Ipilimumab is indicated for the treatment of melanoma in both the metastatic and adjuvant setting. Ipilimumab inhibits cytotoxic T-lymphocyte antigen 4, leading to the augmentation of T-cell activity and an antitumor immune system response. The side effect profile of ipilimumab consists of autoimmune-like events such as dermatitis, colitis, and thyroiditis. These immune-related adverse events can be serious, often resulting in the need for systemic immunosuppression with corticosteroids. We present a case of diffuse, nonnecrotizing granulomatous lymphadenitis and granulomatous vasculitis in a heavily pretreated patient with metastatic melanoma. After completion of 4 cycles of ipilimumab for the treatment of metastatic melanoma, our patient complained of increasing fatigue, drenching night sweats, and chills. Imaging revealed diffuse adenopathy involving several lymph nodes. Biopsy was positive for nonnecrotizing granulomatous lymphadenitis and granulomatous vasculitis. High-dose prednisone was initiated and tapered gradually over 6 weeks, resulting in complete resolution of the granulomatous disease.
Background: CMV remains a major cause of morbidity and mortality after aHSCT. The current standard of care for pre-emptive treatment of CMV viremia is IV ganciclovir (GCV). Oral valganciclovir (VGV) has been shown to be effective for the treatment of CMV retinitis in patients with HIV, and offers the advantage of oral administration. This prospective randomized clinical trial was designed to compare VGV to GCV as pre-emptive therapy for CMV viremia in the post-aHSCT population.
Methods: Pts undergoing aHSCT at risk for CMV viremia, determined by donor and/or recipient CMV positivity, were monitored post-aHSCT by weekly quantitative whole-blood PCR. Due to concerns about oral absorption, pts with Grade III/IV gut GVHD were excluded. Positivity was determined by a VL >10,000 copies/mL or >5,000 copies/mL X 2. Pts were randomized to receive either: GCV 5mg/kg BID for 7 days followed by daily GCV 5mg/kg for 7 days or VGV 900mg BID for 7 days followed by 900mg daily for 7 days. At 14 days, PCR was reassessed. Pts with VL <5000 copies/mL completed a 21 day course of daily GCV or VGV. Pts with VL >5000 copies/mL but < initial value completed a 28 course of daily GCV or VGV. Pts with VL > initial value returned to BID GCV or VGV to complete a 28 day course (pts with 21 day level > day 14 level were removed from the study). Primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy.
Results: 37 pts were enrolled and 19 pts received treatment with VGV while 18 pts received treatment with GCV. Patient characteristics were as follows: median age was 53 (range 18–64); 25 males, 12 females; 25 pts had myeloablative conditioning regimens, 12 had non-myeloablative conditioning; 28 pts had unrelated donors, 9 had matched sibling donors; 32 pts received peripheral blood stem-cell products, 5 received bone marrow stem-cell products. These baseline characteristics were equally distributed across the two arms.
Results: VGV and GCV showed equivalent efficacy as pre-emptive therapy (Table below). Toxicities were similar between the two arms: there were 35 grade III/IV events in the VGV arm and 42 grade III/IV events in the GCV arm. There were 20 grade III/IV hematologic toxicities in the VGV arm with 2 grade III episodes of neutropenia and 1 grade III febrile neutropenia. In the GCV arm, there were 23 grade III/IV hematologic toxicities, with 3 grade III episodes of neutropenia and 2 febrile neutropenic events. There were 2 deaths not related to the study medications or CMV. No patients developed CMV disease.
Conclusions: In this trial VGV was equivalent to GCV with regard to clearance of viremia at 28 days. VGV can be considered an alternative pre-emptive therapy for CMV viremia post-aHSCT in patients without evidence of grade III/IV GVHD of the gut.
RESULTS TOTAL VGV GCV p-value Median Time to viremia (days) 38 (16–98) 35 (20–56) 42 (16–98) 0.046 Median Time to initiation of Tx (days) 45 (27–100) 43 (27–80) 49 (29–100) 0.062 Median VL at d0 (copies/mL) 26191 (8964–244895) 44264 (8964–239400) 22948 (10480–244895) 0.35 Median VL at d14 (copies/mL) 5249 (0–497820) 5469 (0–345124) 2562 (0–497820) 0.83 Viremia cleared at day 14 15/37 (40.5%) 7/19 (36.8%) 8/18 (44.4%) 0.74 Viremia cleared at day 21 28/37 (75.7%) 14/19 (73.7%) 14/18 (77.8%) 1 Viremia cleared at day 28 32/37 (86.5%) 17/19 (89.5%) 15/18 (83.3%) 0.66 Recurrent viremia 9 4 5 0.71 Median Time to recurrence (days) 35 (15–54) 39.5 (30–42) 28 (15–54) 0.39
Background: Currently, High-Dose Chemotherapy (HDCT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in Multiple Myeloma (MM). This therapy improves overall and event-free survival, but is not curative, necessitating further therapies that will enhance and prolong remission duration. PTK787/ZK 222584 is a potent, orally available, angiogenesis inhibitor that blocks all known VEGF receptors in a dose-dependent fashion. Preclinical studies have demonstrated that PTK/ZK is able to inhibit tyrosine phosphorylation of VEGFR-1 in MM cells, as well as inhibit MM cell migration and proliferation. Based on this, a phase II study was designed to assess efficacy and tolerability of PTK/ZK as maintenance therapy for individuals treated HDCT and ASCT for MM.
Study Design: Patients with MM treated with HDCT and ASCT with persistent measurable paraproteinemia or persistent abnormal serum κ/λ ratio were selected for treatment with PTK/ZK. Primary endpoint is overall response rate and secondary endpoints are time to progression, disease free survival, and safety. Patients were initiated on 750mg daily of PTK/ZK, with doses escalated to 1250 mg daily.
Results: Nine patients have received PTK/ZK and their baseline characteristics are as follows: median number of days on PTK/ZK is 129 (range 3–252); median number of cycles administered is 5 (range 1–14); median age is 57 (range 38–71); stage IIIA (7), stage IIA (1), stage IA (1); IgG isotype (7), IgA isotype (2); median β2-microglobulin level was 1.7 (range 1.2–4.2). Of the nine patients who initially received PTK/ZK, four remain on the medication, three patients have stopped due to progressive disease, and two have stopped due to toxicities. One patient has demonstrated a PR (11%), three patients have SD, and three patients had PD. There have been no deaths. Toxicities are as follows: one patient developed grade 3 elevated ALT as well as motor and sensory neuropathy, one patient developed grade 3 neutropenia, and one patient developed grade 3 prolongation of the QTc interval. Two patients were withdrawn from the study due to toxicities, one with grade 3 prolongation of the QTc interval as well as grade 4 Hypertension, and one patient with grade 4 Hypertension alone. The remaining five patients have had no significant adverse drug events.
Conclusion: Continued patient accrual is underway for analysis of time to progression and disease free survival as well as overall response rate. Bone marrow samples are also being evaluated for change in microvessel density by immunohistochemistry with treatment.
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