Relapsed and refractory acute myeloid leukemia (AML) presents one of the most formidable challenges in oncology, lacking a unified and efficient treatment strategy. Dr. Johannes Schetelig, Head of the Cell Therapy Unit at the Technical University of Dresden and Chair of the Clinical Trials Unit within the DKMS, offers invaluable insights into the complexities and evolving approaches in managing this condition. From the nuances of defining refractory AML at various stages to the critical decision-making involved in stem cell transplantation, Dr. Schetelig's expertise sheds light on current practices and future directions. This article delves into the multifaceted strategies for treating relapsed and refractory AML, focusing on patient suitability for stem cell transplantation, predictive clinical characteristics for better outcomes, and proactive measures to prevent relapse post-transplantation. Clinically, what treatment strategy should we adopt for this type of patients? Dr Schetelig: My name is Johannes Schetelig. I am Head of the Cell Therapy Unit at the Technical University of Dresden. At the same time, I have the privilege to Chair the Clinical Trials Unit within the DKMS. The question you are asking about relapsed or refractory AML is a complex one, because when we think about residual leukemia after treatment (what we may call refractory AML), then this might be encountered at different stages. Beginning after the first course of intensive induction chemotherapy: At that time, there is not a standard definition to define resistant AML. But at least in our study group, persisting AML after one course of induction is already considered as a trigger, especially when other features support going for an allogeneic transplant. Genetic features plus poor early response indicate that we are dealing with high-risk acute leukemia. But you can also apply a stricter definition and define refractory AML only after having failed two courses of intensive induction therapy, or at the most advanced stage, after a patient has failed salvage chemotherapy in a relapsed setting. We call this stage relapsed refractory AML. Further, there are multiple ways to define residual or refractory AML. It is most challenging, and I would say dangerous, when morphological leukemia is found after intensive treatment, But, of course, residual leukemia can also be detected at much lower levels, and then the question is whether or not residual leukemia at the molecular level should also be considered as refractory. Our approach within the Study Alliance Leukemia, which is one large German AML study group I belong to, is to distinguish between patients whom we aim to cure with chemotherapy alone without allogeneic stem cell transplantation. For those patients, we do think we need dose-intensive chemotherapy, with or without kinase inhibitors in order to improve outcomes (such as midostaurin or other FLT3 inhibitors that may be approved in the next few years in Europe). And then we think of those patients whom we identify as having high-risk genetic abnormalities early on, which render these patients as adverse-risk AML, according to current standard criteria: For this group of patients, we try to reduce the amount of chemotherapy which we give prior to conditioning for an allogeneic transplantation. The approach is to bring these patients as gently as possible to transplantation, because we are not convinced by the data that suggests that inducing a CR (complete remission) might be beneficial. If you phrase it provocative, then one should say that the principle to induce a CR prior to transplantation is conceptual, and not based on any prospective randomized clinical trials. We now have the ASAP trial that showed that, at the least, inducing a CR with salvage chemotherapy didn’t improve prognosis in a significant way. So, we are hesitant to offer chemotherapy for remission induction prior to HCT to those patients who need transplantation. Among patients with relapsed and refractory AML, which patients are suitable for stem cell transplantation? Dr Schetelig: Again, this is a tricky question, when we think about the contraindications against stem cell transplantation. We are not an aggressive transplant center when it comes to patient age. About the age of 70, we think that individuals have to be assessed very carefully. Of course, there are many patients, who are in there 70s and still have very good performance status, have few comorbidities, and thus qualify for allogeneic transplantation. We think there may be a few patients above the age of 75 who qualify for transplantation, but very few selected patients may. We have never performed an allogeneic transplantation for a patient over the age of 80. We find this is something we respect today as something we wouldn’t consider doing. Even below the age of 70, some patients might not qualify for allogeneic transplantation. Some of those reasons may be related to complications related to the initial stage when leukemia was diagnosed, or complications that occurred during the course of treatment for AML. To give a few examples: when organ failure is present, we don’t think of transplantation. Severe chronic kidney failure is a strong contraindication against transplantation. On the other hand, the HCT-CI (hematopoietic