Blood Podcast Summary

Episode: Novel Differentiation Therapies for AML and Prognostic Value of PET in MM
Date: December 18, 2025
Host: Dr. Laurie Sen, American Society of Hematology

Episode Overview

This episode explores two major recent publications in Blood:

1. The role of MECOM-mediated repression of CEBPA in driving aggressive forms of Acute Myeloid Leukemia (AML), featuring Dr. Vijay Sankaran (Boston Children’s Hospital) and Dr. Rude Delwell (Erasmus Cancer Center).
2. The prognostic utility of pre-maintenance FDG PET/CT response in multiple myeloma (MM) from the Cassiopeia trial, featuring Dr. Francois Cœrber-Bouderet (Nantes University Hospital).

The conversation highlights new mechanistic insights in AML that may open pathways for novel differentiation therapies and discusses how PET/CT response could inform risk assessment and personalization of therapy in MM.

Part 1: MECOM, CEBPA, and Differentiation Block in AML

Background and Motivation

• Dr. Sankaran recaps that for years, AMLs driven by MECOM have shown poor prognosis, often presenting with “very stem cell-like leukemias.” ([01:28])
• The key scientific unknown: "What is MECOM actually doing to drive these aggressive leukemias?"

Key Findings

MECOM as a Primary Repressor

• Both Sankaran’s and Delwell’s groups used genetic engineering to acutely degrade MECOM in AML cells and assess changes in gene expression. ([03:00])
  • "We noticed MECOM actually seemed to be critical to primarily repress genes... When we introduced a small molecule to degrade MECOM... the majority of genes that were changing were upregulated." – Dr. Sankaran ([03:23])
• The standout finding: acute MECOM loss resulted in rapid and robust upregulation of CEBPA (CBP alpha), a master transcription factor for myeloid differentiation.
  • "As we looked further...we found that there was a single target that actually appeared to be absolutely necessary...a region that was regulating the expression of this other key transcription factor, CEBPA." – Dr. Sankaran ([04:02])

Independent Validation

• Dr. Delwell’s group used similar degron-mediated strategies; their results converged with Sankaran’s, reinforcing the conclusion:
  • "If you degrade MECOM very quickly ... CEBPA was very rapidly upregulated. We found exactly the same thing... fully validating each other's data." – Dr. Delwell ([05:13])

Therapeutic Implications

• Dr. Sen notes Wilson & Göttingen’s commentary on the "simplicity of this mechanism" as a “regulatory switch” in leukemia.
• Dr. Sankaran draws a parallel to acute promyelocytic leukemia (APL) and the transformative effect of differentiation therapies there:
  • "By just switching on CEBPA, you can totally cause the cells to differentiate, you can prevent the stem cell features." ([06:51])
  • Such therapies could be game-changing for inversion 3/MECOM-rearranged AMLs, which are typically resistant to conventional chemotherapy and transplantation.

Anticipating Resistance

• Dr. Delwell acknowledges that resistance may emerge with long-term pathway suppression:
  • "This type of leukemia is resistant by definition with current therapies... If we are able to [interfere with MECOM and its partners], I really believe... one day we will be able to really target that bad guy and come with new treatments." ([08:48])

Next Steps for the Field

• Dr. Sankaran highlights broader implications, including gene therapy contexts where MECOM activation is seen:
  • "Understanding these pathways will have broad implications... Our hope is really by better understanding this we can offer more options for patients in the future." ([11:03])
• He references a moving essay by a MECOM-rearranged AML patient (Tatiana Schlossberg), stressing the urgent clinical need for progress. ([11:55])

Notable Quotes

• "There's a very simple regulatory circuit involved in preventing these leukemias from differentiating... just switching on CEBPA, you can totally cause the cells to differentiate." – Dr. Sankaran ([06:51])
• "They are addicted to this oncogene... If we are able to do the same thing here... we may come to a situation that we have now with APL." – Dr. Delwell ([09:25])

Key Timestamps

• [01:28] Background on MECOM in AML
• [03:23] MECOM repression of CEBPA – experimental approach
• [05:13] Parallel and validation between labs
• [06:51] Mechanistic simplicity and therapeutic vision
• [08:48] Resistance and future targets
• [11:03] Translational and patient impact

Part 2: Prognostic Value of Pre-Maintenance FDG PET/CT in Myeloma (Cassiopeia Trial)

Study Overview

• Dr. Cœrber-Bouderet examines the Cassiopeia Phase 3 trial, with an ancillary study ("Cassiopet") focusing on the prognostic value of FDG PET/CT responses in newly diagnosed MM treated with DARA (daratumumab) plus chemotherapy. ([13:48])
• Objective: Assessing the prognostic impact of pre-maintenance PET/CT and its complementary value with bone marrow MRD (minimal residual disease).

Notable Findings

• "The study demonstrated the prognostic value on PFS as well as OS of a complete response based on FDG PET..." – Dr. Cœrber-Bouderet ([15:31])
• Used standardized PET assessment validated in previous European studies.
• Complete metabolic response on PET pre-maintenance (after induction and consolidation but before maintenance) correlates with:
  • Improved progression-free survival (PFS)
  • Improved overall survival (OS)
• Demonstrated complementarity: PET/CT adds value even alongside MRD testing by flow cytometry.

Clinical Implications

• "It is important to combine FDG PET with bone marrow MRD at pre-maintenance to assess the efficacy of the therapy... Multiple myeloma is a very heterogeneous disease, it is important to have the assessment inside and outside the bone marrow." – Dr. Cœrber-Bouderet ([16:32])
• PET provides whole-body mapping, covering both intramedullary and extramedullary disease.

Future Directions

• Commentary by Dr. Jens Hillengas questions if PET is the best future tool, considering advanced MRI or new tracers.
  • "MRI, especially with advanced sequences and diffusion, can improve the sensibility ... but we have to demonstrate this by prospective study the prognostic value of MRI as we already performed for FDG PET." – Dr. Cœrber-Bouderet ([17:28])
• Emphasis on designing future clinical trials that combine imaging (FDG PET, advanced MRI) and MRD at multiple time points. ([18:42])

Key Timestamps

• [13:48] Cassiopeia and Cassiopet study design
• [15:31] Prognostic impact of metabolic PET response
• [16:32] Integrating PET with MRD for assessment
• [17:28] Imaging modalities: PET vs. MRI
• [18:42] Future research directions

Memorable Moments

• The clear convergence between two independent groups (Sankaran and Delwell) lending exceptional credibility to the findings on MECOM and CEBPA, described as the “third time in my career...that we do a study and there's another group really sort of validating” by Dr. Delwell ([05:14]).
• Dr. Sankaran’s reference to a real patient’s journey with MECOM-rearranged AML, underlining the human stakes of this research ([11:55]).

Summary Table: Key Themes and Takeaways

| Segment | Discovery/Insight | Clinical Impact | Future Direction | |----------------------------|-----------------------------------------------------------------------|----------------------------------------------------------------|----------------------------------------| | MECOM in AML | Direct repression of CEBPA blocks differentiation, drives stemness | Potential for differentiation therapies akin to APL | Targeting MECOM or its partners | | PET Response in Myeloma | Complete PET metabolic response pre-maintenance predicts better OS, PFS| PET + MRD at pre-maintenance refines risk stratification | Advanced imaging, multi-modal trials |

For Further Reading

• Both referenced articles are available at bloodjournal.org.
• The episode underscores the excitement and urgency of translating fundamental molecular insights and imaging biomarkers into better outcomes for patients with AML and MM.