The leukemia strikes back: a review of pathogenesis and treatment of secondary AML

Cheung, Edna; Perissinotti, Anthony J.; Bixby, Dale; Burke, Patrick W.; Pettit, Kristen; Benitez, Lydia; Brown, Julia; Scappaticci, Gianni B.; Marini, Bernard L.

doi:10.1007/s00277-019-03606-0

Cited by 36 publications

(25 citation statements)

References 104 publications

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“…However, frail subjects may be particularly prone to mortality, mainly due to sepsis, hemorrhagic complications, and myelosuppression. As the practicality of dose adjustment is now limited by the availability of a fixed molar ratio, the most reasonable strategy would be to use full-dose CPX-351 only in relatively fit patients who are expected to tolerate it [68].…”

Section: Other Therapiesmentioning

confidence: 99%

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options

Iurlo

Cattaneo

Gianelli

2019

IJMS

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Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10–20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6–7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.

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Section: Other Therapiesmentioning

confidence: 99%

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options

Iurlo

Cattaneo

Gianelli

2019

IJMS

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“…Acute myeloid leukemia (AML) is a heterogeneous aggressive malignancy occurring de novo, secondary to antecedent hematological disorders, or following cytotoxic treatments for a primary disease [1][2][3][4]. It is the most common acute leukemia in adults with an annual age-adjusted incidence rate of 3.5/100,000 men and women rising to 15-20/100,000 above the age of 60 years [5].…”

Section: Introductionmentioning

confidence: 99%

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.

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“…34 The development of vadastuximab talirine ceased after an increased number of deaths due to infections were observed in the phase 3 CASCADE study. 35 Incorporating an ADC into a transplant strategy may limit hematologic toxicity…”

Section: Discussionmentioning

confidence: 99%

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

et al. 2020

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38−CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.

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The leukemia strikes back: a review of pathogenesis and treatment of secondary AML

Cited by 36 publications

References 104 publications

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

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