**4. Future perspectives**

The great advances in understanding molecular mechanisms of AML as well as their prognostic significance have changed the therapeutic armamentarium against AML. The drugs discussed in this chapter and many novel molecules being evaluated in clinical trials are on their way to change the current standard of treatment in AML. Ongoing efforts to understand the heterogeneity of AML, the constantly changing genomic landscape, the mechanisms of resistance/refractoriness will be very important in the development of new drugs. The rational use of these drugs, their potency that might be improved by combining them with other modes of therapy will hopefully increase long-term benefits for patients with AML. Furthermore, the development of novel ultrasensitive methods for minimal residual disease detection will also refine the treatment decision making process and probably improve the survival rates. However, new issues such as extrapolation of the results from the clinical trials enrolling carefully selected patients to general practice, the access and cost of these new drugs must be considered in the treatment decision

**255**

**Author details**

Vasko Graklanov

*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

**Declaration of conflicting interest**

process. It is a question of time whether personally tailored therapeutic era is going to be the new standard in the treatment of AML. Till then an increased enrolment of patients with AML into clinical trials evaluating the safety and efficacy of these

new drugs and combinations is strongly encouraged and recommended.

First Department of Internal Diseases, Clinic of Clinical Hematology, Medical

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

University-Plovdiv, UMHAT "St. George", Plovdiv, Bulgaria

\*Address all correspondence to: dr.grklanov@yahoo.com

provided the original work is properly cited.

The authors declare that there is no conflict of interest.

*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

*Acute Leukemias*

the risk of relapse and improved overall survival at 5 years without increased toxicity for GO treatment [128]. Based on these results FDA approved GO for the treatment of adults with newly diagnosed CD33-positive AML on 1 September 2017, and also approved Mylotarg for the treatment of patients aged 2 years and older

Vadastuximab talirine (SGN-CD33A) is a novel anti-CD33 mAb conjugated to 2 molecules of pyrrolobenzodiazepine (PBD). After internalization vadastuximab where transported to the lysosomes where the PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNAand leading to apoptosis. Vadastuximab is highly stable in circulation with relatively less off-target toxicity compared to GO [129]. In a dose-escalation phase 1 study 27 treatment naive patients with CD33 positive AML and median age of 74 years were treated with vadastuximab talirine. Of the 26 efficacy evaluable treatment naive patients, 6 patients achieved CR, 8 patients CRi, and 5 patients achieved a morphologic leukemia-free state [130]. In another phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive AML a total of 131 patients, median age, 73 years were enrolled. The CR + CRi rate was 28%, 50% of patients who responded achieved minimal residual disease negativity. Most AEs were consistent with myelosuppression, nonhematological included fatigue, nausea, and diarrhea [131]. Also vadastuximab talirine was added to a 7 + 3 induction therapy in a phase 1b study in 42 patients with a median age of 45.5 years. The CR/CRi rate was 78%. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. No 30-day mortality or significant hepatotoxicity was observed [132]. Fathi et al. combined vadastuximab talirine with hypomethylating agents in patients with CD33-positive AML. Among 53 patients treated, the median age was 75 years. The CR + CRi rate was 70% and 51% of remissions with minimal residual disease-negative status by flow cytometry. The majority of adverse events were a result of myelosuppression, with some causing therapy delays [133]. A phase III trial (CASCADE, NCT02785900) comparing HMA with or without SGN-CD33A in elderly patients with newly diagnosed AML was terminated because of due to safety reasons, specifically a higher rate of deaths,

including fatal infections, in the SGN33A arm versus the control arm.

The great advances in understanding molecular mechanisms of AML as well as their prognostic significance have changed the therapeutic armamentarium against AML. The drugs discussed in this chapter and many novel molecules being evaluated in clinical trials are on their way to change the current standard of treatment in AML. Ongoing efforts to understand the heterogeneity of AML, the constantly changing genomic landscape, the mechanisms of resistance/refractoriness will be very important in the development of new drugs. The rational use of these drugs, their potency that might be improved by combining them with other modes of therapy will hopefully increase long-term benefits for patients with AML. Furthermore, the development of novel ultrasensitive methods for minimal residual disease detection will also refine the treatment decision making process and probably improve the survival rates. However, new issues such as extrapolation of the results from the clinical trials enrolling carefully selected patients to general practice, the access and cost of these new drugs must be considered in the treatment decision

with relapsed or refractory CD33-positive AML.

**3. Vadastuximab talirine**

**4. Future perspectives**

**254**

process. It is a question of time whether personally tailored therapeutic era is going to be the new standard in the treatment of AML. Till then an increased enrolment of patients with AML into clinical trials evaluating the safety and efficacy of these new drugs and combinations is strongly encouraged and recommended.
