Leukemia Stem Cells, Heterogeneity, and Metabolism

Forum Chairs

Martin
Carroll
,
MD
University of Pennsylvania
Craig
Jordan
,
PhD
University of Colorado
Aaron
Schimmer
,
MD, PhD
University of Toronto

Forum Description

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a generally poor outcome. Despite the ability to achieve remission with aggressive chemotherapy most patients relapse and ultimately succumb to their disease. Relapse disease is frequently due to chemoresistant leukemia stem cells (LSCs). Thus, new therapeutic approaches that are less toxic and better tolerated by older and frailer individuals are required. Moreover, new therapies that target the LSC population to induce cell death or promote their differentiation into more mature cells are required. The last few years have seen tremendous advances in our understanding of LSC biology and potential new therapies to target these cells. Therefore, we believe this is a critical time to convene a group of experts to synthesize new therapeutic directions. Thus, our proposed Forbeck conference will bring together a multi-disciplinary group of leading experts (basic scientists, translational scientists and clinical trialists) to design compelling strategies for translational/clinical studies.

Forum Summary

From September 12th to 14th, 25 experts with diverse point of view met to present data and discuss the theme of leukemic stem cells. The meeting was highly successful in bringing together not simply the known experts in the field but individuals with backgrounds in leukemic research, basic cellular biochemistry, clinical medicine and others to discuss and challenge idea’s in the field. The meeting was highly interactive and lively.

Why was this meeting relevant now?
Although there have been recent advances leading to less toxic therapies for acute myeloid leukemia (AML), the survival of patients after a diagnosis of AML is still poor. This meeting allowed researchers to take a “deep dive” into two discrete area’s of AML pathogenesis where there has been significant new recent information but also significant controversy. First, the investigator’s considered the title theme of leukemic stem cells vs leukemic heterogeneity. It was previously thought that all leukemia cells from a given individual were highly similar to each other. However, it has become clear from numerous lines of evidence that there are significant differences between an individual’s leukemic cells that create a barrier to cure. In one model, cells that are similar to blood stem cells but have leukemic properties are resistant to chemotherapy. Significant discussion was had on how these cells can be characterized, their defining features, whether they are the target of novel therapies, etc. In the stem cell model, these leukemic stem cells give rise to all other leukemic cells. In an alternative model, leukemic cells vary from each other randomly. This random variation may occur through changes in the DNA (genetic variation), the molecules that regulate gene expression (epigenetic variation) and others. Significant discussion of recently described genetic variation was had with proposals and discussions about how to target this variation before it leads to therapeutic resistance.

What came out of this meeting? Conceptual, collaborations any papers or experiments.
Significant conceptual change in the impact of studies of leukemic cell metabolism did occur. One of the recent surprises in leukemic therapy is the success of the drug, Venetoclax, when used in combination with drugs known as hypomethylating agents. Venetoclax is thought to act through inhibition of a cell survival protein called Bcl2. However, the biologic studies of the role of Bcl2 in AML biology have shown conflicting results. An exciting session occurred where three investigators showed work that suggests either that Bcl2 has a previously unknown function or that Venetoclax may work through a different mechanism than proposed. In particular, the three groups have data that Venetoclax may inhibit the leukemic cells machinery for energy production, a biochemical process known as oxidative phosphorylation. Data was presented that combining venetoclax with other agents that further cripple this process is even more effective at killing leukemic cells in the laboratory than combining it with hypomethylating agents. Ideas for how to translate this into clinical trials were discussed. Overall, a major impact of the meeting on this diverse audience was to increase the understanding of the critical role of altered cell metabolism to leukemic development. Additionally there was significant discussion about developing new methodologies for studying cell metabolism in primary human AML cells. We believe that these discussions will quickly lead to new combination treatment approaches that take advantage of this new insight.

What do you see developing in this field from this meeting?
Several developments are likely to result from this meeting. All meeting attendee’s expresses great enthusiasm for the open, interactive “give and take” of the meeting format. Several of the attendee’s organize larger meetings and there were discussion about how to bring this format into these other meetings.

With regards to scientific and therapeutic progress, as noted, significant attention was spent discussing ways forward for new metabolically directed drug combinations in AML. New collaborations have actually already been initiated based on interactions at the meeting.

How does this impact patients today?
As noted above, the discussion of leukemic cell metabolism and studies of the mechanism of Venetoclax activity in AML are likely to be highly impactful. In general, cancer doctors work to develop therapies by combining agents that are toxic to cancer or leukemia cells without causing an increase in side effects. The great breakthrough it was agreed of the Venetoclax-hypomethylating agent combination is that leukemic control or remission can be achieved without a high level of toxicity. Data at the meeting demonstrate that this is not likely to be curative however for the majority of patients. Thus, the focus on adding new agents to this recently developed and lower toxicity regimen is likely to lead to new approaches towards curative therapy. In fact, some such trials have already been opened at the researchers sites and ideas were discusses about how to interpret those trials as they are performed.

Venue & Travel Information

Hilton Denver Inverness

200 Inverness Drive West
Englewood, CO 80112

hilton.com
303-799-5800

Travel Forms

Travel forms are due 30 days prior to the start of the meeting to allow enough time to plan transportation.

Denver International Airport (DIA) is approximately 30 minutes from the meeting location.

  • Arrivals - Thursday around 1 PM, 3 PM and 5 PM
  • Departures - Sunday around 10 AM and 12 PM
TRAVEL FORMS DUE:
August 12, 2019
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
August 12, 2019
submit abstract

Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

Julie-Aurore
Losman
,
MD, PhD
Dana Farber Cancer Institute
Monica
Guzman
,
PhD
Cornell Medical College

Forum Scholars

Shruti Bhatt, PhD
Dana Farber Cancer Institute
Danielle Shin, MD, PhD
Stanford University
Zuzana Tothova, MD, PhD
Dana Farber Cancer Institute
Peter van Galen, PhD
Massachusetts General Hospital