A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.

PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.

Herpes simplex encephalitis as a complication of whole-brain radiotherapy: a case report and review of the literature.

A 55-year-old male recently diagnosed with stage IV lung adenocarcinoma presented with altered mental status approximately 1 week after the completion of 14 fractions of whole-brain radiotherapy (WBRT) for brain metastases. On admission, he was somnolent but oriented and without focal neurological deficits. Brain imaging revealed marked regression of his brain metastases. Laboratory values were only significant for hyponatremia with urine hyperosmolality consistent with syndrome of inappropriate antidiuretic hormone secretion. The patient developed seizures 3 days after admission, at which time cerebrospinal fluid was significant for positive herpes simplex virus (HSV)-1 PCR but with a negative cell count, and acyclovir was started for HSV encephalitis (HSE). After 3 weeks of acyclovir 10 mg/dl i.v. 3 times per day, he had significant neurological recovery and was discharged. Although HSE is a relatively rare condition, it is the most common cause of sporadic encephalitis in Western countries. Since the pathogenesis is believed to be due to the reactivation of latent HSV, it is possible that patients who are immunosuppressed are at higher risk for HSE. In addition, patients who are immunosuppressed or immunocompromised often present atypically, which may delay time to diagnosis and treatment, thus significantly worsening prognosis. This case report intends to raise awareness of this severe condition in the context of patients who have received WBRT and immunosuppressive therapy. In addition, important considerations of diagnosis and treatment of HSE in this patient population are discussed.

Attenuating homologous recombination stimulates an AID-induced antileukemic effect.

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population.