New Agents Abound in Benign Hematologic Disorders

Kleber Yotsumoto Fertrin, MD, PhD, provided insight into the new options that have emerged in the treatment landscape of benign hematologic malignancies.

Kleber Yotsumoto Fertrin, MD, PhD

With the emergence of new agents in benign hematologic disorders and more in the pipeline, the outlook for patients with aplastic anemia, immune thrombocytopenia (ITP), and thrombotic thrombocytopenic purpura (TTP) has considerably brightened.

“These are very exciting times for benign hematologic disorders,” said Kleber Yotsumoto Fertrin, MD, PhD, an assistant professor, at the University of Washington, Seattle Cancer Care Alliance.

Traditionally in aplastic anemia, first-line treatment options were either bone marrow transplant or immunosuppressive therapy (IST). However, in recent years, thrombopoietin receptor agonists (TPO), such as eltrombopag (Promacta), have emerged as the potential new standard of care.

Eltrombopag received FDA approval in November 2018 for use in combination with standard IST to include newly diagnosed adult and pediatric patients aged ≥2 years with severe aplastic anemia (SAA). The approval was based on data from a National Heart, Lung, and Blood Institute-sponsored, Novartis analysis, which showed that treatment with the agent, when given in combination with IST, resulted in an overall response rate of 79% at 6 months.1 Previously, the agent was approved for use in patients with SAA who had an insufficient response to standard therapy, as well as for adults and pediatric patients with ITP who are refractory to other therapies, and for the treatment of thrombocytopenia in patients with chronic hepatitis C virus infection.

TTP treatment has also evolved considerably over the years, first with the introduction of plasma exchange and then with the emergence of the nanobody caplacizumab-yhdp (Cablivi), according to Fertrin. When evaluated in combination with plasma exchange and immunosuppression in the phase III HERCULES trial, the caplacizumab-yhdp regimen led to a significantly shorter time to platelet count response compared with plasma exchange and immunosuppression alone in adult patients with acquired TTP.2 These data led to the February 2019 FDA approval of the regimen in this patient population.

In ITP, the FDA approved a supplemental drug application in June 2019 to expand the use of avatrombopag (Doptelet) to include the treatment of thrombocytopenia in adults with chronic ITP who have had an insufficient response to a prior treatment. In a phase III trial, treatment with the agent led to a platelet count of at least 50,000 per µL at day 8 of therapy in the majority of patients.3 During the 6-month treatment period, the agent also proved to have superior efficacy to placebo in terms of maintaining platelet counts in the target range. Previously, avatrombopag was approved for the treatment of thrombocytopenia in adults with chronic liver disease scheduled to undergo a procedure.

“Avatrombopag has a much better [safety] profile for patients,” said Fertrin. “We do see some patients struggle with avatrombopag because they need to wait 2 to 4 hours before and after meals to take it. [The agent] interacts with several medications, but especially [in terms of] patients with comorbidities, I believe it can be very useful.”

In an interview during the 2019 OncLive® State of the Science Summit on Hematologic Malignancies, Fertrin provided insight into the new options that have emerged in the treatment landscape of benign hematologic malignancies.

OncLive: What are some of the important developments that have been made in the frontline treatment of patients with aplastic anemia?

Fertrin: Transplant is definitely the first-line treatment for most patients, and even for older patients. However, for those who don't have a donor for transplant, we finally have reached a point where we can tweak immunosuppression a little and make it better. For a very long time, we only used immunosuppression and now we finally have evidence to use TPO receptor agonists, such as eltrombopag, and since this is only one of the drugs in the class, we can expect that this will become the standard of practice.

What are some of the factors that you consider in determining eligibility for transplant?

We still see that age [has been a factor]; the older the patient is, the worse the results are. However, we are reaching the point where patients who are at least around age 50 can still consider transplant, [even with an] unrelated donor. We’ve come a long way from requiring identical siblings [as donors] to have the transplant to [using] unrelated donors and having a similar survival [outcome]. Still, [this approach] falls short [compared with] what we can get from immunosuppression for older patients. We're trying to make transplant safer and have better outcomes for our older patients. For the younger patients, however, transplant will be for everyone who has a donor.

What data have we seen with some of the newer agents in the space?

The data [have shown that by] adding the TPO mimetics—a new class of drugs—overall response is much higher in patients who use it upfront. As such, it's definitely moving forward into first-line therapy. The best study with these drugs shows almost double the overall response in these patients. It’s safe to say that it's a very dramatic improvement. We don't yet know how far this can get.

The second thing is, in aplastic anemia, we are dealing with three different lineages that are impaired and even if we thought that TPO mimetics were meant to improve only platelet count, results show that the overall response for all three lineages happen. That, I believe, is the most striking advantage of this treatment.

Could you highlight some of the recent advancements in TTP and ITP?

TTP is a disease that, at first, was almost 100% lethal and then with the development of plasma exchange, things improved a lot. However, we did not have an expectation that we could improve a lot in the way we see with a new drug like caplacizumab-yhdp. In short, [the agent] shortens the length of hospital stay and that has dramatic implications for cost and quality of life (QoL) for these patients. We still have yet to see what it does to long-term outcomes, but we know that this is definitely a very welcome drug for a disease that had very few options available.

Although ITP is not as severe as TTP, what we see is that the patients that are stuck with chronic ITP did not have many options 10 years ago. Now, we reached the point where we have 3 or 4 different drugs to choose from and [physicians] will now be able to choose a more appropriate treatment for each case. We finally have an array of drugs that allows patients more options and [the opportunity to] achieve a better QoL while living with the disease.

Could you speak to the promise of fostamatinib (Tavalisse)?

Fostamatinib is very impressive; it's the first Syk inhibitor for the treatment of patients with chronic ITP; it is different from other drugs in the sense that we don't know if even combinations will be possible in the future. It’s also very interesting that you can offer treatment that will help around at least 30% of patients that have been refractory to 2 or possibly 3 [prior treatments]. Most patients who have tried this drug had used several lines of therapy before.

Therefore, I believe fostamatinib is probably a drug that we will need to know a lot more about because we've only first tried it in the heavily pretreated patients, and we don't really know what it can do to patients who have only failed 1 line of therapy. We anticipate that there will be more trials [with fostamatinib], maybe even first-line trials, in the future.

Are there any other exciting agents in the pipeline?

We know there are other drugs being explored, but I don't know when these trials will report their results. I know, for example, that there is a trial ongoing for avatrombopag in SAA. We have just opened a trial for another drug in ITP, so there are other drugs that are being investigated for these diseases. I don't know exactly when they are going to report this, but we're definitely [looking out for] new results.


  1. FDA Approves Novartis Drug Promacta for First-Line SAA and Grants Breakthrough Therapy Designation for Additional New Indication [news release]. Novartis. Published November 16, 2018. Accessed June 28, 2019.
  2. Scully M, Cataland SP, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Eng J Med. 2019;380:335-346. doi: 10.1056/NEJMoa1806311.
  3. Dova Pharmaceuticals Announces FDA Approval of Supplemental New Drug Application For Doptelet (Avatrombopag) For Treatment of Chronic Immune Thrombocytopenia (ITP). Dova Pharmaceuticals. Published June 27, 2019. Accessed June 28, 2019.