Allogeneic BMT Ups Survival in Relapsed CLL Patients

ORLANDO—Despite early mortality risks, HLA-matched sibling bone marrow transplants (BMTs) offer a greater possibility of cure for patients with relapsed chronic lymphocytic leukemia (CLL) than does chemotherapy, according to a report presented at the 43rd Annual Meeting of the American Society of Hematology (abstract 2011). A second report (abstract 2013) showed that allogeneic transplant led to better event-free survival than autologous transplant.

Mary M. Horowitz, MD, professor of medicine, Medical College of Wisconsin, and scientific director of the International Bone Marrow Transplant Registry (IBMTR), presented the findings of a retrospective study conducted by IBMTR and M.D. Anderson Cancer Center and commissioned by Blue Cross and Blue Shield Association, Chicago (abstract 2011).

"Nontransplant treatments generally have low morbidity; however, they may also have limited efficacy, especially for patients who already have failed multiple prior treatments," Dr. Horowitz said. "In this study, allogeneic transplantation carried substantially higher morbidity and significant initial mortality, but offered greater efficacy and the potential for cure."

The study compared results of salvage allogeneic transplant using an HLA-matched sibling as a donor with the results of non-BMT salvage therapy in patients who had had at least one previous course of therapy for their CLL. The transplant cases (166 patients) came from the IBMTR database, while the chemotherapy cases (126 patients) came from M.D. Anderson. Dates of inclusion were 1990 through 1999.

Patients over 60 were excluded from both datasets, because fewer than 5% of the registry’s patients were 60 or older. Of the patients in the transplant cohort, 70% were under the age of 50, compared with 28% in the traditional chemotherapy group. Gender distribution was similar in both groups.

Distribution of performance scores pretreatment differed, with 79% in the transplant cohort having a Karnofsky score of 90 to 100 vs only 35% of the chemotherapy cohort. Most patients in both groups had scores of 80% or higher.

Outcomes

Using univariate probability outcomes, unadjusted for prognostic factors and patient characteristics, 90% of the chemotherapy patients had persistent or recurrent CLL at 6 years vs 24% in the transplant cohort.

There was an expected and striking difference in treatment-related mortality: 8% in the chemotherapy cohort and 42% in the BMT cohort.

Survival probabilities at 6 years differed significantly: 21% in the chemotherapy group vs 43% in the transplant cohort. Only 3% of the chemotherapy patients were alive and disease-free at 6 years vs 35% of the transplant patients.

Adjusted Findings

When the data were adjusted for prognostic factors, particularly age, performance score distribution, and the number of prior therapies, the relative risk of mortality with transplant vs nontransplant tapered over time.

In the transplant group, the adjusted probability of survival showed a steep drop early followed by a plateau; in the chemotherapy cohort, there was a steady drop in survival, with a crossover at 3.5 years. The 6-year adjusted probability of survival was 26% in the chemotherapy cohort and 40% in the transplant cohort.

Variables associated with mortality in the transplant group were performance scores, gender, Rai stage, age, and number of treatments prior to this episode of salvage therapy. Males, those older than 50, and patients with more advanced disease had poorer outcomes with either type of therapy.

"Early on, in the first couple of years, there’s a significant survival disadvantage in the transplant cohort. Patients in the chemotherapy cohort have a better survival rate," Dr. Horowitz said. "Between year 2½ and 5, there is no significant difference in the survival experience of the two cohorts. But by 5½ years from the transplant, we now see an advantage in the transplant cohort that is statistically significant."

The researchers concluded that the plateau in the BMT survival curve suggests that this treatment may cure some patients who were thought to have incurable disease. "Early mortality is higher in the transplant cohort, but cure of the disease is also higher," she concluded. "Thus, long-term survivals are seen but at the expense of a risk of dying early."

Allo- vs Auto-Transplant

Jordi Esteve, MD, of the University of Barcelona, reported results of the International Project on CLL/Transplant (abstract 2013), an 18-center analysis of allogeneic vs autologous stem cell or bone marrow transplant in 170 CLL patients. Transplants were performed from April 1986 through January 2000, with a median follow up of 35 months.

Among the 124 autologous transplant patients, the complete response rate was 87%; the researchers observed a continuous pattern of relapses and no plateau in survival curves.

The 46 allogeneic transplant patients, all of whom had HLA-identical sibling donors, had a 67% complete response rate and higher treatment-related mortality at 3 months (31% vs 6% in the autologous group).

At 6 years, 68% of the autologous transplant patients had relapsed, compared with 23% of the allogeneic transplant patients. Event-free survival at 6 years was 24% in the autologous transplant cohort vs 42% in the allogeneic transplant patients.

"Autologous stem cell transplant is followed by a high rate of relapse without a survival plateau," Dr. Esteve said. "In contrast, allogeneic transplantation in CLL provides durable responses in a significant fraction of patients, despite higher toxicity. The high toxicity limits the application of allogeneic transplant to subgroups of selected patients."