Recent Clinical Trials in Hematopoietic Cell Transplantation Setting for Hematologic Malignancies


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Syed Abutalib, MD

Syed Abutalib, MD

Here is a brief look at the study findings and clinical implications of several recent and important clinical trials in neoplastic hematology. Attention is focused on hematopoietic cell transplantation in a variety of hematologic malignancies, with investigations addressing the role of maintenance rituximab therapy, the impact of vitamin D deficiency, the optimal graft source, and the efficacy of reduced-intensity regimens.

Rituximab Maintenance in Mantle Cell Lymphoma

Study: Phase III trial of rituximab (Rituxan) maintenance (every 2 months for 3 years) after autologous hematopoietic cell transplantation (auto-HCT) in younger adults (≤ 66 years) with newly diagnosed mantle cell lymphoma1

Key Findings: After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate was 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range = 46.4–54.2 months). 

Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI] = 70%–86%) in the rituximab group vs 61% (95% CI = 51%–70%) in the observation group (P = .001). The rate of progression-free survival at 4 years was 83% (95% CI = 73%–88%) in the rituximab group vs 64% (95% CI = 55%–73%) in the observation group (P < .001). The rate of overall survival was 89% (95% CI = 81%–94%) in the rituximab group vs 80% (95% CI = 72%–88%) in the observation group (P = .04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio [HR] for death = 0.50; 95% CI = 0.26–0.99, P = .04).

Clinical Implications: Rituximab maintenance therapy prolonged event-free survival, progression-free survival, and overall survival among younger adults with mantle cell lymphoma who were treated only with four cycles of R-DHAP prior to auto-HCT.

Impact of Vitamin D Deficiency

Study: Retrospective study of pretransplant vitamin D deficiency (25-hydroxyvitamin D3 < 20 ng/mL) and its association with relapse rates in patients (n = 492) receiving allografts for myeloid and lymphoid neoplasms2 

Key Findings: Pretransplant vitamin D deficiency was associated with higher relapse rates in patients with myeloid malignancies. Results were validated in an independent cohort of 398 patients diagnosed with myeloid disease. A total of 396 (80%) and 348 (87%) patients had vitamin D deficiency before allogeneic hematopoietic cell transplant (allo-HCT) in the training and validation cohorts, respectively. 

In the training cohort, vitamin D deficiency was significantly associated with inferior overall survival (HR = 1.78, P = .007) in multivariable analysis. This was due to a higher risk of relapse (HR = 1.96, P = .006) rather than nonrelapse mortality. 

A significant association of pretransplant vitamin D deficiency with higher relapse rates was observed only in patients diagnosed with myeloid (HR = 2.55, P = .014) but not with lymphatic diseases (HR = 1.60, P = .147). A similar impact of pretransplant vitamin D deficiency on relapse risk in myeloid diseases was also observed in an independent patient cohort (HR = 2.60, P = .017). 

Clinical Implications: Prospective studies on vitamin D status and correction of vitamin D deficiency in the setting of allo-HCT are warranted.

Source of Graft: Blood vs Marrow

Study: Mobilized peripheral blood progenitor cells (n = 190) vs unstimulated bone marrow (n = 481) as a graft source for T-cell–replete haploidentical transplantation using posttransplant cyclophosphamide: A Center for International Blood and Marrow Transplant Research analysis3

Key Findings: Hematopoietic recovery was similar after transplantation of bone marrow and peripheral blood progenitor cells (28-day neutrophil recovery rate = 88% vs 93%, P = .07; 100-day platelet recovery rate = 88% vs 85%, P = .33). Risks of grade II to IV acute (HR = 0.45, P < .001) and chronic (HR = 0.35, P < .001) graft-vs-host disease were lower with transplantation of bone marrow compared with peripheral blood progenitor cells. 

Rituximab maintenance therapy prolonged event-free survival, progression-free survival, and overall survival among younger adults with mantle cell lymphoma who were treated only with four cycles of R-DHAP prior to auto-HCT.
— Syed Abutalib, MD

There were no significant differences in overall survival by graft type (HR = 0.99, P = .98), with rates of 54% and 57% at 2 years after transplantation of bone marrow and peripheral blood, respectively. There were no differences in nonrelapse mortality risks (HR = 0.92, P = .74), but relapse risks were higher after bone marrow grafts (HR = 1.49, P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of bone marrow were limited to patients with leukemia (HR = 1.73, P = .002) and not lymphoma (HR = 0.87, P = .64). 

