Cyclophosphamide remains one of the most successful and widely utilized antineoplastic drugs. Moreover, it is also a potent immunosuppressive agent and the most commonly used drug in blood and marrow transplantation (BMT). It was initially synthesized to selectively target cancer cells, although the hypothesized mechanism of tumor specificity (activation by cancer cell phosphamidases) transpired to be irrelevant to its activity. Nevertheless, cyclophosphamide's unique metabolism and inactivation by aldehyde dehydrogenase is responsible for its distinct cytotoxic properties. Differential cellular expression of aldehyde dehydrogenase has an effect on the anticancer therapeutic index and immunosuppressive properties of cyclophosphamide. This Review highlights the chemistry, pharmacology, clinical toxic effects and current clinical applications of cyclophosphamide in cancer and autoimmune disorders. We also discuss the development of high-dose cyclophosphamide for BMT and the treatment of autoimmune diseases.

Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and anti-metastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.

Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolytic pathway. Elevated LDH is a negative prognostic biomarker not only because it is a key enzyme involved in cancer metabolism, but also because it allows neoplastic cells to suppress and evade the immune system by altering the tumor microenvironment. LDH-A alters the tumor microenvironment via increased production of lactate. This leads to enhancement of immune-suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells (DCs); and inhibition of cytolytic cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). By promoting immune-suppression in the tumor microenvironment, LDH-A is able to promote resistance to chemo/radio/targeted therapy. Here we discuss the evidence that LDH is both a metabolic and an immune surveillance prognostic biomarker and its elevation is harbinger of negative outcome in both solid and hematologic neoplasms.

Over the last 17 years, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (As 2 O 3 ) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, the role of As 2 O 3 in front-line therapy is under investigation. Recent trials in the US have demonstrated that the addition of As 2 O 3 to standard treatment regimens improves survival outcomes in patients with APL and may allow a reduction in cytotoxic chemotherapy exposure. As 2 O 3 has also shown efficacy in other malignancies, particularly multiple myeloma and myelodysplastic syndromes. Therapeutic doses of As 2 O 3 are well tolerated, with no evidence of long-term toxicity. Adverse events include APL differentiation syndrome, electrocardiographic abnormalities, and mild elevations in liver enzymes. This review highlights trials investigating the role of As 2 O 3 in induction and consolidation for newly diagnosed APL, as well as its role in other hematologic malignancies. The chemistry, mechanisms of action, and clinical side effects of As 2 O 3 are also discussed.