ASH Annual Meeting 2019

Highlights of Fred Hutch Presentations at ASH

Immunotherapy | Transplantation | Precision Oncology

Immunotherapy

Efficacy and safety of fully human BCMA CAR T cells in combination with a gamma secretase inhibitor to increase BCMA surface expression in patients with relapsed or refractory multiple myeloma [Read full abstract]
Dr. Andrew Cowan
Saturday, Dec. 7, 1:15 p.m.
Although the median survival for patients with multiple myeloma has improved dramatically, almost all patients will eventually relapse and become resistant to standard therapies. Chimeric antigen receptor T cells (CAR T cells) targeting B cell maturation antigen (BCMA) have shown early promise in MM, with high initial response rates. Responses are often incomplete and durability has been a key concern, with most patients relapsing within 1 year (Raje N et al NEJM 2019). We have previously demonstrated that gamma secretase inhibitors (GSI) increase BCMA surface density, decrease soluble BCMA levels and augment anti-tumor efficacy of BCMA CAR T cells in preclinical models. In a phase I first-in-human trial (NCT03502577), we combined CAR T cells expressing a fully human BCMA scFv with an orally administered gamma secretase inhibitor (JSMD194). 

The Long Road to Develop Adoptive Therapy for T Cells that Can Effectively Target Acute Myeloid Leukemia (AML) and Other Malignancies 
(E. Donnall Thomas lecture) [Read more about this session]
Dr. Philip Greenberg
Monday, Dec. 9, 9-10 a.m.
Why do T-cell therapies work for some patients and not others, and how can they potentially be engineered to overcome these obstacles? 

Transplantation

No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial [Read full abstract]
Dr. Filippo Milano
Saturday, Dec. 7, 9:45 a.m.
Based on pilot study data demonstrating safety and excellent survival [Blood 2014 124:46] in acute leukemia patients undergoing myeloablative cord blood transplant (CBT) plus infusion of an off-the-shelf non-HLA matched expanded CB unit (OTS) for bridging hematopoiesis, a randomized trial was conducted to determine whether myeloablative CBT with or without an OTS would confer more rapid neutrophil (ANC) engraftment and therefore a survival advantage. 

Sirolimus Combined with Cyclosporine (CSP) and Mycophenolate Mofetil (MMF) As Graft-Vs-Host Disease (GVHD) Prophylaxis after Nonmyeloablative (NMA) Hematopoietic Cell Transplantation (HCT) Using HLA Class I or Class II Antigen Mismatched Donors: Results from a Phase II Multi-Center Trial [Read full abstract]
Dr. Brenda Sandmaier
Sunday, Dec. 8, 8 a.m.
The success of HCT is highly dependent on the availability of compatible donors. Depending on ethnicity, fully HLA-matched donors cannot be identified for 25–84% of patients. In an effort to extend the use of HLA-mismatched donors to patients only eligible for NMA HCT, we previously demonstrated that engraftment and long-term survival can be achieved using CSP and MMF immunosuppression after HLA class I antigen-mismatched HCT (Nakamae et al, 2010). Based on this trial, we designed a phase II multi-center trial to assess the efficacy of GVHD prophylaxis with triple immune suppression with CSP, MMF and sirolimus after HLA class I or class II antigen mismatched NMA HCT (fludarabine 90mg/m² and 2–3 Gy TBI). 

Homeostatic regulation of apoptosis governs thymus regeneration [Read full abstract]
Dr. Sinéad Kinsella
Monday, Dec. 9, 8 a.m.
Although the thymus has a remarkable capacity for repair following acute injury, such as that caused by the conditioning required for successful hematopoietic cell transplant (HCT), the mechanisms underlying this endogenous regeneration remain poorly understood. Delayed T cell reconstitution occurs following thymus insult and can exceed more than a year post-transplant due to a delay in full recovery of thymic output, function and T cell repertoire. Therefore, strategies to enhance T cell reconstitution post-transplant represents a rational approach to significantly improve the overall outcome of allo-HCT. We propose that enhancing thymic function will boost T cell reconstitution and substantially increase immune responses following allo-HCT. 

Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)  [Read full abstract]
Dr. Jacob Appelbaum
Monday, Dec. 9, 11:15 a.m.
Measurable residual disease (MRD) following intensive induction chemotherapy for AML is associated with a high risk of relapse and shortened survival even after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, it may be advisable to give additional chemotherapy to reduce or eradicate MRD prior to HSCT. However, this may expose patients to additional toxicity and delay HSCT. We used our institutional database to examine how often additional chemotherapy eliminated MRD and compared survival among patients with MRD according to whether they next received additional chemotherapy or allogeneic HSCT.

Post-Transplant Work Status of Young Adult Survivors of Allogeneic Hematopoietic Cell Transplant: A Report from the Center for International Blood and Marrow Transplant Research (CIBMTR)  [Read full abstract]
Dr. Neel Bhatt
Monday, Dec. 9, 11:15 a.m.
Return to full-time work after hematopoietic cell transplant (HCT) is an important indicator of health recovery and overall function of survivors. Because young adult (YA) HCT patients are at a critical personal and professional developmental phase at the time of their illness, they face unique challenges potentially impacting their ability to work post-HCT. We aimed to assess the post-HCT work status of YA patients undergoing allogeneic HCT and examine pre-HCT factors associated with their work status at the 1-year time-point post-HCT. 

Clonal Hematopoiesis in Donor-Recipient Pairs after Allogeneic Hematopoietic Cell Transplantation  [Read full abstract]
Dr. Masumi Ueda
Monday, Dec. 9, 11:45 a.m.
After allogeneic hematopoietic cell transplantation (HCT), a relatively small number of donor hematopoietic cells must reconstitute the entire recipient hematopoietic system, while the donor is left with a near normal pool of hematopoietic cells. We hypothesized that the increased replicative demand on donor cells in the recipient after allogeneic HCT will accelerate telomere shortening and magnify the genetic alterations that are associated with normal aging, including clonal hematopoiesis. We aimed to compare mutation frequency in genes associated with clonal hematopoiesis of indeterminant potential (CHIP) and myeloid diseases between donors and recipients, with a focus on transplant pairs with older donors. 

Precision Oncology

Talks by researchers from the lab of Dr. Soheil Meshinchi will map genetic mutations to patient outcomes.

Response to Sorafenib in FLT3/ITD AML is dependent on co-occurring mutational profile [Read full abstract]
Dr. Katherine Tarlock
Saturday, Dec. 7, 10:30 a.m.

Somatic Bzip mutations of CEBPA are associated with favorable outcome regardless of presence as single vs. double mutation  [Read full abstract]
Dr. Katherine Tarlock
Saturday, Dec. 7, 12 p.m.

Structural variants involving MLLT10/AF10 are associated with adverse outcomes in AML regardless of the partner gene – a COG/Tpaml study  [Read full abstract]
Rhonda Ries
Sunday, Dec. 8, 1 p.m.

Correlation of CD123 expression level with disease characteristics and outcomes in pediatric acute myeloid leukemia: A report from the Children’s Oncology Group  [Read full abstract]
Dr. Adam Lamble
Sunday, Dec. 8, 12:30 p.m.

Gene expression signature predicts deep molecular response (DMR) in chronic myeloid leukemia (CML): An exploratory biomarker analysis from ENESTnd  [Read full abstract]
Dr. Jerald Radich
Monday, Dec. 9, 11:30 a.m.
Achieving sustained DMR (variably described as ≥ MR⁴ or ≥ MR^4.5) is an emerging treatment goal for patients with CML. DMR is associated with excellent long-term clinical outcomes and a higher likelihood of successful treatment-free remission (TFR) upon discontinuation of tyrosine kinase inhibitor (TKI) therapy. Biological predictors of patients likely to achieve DMR are unknown. Here, we present an exploratory analysis of gene expression signatures in order to predict DMR to TKI therapy, as well as understand the biological underpinnings that allow a DMR, based on patients treated with imatinib or nilotinib in the ENESTnd study (NCT00471497).