Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin.

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.

Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a.

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML.

The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia.

INTRODUCTION: FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research. AREAS COVERED: This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy. EXPERT OPINION: In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.

Combined Oral Fentanyl Citrate and Midazolam as Premedication for Bone Marrow Aspiration and Biopsy in Patients with Hematological Malignancies: A Randomized, Controlled and Patient-Blinded Clinical Trial.

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 µg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0-10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested.

Axitinib in Ponatinib-Resistant B-Cell Acute Lymphoblastic Leukemia Harboring a T315L Mutation.

Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs.

Prognostic role of serum concentrations of high-sensitivity C-reactive protein in patients with metastatic colorectal cancer: results from the ITACa trial.

Serum levels of C-reactive protein are (CRP) higher in patients with neoplastic conditions and numerous studies have been performed to clarify the etiologic and prognostic role of the high-sensitivity CRP (hs-CRP) in cancer. Our study was conducted on patients enrolled in the prospective randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" to assess hs-CRP levels and their impact on overall survival (OS) and progression-free survival (PFS). Serum samples from 132 ITACa patients were collected at baseline and 2 months after starting first-line chemotherapy. The supernatant was immediately transferred to cryovials and stored at -80°C. After thawing, hs-CRP was measured with the Cobas c501 analyzer. High levels of hs-CRP (≥ 13.1 mg/L) were associated with poorer median PFS (p < 0.0001) and OS (p < 0.0001) than low hs-CRP levels (< 13.1 mg/L). hs-CRP values in 107 patients were evaluated again after 2 months of therapy, revealing that patients with low hs-CRP levels in both baseline and second serum samples had the best median PFS and OS. Our study confirms the prognostic value of hs-CRP in patients with metastatic colorectal carcinoma.

IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified. METHODS: T cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student's t tests and confirmed with the non parametric Wilcoxon signed-rank test. RESULTS: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients. CONCLUSIONS: In AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

Romiplostim as early treatment of immune thrombocytopenia with severe immunodeficiency.

Immunosuppressive agents are the standard therapeutic approach for immune thrombocy-topenia (ITP). Their prolonged use may increase the risk of infectious complications, particularly when the patient is already at higher infectious risk. In this setting, the use of drugs with a mechanism of action alternative to immunosuppression, like thrombopoietin receptor agonists (TRAs), may find particular indication. We report the unique case of a patient with severe immunodeficiency and ITP, who experienced a serious infectious complication while on steroids treatment, and who was successfully treated with Romiplostim second-line. The present experience supports the effectiveness and safety of TRAs as early treatment of ITP patients with drug-induced immunodeficiency or with active infections.

Prolonged 18FDG-PET negative complete remission in a heavily pretreated, elderly patient with diffuse large B cell lymphoma treated with lenalidomide, low dose dexamethasone, and colony stimulating factor (Rd-G).

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoid malignancy among adults in the developed world and accounts for about a third of all patients newly diagnosed with non-Hodgkin lymphoma each year. The prognosis of patients with DLBCL has improved over the past 10 years since the advent of chemoimmunotherapy regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). However, a significant number of patients still experience disease relapse or progression after first or second line therapy, and ~40% of patients will die within 5 years. In particular, elderly patients and those ineligible for high-dose chemotherapy due to comorbidities require effective salvage treatment options with favorable toxicity profile. Several novel therapeutic approaches have been proposed for these patients including monoclonal antibodies, radioimmunotherapy, proteasome inhibitors, mTOR inhibitors, and the immunomodulatory drugs such as thalidomide and lenalidomide.

Successful treatment of multi-resistant Pseudomonas aeruginosa osteomyelitis after allogeneic bone marrow transplantation with a combination of colistin and tigecycline.

A case of osteomyelitis caused by multidrug-resistant Pseudomonas aeruginosa is reported in a patient who underwent allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. The patient was successfully treated by prolonged administration of a full dose of colistin and tigecycline, and surgical curettage with the positioning of resorbable calcium sulfate pellets loaded with colistin.

Resolution of a Pseudomonas aeruginosa outbreak in a hematology unit with the use of disposable sterile water filters.

We observed a significant increase of Pseudomonas aeruginosa bacteremias during 2002. Eighty-five microbiological samples were taken from different potential sources of infection. Twenty-nine out of 46 specimens obtained from water taps, shower heads and siphons tested positive for Pseudomonas aeruginosa. Weekly pharyngeal and rectal swabs in high risk patients, use of tap water after running the tap for at least 5 minutes and use of weekly disposable sterile filters in all taps and showers resulted in a significant decrease in Pseudomonas aeruginosa bacteremias. Moreover, we observed a significant reduction in Pseudomonas aeruginosa-positive surveillance cultures after implementation of these measures.