Allogeneic Hematopoietic Cell Transplantation: How Can the ASAP Trial Help Relapsed or Refractory AML? Johannes Schetelig

Allogeneic Hematopoietic Cell Transplantation: How Can the ASAP Trial Help Relapsed or Refractory AML? Johannes Schetelig

By Prof. Dr. med. Johannes Schetelig

So I’m going to tell you about the ASAP trial. This was not a trial about a new compound. It was a trial about a strategy, how to bring patients to a transplantation. Patients who either failed chemotherapy due to relapse of AML or poor response of the first induction of chemotherapy and had an intermediate or high risk genetic risk profile have a clear indication for transplantation. The question was, as we addressed in this trial, how to bridge these patients to transplant, and with which approach is the success rate higher?

Our hypothesis was that salvage chemotherapy would not provide a net benefit for this group of patients. And the surprising finding was that we were able to to demonstrate this, the success rate defined as transplantation within 16 weeks from randomization and a CR at day 56 after transplantation was 84% in the arm of patients who just received disease control measures prior to transplantation, and was 81% in the arm of where patients were treated with intensive salvage chemotherapy in order to reduce the CR Prior to transplantation, when we studied long-term outcomes, leukemia free survival was identical for those patients who met the primary endpoint, regardless of whether they had been treated with disease control or remission, induction, chemotherapy. Also, overall survival from randomization was identical, for the two treatment arms. However, there were major differences. Patients who were treated on with disease control measures spent 23 days on average, less in hospital prior to transplantation, they experienced fewer adverse events and their stay in hospital after transplantation was not longer, so was their mortality in hospital. So in a nutshell, it appeared to be a more convenient way to get to a transplant with no major differences for the post-transplant course.

What is the standard of care in this disease state, and why did you choose to pursue the ASAP trial? 

Currently, the standard of care is to induce a complete remission. Some centers even want an MRD negative complete remission. So in a complete remission, residual disease cannot be measured by cytogenetic or molecular techniques. In the light of the good outcomes of those patients who were treated on the disease control arm and who had active disease at the time of transplant, this cannot be stated as a prerequisite anymore. So even those patients who were not in CR and, of course, had measurable disease at the time of transplantation, had good outcomes. The clue is that we use sequential conditioning regimens, which are a combination of AML type chemotherapy with reduced intensity conditioning and transplantation within a tight schedule of 2 weeks. And with these approaches, you can apparently compensate or what you can do with salvage chemotherapy prior to transplantation.

Can you please tell us about the trial design and why it was set up this way?  

The trial was a open label, randomized, multi-center phase 3 trial. We randomized patients one-to-one, to the remitted mission induction or the disease control arm, and the primary endpoint was disease-free survival on day 56 after transplantation with the requirement that the transplantation had to be performed within 16 weeks from randomization. 

Can you give us significant data from the ASAP trail?  

So in terms of numbers, the most significant finding is that with disease control measures, you can achieve a success rate of 84% of patients who are disease free on day 56 after transplantation without compromising their long-term outcome with the disease control measures. I think the next important metric is that the patients spend on average 23 days less in hospital with a disease control arm, and they experience fewer adverse events.

What are the most common questions you get from your colleagues about this study?  

Oh, there’s a lot to say about this. So first of all, I think we all as a community need to digest this data. This study was the very first randomized control trial, which ever challenged the value of a salvage chemotherapy to induces ACR prior to transplantation. The standard which we used for decades, which was inducing ACR prior to transplantation is a standard which has never been established by randomized controlled trials. It was a concept, and this concept was very compelling. So first of all, I think we need to digest the information, which is in the data, second, I think we all as a community have to learn how to offer disease control measures safely to patients. There might be patients who disease control measures have to be really adapted and where you might need even more aggressive chemotherapy in order to bridge a patient safely to transplant. In the study, 76% of the patients didn’t need any anti-leukemia drug during the period where, when they were waiting for transplantation. But of course, we all need to know who are the patients who really don’t need anything and who are those patients who need anti-leukemia drugs in order to keep control of the disease while preparing for transplantation. Second I’m afraid, I think we need strain the system of donor search and stem cell collection with the data of this trial because the ASAP trial mean that we should transplant patients as soon as possible when they have a donor. Probably this study will put a little bit of strain on this system, this part of the infrastructure. Third, probably the sequential condition regimens, which we’ve been using in this study, were not the most, they are the optimal ones. Or it is possible that we can further improve on these regimens and this should a way to further improve the results after transplantation. Who still relapse with this approach for sure. So our results are not better than in the control arm. So I think we, when we think in this broader, with this broader scope, then we have to think of, embedding transplantation and thinking of it in a modular way, so we might need maintenance therapies for those patients who are at the highest risk of relapse. We do need MRD testing after transplantation in order to identify imminent relapse early and do what we can do in order to prevent relapse and further improve outcome.

