Poly(ADP-Ribose) Polymerase Inhibitors and Myeloid Neoplasm Risk—Clues to a Mechanistic Connection?

ABSTRACT Hypereosinophilia is defined as persistent eosinophilia (>1.5 × 109/L). Hypereosinophilic syndrome (HES) is a term used to describe a group of disorders characterized by sustained hypereosinophilia associated with end-organ damage. Based on underlying molecular mechanism of eosinophilia, there are different subtypes of HES. Diagnosis of HES subtype can be challenging, especially in the absence of overt lymphoid/myeloid neoplasms or discernable secondary causes. Long-term outpatient follow-up with periodic complete blood count and repeated bone marrow biopsy may be needed to monitor disease activity. Somatic signal transducer and activation transcription 5b (STAT5b) N642H mutation was recently found to be associated with myeloid neoplasms with eosinophilia. We report a case of HES who presented with pulmonary embolism and acute eosinophilic pneumonia, found to have recurrent STAT5b N642H mutation by next-generation sequencing, suggesting possible underlying myeloid neoplasm.

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Incidence of myelodysplastic syndrome and acute myeloid leukemia in patients receiving poly-ADP ribose polymerase inhibitors for the treatment of solid tumors: A meta-analysis of randomized trials

Gynecologic Oncology ◽

10.1016/j.ygyno.2021.03.011 ◽

2021 ◽

Author(s):

Roni Nitecki ◽

Alexander Melamed ◽

Allison A. Gockley ◽

Jessica Floyd ◽

Kate J. Krause ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Solid Tumors ◽

Myeloid Leukemia ◽

Randomized Trials ◽

Meta Analysis ◽

Polymerase Inhibitors ◽

Acute Myeloid

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Clonal hematopoiesis in adult pure red cell aplasia

Scientific Reports ◽

10.1038/s41598-021-81890-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Naohito Fujishima ◽

Junki Kohmaru ◽

Souichi Koyota ◽

Keiji Kuba ◽

Tomoo Saga ◽

...

Keyword(s):

Amino Acid ◽

Gene Mutations ◽

Pure Red Cell Aplasia ◽

Amino Acid Sequences ◽

Driver Mutations ◽

Red Cell ◽

Clonal Hematopoiesis ◽

Red Cell Aplasia ◽

Myeloid Neoplasm ◽

Immune Mediated

AbstractIdiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

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Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: a clinicopathological study of 66 cases comparing cases with prior history of treatment to those without

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-207334 ◽

2021 ◽

pp. jclinpath-2020-207334

Author(s):

Catherine Luedke ◽

Yue Zhao ◽

Jenna McCracken ◽

Jake Maule ◽

Lian-He Yang ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

The Other ◽

Prior History ◽

Myeloid Neoplasm ◽

Myeloid Neoplasms ◽

History Of ◽

Cytogenetic Profile ◽

Group 2 ◽

Group 1

AimsMyeloid neoplasms occur in the setting of chronic lymphocytic leukaemia (CLL)/CLL-like disease. The underlying pathogenesis has not been elucidated.MethodsRetrospectively analysed 66 cases of myeloid neoplasms in patients with CLL/CLL-like disease.ResultsOf these, 33 patients (group 1) had received treatment for CLL/CLL-like disease, while the other 33 patients (group 2) had either concurrent diagnoses or untreated CLL/CLL-like disease before identifying myeloid neoplasms. The two categories had distinct features in clinical presentation, spectrum of myeloid neoplasm, morphology, cytogenetic profile and clinical outcome. Compared with group 2, group 1 demonstrated a younger age at the diagnosis of myeloid neoplasm (median, 65 vs 71 years), a higher fraction of myelodysplastic syndrome (64% vs 36%; OR: 3.1; p<0.05), a higher rate of adverse unbalanced cytogenetic abnormalities, including complex changes, −5/5q- and/or −7/7q- (83% vs 28%; OR: 13.1; p<0.001) and a shorter overall survival (median, 12 vs 44 months; p<0.05).ConclusionsMyeloid neoplasm in the setting of CLL/CLL-like disease can be divided into two categories, one with prior treatment for CLL/CLL-like disease and the other without. CLL-type treatment may accelerate myeloid leukaemogenesis. The risk is estimated to be 13-fold higher in patients with treatment than those without. The causative agent could be attributed to fludarabine in combination with alkylators, based on the latency of myeloid leukaemogenesis and the cytogenetic profile.

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Myeloid Neoplasm with PDGFRA Rearrangement Manifesting as a Retromolar Pad Mass

Head and Neck Pathology ◽

10.1007/s12105-021-01305-9 ◽

2021 ◽

Author(s):

Amy S. Duffield ◽

Jonathan Webster ◽

B. Douglas Smith ◽

Julius S. Necciai ◽

Austin McCuiston ◽

...

Keyword(s):

Myeloid Neoplasm

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New Insights into the Pathogenesis of Systemic Mastocytosis

International Journal of Molecular Sciences ◽

10.3390/ijms22094900 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4900

Author(s):

Zhixiong Li

Keyword(s):

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Systemic Mastocytosis ◽

Treatment Strategies ◽

The United States ◽

European Medicines Agency ◽

Myeloid Neoplasm ◽

Organ Systems ◽

United States Food ◽

Kit D816v

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.

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