Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogene sis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient's quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible biological pathways underlying neurotoxicity.
Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first “target therapy” to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a ‘repurposed drug’ that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.
Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.
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