Increasing the punch of reduced-intensity transplants

In this issue of Blood, Pagel and colleagues describe their experience in the pioneering use of a RIT-enhanced reduced-intensity preparative regimen for hematopoietic cell transplantation for older patients with advanced AML.

Like many malignant blood disorders, acute myeloid leukemia (AML) continues to be a highly lethal disease, striking with no apparent logic, but especially affecting the aging person. In fact, the incidence of AML increases 20-fold from the decades of 20 to 30 through 70 to 80 years. Most patients with AML are more than 60 years old. This is the age now found by many clinical trials as the upper age barrier to successful therapy. Patients over the age of 60 years do especially poorly with long-term survival (not necessarily adjusted for age and actuarial life expectancies), usually quoted in the 5% to 10% range. Hematopoietic stem cell transplantation has been shown to increase the odds of survival for younger patients, but its application to the older adult has been slow and tentative.¹ 

The most significant recent change in the field of hematopoietic cell transplantation is the use of reduced-intensity conditioning regimens, especially designed for older patients or those with significant medical comorbidities.²  Because most patients with transplantable illnesses are “older” adults, this is quite important, as it has permitted the use of hematopoietic stem cell transplantation (HSCT) in patients who heretofore were considered “too old.” Yet, the trade-off for a less intense preparative regimen, although well tolerated, has been a higher relapse rate. The study by Pagel et al may light the way toward better outcomes.³  They demonstrate in a phase 1 study a novel method to intensify the preparative regimen without increasing toxicity.

In this phase 1 clinical trial, they used an ¹³¹I-coupled Bi-anti-CD45 antibody (BCA) administered along with a fludarabine and low-dose total body radiation (TBI) preparative regimen. They studied 58 patients with advanced AML or high-risk myelodysplastic syndrome, most of whom had persistent malignancy at the time of transplantation. Remarkably, all patients achieved a complete response and had 100% donor-derived CD3- and CD33-positive cells in the blood by day 28. Seven of the 58 patients died of non–relapse-related causes by day 100. The estimated probability of recurrent AML was 40% at 1 year, and the 1-year survival rate estimate was 41%.

The use of reduced-intensity preparative regimens is now widely accepted and used for older and infirm patients.^4-6  The Seattle group has been in the vanguard of the development of reduced-intensity transplantation preparative regimens.⁷  It is notable that the patients treated by Pagel et al were deemed ineligible for their standard reduced-intensity preparative regimen of fludarabine and TBI alone. The survival rate of 41% is quite remarkable, given that background. Toxicity to extra-medullary organs was low, and treatment-related mortality was reasonable and low.

Targeting CD45⁺ hematopoietic cells is not the only way to target the marrow space with additional radiation. Other hematopoietic antigens can also be targeted.⁸  Alternative methods include the use of external beam radiation using intensity-modulated radiotherapy techniques⁹  and bone-seeking radionuclide therapy.¹⁰  These approaches are promising but have not been studied in substantial numbers of patients. The advantage of these alternative approaches is their exportability, and potentially greater reliability, with higher dosing to the marrow compared with antibody-delivered therapy. However, there may be possible advantages to protocols combining radioimmunotherapy (RIT) and external beam therapy. RIT has the advantage of targeting extramedullary disease as well as medullary disease.

AML in the older patient is a pressing medical problem. Chemotherapy alone results in few cures. Approaches to augmenting the efficacy of hematopoietic cell transplantation without unduly increasing toxicity are urgently needed. Reducing the intensity of therapy to uninvolved organs while boosting treatments to the sites of disease is a promising approach to achieving more cures for patients with this lethal disease.