Phase II trial of natalizumab with corticosteroids as initial treatment of gastrointestinal acute graft-versus-host disease.

The α4ß7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38-74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22-62%) and 2-year NRM was 52% (95% CI 29-71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission.

We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow-up was 27·2 months post-HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post-HCT; 43 controls were alive without relapse at this cut-off. Sorafenib patients had improved 2-year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2-year PFS (82% vs. 53%, P = 0·0081) and lower 2-year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post-HCT sorafenib in FLT3-ITD AML, and support further evaluation of post-HCT FLT3 inhibition.

A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial.

Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell-replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.).

Current and novel therapies in acute GVHD.

Despite improvements in our understanding of transplant immunology and clinical and supportive care, acute graft-versus-host disease (GVHD) remains a clinical challenge and a major cause of morbidity and mortality for patients after allogeneic hematopoietic stem-cell transplantation. While systemic corticosteroid is standard primary therapy for acute GVHD, there is no established standard treatment in the steroid-refractory setting. New generations of monoclonal antibodies, biologics, and chemotherapeutics with immunomodulatory effects have been developed over the past decade, and are being tested as novel therapies in this disease. Many of these agents - including, among others, mycophenolate mofetil, anti-tumor necrosis factor-alpha antibodies, denileukin diftitox, and anti-interleukin-2Ralpha-chain antibodies - have demonstrated promising activity in steroid-refractory acute GVHD. Despite the high response rates, however, long-term survival remains poor due to a high incidence of infections. The key to improving acute GVHD outcomes may, in fact, rest upon successful initial therapy, and timely taper of corticosteroids to promote healthier immune reconstitution. Clinical trials combining these newer agents with systemic corticosteroids as initial treatment are under way, and will determine whether fortifying initial therapy will indeed reduce the development of steroid-refractory GVHD and improve long-term outcomes. In this article, we review current and novel agents available for acute GVHD, and discuss newer investigational approaches - such as phototherapy and cellular therapies - in the management of this common transplant complication.

Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.

Iron overload could be a significant contributor to treatment-related mortality (TRM) for patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). We studied 590 patients who underwent myeloablative allogeneic HSCT at our institution, and on whom a pretransplantation serum ferritin was available. An elevated pretransplantation serum ferritin level was strongly associated with lower overall and disease-free survival. Subgroup multivariable analyses demonstrated that this association was restricted to patients with acute leukemia or myelodysplastic syndrome (MDS); in the latter group, the inferior survival was attributable to a significant increase in TRM. There was also a trend toward an increased risk of veno-occlusive disease in patients with high ferritin. Our results argue that iron overload plays an important role in transplantation outcome for patients with acute leukemia or MDS, as it does in thalassemia. They also suggest future prospective trials to examine the potential benefit of chelation therapy in this setting.