Sorafenib induced Hand Foot Skin Rash in FLT3 ITD mutated Acute Myeloid leukemia- A case report and review of literature

Sorafenib is a novel small molecule multiple kinase inhibitor which has been used for metastatic renal cancer, hepatocellular cancer. Sorafenib induced skin rash has been discussed as a side effect in trials in both FLT3 wild type and mutated acute myeloid leukemia (AML) as monotherapy or as combination with other chemotherapeutic agents . We describe a patient with FLT 3 ITD mutated AML who was started on adjunctive Sorafenib therapy. Skin reactions manifested as NCI Grade III palmoplantar erythrodysesthesia (PPE), requiring drug discontinuation. Several pathogenic mechanisms have been implicated in Sorafenib induced skin reactions, but none has been conclusively proven. While treatment options are varied for early stage skin reactions, drug discontinuation remains the only possible therapy presently for severe grade skin reaction.

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Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy

International Journal of Hematology ◽

10.1007/s12185-020-03074-7 ◽

2021 ◽

Author(s):

Fumi Nakamura ◽

Honoka Arai ◽

Yasuhito Nannya ◽

Motoshi Ichikawa ◽

Shiho Furuichi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Major Molecular Response ◽

Tyrosine Kinase Inhibitor Therapy ◽

Acute Myeloid

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NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions

Science China Life Sciences ◽

10.1007/s11427-015-4968-3 ◽

2015 ◽

Vol 58 (12) ◽

pp. 1288-1298 ◽

Cited By ~ 7

Author(s):

YaJie Wang ◽

Chen Chen ◽

Fang Dong ◽

ShiHui Ma ◽

Jing Xu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Nk Cells ◽

Significant Role ◽

Myeloid Leukemia ◽

Early Stage ◽

Acute Myeloid

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A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

Blood Cancer Journal ◽

10.1038/bcj.2015.19 ◽

2015 ◽

Vol 5 (3) ◽

pp. e297-e297 ◽

Cited By ~ 40

Author(s):

E Saland ◽

H Boutzen ◽

R Castellano ◽

L Pouyet ◽

E Griessinger ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Xenograft Model ◽

Chemotherapeutic Agents ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy

Cancers ◽

10.3390/cancers13194785 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4785

Author(s):

Enrico Kittel-Boselli ◽

Karla Elizabeth González Soto ◽

Liliana Rodrigues Loureiro ◽

Anja Hoffmann ◽

Ralf Bergmann ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Immune Escape ◽

Early Stage ◽

Logic Gates ◽

Boolean Logic ◽

In Vivo Models ◽

Peptide Epitope ◽

Acute Myeloid

Clinical translation of novel immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML) is still at an early stage. Major challenges include immune escape and disease relapse demanding for further improvements in CAR design. To overcome such hurdles, we have invented the switchable, flexible and programmable adaptor Reverse (Rev) CAR platform. This consists of T-cells engineered with RevCARs that are primarily inactive as they express an extracellular short peptide epitope incapable of recognizing surface antigens. RevCAR T-cells can be redirected to tumor antigens and controlled by bispecific antibodies cross-linking RevCAR T- and tumor cells resulting in tumor lysis. Remarkably, the RevCAR platform enables combinatorial tumor targeting following Boolean logic gates. We herein show for the first time the applicability of the RevCAR platform to target myeloid malignancies like AML. Applying in vitro and in vivo models, we have proven that AML cell lines as well as patient-derived AML blasts were efficiently killed by redirected RevCAR T-cells targeting CD33 and CD123 in a flexible manner. Furthermore, by targeting both antigens, a Boolean AND gate logic targeting could be achieved using the RevCAR platform. These accomplishments pave the way towards an improved and personalized immunotherapy for AML patients.

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The Salt-Inducible Kinase inhibitor YKL-05-099 suppresses MEF2C function and acute myeloid leukemia progressionin vivo

10.1101/636969 ◽

2019 ◽

Author(s):

Yusuke Tarumoto ◽

Shan Lin ◽

Jinhua Wang ◽

Joseph P. Milazzo ◽

Yali Xu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Disease Progression ◽

Cell Lines ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Clinical Investigation ◽

Genetic Targeting ◽

Acute Myeloid

AbstractLineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a Salt-Inducible Kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF MEF2C. In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. Here, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells underin vitroandin vivoconditions. Similar phenotypes were obtained when exposing cells to YKL-05-099, which caused cell cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele ofSIK3, we found that the anti-proliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated two different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progressionin vivoand extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-positive AML and provide a rationale for developing drug-like inhibitors of SIK3 for definitive pre-clinical investigation and for studies in human patients with leukemia.Key PointsAML cells are uniquely sensitive to genetic or chemical inhibition of Salt-Inducible Kinase 3in vitroandin vivo.A SIK inhibitor YKL-05-099 suppresses MEF2C function and AMLin vivo.

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