A phase 2 trial suggests total marrow and lymphoid irradiation before stem cell transplantation may improve survival in relapsed or refractory acute leukaemia without substantially increasing toxicity.
A targeted radiation approach delivered before allogeneic stem cell transplantation has shown encouraging survival outcomes in patients with relapsed or refractory acute leukaemia, a group traditionally considered to have few curative options and dismal long-term survival.
The single-centre phase 2 trial tested total marrow and lymphoid irradiation (TMLI) alongside high-dose cyclophosphamide and etoposide in 106 patients aged 16 to 60 with relapsed or refractory acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL).
“Our novel total marrow and lymphoid irradiation-based approach offers an HCT option to otherwise ineligible patients,” the researchers wrote.
“Of note, patients with acute myeloid leukaemia who received fewer previous regimens benefit the most, suggesting that patients with refractory or relapsed acute myeloid leukaemia should be considered for a total marrow and lymphoid irradiation-based regimen once a suitable donor is identified.
“Patients with acute lymphoblastic leukaemia might also benefit from this regimen, although there are now competing treatments including CAR T-cell therapy.
“This total marrow and lymphoid irradiation-based approach could be useful after failure of CAR T-cell treatment or consolidation after CAR T cells.”
Findings from the US study have been published this month in The Lancet Haematology.
The researchers reported a two-year progression-free survival of 34% and overall survival of 46%, outcomes they said compared favourably with historical transplantation data in similar high-risk populations.
The regimen uses TMLI to intensify radiation doses directly to bone marrow and lymphoid tissues while sparing healthy organs from the broader toxic exposure associated with conventional total body irradiation.
Patients received 2000cGy of TMLI over five days before chemotherapy and haematopoietic cell transplantation.
Historically, patients with refractory acute leukaemia undergoing transplantation have recorded three-year overall survival rates below 20%, with escalating radiation doses often limited by treatment-related mortality and graft-versus-host disease.
Related
In the new study, 97% of evaluable patients achieved complete remission or complete remission with incomplete blood count recovery by day 30 post-transplant. Median follow-up was 1.8 years overall and 3.1 years for surviving patients.
Toxicities remained substantial but were considered manageable. Grade 3 or 4 cytopenias occurred in 91% of patients, metabolic disorders in 78%, oral mucositis in 42% and diarrhoea in 24%. One patient died from sinusoidal obstruction syndrome linked to the conditioning regimen.
Notably, the researchers reported low non-relapse mortality rates despite the intensified radiation approach, with cumulative non-relapse mortality sitting at 15% at two years. No cases of radiation pneumonitis were observed.
The researchers said organ-sparing radiation delivery appeared to reduce off-target toxicity while still achieving effective cytoreduction before transplantation.
Among patients with AML, outcomes worsened with each additional prior treatment regimen, suggesting earlier referral for transplantation-based strategies may be beneficial. Patients with lower peripheral blast counts and fewer previous salvage therapies appeared to derive the greatest benefit.
The researchers acknowledged several limitations, including the single-centre design, lack of a randomised control arm and relatively small ALL cohort. Funding constraints also prevented full planned recruitment.
Even so, they argued the findings support TMLI-based conditioning as a potentially safer way to intensify radiation delivery in patients with otherwise poor prognoses.
Relapse remained the dominant cause of treatment failure, prompting calls for future studies combining TMLI transplantation approaches with maintenance therapies or post-transplant immunologic strategies designed to strengthen graft-versus-leukaemia effects while limiting graft-versus-host disease.
