Joshua F. Zeidner, MD, associate professor of medicine, chief, Leukemia Research, associate chief of research, Hematology, University of North Carolina (UNC)–Chapel Hill, UNC Lineberger Comprehensive Cancer Center, discusses the risk of transformation to acute myeloid leukemia (AML) in higher-risk myelodysplastic syndromes (HR-MDS). 

Patients with HR-MDS that transforms to AML, especially those who received a hypomethylating agent (HMA) in the first-line setting, have poor outcomes. The median overall survival ranges from approximately 4 to 6 months in this population, Zeidner says. Notably, effective therapies are not available for patients with newly transformed AML from MDS who were exposed to HMAs, Zeidner explains. This is because most treatments for patients with AML include HMAs, but patients who progress on HMAs likely become resistant to these agents. 

Findings from a poster, which were presented during the 2021 European Hematology Association Congress, demonstrated that patients with MDS who transformed to AML had worse outcomes compared with patients who had MDS and did not transform to AML, Zeidner says. As such, these data are in-line with previous reports and shed light on the need to develop novel therapies that delay or prevent transformation to AML, Zeidner concludes.

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Joshua F. Zeidner, MD, discusses the risk of transformation to acute myeloid leukemia in higher-risk myelodysplastic syndromes.



Dr. Zeidner on Transformation to AML in Higher-Risk MDS 

Joshua F. Zeidner, MD, discusses data from the following presentation:

Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes

The objectives of this exploratory analysis are to assess the impact of the addition of pevonedistat to azacitidine on patient-reported outcomes (PROs) and to evaluate the treatment impact on PROs by characterizing their relationship with clinical response and transformation to AML.

The phase 2, randomized, open-label, global, multicenter study included patients with higher-risk MDS (n=67), higher-risk CMML (n=17), and low-blast AML (n=36).

Patients were randomized 1:1 to receive pevonedistat (20 mg/m2 IV on days 1, 3, 5) plus azacitidine (75 mg/m2 [IV or subcutaneous (SC)] on days 1-5, 8, 9) or azacitidine (75 mg/m2 [IV or SC] on days 1-5, 8, 9).

Results in the intent-to-treat (ITT) population1:

Median event-free survival (EFS): 21.0 vs 16.6 months (HR, 0.67; 95% CI, 0.42-1.05; 

Median overall survival (OS): 21.8 vs 19.0 months
(HR, 0.80; 95% CI, 0.51-1.26; 

Overall response rate (ORR; [CR + CRi + PR + HI]): 71% (n=39/55) vs 60% (n=32/53)

Post-hoc analyses presented here are in the PRO population (n=112).

PRO population all patients with PRO assessment at baseline and greater than or equal to postbaseline PRO assessment in ITT population

PROs included as exploratory end points in P-2001 study (NCT02610777)

European Organisation for Research and Treatment of Cancer quality of life questionnaire—core 30 items (EORTC QLQ-C30) administered at the first day of each cycle, at the end of treatment (EOT) visit, and post-EOT visits

KEY PRO scores of interest: physical functioning, global health status/quality of life, fatigue, and dyspnea

Rate of available PROs and rate of PROs completion over time as recommended by the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints (SISAQOL) group2

Assessment of change in key PROs over time and compared between arms using repeated measurement mixed models

Description of key PROs after clinical response depending on the type of response (CR, PR, CRi, or HI)

Description of key PROs before and after HI in patients with higher-risk MDS/CMML who progressed to AML

No significant difference in the change over time in key PROs between pevonedistat combination and azacitidine

No statistically significant change in score over the study

No impact of missing data due to progression or death on results (sensitivity analysis)

Improvement (nonsignificant) in physical functioning and fatigue was observed after patients experienced CR as best overall response (n=27) compared with baseline

Improvement defined as any positive change for physical functioning and quality of life scores, and any negative change for fatigue and dyspnea scores

Similar trend in overall health and dyspnea as well as PR response

No trend of improvement in HI in key PROs

After transformation to AML, higher-risk MDS/CMML patients reported poorer physician functioning and more severe fatigue

Findings suggest that the addition of pevonedistat to azacitidine has a similar AE profile to azacitidine alone and does not lead to decrement in the key PROs.

Achievement of CR was associated with nonsignificant improvement in PROs compared with baseline independently of the treatment received.

In P-2001, CR rates were higher with pevonedistat plus azacitidine vs azacitidine alone.

Transformation was associated with the worsening of PROs.

Thus, delaying transformation to AML should be a goal of therapy for patients with higher-risk MDS/CMML and may be considered a patient-relevant end point to assess quality of life.

PROs analyses were exploratory end points and should be cautiously interpreted.

Additional analyses are planned with the P-2001 PRO data

1. Ades L et al. ASCO 2020 annual meeting. Abstract 7506.

Joshua F. Zeidner, MD, presents data from the 62nd American Society of Hematology (ASH) Annual Meeting on an exploratory analysis of patient-reported outcomes from a randomized phase 2 trial of pevonedistat plus azacitidine vs azacitidine in higher-risk myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) or low-blast acute myeloid leukemia (AML).

Joshua F. Zeidner, MD, University of North Carolina, Lineberger Comprehensive Cancer Center

Articles

Dr. Zeidner on Transformation to AML in Higher-Risk MDS

Rapid Readouts: Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk MDS/CMML or LB AML