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Letters to the Editor
Table 3. Summary of pharmacokinetic parameters following a single infusion of BI 836858 in patients with relapsed or refractory acute myeloid leukemia (n=25, infusion duration 3-6 hours in different dose groups).
AUC0-∞ ng.h/mL
10 mg† (n=12) 23,400 (137) 20 mg‡ (n=6) 97,900 (114)
AUC0-∞, norm (ng.h/mL)/mg
2,340 (137) 4,890 (114)
Cmax ng/mL
873 (207) 3,270 (35.4)
Cmax, norm (ng/mL)/mg
87.3 (207) 164 (35.4)
tmax hours
4.43 (3.00-7.00) 6.10 (5.00-8.80)
t1⁄2 hours
11.3 (64.3) 21.4 (91.7)
CL mL/min
7.11 (137) 3.40 (114)
Vss L
7.01 (53.0) 6.30 (29.4)
Pharmacokinetic parameters*
40 mg‡ (n=7) 296,000 (256) 7,400 (256) 6,100 (82.1) 152 (82.1) 5.87 (5.00-8.45) 34.5 (107) 2.25 (256) 6.86 (69.5)
*Shown are geometric mean (%gCV) non-compartmental pharmacokinetic parameters of BI 836858 except for tmax which is shown as median (range); †infusion range from 3-6 hours; ‡5-hour infusion. AUC0-∞: area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity; CL: clearance; Cmax: max- imum concentration; gCV: geometric coefficient of variance; NA: not assessable; NC: not calculated; norm: normalized to administered dose; R/R AML: relapsed or refractory acute myeloid leukemia; tmax: time point at which maximum concentration is reached; t1⁄2: apparent half-life;Vss: volume of distribution at steady state
tration of 40 mg BI 836858, indicating target engage- ment (Online Supplementary Figure S2). In the 40 mg dose cohort, CD33+ blasts were undetectable in the bone mar- row of five of seven patients on cycle 1 day 8, suggesting target saturation. Conversely, in the 10 mg cohort, the majority of patients had detectable CD33+ blasts at this time point. Most patients had low NK counts (CD3-neg- ative, CD16-positive, CD56-positive) in the blood and bone marrow at screening (Online Supplementary Figure S3). Peripheral blood NK cells were below the lower limit of normal (<30 cells/mL), within the lower end of normal range (30-150 cells/mL), normal (>150 cells/mL) and missing in 30%, 56%, 11% and 4% of patients, respectively. Of note, there was a transient decline in NK cell counts at cycle 1 day 4 compared to the screening values in patients across all treatment cohorts. NK cells in the bone marrow ranged from very few to 7%. In both blood and bone marrow, there were no significant changes in the numbers of activated NK cells (expressing CD69 or CD158b) during treatment (data not shown). Monocyte counts were also below, or at the very end of the lower limit of the normal range in the majority (59%) of patients.
No responses to treatment were detected; 23 patients (85%) were removed from the study due to lack of response with persistent AML, two (7%) patients were not evaluable, and two (7%) did not have a post-baseline assessment. Median PFS was 29 days (95% confidence interval: 27-50). There were no notable changes in the percentage of myeloid blasts in the bone marrow during the treatment period.
To conclude, this study provides valuable information about the safety, efficacy, pharmacokinetics and pharma- codynamics of BI 836858 in patients with R/R AML which may have important implications for potential future development of immunotherapies in this setting. BI 836858 had predictable and manageable tolerability with no unexpected AE. However, although there was evidence of target engagement in the blood and to some extent in the bone marrow, no responses to BI 836858 were observed. The primary objective of MTD was not met due to premature termination. We hypothesize that the low levels of baseline effector cells observed in this study were relevant to the lack of efficacy of BI 836858. Other studies indicate that baseline NK cell phenotype and function is defective in patients with AML.11 Interestingly, phenotypic and functional abnormalities of NK cells appear to be partially restored in AML patients achieving a complete remission (CR).11 As BI 836858 relies on ADCC for functionality, the low levels of effec- tor cells detected in the patient population, and the lack of pharmacodynamic effects (see Online Supplementary Appendix), underpinned the decision to terminate the study based on a lack of perceived benefit over risk.
In contrast to the current study, lintuzumab conferred objective responses including CR in a phase I dose esca- lation trial in R/R AML.12 Given that BI 836858 was a similar design to lintuzumab (both were fully humanized IgG1 monoclonal antibodies, though BI 836858 was Fc engineered to increase ADCC) and was considered supe- rior to lintuzumab in preclinical experiments,9 it is not clear why it did not show clinical activity in this phase I study. Lintuzumab is dependent on engagement of sever- al immune effector cells including macrophages/mono- cytes (that facilitate ADCP)13 as well as NK cells (that facilitate ADCC).13 The impact of BI 836858 on immune effector cell function in patients requires more evalua- tion. It is possible that differences in internalization kinetics of CD33 following engagement with lintuzumab or BI 836858 may influence immunogenicity. While inter- nalization is slower with BI 836858 and this correlates with superior ADCC in cell-based assays,9 it is uncertain how this may influence other effector functions. Also, lack of efficacy could potentially relate to pre-adminis- tration of glucocorticoids. Despite steps to reduce gluco- corticoid dose as soon as possible, administration may interfere with NK cell function, as indicated in previous preclinical studies.14,15 However, unpublished observa- tions suggest that BI 836858 may activate NK cells when combined with decitabine, despite premedication with glucocorticoids. Further clinical studies have been designed to assess combination regimens that may potentiate the activity of BI 836858 by increasing effec- tor immune function. For example, based on preclinical evidence that decitabine increased BI 836858 activity via upregulation of the NK group 2D ligand,9 a phase II study is exploring the efficacy and safety of this combi- nation (clinicaltrials gov. Identifier: NCT02632721). Other BI 836858-based combinations are also being assessed in a multi-sub-study phase Ib/II trial (clinicaltri- als gov. Identifier: NCT03013998). These studies will include post-remission therapy when immune effectors might be more numerous and active.
Sumithira Vasu,1 Jessica K. Altman,2 Geoffrey L. Uy,3 Martin S. Tallman,4 Ivana Gojo,5 Gerard Lozanski,6 Ute Burkard,7 Annika Osswald,7 Pamela James,8 Björn Rüter8 and William Blum9
1Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 2Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA; 3Washington University School of Medicine, Siteman Cancer Center, St Louis, MO, USA; 4Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; 5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 6Department of Pathology, The Ohio State University, Columbus, OH, USA;
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haematologica | 2022; 107(3)