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Erschienen in: Annals of Hematology 6/2021

Open Access 13.03.2021 | Letter to the Editor

Treatment of therapy-related acute myeloid leukemia and underlying multiple myeloma with decitabine/venetoclax and daratumumab

verfasst von: Khalid Shoumariyeh, Johannes Jung, Michael Rassner, Sandra Maria Dold, Veronika Riebl, Milena Pantic, Georg Herget, Reinhard Marks, Michael Lübbert, Ralph Wäsch, Monika Engelhardt

Erschienen in: Annals of Hematology | Ausgabe 6/2021

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Supplementary Information

The online version contains supplementary material available at https://​doi.​org/​10.​1007/​s00277-021-04490-3.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dear Editor,
With increased survival of patients with multiple myeloma (MM), therapy-related myelodysplastic syndrome (t-MDS) and t-acute myeloid leukemia (AML) may occur more frequently [1, 2]. We present here a patient with high-risk (HR) MM, who developed t-MDS and subsequent t-AML. AML treatment with decitabine/venetoclax resulted in complete remission (CR) of the t-AML, while progressive disease of MM was treated with daratumumab. We hypothesize that upregulation of CD38 in bone marrow plasma cells (BMPCs) after decitabine/venetoclax may have enhanced MM response. Additionally, we performed a review of the literature (Suppl. Table 1).
In June 2015, a 64-year-old female was diagnosed with IgG kappa (κ) MM. IgG levels were 46g/L, κ-serum-free light chains (SFLC) 75.4mg/L and ß2-microglobulin 8.2mg/L (Fig. 1A). Anemia with a hemoglobin (Hb) of 8.4g/dL and osteolytic lesions were present. BMPC infiltration was 90%, and fluorescence in situ hybridization (FISH) revealed hyperdiploidy and del17p13 (Fig. 1B (a) and C). The MM was classified as International Staging System (ISS) III, R-ISS III, with 2/4 CRAB criteria. The patient’s revised myeloma comorbidity index was intermediate-fit [3].
First-line therapy with bortezomib, cyclophosphamide, and dexamethasone was followed by autologous stem cell transplantation and maintenance therapy with lenalidomide (Fig. 1A). After 1½ years (11/2017), lenalidomide was discontinued due to worsening anemia (Hb 10g/dL) and leukopenia (2.8x106/L). BM assessment did not reveal increased PCs or MDS, and serological parameters indicated stable disease.
In January 2019, pancytopenia worsened (Hb 8.4g/dL, leukocytes 0.59x106/L, platelets 12x106/L) and κ-SFLCs increased (Fig. 1A). Another BM biopsy revealed BMPCs of 50% and myeloid blasts of 22% (Fig. 1B (b)). Molecular analyses identified mutations in DNMT3A and IDH1 (Fig. 1C). Coexistence of MM and t-AML (Fig. 1D, left) was confirmed by 10-color multiparameter flow cytometry (MFC) analysis of the BM [4].
Due to frailty at that time, she was ineligible for intensive AML induction therapy. Therefore, treatment with decitabine/venetoclax was started in February 2019. A BM biopsy in March 2019 confirmed CR of the t-AML (Fig. 1B (c)). However, PCs assessed by immunohistochemistry for CD38 had increased to 90%, and MFC confirmed aberrant PCs (aPCs) (Fig. 1D, right); therefore 2nd line daratumumab treatment was initiated (Fig. 1A). This induced VGPR and peripheral blood (PB) counts improved (Hb 10.2g/dL, leukocytes 3.2x106/L, platelets 94x106/L).
In June 2019, after worsening pancytopenia re-emerged and myeloid blasts were detectable in PB smears, decitabine/venetoclax was re-initiated. The BM biopsy in August 2019 showed persisting (30%) immature myeloid blasts (Fig. 1B (d)), upon which melphalan per os was started [5]. The patient died 2 months later of t-AML/MM progression, 50 months after the diagnosis of HR MM, and 9 months after t-AML.
In summary, after decitabine/venetoclax induction and favorable t-AML-response, MM progression required 2nd line daratumumab treatment, resulting in VGPR and improvement of PB counts. Notably, decitabine/venetoclax may have resulted in upregulation of CD38 (Fig. 1 D and E), possibly augmenting the response to daratumumab, although single-cell CD38 expression on aPCs before and after decitabine/venetoclax was not performed. In line with this hypothesis, Choudhry et al. showed that treatment of MM cell lines and primary patient samples with the demethylating agent 5-azacytidine resulted in CD38 upregulation [6]. Moreover, ATRA and the pan-deacetylase-inhibitor panobinostat may increase expression of CD38 in MM [7, 8]. Similarly, Zhao et al. demonstrated upregulation of CD38 on CD8-positive T-cells of AML patients receiving decitabine [9]. Furthermore, daratumumab has been shown to be effective in targeting adult CD38-positive AML and T-cell acute lymphoblastic leukemia (T-ALL) as well as pediatric T-ALL blasts in a preclinical patient-derived xenograft mouse model, and a phase II study (NCT03384654) investigating the efficacy of daratumumab in relapsed and refractory T-ALL is currently ongoing [10, 11]. Recently, Berthon et al. reported about a patient with simultaneous AML and MM who concomitantly received 5-azacytidine and daratumumab during MM relapse (Suppl. Table 1) [12]. Clinical trials are currently under way to investigate whether pretreatment with demethylating agents enhances the efficacy of daratumumab.

Acknowledgements

The authors thank distinguished IMWG, EMN, DSMM, and GMMG myeloma experts for their advice, recommendations, and insightful, inspiring comments.

Declarations

Ethics

Informed consent was obtained from the patient for being included in this study.

Conflict of interest

JJ, MR, SMD, VR, MP, GH, RM, ML have no financial or other relationships that might lead to a conflict of interest. KS has received travel support from Abbvie and consultancy fees from Novartis. RW has received research and travel support from Sanofi, Gilead, Jazz, Celgene, and Amgen and has received consultancy fees from Sanofi, Pfizer, Gilead, Novartis, Amgen, and Takeda. ME has received educational and trial support from Amgen, Takeda, BMS, Janssen, and Novartis, in all unrelated to this case.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Supplementary Information

Literatur
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Metadaten
Titel
Treatment of therapy-related acute myeloid leukemia and underlying multiple myeloma with decitabine/venetoclax and daratumumab
verfasst von
Khalid Shoumariyeh
Johannes Jung
Michael Rassner
Sandra Maria Dold
Veronika Riebl
Milena Pantic
Georg Herget
Reinhard Marks
Michael Lübbert
Ralph Wäsch
Monika Engelhardt
Publikationsdatum
13.03.2021
Verlag
Springer Berlin Heidelberg
Erschienen in
Annals of Hematology / Ausgabe 6/2021
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-021-04490-3

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