Caution: Higher Radiation Dose Linked to Worse NHL Outcomes

Neil Osterweil

February 21, 2020

ORLANDO, Florida — Increasing the dose of total body irradiation (TBI) given to patients with non-Hodgkin lymphoma (NHL) who are undergoing reduced-intensity conditioning prior to stem cell transplant may lead to worse survival, investigators caution.

The finding comes from a study in 413 adults with NHL who underwent a first allogeneic hematopoietic stem cell transplant (alloHCT) with a fludarabine-based reduced-intensity conditioning regimen that included TBI.

Dr Mehdi Hamadani

In this patient population, relapse is the most common cause of therapy failure. One approach to decreasing relapse risk has been to increase the intensity of the radiation component from 2 Gy to 4 Gy, but the effect of the higher radiation doses on nonrelapse mortality is uncertain, explained lead investigator Mehdi Hamadani, MD, from the Medical College of Wisconsin in Milwaukee.

The results showed a significantly higher incidence of nonrelapse mortality and significantly worse overall survival for patients who received the higher radiation dose.

"Relative to the more standard fludarabine/2-Gy TBI conditioning, the 4-Gy TBI-based approach does not seem to increase the risk of graft-vs-host disease, either acute or chronic, [but] it provides no benefit in terms of graft failure. This higher 4-Gy TBI approach is associated with a significantly increased risk of nonrelapse mortality that clearly translates into inferior survival with this approach," Hamadi reported.

The study was presented here at Transplantation and Cellular Therapy (TCT) 2020, a joint meeting of the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research (CIBMTR).

Mazyar Shadman, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, who was comoderator of the session at which the study was presented, told Medscape Medical News, "It's mainly an institutional decision: you see a patient and you think they have high-risk disease, so you go up a little bit on the dose, but the data were actually very informative. You're not getting any better disease control, and you have more toxicity, so I think this is a very important study; I think a nonrandomized trial has its limitations, but it's still very helpful," he said.

Study Details

The investigators studied data on 413 adults with NHL in the CIBMTR registry who received a first alloHCT from either a matched-related or unrelated donor from 2008 through 2017 and who underwent a reduced-intensity conditioning regimen with fludarabine plus either 2 Gy (349 patients) or 4 Gy (64 patients) of TBI.

The baseline characteristics of the two cohorts were generally similar except that in the 4-Gy group, a higher proportion of patients had Karnofsky Performance scores >90% (P = .01), and a lower proportion of patients had a Hematopoietic Cell Transplantation-specific Comorbidity Index of ≥3 (P = .003).

The investigators found that compared with the 2-Gy TBI dose, the 4-Gy dose was associated with a hazard ratio (HR) for nonrelapse mortality of 1.79 (P = .02) and an HR for inferior overall survival of 1.51 (P = .03).

In contrast, there were no significant differences between the dosing groups for either NHL relapse/progression (HR, 0.78; P = .33) or progression-free survival (HR, 1.09; P = .61).

The 5-year adjusted nonrelapse mortality rate for the 2-Gy group was 28%, compared with 47% for the 4-Gy group (P = .005). Other adjusted 5-year outcomes were as follows: risk for relapse/progression, 35% vs 29%; progression-free survival, 37% vs 24% (P = .03); and overall survival, 51% vs 31% (P = .001).

The rate of graft failure at 100 days was 0.6% in the 2-GY group, compared with 1.6% in the 4-Gy group, but this difference was not significant.

The most common cause of death in each group was relapse.

Session comoderator Yago Nieto, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, commented in an interview with Medscape Medical News that a conditioning regimen with fludarabine and 4-Gy TBI is not commonly used in the United States.

He also noted that Hamadani and colleagues evaluated patients with lymphoma of several histologies. He pointed out that radiosensitivity specifically to TBI differs between aggressive and indolent lymphomas.

"Indolent lymphoma is more sensitive to TBI than diffuse large B-cell lymphoma, for example. The numbers for each subgroup in this study were small, and I don't think it's empowered to address this question, but one could speculate that patients with follicular lymphoma might benefit more from a higher TBI dose than those with aggressive histologies," he said.

No source of funding for the study has been disclosed. Hamadani, Nieto, and Shadman have disclosed no relevant financial relationships.

Transplantation and Cellular Therapy (TCT) 2020: Abstract 24. Presented February 19, 2020.

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