Practice Update: Haematology & Oncology

CONFERENCE COVERAGE

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Double stem cell transplant improves outcomes for children with high-risk neuroblastoma After 3 years, 61.4% of children with high-risk neuroblastoma who received a double autologous stem cell transplant were alive and cancer-free, compared to 48.4% of those who received a single transplant. Side effects were similar

between single and double transplant. D r Julie R. Park of the University of Washington School of Medicine, Seat- tle, explained that historically, less than 50% of children with high-risk neuroblastoma live 5 or more years after diagnosis. A phase 3 trial performed by the Children’s Oncology Group found that adding a second autologous stem cell transplant to standard therapy im- proves outcomes for these patients. The trial enrolled children newly diagnosed with high-risk neuroblastoma, who were a median age of 3.1 years. The majority of pa- tients (88%) had stage 4 disease and 38.2% had tumour MYCN amplification, a high-risk genetic abnormality. All patients received six cycles of a multi- agent induction chemotherapy regimen including an initial two cycles of high-dose cyclophosphamide/topotecan followed by col- lection of stem cells from the blood to be used for subsequent transplantation. At completion of the induction therapy, patients were randomly assigned to receive a single autologous stem cell transplant with car- boplatin-etoposide-melphalan chemotherapy or a double (tandem) autologous stem cell trans- plant with thiotepa-cyclophosphamide prior to the first transplant followed by modified car- boplatin-etoposide-melphalan chemotherapy

Dr Park said, “We know that most neu- roblastoma recurrences occur within 2 to 3 years from diagnosis and that patients who had not had a recurrence at 3 years have a better chance of long-term survival.” She continued, “The study was not designed to observe a difference in overall survival, as this would take many years and cannot be adequately controlled for additional therapies received after an initial disease recurrence. The researchers will continue to follow pa- tients for 10 years. Outcomes were better among patients who enrolled into the immunotherapy trial that included anti-GD2 antibody + cytokines after transplant. Among those patients, the 3-year event-free survival rate was significantly higher for those who had been assigned to tandem transplant (73.2%) than for those assigned to a single transplant (55.5%). The 3-year overall survival rate was significantly higher with a tandem transplant than with a single trans- plant (85.6% vs 75.8%). The rates of severe toxicities were similar between treatment groups. Fewer treatment- related deaths occurred among patients who received a tandem transplant than among those who received a single transplant (two vs eight).

prior to the second transplant. In the tandem transplant group, patients received the two transplants in the span of 6 to 8 weeks. In the single autologous stem cell transplant group, 129 out of 179 patients were subse- quently enrolled onto a trial delivering the anti-GD2 antibody dinutuximab + cytokine immunotherapy after single-transplant con- solidation therapy. A similar proportion of patients, 121 out of 176, received this im- munotherapy following tandem transplant consolidation therapy. The primary endpoint was 3-year event-free survival or the percentage of patients without an event at 3 years after randomisation. An event was defined as worsening or recurrence of cancer, diagnosis of a second cancer, or death from any cause. Among all patients on the study, 3-year event-free survival from enrolment was 51% and 3-year overall survival 68.3%. Among patients randomised, the 3-year event-free survival rate from the time of randomisation was significantly higher following tandem transplant (61.4%) than following a single transplant (48.4%). The 3-year overall survival rate was slightly higher in the tandem trans- plant group than the single-transplant group (74% vs 69.1%, difference not significant.)

Dr Park concluded, “This finding will change the way we treat children with high- risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments. The regimen we use for high-risk neuroblastoma, however, is also the most aggressive and toxic regimen we give to children with cancer. For that reason, future research needs to focus on both explor- ing possible late effects of current therapy and developing newer less toxic therapies.”

