TY  - JOUR
A1  - Fuhr, Viktoria
A1  - Heidenreich, Shanice
A1  - Srivastava, Mugdha
A1  - Riedel, Angela
A1  - Düll, Johannes
A1  - Gerhard-Hartmann, Elena
A1  - Rosenwald, Andreas
A1  - Rauert-Wunderlich, Hilka
T1  - CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma
JF  - Cell Death Discovery
N2  - Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.
KW  - cancer metabolism
KW  - cell death
KW  - target validation
KW  - targeted therapies
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300817
SN  - 2058-7716
VL  - 8
ER  - 
TY  - JOUR
A1  - Zhou, Xiang
A1  - Steinhardt, Maximilian Johannes
A1  - Düll, Johannes
A1  - Krummenast, Franziska
A1  - Danhof, Sophia
A1  - Meckel, Katharina
A1  - Nickel, Katharina
A1  - Grathwohl, Denise
A1  - Leicht, Hans‐Benno
A1  - Rosenwald, Andreas
A1  - Einsele, Hermann
A1  - Rasche, Leo
A1  - Kortüm, Martin
T1  - Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma
JF  - European Journal of Haematology
N2  - We herein report the case of a 73‐year‐old male patient who was diagnosed with leukemic non‐nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second‐line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single‐agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2‐4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression‐free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab‐intolerant patient with an ibrutinib‐resistant MCL. This case suggests that obinutuzumab‐ and venetoclax‐based combination therapy might be salvage therapy in patients with ibrutinib‐resistant MCL.
KW  - mantle cell lymphoma
KW  - obinutuzumab
KW  - venetoclax
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215513
VL  - 104
IS  - 4
SP  - 352
EP  - 355
ER  -