Treosulfan – based conditioning in allogeneic hematopoietic stem-cell transplantation for lymphoid malignancies: Long term follows up. Free

Introduction:

Treosulfan was recently approved by the FDA for the use in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Prior studies have shown that Treosulfan is associated with strong anti-leukemia effect combined with relatively low non-relapse mortality (NRM) rate and reduced rate of graft-versus-host disease (GVHD). However, most of the data derives from HSCT in myeloid malignancies and there is limited data on the outcome of HSCT with Treosulfan conditioning in lymphoid malignancies.

Methods:

We have used the combination of fludarabine and treosulfan as the preferred conditioning regimen for allogeneic HSCT in patients (pts) with lymphoid malignancies, considered eligible for low to intermediate transplant conditioning intensity, since the year 2009. Treosulfan dose (10-14gr/m^2 x3d) was determined based on patient and disease characteristics. GVHD prophylaxis included cyclosporine and methotrexate or mycophenolate ATG was added to unrelated donor HSCT. Post-transplant cyclophosphamide was used in a minority of transplants. This is a retrospective analysis of HSCT outcomes focusing on long-term survival.

Results:

The study included 215 pts, median age 53 years (range, 19-74). The underlying malignancy was acute lymphoblastic leukemia (ALL, n=36), B- cell aggressive lymphoma (NHL, n=62), B-cell low grade lymphoma (LGL, n=17), mantle cell lymphoma (MCL, n=9), Hodgkin lymphoma (HL, n=37), Richter transformation of chronic lymphocytic leukemia (n=13), T-cell lymphoma (TCL, n=35) and T-cell prolymphocytic lymphoma (T-PLL, n=6). The median number of prior lines of therapy was 4 (range, 1-9) and 86 pts (35%) had a prior autologous transplantation. Disease status at HSCT was CR1/2 (n=71), PR/ CR≥3 (n=102), refractory (n=42). Comorbidity score was 0 (n=105), 1-2 (n=88) and ≥3 (n=22). The donor was an HLA-matched sibling (n=101), matched-unrelated (n=91), mismatched unrelated/ haploidentical (n=23). The total Treosulfan dose used was 30 gr/m2 (n=47), 36 gr/m2 (n=132) or 42 gr/m2 (n=36).

With a median follow-up of 6.6 years (range, 0.3-15.4), 108 are alive and 107 have died. The estimated 10-year overall survival (OS) rate is 45% (95%CI, 38-53). The 10-year cumulative incidence of NRM and relapse-related mortality was 24% (95%CI, 19-31) and 31% (95%CI, 25-39), respectively. The rates of acute GVHD grade II-IV and III-IV at day 180 after HSCT were 20% (95%CI, 15-27) and 9% (95%CI, 6-15), respectively. The rate of chronic GVHD at 1 year after HSCT was 33% (95%CI 27-40), The 10-year OS by disease type was 54% (95%CI, 36-73), 28% (95%CI, 15-40), 71% (95%CI, 49-92), 56% (95%CI, 23-88), 61% (95%CI, 43-79), 48% (95%CI, 19-78), 41% (95%CI, 23-59) and 42% (95%CI, 0-85) for ALL, NHL, LGL, MCL, HL, Richter transformation, TCL and T-PLL, respectively (P=0.09). The 10-year OS was 55% (95%CI, 44-66) and 33% (95%CI, 23-55) for pts age <55 and ≥55 years, respectively (P=0.001). The 10-year OS was 50% (95%CI, 34-65), 49% (95%CI, 39-60) and 26% (95%CI, 12-40) for pts in CR 1/2, PR/ CR≥3 and refractory disease at HSCT, respectively (P=0.009). It was 57% (95%CI, 46-68) and 36% (95%CI, 25-46) for pts with 1-3 or ≥4 prior lines of therapy, respectively (P=0.002). It was 59% (95%CI, 47-70), 35% (95%CI, 24-47) and 25% (95%CI, 6-44) for pts with a comorbidity score of 0, 1-2 and ≥3, respectively (P=0.005). The donor type, Treosulfan dose used, prior autologous transplantation and year of HSCT did not predict OS in the univariate analysis. Multivariate analysis identified advanced age [HR 1.76 (1.13-2.74), P=0.01)], refractory disease [HR 1.74 (0.94-3.24), P=0.08)], ≥4 lines of prior therapy [HR 1.83 (1.09-3.06), P=0.02)] and a comorbidity score of ≥3 [HR 2.14 (1.11-4.12), P=0.02)] as predictors for inferior OS. The 10-year OS of pts with none of these poor risk factors was 69% (95%CI, 53-85).

Conclusions:

Treosulfan- based conditioning can allow promising long-term OS in pts with a variety of lymphoid malignancies. Consistent with data form HSCT in myeloid malignancies, it is associated with potent anti-malignancy effect combined with relatively low NRM and GVHD rates. HSCT outcomes should be interpreted in view of the novel therapeutic options that were introduced in recent years for the treatment of various lymphatic malignancies. However, the current long-term data may indicate that HSCT with Treosulfn – based conditioning may still have a role in several lymphoid categories and selected groups of pts.