Clinical Implications: These retrospective data indicate that the current practice of utilizing either bone marrow or peripheral blood grafts are valid options. Prospective randomized study is warranted for a definitive answer.

Reduced-Intensity Regimen vs Myeloablative Conditioning in Myelodysplastic Syndromes

Study: Reduced-intensity regimen vs myeloablative conditioning followed by allo-HCT for younger adults (unrelated-donor transplant recipients aged 18–60 years and related-donor transplant recipients aged 50–65 years) with myelodysplastic syndromes: A prospective randomized phase III study on behalf of the European Group for Blood and Marrow Transplantation4 

Key Findings: In the study, the reduced-intensity regimen regimen consisted of busulfan (8 mg/kg orally or 6.4 mg/kg intravenously) and fludarabine (150 mg/m2), and myeloablative conditioning consisted of busulfan (16 mg/kg orally or 12.8 mg/kg intravenously) and cyclophosphamide (120 mg/kg). The cumulative incidence of relapse at 2 years was 17% (95% CI = 8%–26%) after the reduced-intensity regimen and 15% (95% CI = 6%–24%) after myeloablative conditioning (P = .6), which resulted in 2-year relapse-free survival and overall survival rates of 62% (95% CI = 50%–74%) and 76% (95% CI = 66%–87%), respectively, after the reduced-intensity regimen, and 58% (95% CI = 46%–71%) and 63% (95% CI = 51%–75%), respectively, after myeloablative conditioning (P = .58 and P = .08, respectively). 

Clinical Implications: This prospective, randomized trial provides evidence that the reduced-intensity regimen resulted in at least a 2-year relapse-free survival similar to myeloablative conditioning and a trend favoring the reduced-intensity regimen over myeloablative conditioning for overall survival. 

Reduced-Intensity Regimen in CLL

Study: Ten-year follow-up of the multicenter CLL3X trial of the German CLL Study Group, which evaluated a reduced-intensity regimen for allo-HCT in patients with high-risk chronic lymphocytic leukemia (CLL)5

A reduced-intensity regimen for allo-HCT can provide sustained disease control in a sizable proportion of patients with high-risk CLL independent of TP53 status.
— Syed Abutalib, MD

Key Findings: Between 2001 and 2007, CLL3X enrolled 100 patients (median age = 53 years), of whom 90 patients received allografts from related (40%) or unrelated (60%) donors using fludarabine alkylator–based reduced-intensity regimens. A total of 24% had refractory disease at allo-HCT, and 35% had a TP53 deletion and/or mutation. With a median follow-up of survivors of 9.7 years (range = 0.6–15.2 years), 10-year nonrelapse mortality was 20% (95% CI = 15%–36%), relapse incidence was 46% (95% CI = 43%–67%), progression-free survival was 34% (95% CI = 23%–44%), and overall survival of all 90 patients receiving allografts was 51% (95% CI = 40%–62%), without significant effects of TP53 lesions on outcomes.

Clinical Implications: A reduced-intensity regimen for allo-HCT can provide sustained disease control in a sizable proportion of patients with high-risk CLL independent of TP53 status. Patients who have achieved minimal residual disease clearance at 12 months after allo-HCT had an 87% probability of remaining disease-free for at least 10 years. ■

Dr. Abutalib is Assistant Director in the Stem Cell Transplant & Cell Therapy Program at Cancer Treatment Centers of America in Chicago.

DISCLOSURE: Dr. Abutalib reported no conflicts of interest.

REFERENCES

1. Le Gouill S, Thieblemont C, Oberic L, et al: Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 377:1250-1260, 2017.

2. Radujkovic A, Kordelas L, Krzykalla J, et al: Pretransplant vitamin D deficiency is associated with higher relapse rates in patients allografted for myeloid malignancies. J Clin Oncol 35:3143-3152, 2017.

3. Bashey A, Zhang MJ, McCurdy SR, et al: Mobilized peripheral blood stem cells versus unstimulated bone marrow as a graft source for T-cell-replete haploidentical donor transplantation using post-transplant cyclophosphamide. J Clin Oncol 35:3002-3009, 2017.

4. Kröger N, Iacobelli S, Franke GN, et al: Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: A prospective randomized phase III study of the EBMT (RICMAC Trial). J Clin Oncol 35:2157-2164, 2017.

5. Krämer I, Stilgenbauer S, Dietrich S, et al: Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood 130:1477-1480, 2017.



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