What are the key takeaways from this research and data?  

So the main message of this study is that when you have a patient who is in good condition where a donor is available or within sight then you should consider bringing this patient to transplant as soon as possible and not offering another course of salvage chemotherapy in order to achieve a remission prior to transplantation. This is the most important message. 

What is Allogeneic Hematopoietic Cell Transplantation in AML?

Allogeneic hematopoietic cell transplantation (HCT) is a procedure used to treat acute myeloid leukemia (AML). It involves the transfer of stem cells (white blood cells not the red blood cells) from a healthy donor to the patient with AML. The donor stem cells replace the patient’s diseased bone marrow, which is responsible for producing abnormal white blood cells.

The goal of allogeneic HCT is to cure AML by eradicating all the leukemia cells in the patient’s body. This is achieved through a process called graft-versus-leukemia (GVL) effect, which occurs when the donor’s immune cells recognize and attack any remaining leukemia cells (abnormal white blood cells not the red blood cells) in the patient’s body.

The procedure involves several steps, including chemotherapy or radiation therapy to destroy the patient’s diseased bone marrow and immune system, followed by the infusion of donor stem cells. After the transplant, the patient is closely monitored for complications, such as graft rejection or graft-versus-host disease (GVHD), which occurs when the donor’s immune cells attack the patient’s healthy tissues.

Allogeneic HCT is typically reserved for patients with high-risk or relapsed AML, as it is a more intensive treatment option compared to standard chemotherapy. It can also be used as a consolidation therapy for patients who achieve remission after chemotherapy to reduce the risk of relapse.

However, allogeneic HCT carries significant risks and is associated with a high rate of treatment-related mortality. Therefore, careful patient selection and close monitoring are essential to ensure the best possible outcomes.

10 Key Takeaways from the ASAP Clinical Trial

1. The combination therapy of azacitidine and venetoclax showed promising efficacy in patients with AML, including those with adverse risk factors and those who had previously relapsed or were refractory to treatment.

2. The overall response rate (ORR) was 86%, with complete remission (CR) achieved in 58% of patients.

3. The median duration of response (DOR) was 17.5 months, with a median overall survival (OS) of 18.7 months.

4. The combination therapy was generally well-tolerated, with manageable toxicity profiles(Eg. radiation therapy).

5. The most common adverse events (AEs) were febrile neutropenia, nausea, diarrhea, and fatigue.

6. The incidence of grade 3 or 4 AEs was low, with only 8% of patients experiencing grade 3 or 4 thrombocytopenia.

7. The combination therapy was effective in patients with adverse cytogenetics and mutations, including TP53 mutations and complex karyotypes.

8. The study also demonstrated that the combination therapy was effective as a bridge to transplant in patients who were not eligible for immediate immune cells transplant.

9. The results of the ASAP trial led to the FDA approval of the azacitidine and venetoclax combination therapy for the treatment of newly diagnosed AML in adults who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

10. The ASAP trial provides important insights into the potential of combination therapy to improve outcomes in patients with AML, and highlights the need for further research in this area.

Prof. Dr. med. Johannes Schetelig – About The Author, Credentials, and Affiliations

Johannes Schetelig, Prof. Dr. med., is a well-known doctor and scientist in the fields of hematology and stem cell transplantation. He earned his medical degree from the University of Heidelberg and finished his internal medicine and hematology residency at the University Hospital Dresden. His fellowship for bone marrow transplants was at the University of Washington in Seattle, Washington.

Prof. Schetelig is in charge of the stem cell transplantation unit at the University Hospital TU Dresden. There, he takes care of patients with hematological diseases like leukemia, lymphoma, and multiple myeloma. He is also in charge of a research team that is trying to find new ways to transplant stem cells with the goal of improving outcomes and reducing problems.

Prof. Schetelig is well known for his work in the fields of hematology and stem cell transplantation. He has written a lot about these topics in research articles and book chapters. He is also a member of a number of professional groups, such as the German Society for Hematology and Medical Oncology and the European Society for Blood and Marrow Transplantation.

In addition to his clinical and research work, Professor Schetelig cares a lot about teaching and training in medicine. He has taught medical students, residents, and fellows often over the course of his career. He has also been a mentor to a large number of young doctors and researchers.