemental Methods. Gating is on the blast population and therefore represents patients with residual, detectable ALL. (B) MFI of CD38 from 10 T-ALL patients previously enrolled on the Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma (AALL0434) study from initial diagnosis and at first relapse. MFI, median fluorescence intensity.

Figure 2.

In vivo efficacy of daratumumab in ETP T-ALL and non-ETP T-ALL. PDX models were treated with isotype control or daratumumab weekly for 3 to 8 weeks depending on the rate of leukemia progression in control animals. Experiments were also varied based on daratumumab treatment at “low” vs “high” disease burden. The mice were treated an average of 4 doses at the high disease burden and 7 at low disease burden. The duration of treatment was determined by the need to euthanize control animals because of overwhelming disease burden. Each experiment represents n = 5 mice per treatment group. (A) Trials of mice treated at high disease burden that did not experience toxicity are shown for T-ALL and ETP T-ALL xenografts. (Left) Histogram of CD38-PE (red) with the corresponding MFI compared with an unstained (blue) and isotype control (green) to demonstrate positivity above background. Graphed are means and standard deviations of absolute blast count on the vertical axis and weeks of treatment on the horizontal axis. Treatment groups (red) were compared with mice treated with isotype antibody control (blue) for each PDX model using a nonparametric Mann-Whitney U test. P values are shown. ID-TALL33 was only bled once at the time of harvest because of the aggressiveness of disease progression. Mice engrafted from this sample do not tolerate serial bleeds; therefore, blood and spleen data are shown only at the time euthanization. (B) Experiments performed at low disease burden of samples that experienced toxicity when tested at high disease burden. Two samples, ID-TALL8 and ID-ETP12, represent repeated trials of daratumumab tested at low disease state; they did not respond at the high disease state.