Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts

The Current Understanding of and Treatment Paradigm for Newly-Diagnosed TP53-Mutated Acute Myeloid Leukemia

About 10% of newly diagnosed and 20–30% of therapy-related acute myeloid leukemia (AML) harbors a TP53 mutation (mTP53-AML). Unfortunately, this biological subset predicts one of the worst prognoses among patients with AML, specifically a median overall survival of about 7 months with fewer than 10% of patients eventually cured of disease. Although remission rates appear to be increased with venetoclax-based, less-intensive regimens when compared with contemporary, intensive chemotherapy (55–65% vs. 40%), survival appears to be no different between the two approaches. Attempts to discern whether or not the prognosis of mTP53-AML is universally poor have centered around the study of concurrent cytogenetic risk and predicted TP53 allelic state, measurable residual disease status and the impact of conditioning intensity for patients proceeding to allogeneic hematopoietic stem cell transplantation. We discuss these considerations in this review and offer the current treatment approach to TP53-mutated AML

Oral therapy for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a revolution in progress

Patients with myeloid neoplasms such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) are generally older, and many are not eligible for curative intent intensive therapies and/or allogeneic hematopoietic stem cell transplantation. While lower intensity, hypomethylating agent (HMA)-based therapies such as azacitidine+venetoclax have improved patient outcomes significantly, responses are not durable, and most patients die from disease-related complications. The approvals of oral HMAs such as cedazuridine-decitabine (C-DEC) and oral azacitidine (CC-486) have kindled the hope that myeloid malignancies may soon be treated with total oral therapy. We review all-oral therapies including the approvals of C-DEC and CC-486 in MDS and AML, respectively, in addition to emerging all-oral therapies, both monotherapy and combination, in higher-risk (HR) MDS and AML. Oral HMAs have the potential to be a convenient and efficacy-equivalent treatment option for patients with HR-MDS or AML and improve their quality of life by reducing clinic visits for medication administration. Total-oral therapy combinations, largely including an oral HMA 'backbone,' are in the early phases of clinical development, and it is our hope that well-designed trials employing these agents may soon allow the identification of optimal regimens that deliver effective disease-directed therapy with good tolerability

The Current Understanding of and Treatment Paradigm for Newly-Diagnosed <i>TP53</i>-Mutated Acute Myeloid Leukemia

About 10% of newly diagnosed and 20–30% of therapy-related acute myeloid leukemia (AML) harbors a TP53 mutation (mTP53-AML). Unfortunately, this biological subset predicts one of the worst prognoses among patients with AML, specifically a median overall survival of about 7 months with fewer than 10% of patients eventually cured of disease. Although remission rates appear to be increased with venetoclax-based, less-intensive regimens when compared with contemporary, intensive chemotherapy (55–65% vs. 40%), survival appears to be no different between the two approaches. Attempts to discern whether or not the prognosis of mTP53-AML is universally poor have centered around the study of concurrent cytogenetic risk and predicted TP53 allelic state, measurable residual disease status and the impact of conditioning intensity for patients proceeding to allogeneic hematopoietic stem cell transplantation. We discuss these considerations in this review and offer the current treatment approach to TP53-mutated AML

Are We Moving the Needle for Patients with <i>TP53</i>-Mutated Acute Myeloid Leukemia?

The currently available therapeutic options for patients with TP53-mutated acute myeloid leukemia (AML) are insufficient, as they translate to a median overall of only 6–9 months, and less than 10% of patients undergoing the most aggressive treatments, such as intensive induction therapy and allogeneic hematopoietic stem cell transplantation, will be cured. The lack of clear differences in outcomes with different treatments precludes the designation of a standard of care. Recently, there has been growing attention on this critical area of need by way of better understanding the biology of TP53 alterations and the disparities in outcomes among patients in this molecular subgroup, reflected in the development and testing of agents with novel mechanisms of action. Promising preclinical and efficacy data exist for therapies that are directed at the p53 protein rendered dysfunctional via mutation or that inhibit the CD47/SIRPα axis or other immune checkpoints such as TIM-3. In this review, we discuss recently attractive and emerging therapeutic agents, their preclinical rationale and the available clinical data as a monotherapy or in combination with the currently accepted backbones in frontline and relapsed/refractory settings for patients with TP53-mutated AML