57th ASH Annual Meeting Wrap-Up: Hematology's Own Cambrian Explosion

Harvard paleontologist Dr. Stephen Jay Gould known for his theory of “punctuated equilibrium,” which, as a neophyte like me understands it, argues that evolution is not a smooth upward trajectory as envisioned by Charles Darwin. Instead, the fossil record shows evolution to be a bumpy road characterized by very long periods of developmental stasis followed by stretches of remarkably rapid, revolutionary changes as natural selection gallops forward. As I look back on another year of results and ideas presented at the 2015 ASH Annual Meeting, I wonder if our profession’s accomplishments are showing a similar pattern. If so, it seems that we are in the midst of one of those epochs of rapid change.

Take lymphoma treatment, for example. For decades, tumor growth rate was the sole target with which to approach therapy — the clearest way to leverage the difference between normal cells and the cancer cell. In 1997, after decades of improvements in the tools and trade of molecular biology, better understanding of cellular processes led to the approval of rituximab, one of the initial landmark “targeted” agents in cancer care.

Less than 20 years have passed since that approval, and now most of the treatments that are being tested in lymphoma capitalize on our growing understanding of the molecular behavior of the cancer cell. Translational research, for example, is responsible for remarkable gains in the treatment of chronic lymphocytic leukemia (CLL). This year, the Late-Breaking Abstracts (LBA) session held on Tuesday morning included results from two studies of novel agents for relapsed/refractory CLL. One study presented by Dr. Andrew Zelenetz demonstrated what happens when an inhibitor of the PI3 Kinase pathway, idelalisib, is added to bendamustine and rituximab (BR). In a randomized, double-blind, placebo-controlled phase III study, the three-drug combination showed an impressive improvement in progression-free and overall survival over BR alone. In that same session, Dr. Stephen Stilgenbauer presented results from a phase II study, which used a BCL-2 inhibitor (venetoclax; ABT-199), in patients with del(17p) relapsed or refractory CLL, also with impressive results in this notoriously challenging subset.

Multiple myeloma (MM), which was long-known as a specialty of therapeutic nihilism, has become a poster child for rapid translation of molecular discoveries into the clinic. In 2015, the FDA approved four agents for the disease, panobinostat, ixazomib, daratumumab, and elotuzumab, each of which takes advantage of a different mechanistic vulnerability of the myeloma cell. At this year’s meeting, attendees were presented with numerous new studies that incorporated these agents either alone or in combination with established therapies. For example, Dr. Saad Usmani presented combined results of two studies that treated a total of 148 patients with late-stage MM with daratumumab, a monoclonal antibody to CD138, for an overall response rate of 31 percent. In the LBA session, the first in-human results using chimeric-antigen receptor (CAR) T-cells that target the B-cell maturation antigen in patients with advanced MM were presented. Dr. Syed Abbas Ali led the study, which showed similar types of toxicities that have been observed with anti-CD19 CAR T-cells (e.g., cytokine release syndrome) and impressive antimyeloma activity, including clearance of bone marrow plasma cells, and a stringent complete remission at the highest dose level.

Targeted therapy is beginning to reach the myeloid world as well. Long held out as “too heterogeneous” for a targeted approach, the last two ASH annual meetings have demonstrated the important role that inhibitors of the FLT-3 ligand play in the treatment of acute myeloid leukemia (AML). During the Plenary Scientific Session, Dr. Richard Stone revealed the important findings of the RATIFY study, a CALGB/Alliance effort that took years of work in accrual and logistical management. This study randomly assigned patients (ages 18 to 60 years) with newly diagnosed, FLT3-mutated (ITD or TKD) AML to 7+3 alone or in conjunction with the FLT3/multikinase inhibitor, midostaurin. The study showed that addition of midostaurin improved the event-free and overall survival of patients (whether censored or uncensored for transplantation), with this genetically defined subgroup of AML. These data pave the way for drug approval, and may herald an end to the four-decade period of relative stasis in the field of AML therapeutics. The momentum is not limited to areas of malignant disease. The last few years have witnessed an explosion in novel anticoagulants, targeted at a much more subtle understanding of the body’s clotting mechanisms. And since the discovery of thrombopoietin (TPO) more than 20 years ago, numerous biologic insights have been made regarding its interaction with its receptor c-mpl. This signaling pathway’s role in megakaryocyte production and regulation of platelet mass has been therapeutically exploited, leading to drug approvals of the TPO mimetics romiplostim and eltromboag in patients with idiopathic thrombocytopenic purpura. TPO also has an established role in regulating hematopoietic stem cells, which led Drs. Cynthia Dunbar and Neal Young of the National Institutes of Health (NIH) to first evaluate its efficacy in patients with refractory severe aplastic anemia (SAA). This year, presenting results of a NIH–led phase II study, Dr. Danielle Townsley outlined the benefits of the TPO agonist eltrombopag on count recovery and response rates when added to up-front immunosuppressive therapy for patients with SAA (see Dr. Tracy George’s Year’s Best article for a more in-depth review of this subject).

The Plenary Scientific Session also highlighted biologic and molecular discoveries that may pave the way for the next wave of therapies. Researchers elegantly demonstrated how control over the gene for fetal hemoglobin is exerted by the transcription factor leukemia/lymphoma–related factor (LRF)/ZBTB7A. The next step is to determine whether one can safely modulate LRF’s usual suppression of fetal hemoglobin to mitigate the clinical consequences of sickle cell disease. Similarly, the first in vitro evidence on how to modulate the spliceosome in myeloid malignancies was presented by Dr. Stanley Chun-Wei Lee on behalf of the laboratory of Dr. Omar Abdel-Wahab at Memorial Sloan Kettering Cancer Center. For the myriad blood cancers with driver mutations in the spliceosome, such progress bodes well for future therapies.

Recognizing the challenges of keeping up with developmental changes in the diseases we treat, in the last several years ASH has added several additional in-depth sessions that cut across diseases. This year, there were two well-attended Friday scientific workshops: one on the myeloid diseases and the other on hematology and aging. On Saturday, there was a special interest session on newly approved drugs, shedding light on the right time and place to utilize drugs like blinotumumab, panobinostat, and idarucizumab. Attendees even had an hour-long educational session on social media and Twitter, and the many ways these ubiquitous technologies might be productively used by physicians and patients.

We will never know, limited in perspective as we are by time, just what these past few years mean in the whole of our profession’s trajectory. However, I’m sure that I’m not alone in being grateful to have the opportunity to treat patients during a period ”punctuated” by the breakneck pace of emerging therapeutics borne from the knowledge and tools of precision medicine.