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AML Treatment Changes
My Top Picks for AML Abstracts in Atlanta

Released: November 20, 2017

Expiration: November 19, 2018

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At the 2017 American Society of Hematology (ASH) annual meeting, a number of abstracts will be presented that may have exciting implications for patients with acute myeloid leukemia (AML). Here are a few of my top picks.

Anti-TP53 Peptide: ALRN-6924
The tumor-suppressor gene TP53 has a well-recognized role in the development of many cancers and it is known to be mutated in up to 50% of all solid tumors. However, its role in AML has been less clear, being a mutation in fewer than 10% of cases. Recently, it has been discovered that TP53 can be functionally inactivated through overexpression of the endogenous inhibitors MDMX and MDM2, which is very common in AML. This led Carvajal and colleagues to attempt to combat loss of TP53 activity by blocking the interaction of TP53 with MDMX and MDM2 using a stapled alpha-helical peptide, ALRN-6924. Results from this preclinical study suggest that TP53 is targetable in AML, and we hope that this will one day be translated into improved treatment outcomes.

Venetoclax
A promising development in AML is the advent of the BCL-2 inhibitor venetoclax, as seen in results of 2 companion trials to be presented at ASH 2017. Both combination trials were conducted in older, treatment-naive patients who were considered unfit for intensive chemotherapy. Wei and colleagues conducted a large phase I/II study of venetoclax plus traditional low-dose cytarabine, and Pollyea and colleagues will present data from a phase Ib study of venetoclax in combination with the hypomethylating agent azacitidine.

In the first study, low-dose cytarabine was given for 10 days, and venetoclax was dose-escalated from 50 mg/day to either 600 mg/day (n = 61) or 800 mg/day (n = 10). Results showed significantly more CRs with venetoclax combination therapy compared with historical controls. Of the 61 patients treated with venetoclax 600 mg/day, 62% achieved either a CR or a CRi, and the median duration of response was 15 months. A total of 46% of patients remained alive at 1 year, despite only 1 subject undergoing an allogeneic stem cell transplantation. The 30-day mortality rate was approximately 3%, all related to progressive disease.

This group also examined the impact of the combination on various molecular mutations, including DNMT3A, FLT3-ITD, and SRSF2, and found very high rates of remission, well over 75% responses, in these subsets. The combination was less effective for patients with mutated TP53, showing a CR/CRi rate of approximately 44%. Taken together, older patients with poor-risk AML and/or those unfit for current standard-of-care chemotherapy appear to have better responses when venetoclax is added to traditional low-dose cytarabine. A phase III study of this combination is under way in a similar patient population.

In the second study, traditionally dosed azacytidine was combined with venetoclax 400 mg/day (n = 23) or 800 mg/day (n = 9) (1 patient received 1200 mg/day) and showed an ORR (CR/CRi/PR/morphologic leukemia-free state) of 91%; more than half the patients (58%) achieved a CR. Interestingly, several poor risk subsets appeared to do better on the combination than would have been expected with single agent azacytidine: all 5 patients with a monosomal karyotype, all 5 with FLT3-ITD, and both patients with mutated TP53 responded to the combination. Of the 3 patients who proceeded to stem cell transplantation, none have relapsed at 4, 8, and 14 months following transplantation. As in the first study, no significant toxicity was associated with venetoclax, although many patients had adverse events commonly seen with leukemia therapy (infections, fevers, cytopenias).

Pollyea’s team also studied the impact of the combination on early AML progenitors, so called leukemia stem cells, through serial sampling and deep sequencing. Results showed rapid, extensive, and successful targeting of these primitive cells, suggesting that this combination may lead to potentially deep MRD-free remissions.

Nivolumab
Many clinicians hope that immune checkpoint inhibitors targeting CTLA-4, PD‑1, and PD‑L1 may play a role in treating patients with AML and other myeloid diseases. Ravandi and colleagues will present early results from an ongoing phase II study of the addition of the PD-1 antibody nivolumab to induction treatment with traditional cytarabine and idarubicin chemotherapy.

Patients with AML (N = 30, plus 2 with high-risk MDS) received 1-2 cycles of induction, and then were initiated on nivolumab 3 mg/kg starting around day 24. The nivolumab “maintenance” treatment was given every 2 weeks for up to a year. The majority of patients had adverse or intermediate risk AML, according to the European LeukemiaNet criteria. Although early, patients have received a median of 6 doses of nivolumab, and 9 patients went on to allogeneic stem cell transplantation.

At a median follow-up of 8.3 months, neither the median OS nor the median relapse-free survival among responders had been reached. Importantly, the 4- and 8-week mortality rates were both about 6%, with only 5 patients experiencing grade 3/4 immune-mediated toxicities. It will be of great interest to see whether patients with the worst prognosis can maintain a meaningful response following induction treatment with just traditional chemotherapy.

Perceptions of Prognosis and Risk
Challenges in caring for patients with AML include mismatched perceptions of patients and oncologists regarding prognosis and treatment risks. El-Jawahri and colleagues conducted a longitudinal questionnaire-based study of newly diagnosed patients older than 60 years of age who were undergoing treatment for AML. The treatment could either be intensive or nonintensive, and the survey asked 50 patients enrolled in each arm how they perceived the impact of planned treatment on their health and probability of survival.

The results showed that 91% of patients perceived their chance of dying due to treatment as at least “somewhat likely,” while 80% of their oncologists suggested that patients were “very unlikely” to die from treatment. Similarly, 90% of patients indicated that it was “somewhat likely” or “very likely” that they would be cured using either nonintensive or intensive therapy, but 58% of oncologists using intensive therapy and 90% of those using nonintensive therapy reported that their patients were “unlikely” to be cured with treatment. Despite the poor prognosis associated with the treatment of elderly AML, more than 75% of the patients had not yet had a conversation about end-of-life care with their primary treating team 24 weeks after initiating treatment.

This may not be a surprise to oncologists, as we realize that patients often hear what they want to hear. However, this finding emphasizes that, as physicians, we need to work harder to make sure that patients undergoing AML treatment, particularly older patients, better understand the possible benefits and known limitations of treatment, including the low likelihood of a complete remission or cure.

Summary
This is just a sampling of what to expect at ASH 2017. There will also be updates on the latest AML approvals—CPX-351, enasidenib, gemtuzumab ozogamicin, and midostaurin—as well as new data on investigational agents, including quizartinib, gilteritinib, ivosidenib, guadecitabine, and more.

To learn more about the latest AML treatment strategies for optimal care of your patients, please join me and my colleagues at our case-based satellite symposium, “Progress in Acute Myeloid Leukemia: Adapting Treatment to Individual Patients,” to be held at the Atlanta Marriott Marquis on Friday, December 8, at 6 PM. I hope to see you there!

What data are you most looking forward to at ASH? Share your thoughts in the comment box below.

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