Treatment-related Toxicity Grade Research Articles

Daratumumab for treatment-refractory antibody-mediated diseases in neurology.

A fraction of patients with antibody-mediated autoimmune diseases remain unresponsive to first-/second-line and sometimes even to escalation immunotherapies. Because these patients are still affected by poor outcome and increased mortality, we investigated the safety and efficacy of the plasma cell-depleting anti-CD38 antibody daratumumab in life-threatening, antibody-mediated autoimmune diseases. In this retrospective, single-center case series, seven patients with autoantibody-driven neurological autoimmune diseases (autoimmune encephalitis, n=5; neurofascin antibody-associated chronic inflammatory demyelinating polyneuropathy associated with sporadic late onset nemaline myopathy, n=1; seronegative myasthenia gravis, n=1) unresponsive to a median of four (range = 4-9) immunotherapies were treated with four to 20 cycles of 16mg/kg daratumumab. Daratumumab allowed a substantial clinical improvement in all patients, as measured by modified Rankin Scale (mRS; before treatment: mRS=5, n=7; after treatment: median mRS=4, range = 0-5), Clinical Assessment Scale in Autoimmune Encephalitis (from median 21 to 3 points, n=5), Inflammatory Neuropathy Cause and Treatment disability score (from 7 to 0 points, n=1), and Quantitative Myasthenia Gravis score (from 16 to 8 points, n=1). Daratumumab induced a substantial reduction of disease-specific autoreactive antibodies, total IgG (serum, 66%, n=7; cerebrospinal fluid, 58%, n=5), and vaccine-induced titers for rubella (50%) and tetanus toxoid (74%). Treatment-related toxicities Grade 3 or higher occurred in five patients, including one death. Our findings suggest that daratumumab provided a clinically relevant depletion of autoreactive long-lived plasma cells, identifying plasma cell-targeted therapies as promising escalation therapy for highly active, otherwise treatment-refractory autoantibody-mediated neurological diseases.

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

3 fraction pencil-beam scanning proton accelerated partial breast irradiation: early provider and patient reported outcomes of a novel regimen

Background and purposeTo report dosimetry and early adverse effects, aesthetic, and patient-reported outcomes of a prospective study of 3-fraction pencil-beam scanning (PBS) proton accelerated partial irradiation (APBI).Materials and methodsEligibility included women age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤2.5 cm. The prescription was 21.9 Gy (RBE 1.1) in 3 daily fractions to the post-operative tumor bed with a 1 cm expansion. Toxicities were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, 10-point Linear Analog Scale Assessment, Patient-Reported Outcomes Version of the CTCAE, and the Harvard Breast Cosmesis Scale.ResultsSeventy-six women were treated between 2015 and 2017. The median breast volume receiving 50% of prescription or more was 28%. Median mean heart, mean ipsilateral lung, and maximum skin dose were 0 Gy, 0.1 Gy, and 20.6 Gy, respectively. With a median follow-up of 12 months, no treatment-related toxicity grade ≥ 2 has been observed. Most common grade 1 adverse events were dermatitis (68%) and skin hyperpigmentation (18%). At 12 months, the only persistent toxicities were one patient with grade 1 breast edema and one patient with a grade 1 seroma. 90% of patients reported quality of life as ≥7 out of 10 (0 indicating “as bad as it can be” and 10 indicating “as good as it can be”) and 98% of patients reported excellent or good cosmesis.Conclusion3-fraction PBS proton APBI is well tolerated with low rates of physician and patient reported early adverse effects. Follow-up is ongoing to assess late toxicities and disease control outcomes. Further investigation of this novel adjuvant treatment strategy is warranted.

Pegylated Liposomal Doxorubicin as Single-Agent Treatment of Low-Grade Non-Hodgkin's Lymphoma: A Phase II Multicenter Study

The purpose of this study was to determine the objective response rate, median duration of response, time to disease progression, and survival time and to evaluate the safety of pegylated liposomal doxorubicin in previously treated patients with low-grade non-Hodgkin's lymphoma. Thirty-two patients with low-grade non-Hodgkin's lymphoma were treated and analyzed. Pegylated liposomal doxorubicin 30 mg/m2 was administered intravenously as a single dose on day 1 of each 3-week cycle. Patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had stage II-IV disease. The median baseline left ventricular ejection fraction was 60%, and the median age was 68 years. In 29 evaluable patients, there were 3 (10%) complete responses, 6 (21%) partial responses, 11 (38%) patients with stable disease, and 9 (31%) with progressive disease. The median number of cycles was 4 (range, 1–22 cycles). The median duration of response (complete response plus partial response) was 11.0 months (range, 2.3–37.0 months). The estimated median time to progression was 5.6 months (range, 1.1–40.5 months) and the estimated median survival was 29.6 months (range, 3.9–41.6 months). Treatment-related toxicities grade ≥ 3 included neutropenia (25%) and palmoplantar erythrodysesthesia (9%). Only 1 clinically significant cardiac toxicity was observed. There were 17 deaths; none were treatment related. Single-agent pegylated liposomal doxorubicin 30 mg/m2 every 3 weeks, is associated with antitumor activity in the treatment of low-grade non-Hodgkin's lymphoma, as shown by an objective response of 31%, and produced no significant cardiac or hematologic toxicity. Based on these results, pegylated liposomal doxorubicin should be further evaluated in combination with other agents in low-grade non-Hodgkin's lymphoma.