cell transplantation-specific comorbidity index) is a measure that helps us to assess patients and to categorize them into patients with higher or lower risk for non-relapse mortality especially, but this is not a perfect measure. Many patients with HCT-CI scores above 3 benefited from transplantation in our hands. This index is far from perfect as some patients may be very sick despite having a low HCT-CI risk. In the end, our belief is that a good hematologist should be able to assess fitness for hematopoietic stem cell transplantation. At least what we recommend is approaching your local transplant center to get in contact and discussing with the transplant physicians whether or not the patient might be suitable for allogeneic transplantation. Among relapsed and refractory AML patients, what clinical characteristics generally predict better outcomes after transplantation? Dr Schetelig: Based on our interpretation of the published data and our own data, the AML biology is the foremost predictor of outcome after transplantation. We think it is more important than disease stage, and more important than whether or not residual leukemia is present prior to transplantation. There is, of course, a huge range of scenarios. If you think of just patients with de novo AML, or of patients with relapsed AML. Favorable-risk AML, for example, often shows good responses to salvage chemotherapy, with or without venetoclax. Those patients often have chemo-sensitive disease, and those patients have a very favorable prognosis also after transplantation. The opposite end of the spectrum is marked by patients with complex karyotypes harboring TP53 mutations. This is a group of patients where we do have a lot of debate. We are a little more restrictive when it comes to additional comorbidities or additional features that may have an impact on transplant outcome, because, per se, this is a group of patients with a very high-risk of relapse after allogeneic transplantation. We do need much better maintenance strategies in order to reduce the risk of relapse, especially for this group of patients. Patients with relapsed and refractory AML still face the risk of relapse after transplantation. What active measures can be taken to prevent relapse after transplantation? Dr Schetelig: The most important thing to reduce the dangers associated with the risk of relapse is to identify relapse as early as possible. I think that, from now on, we should aim at detecting all relapses that occur in the first two years after first-line treatment by using molecular markers. So relapse should first be detected at a molecular level so there is enough time to think about next treatment steps, and patients should not experience morphological relapse. This is easy to say, and hard to translate into clinical practice. There are, of course, some patients who when you try to cure with chemotherapy alone don’t have good markers, but the majority of patients whom we attempt to cure with chemotherapy alone do have markers, either NPM1 mutations or core-binding factor (CBF) translocations, which are very suitable for minimal residual disease (MRD) monitoring. I think this is the most important thing to keep in mind – we do have to try to monitor those patients tightly so we identify molecular relapse at an earlier time point. This is something that, again, our group demonstrated at this year’s EBMT: If you transplant those patients without any treatment of the molecular relapse right away, they have an excellent prognosis. When we think of those patients, those patients don’t feel any complaints from their leukemia. They have a normal blood count. They are suitable to go directly to transplantation. This is something we should aim for in order to improve outcomes. It is much more difficult when we have patients with truly primary refractory disease after one, two or even more lines of intensive and salvage chemotherapy. For those patients we need to develop new drug combinations, which may get approval in Europe. They probably are approved in other parts of the world already. BCL-2 inhibitors, e.g. are very attractive for the treatment of acute myeloid leukemia. This is an ongoing field of research. Of course, we have other drugs like menin inhibitors, and IDH1 and IDH2 inhibitors. So, we will get more drugs into our hands in order to safely treat patients, and hopefully to lower the comorbidities associated with treatment. Already now, when we treat patients with FLT3-ITD or FLT3-TKD, we offer FLT3 inhibitors, because we feel this oral treatment is well-tolerated and has a very favorable risk-to-benefit ratio. We offer this to all patients who have approved status for this type of drugs. The hope is that we identify treatments with a favorable risk-to-benefit profile for more patients. When we deal with a patient with relapse of NPM1-mutated AML with FLT3-ITD, we offer gilteritinib, but we don’t wait until complete remission has been achieved. We give it for 3 or 4 weeks. We take the amount of time that we gain with this treatment to organize transplantation, but the aim is still to go for transplantation as soon as possible, and then to continue this effective drug after transplantation. This is building on data that has been produced from the ADMIRAL and MORPHO trials.