Low-dose chemotherapy + anti-CD19 CAR T cells can induce remission of advanced lymphoma Anti-CD19 chimeric antigen T (CAR T) cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemo- therapy, reports a study of 22 patients with diffuse large B-cell lymphoma who were treated with the regimen. D r James Kochenderfer, of the National Cancer Institute, Bethesda, Maryland, explained that T cells genetically modified to express CARs targeting CD19 exert potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti- malignancy efficacy of adoptively transferred T cells. An increase in serum interleukin-15 is one mechanism underlying this enhancement. Dr Kochenderfer and colleagues, as well as others, have reported patients treated with high-dose chemotherapy prior to anti-CD19 CAR T cell infusions. The present cohort of 22 patients received low-dose conditioning chemotherapy followed by infusion of anti-CD19 CAR T cells. Eighteen of 22 treated patients received 300 mg/m 2 cyclophosphamide daily for 3 days. Four patients received 500 mg on the same schedule. All patients received fludarabine 30 mg/m 2 for 3 days on the same days as cyclophosphamide. Patients received a single dose of CAR T cells 2 days after completing chemotherapy. Blood CAR T cells and serum cytokines were analysed in all patients. Nineteen patients with various subtypes of diffuse large B-cell lymphoma demonstrated the following remissions: eight complete and five partial remissions, two stable disease, and four progressive disease. One patient with mantle cell lymphoma obtained a complete remission. Two patients with follicular lymphoma obtained complete remissions. Durations of response range from 1 to 20 months, and 10 remissions are ongoing. All but four patients suffered either chemotherapy-refractory lymphoma or lymphoma that had relapsed after autologous stem cell transplantation. The most prominent toxicities were neurological. Others included fever and hypotension. The median peak blood CAR+ cell level was 47 (range 4–1217) per microliter. Patients who obtained complete or partial remissions had higher peak blood CAR+ cell levels than those who experienced stable or progressive disease. The mean serum interleukin-15 level was 4 pg per milliliter before the conditioning chemotherapy and 32 pg per milliliter after chemotherapy (P < 0.0001). Dr Kochenderfer concluded that anti-CD19 CAR T cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemotherapy. In the near future, CAR T cells will likely be a standard therapy for B-cell lymphomas.

Early efficacy and clinical activity are seen with durvalumab, in advanced non-small-cell lung cancer Durvalumab monotherapy demonstrated a manageable safety profile with early evidence of clinical benefit in treatment-naïve squamous or nonsquamous advanced non-small-cell lung cancer, reports an ongoing phase 1–2 dose- ranging study. S cott Joseph Antonia, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, explained that the pro-

wild type; 57 anaplastic lymphoma kinase wild type; 55 KRAS wild type; 29 squamous; 30 non- squamous; median age 66 [range 31–83] years; 64%male; 96% current/prior smokers; European Cooperative Oncology Group 0/1: 37%/63%) received a median of eight (range 1–27) doses. Drug-related adverse events were reported in 51% of patients. The most frequent were fatigue (15%), diarrhoea (12%), and decreased appetite (10%). Grade ≥ 3 drug-related adverse events were reported in 9% of patients. Drug-related adverse events led to discontinuation in four patients (7%). The most frequent adverse event was diar- rhoea (n = 2). Fifty-two patients (23 squamous; 29 nonsquamous) were evaluable for response with ≥ 12 weeks of follow-up. The objective response rate (confirmed com- plete and partial response) was 25% (11/43 PD-L1 + ; 1/8 PD-L1 – ). The disease control rate at ≥ 12 weeks was 56% (24/43 PD-L1 + ; 4/8 PD-L1 – ). The objective response rate was similar for squamous (26%) and nonsquamous cancers (24%). Responses are ongoing in nine of 13 responding patients (duration of response range 5.7+ to 70.1+ weeks). Dr Antonia concluded that durvalumab monotherapy demonstrated a manageable safety profile with early evidence of clinical benefit in treatment-naive squamous and nonsquamous advanced non-small-cell lung cancer. Develop- ment of durvalumab alone and in combination is ongoing in advanced non-small-cell lung cancer.

grammed death-1/programmed death-ligand 1 (PD-1/L1) axis is an important immune inhibi- tory pathway contributing to tumour cell escape from immunosurveillance. A phase 1–2 dose escalation and dose ex- pansion study is ongoing to evaluate the safety and efficacy of durvalumab, a modified human immunoglobulin G1 monoclonal antibody that blocks PD-L1 binding to PD-1 and cluster of differentiation (CD) 80, in patients with ad- vanced non-small-cell lung cancer or other solid tumour types. Durvalumab 10 mg per kilogram of body weight is given every 2 weeks for up to 12 months to treatment-naive patients with his- tologically or cytologically documented stage 3B/4 squamous (or nonsquamous) non-small- cell lung cancer. Retreatment is permitted if disease pro- gresses after 12 months of therapy. Response is investigator-assessed per Response Evaluation Criteria in Solid Tumors v1.1. Results were presented by histology and PD- L1 status (PD-L1 + defined as ≥ 25% of tumour cells expressing membrane PD-L1). Fifteen patients were initially enrolled regardless of PD-L1 status. After a protocol amendment, enrollment was restricted to PD-L1 + patients. As of 2015, 59 patients (48 PD-L1 + ; nine PD-L1 – ; 58 epithelial growth factor receptor

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY