M B Agarwal
Acute myeloblastic leukaemia (AML) is a heterogeneous disease where patients can be cured while others can succumb within a few days of diagnosis and beginning treatment. The major reason for non-curability is resistance to present treatment. Treatment related mortality (TRM) is gradually reducing, however, deaths occur due to relapses resistant to present treatment. Knowledge of the pre-treatment mutational status has helped the clinicians in improving their ability to assign initial treatment and also in detecting minimal residual disease (MRD) which influences subsequent management. During last 3 years, several new drugs have received US FDA approval and their role in treatment of AML has become significant.
Pre-treatment risk stratification: Age is an important factor. AML is a disease of elderly. Median age at diagnosis is 65-70 years. Over 50% of patients above the age of 65 years failed to receive standard chemotherapy within 3 months of diagnosis. As the age advances, more and more patients receive best supportive therapy or hypomethylating agents (HMAs) rather than 7+3.
Factors associated with TRM: Differentiating TRM from resistant is useful. Performance status (PS), blood counts, renal function, albumin are major determinant of TRM. Age is probably a surrogate for other TRM covariates. Comorbidities, site of treatment, cohabitation status and educational level have major influence of survival, usually through TRM.
Factor associated with resistance: Genetics encompassing both classical cytogenetics and the mutational status of various genes is the most important predictor of resistance i.e. failure to enter CR despite not incurring TRM or relapse. The single most adverse factor is TP53 mutation, commonly associated with complex cytogenetics. FLT3 ITD mutation is regarded as unfavourable, especially if the ratio of mutated to normal alleles is > 0.5. In the era of Midostaurin, this is, however, changing we will discuss these at length.
Newer drugs: Besides standard chemotherapy i.e. 7+3 followed by consolidation with high dose cytosine arabinoside in patients with low or standard risk molecular genetics vs allogenic transplant in others with high risk molecular profile, today one has MRD guided approach as well as availability of various FDA approved newer molecules that include FLT inhibitors (Midostaurin and others), CPX 351 (Vyxeos), Venetoclax (bcl2 inhibitor), IDH1 and IDH2 inhibitors (Ivosidenib and Enasidenib), GO (Gemtuzumab Ozogamicin) and HMAs including 10-day decitabine.
Correspondence: Professor M B Agarwal, Head of the Department of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India. Email ID: [email protected]. Mobile: +91 9820024850.