Emerging small molecular inhibitors as targeted therapies for high-risk acute myeloid leukemias.

INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive disease which has traditionally been treated with intensive chemotherapy. Survival in patients with high-risk cytogenetic and molecular subsets has been poor with this approach due to suboptimal responses seen with intensive chemotherapy and due to many patients with higher risk disease being older and unable to tolerate intensive therapies. In recent years, several targeted therapies have been under investigation for patients with high-risk AML subsets. AREAS COVERED: This review covers four different subsets of high-risk AML including TP53-mutated, KMT2A-rearranged, FLT3-mutated, and secondary AML developing after prior hypomethylating agent exposure. The research discussed in this review focuses on small molecule inhibitors that have been studied in the treatment of these high-risk AML subsets. EXPERT OPINION: There are several small molecule inhibitors that have demonstrated promise in these high-risk AML subsets. Longer follow-up and ongoing investigation are needed to continue to optimize therapy for patients with high-risk AML.

Small-cell breast carcinoma with response to atezolizumab: a case report.

Background: Small-cell carcinoma of the breast is a rare disease with little research outlining molecular targets or optimal therapeutic management. We summarize a young female patient with poorly differentiated high-grade carcinoma with neuroendocrine features/small-cell carcinoma. Case presentation: A 31-year-old female presented with a large left breast mass. Initial biopsy revealed small-cell, triple-negative breast carcinoma. Treatment consisted of cisplatin and etoposide but was poorly tolerated and discontinued after one cycle. Combination abraxane/atezolizumab resulted in transient partial response in tumor size with 7 months of progression-free stability. Worsening metastatic disease was found 8 months after initial biopsy on radiologic studies and the patient expired 10 months after initial biopsy. Conclusion: Transient benefit in response to combination abraxane/atezolizumab was demonstrated.

Immunotherapy is an emerging area in cancer research which utilizes the body's immune system to target cancerous cells. This offers oncologists an effective alternative to standard chemotherapy options, which often have significant side effects. Additionally, biomarkers including PD-L1 positivity to predict response to immunotherapy are currently under investigation. The patient presented with a rare type of aggressive breast cancer that previously had few treatment options. This report demonstrates the use of biomarker assessment (PD-L1) to predict immunotherapy response. The patient responded well to immunotherapy, and radiologic scans demonstrated tumor reduction. Further research into this field has the implication to improve treatments, decrease side effects of chemotherapy and improve patient outcomes for many cancers.

Relationship of hypothyroidism and immune response to pegylated IL-10/nivolumab.

Aim: We describe a case of an advanced disease non-small-cell lung cancer patient with low PD-L1 expression, but high tumor mutation burden (35 muts/Mb) who developed immune-related hypothyroidism and achieved subsequent partial response, while on clinical trial (NCT03382912) with nivolumab and PEGylated IL-10 (Pegilodecakin, ARMO BioSciences/Eli Lilly and Company, IN, USA). Results/conclusion: Results suggest positive antitumor activity to combination IL-10/nivolumab despite low PD-L1 expression but in likely relationship to high tumor mutation burden and in association with immune-mediated thyroid dysfunction in this case.

HER2-positive metastatic cervical cancer responsive to first and second-line treatment: A case report.

Cervical cancer is the fourth most common malignant disease among women, with metastatic disease having a dismal survival rate compared to localized disease when using standard combination chemotherapy. Next-generation sequencing (NGS) of tumors has allowed for targeted treatments of cancers in patients who have progressed on first-line therapy. We present a case of a 46 year-old female with advanced cervical adenocarcinoma and metastatic recurrence in the lungs found to have HER2 mutation who underwent first and second-line HER2-targeted therapy with sustained disease response. We review the standard of care for advanced cervical cancer, toxicity profiles of chemotherapy and immunotherapy that were employed, the economics of NGS and targeted treatment, and future directions for HER2-targeted therapy. This case report highlights a patient with metastatic cervical cancer responsive to first and second-line HER2-targeted therapy.

