For those with relapsed or refractory (r/r) acute myeloid leukemia (AML) successive conditioning before allogeneic stem cell transplantation (alloSCT) can be a potentially curative treatment option for patients. Additionally, earlier response to treatment during conditioning suggests chemotherapy-responsive disease which may have prognostic value. A study published in British Journal of Haematology assessed whether early bone marrow blast clearance following high-dose of melphalan on day 5 and administered 11 days before alloSCT as part of a sequential conditioning protocol affects the outcomes in patients with r/r AML following transplant.
In this retrospective study, a total of 176 patients with r/r AML with a median age of 61 years (range: 19-76) who underwent alloSCT between 2014 and 2023 were enrolled in the analysis. All patients were treated with high-dose melphalan (100-140 mg/m2) 11 days prior to alloSCT—with 71 receiving 100 mg/m2 due to toxicity considerations—followed by either fractionated TBI with 4 x 2 Gy (n = 65) or chemotherapy regimens, including busulfan (n = 92) or treosulfan (n = 19) in combination with fludarabine from day 5 before alloSCT. Additionally, patients with extramedullary disease and without any evidence of active bone marrow disease, patients beyond their first alloSCT, and patients who received transplants from haploidentical donors were not included in the analysis.
The initial bone marrow blast count was assessed within 28 days prior to the high-dose melphalan conditioning; however, there was 1 patient with stable disease who had their blast count assessed 37 days prior to melphalan. Early bone marrow assessments were routinely performed following the application of melphalan and prior to the continuation of the second part of the conditioning regimen.
The investigators assessed blast count by cytological and flow cytometric evaluation of a bone marrow aspirate on day 6 (±2 days; 1 patient on day 3) prior to transplantation. Blast clearance was defined as a cytological blast count of less than 5% and less than 0.1% cells with a leukemia-associated immunophenotype on flow cytometry. Flow cytometry included at least the surface markers CD45, CD33, CD34, and CD117, and blast clearance by 1 assessment method was considered to be sufficient to define the achievement of blast clearance, if 1 of these 2 modalities was not evaluable.
Overall survival (OS) and relapse-free survival (RFS) were assessed. Additionally, measurable residual disease (RFSMRD) relapse was assessed and included post-transplant relapse/persistence of defined molecular and cytogenetic markers, decreasing CD34+ bone marrow chimerism (<95%) or hematologic relapse. Further, both mixed and subpopulation (CD34+, CD3+) chimerism monitoring was performed routinely around days 60 and 100, as well as at 6- and 12-months post-transplantation. In high-risk patients (eg, patients who failed to achieve blast clearance or had persistent cytopenia), chimerism monitoring was performed earlier.
Key Takeaways
- Sequential Conditioning Before Allogeneic Stem Cell Transplantation (alloSCT) in Relapsed or Refractory (r/r) Acute Myeloid Leukemia (AML): The study demonstrates that sequential conditioning, involving high-dose melphalan followed by alloSCT, can be an effective and potentially curative treatment for patients with r/r AML. Early response to treatment, indicated by bone marrow blast clearance, is associated with chemotherapy-responsive disease and has prognostic value.
- Significant Outcomes in Survival and Relapse: The findings show that approximately 61% of patients achieved primary disease control after at least 1 course of induction therapy, and following alloSCT, the 3-year overall survival (OS) and relapse-free survival (RFS) rates were approximately 52% and 47%, respectively. Additionally, about 98% of patients achieved complete donor cell chimerism by day 60 post-transplantation, indicating efficacy.
- Need for Improved Conditioning Regimens: The study highlights the need for prospective clinical trials to further enhance outcomes for patients with r/r AML. One suggested approach is to integrate agents like venetoclax or radioimmune conjugates into conditioning regimens, aiming to synergize with chemotherapy and potentially reduce non-hematologic toxicity, thereby improving patient survival and reducing relapse rates.
According to the findings, approximately 61% of patients (n = 108) had primary disease after at least 1 course of induction therapy, and of these patients, 74% (n = 80) had received 1 course of induction therapy and the remainder (26%; n = 28) received more than 1. Further, approximately 18% of patients (n = 31) received stem cell transplants from HLA-mismatched unrelated donors. In addition, 24% (n = 42) had a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCI-CI) of more than 3 points, and prior to conditioning therapy, approximately 15% (n = 26) and 39% (n = 68) of patients had grades 3 and 4 neutropenia, respectively.
The median follow-up for patients was 4.8 years (range: 0.07-9.1). According to the investigators, of the 130 patients who received a chimerism monitoring up to day 60 post-transplantation, 127 (98%) had achieved a complete donor cell chimerism of 95% or more, either blood or bone marrow. Additionally, the estimated OS and RFS at 3 years in all patients was approximately 52% (95% CI, 45%-60%) and 47% (95% CI, 40%-55%), respectively. In addition, the estimated RFSMRD as combined end point of either overt relapse, death, or MRD relapse was approximately 40% (95% CI, 33%-48%) after 3 years. Further, the investigators observed that patients with MRD relapse and without evidence of overt relapse demonstrated a 2-year survival of about 38% (95% CI, 24%-58%), and at 3 years, the calculated probabilities of relapse was 27% (95% CI, 20%-34%) and non-relapse mortality was 26% (95% CI, 20%-33).
The median pre-treatment leukemic burden was about 30% (range 5%–98%). The authors observed that compared with patients who had 5% to 19% bone marrow blasts (3-year OS: 66%, 95% CI 56%-79%), patients with blasts 50% or greater (HR 1.94, 95% CI 1.14-3.33) had inferior OS. Further, patients with 20% to 49% blasts (HR 1.68, 95% CI, 0.98-2.88) demonstrated non-significantly reduced survival. A subgroup analysis of patients who received total body irradiation-based conditioning (n = 65) and patients receiving chemotherapy-based conditioning (n = 111) demonstrated that the negative prognostic impact of a higher leukemic burden before receiving alloSCT was limited to patients who were treated with chemotherapy-based regimens.
Blast clearance was assessed at a median of 6 days before alloSCT, and patients who had achieved blast clearance following high-dose melphalan had a significantly lower pre-alloSCT leukemic burden than patients who did not achieve blast-free aplasia. Similarly, the patients who did not achieve early blast clearance demonstrated more severe and prolonged neutropenia before the start of conditioning therapy; however, the authors note that other patient characteristics showed a balanced distribution between the 2 patient groups.
The investigators said that the findings show a need for prospective clinical trials to further improve the outcomes of patients with r/r AML. They suggest 1 potential approach is to include agents such as venetoclax or radioimmune conjugates into conditioning regimens that have synergistic effects along with chemotherapy to potentially prevent the increase of non-hematologic toxicity.
Reference
Ronnacker, J, Urbahn, M-A, Reicherts, C, et al. Early blast clearance during sequential conditioning prior to allogeneic stem cell transplantation in patients with acute myeloid leukaemia. Br J Haematol. 2024; 00: 1–11 doi:10.1111/bjh.19552
