Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy.

BACKGROUND: Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg(-1) among patients participating in an expanded access programme in Italy. METHODS: Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg(-1) every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events. RESULTS: Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported. CONCLUSIONS: For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.

153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients.

BACKGROUND: Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months. PATIENTS AND METHODS: Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion. RESULTS: The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months. CONCLUSIONS: Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

High BRAF variant allele frequencies are associated with distinct pathological features and responsiveness to target therapy in melanoma patients.

BACKGROUND: BRAF mutant melanoma patients are commonly treated with anti-BRAF therapeutic strategies. However, many factors, including the percentage of BRAF-mutated cells, may contribute to the great variability in patient outcomes. PATIENTS AND METHODS: The BRAF variant allele frequency (VAF; defined as the percentage of mutated alleles) of primary and secondary melanoma lesions, obtained from 327 patients with different disease stages, was assessed by pyrosequencing. The BRAF mutation rate and VAF were then correlated with melanoma pathological features and patients' clinical characteristics. Kaplan-Meier curves were used to study the correlations between BRAF VAF, overall survival (OS), and progression-free survival (PFS) in a subset of 62 patients treated by anti-BRAF/anti-MEK therapy after metastatic progression. RESULTS: A highly heterogeneous BRAF VAF was identified (3%-90%). Besides being correlated with age, a higher BRAF VAF level was related to moderate lymphocytic infiltration (P = 0.017), to melanoma thickness according to Clark levels, (level V versus III, P = 0.004; level V versus IV, P = 0.04), to lymph node metastases rather than cutaneous (P = 0.04) or visceral (P = 0.03) secondary lesions. In particular, a BRAF VAF >25% was significantly associated with a favorable outcome in patients treated with the combination of anti-BRAF/anti-MEK drug (OS P = 0.04; PFS P = 0.019), retaining a significant value as an independent factor for the OS and the PFS in the multivariate analysis (P = 0.014 and P = 0.003, respectively). CONCLUSION: These results definitively support the role of the BRAF VAF as a potential prognostic and predictive biomarker in melanoma patients in the context of BRAF inhibition.

Allogeneic hemopoietic stem cell transplantation in solid tumors.

The existence of a graft versus tumor (GVT) effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation is well established as a critical component for the success of the procedure in several hematologic malignancies. Although it has been suggested that a GVT effect might also be generated in patients affected by refractory solid tumors, the morbidity of conventional allogeneic hematopoietic stem cell transplantation has limited its investigation in these diseases. Recently introduced allogeneic nonmyeloablative regimens have greatly decreased morbidity and mortality related to transplants which retain a powerful GVT. On this basis, it has become possible to explore the existence of alloreactivity toward solid tumors. The present article reviews the early clinical results of this novel immunotherapeutic approach for solid tumors.

Serial in vitro transfer of tuberculin hypersensitivity by sensitised lymphocytes.

An account is given of the experimental serial in vitro transfer of PPD-specific delayed hypersensitivity to peripheral leukocytes using PPD-specific TF solely as the initial source. Transfer was assessed by means of the leukocytes migration inhibition test, the lymphocytes locomotion test and the leukocytes adherence inhibition test. These tests were positive in all the experiments. It is suggested that these results indicates that TF does not act in itself but triggers a reaction that expands the effect of hypersensitivity.

Serial in vitro transfer of hypersensitivity to cancer antigens by sensitised lymphocytes.

An account is given of the experimental serial in vitro transfer of antigen-specific delayed hypersensitivity to peripheral leukocytes, using antigen-specific Transfer factor solely as the initial source. Transfer was assessed with the leukocyte migration, lymphocyte locomotion and leukocyte adherence inhibition tests. The positive test results observed in all the experiments suggest that Transfer factor does not act as such, but triggers a reaction that expands the effect of hypersensitivity.

Cytokine induced killer cells as adoptive immunotherapy strategy to augment graft versus tumor after hematopoietic cell transplantation.

Donor lymphocyte infusion (DLI) is used to increase the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplant (HCT). The limited spectrum of activity and high risk of graft versus host disease (GVHD) remain major limitations of this approach. The finding of new cell populations for adoptive immunotherapy, with the ability to separate GVT from GVHD, would be useful. Here we review the main basic, preclinical and clinical research on cytokine-induced killer (CIK) cells, highlighting the aspects of their antitumor and alloreactive potentials that might favourably affect the balance between GVT and GVHD. CIK cells are ex vivo-expanded T lymphocytes sharing NK markers and endowed with a potent MHC-unrestricted antitumor activity against haematological and solid malignancies. Studies in preclinical animal models have demonstrated their low GVHD potential when infused across MHC-barriers, and recent clinical studies seem to confirm these findings in patients with hematological malignancies relapsing after HCT. If consolidated with larger clinical trials, adoptive immunotherapy with CIK cells might represent an effective alternative to classic DLI, helping HCT to succesfully meet current challenges like the extension across major HLA-barriers and application to solid tumors.

Therapy with mycophenolate mofetil for refractory acute and chronic GVHD.

We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.

Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.