Issue Archive

Imetelstat is an oligonucleotide telomerase inhibitor recently approved by the US Food and Drug Administration for adults with lower-risk myelodysplasia who are red cell transfusion–dependent and are ineligible for or failed prior erythropoiesis-stimulating agent therapy. In this Blood Spotlight, Abaza and DeZern succinctly review the biologic basis for this agent and the clinical data leading to approval. The authors provide a useful outline of how imetelstat may be incorporated in treatment options for lower-risk myelodysplasia.

Sterile alpha motif domain–containing protein 9 (SAMD9) and SAMD9-like (SAMD9L) syndromes are relatively new leukemia predisposition syndromes caused by germ line mutations in SAMD9 and SAMD9L genes that result in multisystem abnormalities, including bone marrow failure, immunodeficiency, and a risk for myelodysplasia and monosomy 7. Sahoo and colleagues review these disorders using registry data to better understand their clinical spectrum, challenges in genetic testing, molecular biology, clonal evolution, and treatment strategies. The authors emphasize the need for natural history studies, particularly for patients acquiring monosomy 7, to inform evidence-based surveillance and optimize transplant timing.

Pegcrisantaspase (PegC), a pegylated form of Erwinia asparaginase used for patients with acute lymphoblastic leukemia who have hypersensitivity to Escherichia coli–derived asparaginase products, depletes cells of glutamine and affects protein translation. In a phase 1 clinical trial of PegC in combination with venetoclax in adults with relapsed and refractory acute myeloid leukemia, Liu and colleagues report a 33% rate of either a complete remission (CR) or a CR with incomplete blood count recovery. Given that this cohort has limited treatment options, these promising findings merit further evaluation.

The TP53 mutation is the most significant negative prognostic feature in mantle cell lymphoma (MCL), and more effective treatment for these high-risk patients is needed. Kumar and colleagues report on a multicenter phase 2 study of zanubrutinib, obinutuzumab, and venetoclax in untreated patients with TP53-mutated MCL and show a high response rate in 25 patients, with 22 attaining a complete response and a 2-year progression-free survival of 72%. These promising results support future evaluation of this regimen and possible use of consolidation regimens to further extend the observed benefits.

CD47 is overexpressed on the surface of many cancer cells, providing a “don’t eat me” signal that allows the tumor cells to evade phagocytosis; however, immunotherapy approaches targeting CD47 have largely proved disappointing in the clinic. Ma et al report on a novel, bivalent CD47 immunotoxin that demonstrates strong antitumor responses in vitro and in vivo in a mouse model of T-cell acute lymphoblastic leukemia, without affecting CD47 on red blood cells. The authors’ data suggest an approach that improves therapeutic efficacy while minimizing side effects like anemia, supporting the rationale for future clinical trials.

Hyperdiploidy is considered an initiating event in multiple myeloma, but it is not clear how long the time is from the first genetic event to a diagnosis of myeloma. Samur et al used whole-genome sequencing and advanced analyses to suggest that the presence of clonal plasma cells likely precedes the clinical detection of a monoclonal protein by decades. While this discovery is biologically intriguing, further research is required to assess its clinical relevance and whether early screening could help intercept cases that might progress to myeloma.