Bifidobacterium spp: the promising Trojan Horse in the era of precision oncology.

Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.

Natural killer cells: a review of biology, therapeutic potential and challenges in treatment of solid tumors.

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.

Interleukin 10-Mediated Response and Correlated Anemia in a Patient with Advanced Non-Small Cell Lung Carcinoma.

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response.

Case series of unique adverse events related to the use of ibrutinib in patients with B-cell malignancies-A single institution experience and a review of literature.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor has reformed the treatment of various B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although generally well tolerated, here we describe our institutional experience of unique adverse effects encountered with the use of ibrutinib in patients with B-cell lymphomas. METHODS: This is a retrospective observational study done at a tertiary care facility, to evaluate adverse events in patients with B-cell malignancies on treatment with ibrutinib between 2014 and 2018. Further details including type of malignancy, cytogenetics, interventions for treatment of the side effect, and outcomes were obtained through electronic health record. CASE SERIES: We found 10 patients with unique adverse events related to ibrutinib. Among those, six had chronic lymphocytic leukemia, two had Waldenstrom's macroglobulinemia, and two had mantle cell lymphoma. The events included palindromic rheumatoid arthritis, diffuse spongiotic dermatitis, bullous pemphigoid, recurrent hemorrhagic stroke, peripheral neuropathy, recurrent paronychia, intramedullary fibrosis, recurrent joint pains, pulmonary aspergillosis, dyspnea with exacerbation of atrial fibrillation, and resolution of autoimmune hemolytic anemia. CONCLUSION: Our case series illustrates the wide variety of unique events recognized in patients treated with ibrutinib, some of which required cessation and most had dose reduction of the treatment. Thus, stressing the importance of early identification and intervention for the events to avoid worsening of toxicity and inability to continue treatment in such patients.

Cerebral aspergillosis in a patient on ibrutinib therapy-A predisposition not to overlook.

Ibrutinib has revolutionized the treatment of B-cell malignancies since its approval for chronic lymphocytic leukemia. It is also used in mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom's macroglobulinemia, among others. It is a Bruton's tyrosine kinase inhibitor that acts on B-cell receptor signaling pathway and predisposes to various infections due to its effects on neutrophils, monocytes and T cells. We present a case of cerebral invasive aspergillosis in a patient being treated with ibrutinib for relapsed chronic lymphocytic leukemia. It was hard to associate the condition to ibrutinib versus the chronic lymphocytic leukemia. The patient was successfully treated with a combination of voriconazole and micafungin, resulting in complete recovery and no residual deficits. This highlights the importance of recognizing the rare complication in those on ibrutinib and initiating the treatment immediately with appropriate antifungal agents to improve prognosis of this potentially fatal condition.

A case of autoimmune haemolytic anaemia after 39 cycles of nivolumab.

With growing use of nivolumab, rare but serious side effects have surfaced in some patients. We present a case of autoimmune haemolytic anaemia that developed after 39 cycles of nivolumab. A 78-year-old man with metastatic lung adenocarcinoma, refractory to multiple lines of chemotherapy was switched to nivolumab. After around 2 years of stable course on nivolumab, he developed transfusion-dependent anaemia with haemoglobin of 8.6 g/dL. Nivolumab was held immediately. Bone marrow biopsy findings were inconclusive of myelodysplastic syndrome. Further testing was suggestive of haemolysis with haptoglobin <10 mg/dL, elevated reticulocyte count and identification of immunoglobulin G antibody. Haemoglobin improved significantly with initiation of 1 mg/kg prednisone in addition to rituximab weekly × four doses. The development of transfusion-dependent anaemia with the exposure to cytotoxic chemotherapy usually raises the question for myelodysplastic syndrome. In contradiction, our patient was diagnosed to have a haematological autoimmune complication related to immunotherapy.