Treating Acute Leukemia: Addressing the Cancer Cells Left Behind

At a Glance

  • Despite advances in treatments and technology, leukemia remains a devastating and largely incurable disease for adults.
  • Studies show patients who have a higher percentage of leukemia stem cells after chemotherapy demonstrate poorer outcomes.
  • Physicians and researchers at Weill Cornell Medical Center are using next generation genome sequencing and novel ultra-sensitive molecular assays to understand how leukemia and their stem cells respond when challenged with various drugs.

“ The ultimate goal of our research is to understand the molecular evolution of acute leukemias from diagnosis, minimal residual disease, and relapse to develop a high resolution map for identifying therapeutic opportunities with greater precision.”

— Dr. Duane C. Hassane

Despite tremendous technologic advances, the world of acute leukemias has not yet reaped the therapeutic benefits like lymphomas and other types of cancer. Acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) remain devastating and largely incurable diseases in adults.

“A major part of our current research efforts is going after minimal residual disease, which is what we believe to be the Holy Grail in acute leukemia,” says Gail J. Roboz, MD, Professor of Medicine at Weill Cornell Medicine, and Director of the Clinical and Translational Leukemia Program at NewYork-Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine. Minimal residual disease — the term given to leukemic stem cells (LSCs) that survive standard chemotherapies – is a critical area of focus for Dr. Roboz and Duane C. Hassane, PhD, Assistant Professor of Computational Biomedicine in Medicine at Weill Cornell Medicine. “It is well known that standard chemotherapeutics fail to eradicate a resistant population of leukemic cells, sometimes referred to as leukemic stem cells, in acute leukemia, and it is well-described that residual cells after chemotherapy are probably what ultimately cause relapse.”

By surviving chemotherapy, the LSCs can regrow the acute leukemia, resulting in a relapse, typically within eight months of remission. Clinical evidence shows that patients who have a higher percentage of LSCs demonstrate poorer outcomes. Despite this evidence, characterizing, measuring, and treating these residual cells have proven elusive.

“If you can imagine that chemotherapy might get rid of a large volume of the bulk disease of leukemia, you might also imagine that the cells that remain are the strongest and most powerful, persevering no matter what therapy is given to the patient,” says Dr. Roboz. “There are a variety of theories as to the characteristics of the cells in acute leukemias that remain after chemotherapy. One theory suggests that if they are biologically fundamentally different from the bulk leukemic cells, then the residual cells may work in a way that is simply not sensitive to the effects of chemotherapy.”

Additionally, Dr. Roboz notes that these residual cells may be able to hide or position themselves within the bone marrow microenvironment where chemotherapy is unable to penetrate. The literature also points to niche type theories in which the leukemic cells, in an almost parasitic manner, harness the resources of the bone marrow microenvironment to establish a shield to protect themselves from the effects of whatever therapy is being deployed.

Dr. Roboz says that while leukemia treatment may have successfully eradicated or reduced the cells, one clone quickly brings rise to others. “Acute myeloid leukemia, for example, is molecularly very heterogeneous in its initial presentation, and the disease that relapses may be molecularly different from the original,” she explains. “Many in the field say that AML is polyclonal at presentation and then monoclonal at relapse. What’s not fully understood is whether or not the therapy that the patient is getting manipulates, in a reliable or reproducible way, what we might see molecularly when the patient relapses.”

Improving Survival with Sustained Remission

It is critical to develop treatment strategies to maintain remission for those patients who achieve it, in addition to developing novel approaches for patients who do not achieve remission, Dr. Roboz says. “If we could better identify, characterize, and ultimately treat the left-over leukemia cells that remain once the patient is in remission, it would be an enormous advance. Finding the residual cells that are either well-hidden, or that are different from the cells that you started out with, is proving to be a very difficult task.”

The answers may reside in Dr. Hassane’s laboratory, where the team performs translational research that uses genomics, including novel liquid biopsy and genome sequencing platforms, to develop new ways of improving cancer treatment. In collaborations with Weill Cornell physicians and researchers, he is producing genome-scale portraits of how various types of cancer therapeutics affect the behavior, survival, and gene regulatory networks in cancer stem cells with a major focus on acute leukemias.

“The ultimate goal of our research is to understand the molecular evolution of acute leukemias from diagnosis, minimal residual disease, and relapse to develop a high resolution map for identifying therapeutic opportunities with greater precision,” says Dr. Hassane.

leukemic stem cells

The laboratory of Dr. Duane Hassane uses state-of-the-art genome analytics and other advanced technologies to detect and ablate leukemic stem cells.

He and his colleagues want to push the envelope in minimal residual disease assessment using next generation genome sequencing and novel ultra-sensitive molecular assays to understand how leukemias and their stem cells respond when challenged with various drugs. Developing blueprints for defining the genes and pathways to destroy LSCs can lead to the identification of drugs and drug combinations tailored to each patient as well as inform the timing of therapeutic intervention.

Dr. Hassane is employing a plurality of cutting-edge technologies to piece together an individual patient’s entire genomic portrait.

“This is where the concept of personalized medicine comes in,” says Dr. Roboz. “The question here is how to put together several different technologies to get a complete picture of what’s going on with the patient. This is being pursued in a very selective and individual manner, looking very carefully at that particular patient’s molecular phenotype. It is an approach unique to Dr. Hassane’s research.”

Dr. Hassane adds, “Next-generation sequencing and other advanced technologies are taking us from where we were a few years ago from the equivalent of a ‘black and white television’ view of tumor heterogeneity, to something closer to ‘Ultra HD.’”

While the research is promising, it is still in the experimental stage, Dr. Hassane says. “Sometimes the most valuable testing and the most relevant results are emerging from a research laboratory and not a commercial laboratory. Through truly translational scientific collaborations we are aiming to try to figure out the best way to implement them clinically.”

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