Reduced Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes When Compared to Fludarabine and Busulfan Following Allogeneic Hematopoietic Cell Transplantation for Lymphoid Malignancies

Background

Reduced intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation (allo-HCT) to minimize transplant-related mortality while still exploiting the graft-versus-tumor effect. It remains unclear if RIC preparative regimens need to be tumor specific. In B cell malignancies, RIC regimens containing rixtuximab, an antiCD20 antibody with anti-neoplastic activity, are commonly used. Rituximab-containing conditioning regimens have been shown to be associated with favorably event-free survival in a phase II study (Sauter et al, BMT, 2013). However, the long-term outcomes of rituximab-containing versus non-rituximab containing regimens for allo-HCT in B cell malignancies remain to be determined.

Methods

We retrospectively analyzed 94 patients who received an allo-HCT for a B cell neoplasm between 1/1/2005 and 12/31/2013 at Vanderbilt University Medical Center and the Veterans Administration Medical Center, Nashville. Of these, 33 received conditioning with Fludarbine, Cyclophosphamide, and Rituximab (FCR) and 61 received conditioning with Fludarabine and Busulfan (FluBu). For graft-versus-host-disease (GVHD) prophylaxis, patients receiving FCR received a calcineurin inhibitor and methotrexate, and patients receiving FluBu received a calcinuerin inhibitor and mycophenolate mofetil. Additionally, patients with related-donor transplants received anti-thymocyte globulin. Patient-, disease-, and treatment-related characteristic are summarized in Table 1.

Results

Patients who received FCR had more related-donor transplants compared to patients who received FluBu (66.7% vs. 42.6%, p = 0.038). The median follow-up from day of cell infusion for all patients was 36.9 (1.1 – 127.3) months, and 41.8 months (6.4 – 83.5) and 68.4 months (2.7 – 313.8 ), for the FCR and FluBu groups, respectively (p = .97 ). 

The 2-year overall survival was superior in patients who received FCR (72.7% vs. 54.1%, p = 0.031) (Figure 1).  Two-year progression-free survival was also superior in patients who received FCR (63.6% vs. 49.2%, p = 0.04).  There was no difference in the 100-day cumulative incidence of grade II-IV acute GVHD (45.5% vs. 63.9, p = 0.12) or grade III-IV acute GVHD (9.1% vs 16.4%, p = 0.53) for patients who received FCR compared to FluBu.  However, the 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR compared to FluBu (27.3% vs 51.7%, p = 0.031).

In a multivariable analysis adjusted for diagnosis (CLL/SLL vs. other B cell malignancies) and donor type (related vs. unrelated), only the conditioning regimen (FluBu vs. FCR: hazard ratio [HR] 1.95, 95%CI 0.98 – 3.85, p = 0.049) and CIBMTR disease risk (low vs. intermediate/high risk: HR 0.5, 95%CI 0.35 – 1.01, p = 0.053) were independent predictors of overall survival. 

Conclusions
This study shows that use of a rituximab-containing RIC regimen in allo-HCT for lymphoid malignancies is associated with improved overall survival. In addition, a rituximab-containing regimen is associated with decreased incidence of chronic GVHD. If validated in a larger prospective cohort, these findings make rituximab-containing regimens preferable for B cell malignancies requiring allo-HCT.

Table 1

Variables	FCR	FluBu	p-value
Recipient Age (Median, Range)	52.9 (43.6 – 64)	55.3 (33.3 – 70.1)	0.95
Donor Type			0.038
Related	66.7%	42.6%
Unrelated	33.3%	57.4%
Primary Disease			0.34
Chronic Lymphocytic Leukemia/        Small Cell Lymphoma	39.4%	27.9%
Mantle Cell Lymphoma	24.2%	14.8%
Diffuse Large B-Cell Lymphoma	12.1%	27.9%
Follicular Cell Lymphoma	21.2%	26.2%
Other B Cell Lymphoma	3.1%	3.2%
CIBMTR Disease Risk			0.61
Low	71%	78%
Intermediate/High	29%	22%

Figure 1