Johannes Schetelig, MD, MSc, is director of medical research at Deutsche Knochenmarkspenderdatei; as well as a professor at Technical University Dresden

Shetling

“One feature which that should be should be mentioned is that we had to stop the trial prematurely purely due to recruitment, and this highlights a specific challenge for clinical trials.”

Johannes Schetelig, MD, director of medical research at DKMS; as well as an a professor at Technical University Dresden, discussed the operational challenges encountered during the phase 2/3 HAMLET trial (NCT03275636), which aimed to compare survival outcomes following haploidentical related donor hematopoietic stem cell transplantation (HSCT) with those from single human leukocyte antigen (HLA) loci–mismatched unrelated donor transplantation in patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS).

The trial was terminated prematurely due to poor accrual, a limitation that Schetelig noted underscoreds a central difficulty in conducting randomized studies in the transplantation setting, Schetelig began. Successful enrollment in such trials requires coordinated support from referring physicians, transplant centers, patients, and families, he noted.

In HAMLET, recruitment was hindered by strong preexisting preferences regarding donor source. Both physicians and patients frequently expressed fixed positions, with —some favoring the perceived genetic advantages and familial connection of a related donor, and others preferring the potentially broader availability and institutional experience with unrelated donors. These preferences, present in both directions, led many eligible patients to decline randomization, thereby therefore constraining the recruitment pool.

Schetelig highlighted that this resistance reflects a deeper challenge when trial arms represent established clinical practices supported by retrospective outcomes data. In these situations, equipoise—the condition in which clinicians and patients view both interventions as reasonably comparable—may be difficult to achieve. Without equipoise, willingness to accept randomization diminishes, particularly in the transplant context where donor choice is often highly individualized and emotionally charged.

Schetelig also noted that this study suggests that future comparative studies in HSCT may benefit from alternative designs that address patient and physician preference bias while maintaining scientific rigor. Potential strategies include adaptive trial frameworks, preference-based randomization, and integration of prospective registry data. These methods may allow for broader participation while still generating high-quality comparative evidence.

Ultimately, Schetelig emphasized concluded that while although the trial could not meet its accrual target, the lessons learned are valuable for shaping future transplantation research.

Videos

Johannes Schetelig, MD, discusses challenges with assessing haploidentical related vs mismatched unrelated donor transplantation in high-risk AML/ALL/MDS

Dr Schetelig on Challenges Assessing Haploidentical vs Mismatched Transplantation in AML/ALL/MDS

Dr Schetelig on Haploidentical vs Mismatched Transplant Efficacy in AML/ALL/MDS

Johannes Schetelig, MD, director of medical research at DKMS; as well as a professor at Technical University Dresden, discussed findings from the phase 2/3 HAMLET trial (NCT03275636) comparing survival outcomes with haploidentical related and single human leukocyte antigen loci–mismatched unrelated donor transplantation in patients with high-risk acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome.

Johannes Schetelig, MD, discusses outcomes with haploidentical related vs mismatched unrelated donor transplantation in high-risk AML, ALL, and MDS.

Johannes Schetelig, MD, MSc, head, Stem Cell Transplantation Unit, University Hospital TU Dresden, head, DKMS Clinical Trials Unit, discusses whether patients with active relapsed/refractory acute myeloid leukemia (AML) should receive remission induction chemotherapy prior to undergoing allogenic hematopoietic stem cell transplant (allo-HCT).

In the United States, there is a notable reluctance among physicians to regard immediate transplantation as a viable therapeutic option for patients with AML, Schetelig begins. This hesitancy stems from historical evidence illustrating suboptimal outcomes associated with promptly proceeding to transplant in this patient cohort, he explains. The typical clinical scenario involves patients who have exhausted multiple treatment approaches attempting to achieve a complete remission, Schetelig says, noting that these patients are often the most challenging cases.

Despite a growing emphasis on the significance of early transplantation in certain European countries, conventional treatment strategies involve the use of targeted therapy to induce complete remission before proceeding to transplant, Schetelig continues. Targeted therapy combinations are the preferred initial choice, and these approaches have shown promise in select patient populations, Schetelig states. Patients who remain unresponsive to these therapies in the first- or second-line will go on to receive intensive combination chemotherapy. However, there is a lack of retrospective and prospective evidence showing that patients benefit more from these intensive chemotherapy approaches prior to transplant, Schetelig emphasizes.

For example, the phase 3 ASAP trial (NCT02461537) assessed whether patients would experience greater overall survival (OS) and disease-free survival (DFS) benefit with sequential conditioning and immediate allo-HCT vs intensive induction chemotherapy followed by allo-HCT to induce a complete response (CR) before transplantation. Results demonstrated that watchful waiting and sequential conditioning prior to allo-HCT produced OS and CR rates that were comparable those who received induction chemotherapy. 

Although salvage chemotherapy prior to allo-HCT does not produce inferior survival outcomes vs immediate allo-HCT, these data confirm that it does not provide a sufficient survival advantage. Accordingly, watchful waiting prior to alloHCT should be considered as a viable approach in this population.

Johannes Schetelig, MD, MSc, discusses whether patients with active relapsed/refractory acute myeloid leukemia (AML) should receive remission induction chemotherapy prior to undergoing allogenic hematopoietic stem cell transplant (allo-HCT).
 

Johannes Schetelig, MD, MSc

Articles

Dr Schetelig on Challenges Assessing Haploidentical vs Mismatched Transplantation in AML/ALL/MDS

Dr Schetelig on Haploidentical vs Mismatched Transplant Efficacy in AML/ALL/MDS

Dr. Schetelig on the Use of Induction Chemotherapy Prior to Allo-HCT in Relapsed/Refractory AML