Currently, the prognosis of Ph+ acute lymphoblastic leukemia (Ph+ ALL) patients relapsing after an allogenic hematopoietic stem cell transplantation (allo-SCT) remains poor, with few therapeutic ...options available. Here we present the case of a 32 years old patient with dasatinib-resistant post-transplant molecular relapse of ALL, who received, as second-line therapy, the combination of ponatinib and donor lymphocyte infusion (DLI). The therapy was safe and the patient achieved a sustained minimal residual disease negative disease, still ongoing after 22 months, which was accompanied by several changes in the immune populations distribution within the bone marrow (i.e., the increase in the CD8/CD4 lymphocytes ratio). Our report provides evidence of the efficacy of the third generation TKI inhibitor ponatinib in combination with DLI as second line therapy for Ph+ ALL relapsing after an allo-SCT.
Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication and main 5′-fluorouracil (5′-FU) target. TSPP/VAC1 is a multi-arm trial phase-Ib trial program aimed to investigate ...the toxicity and biomodulatory activity of a poly-epitope-peptide vaccine to TS (TSPP) in cancer patients (pts). Here, we present the results of the TSPP/VAC1/arm C trial aimed to evaluate TSPP in combination with chemo-immunotherapy in pretreated metastatic colo-rectal cancer (mCRC) pts. Twenty-nine pts, 14 males and 15 females, received poly-chemotherapy with gemcitabine GEM; 1,000 mg/sqm, day-1, oxaliplatin OX; 80 mg/sqm, day-2, levofolinate 100 mg/sqm, days 1-2, bolus/infusional 5′-FU 400 mg/800 mg/sqm, days 1-2, sargramostim 50 μg, days 3-7/q30, and interleukin-2 sc. 0.5 MIU twice a day, days 8-14/18-30 GOLFIG-regimen. Seventeen pts received sc. TSPP injections at escalating dosage 3 pts, 100 µg (DL-1); 3 pts, 200 µg (DL-2) and 11pts, 300 µg (DL-3) one week after each chemotherapy cycle (concomitant module), while 10 out 12 pts received TSPP (300 µg) after 12 GOLFIG courses dose level (DL)-0 (sequential module). TSPP MTD was not achieved. Adverse events consisted in swelling/erythema at injection sites (17 cases), G1-2 haematological (16 cases) and gastro-enteric events (12), fever, rhinitis, conjunctivitis, and poly-arthralgia and rise in auto-antibodies ANA, ENA, c-ANCA, p-ANCA in the DL1-3 pts. Both treatment-modules showed immunomodulating and antitumor activity (disease-control-rate, DL1-3 and DL0 were 70.6% and 83.3%, respectively) with a better survival recorded in the second group median OS DL1-3 vs. DL0 = 8 vs. 16 mo, p = 0.049. The promising long-term survival produced by the sequential treatment module deserves further phase II evaluation.
Cetuximab is a human-murine chimeric monoclonal antibody to the epidermal growth factor receptor, active for advanced colorectal cancer treatment in combination with chemotherapy. Cetuximab mainly ...acts by inhibiting epidermal growth factor receptor-mediated pathways in cancer cells; however, in the human host, its IgG1 backbone may offer additional antitumor activity that includes FcγRs-mediated antibody-dependent cell cytotoxicity, phagocytosis, cross priming, and tumor-specific T-cell-mediated immune response. These mechanisms are still under active investigation. At this purpose, we have performed an immunologic investigation in advanced colon cancer patients enrolled in an ongoing phase II trial aimed to test the toxicity and the biological and antitumor activity of a novel biochemotherapy regimen combining polychemotherapy with gemcitabine, irinotecan, levofolinic acid, and fluorouracil with cetuximab and with subcutaneous low-dose metronomic aldesleukin (GILFICet regimen). The peripheral blood mononuclear cells of the first 20 patients enrolled in the GILFICet trial were collected at baseline and after 6 treatment cycles and examined for immune-phenotype change by flow cytometry. Colon cancer-specific T-cell lines were also generated ex vivo from these samples and subsequently characterized for immune phenotype, functional activity, and antigen specificity. We found a treatment-related increase of circulating dendritic cells, natural killer cells, central memory T cells, and activated T cells with a T-helper 1 (Th1)-cytotoxic phenotype. In addition, the ex-vivo characterization of antigen-specific T cells derived from the treated patients revealed a significant increase in proliferating cytotoxic T-lymphocyte precursors specific for carcinoembryonic antigen and thymidylate synthase derivative epitope peptides. On these basis, we concluded that the GILFICet regimen exerts substantial immune-modulating activity that significantly affects tumor antigen-specific T-cell compartment with potential antitumor activity.
Polycaprolactone (PCL) is a biocompatible and biodegradable polymer widely used for the realization of 3D scaffold for tissue engineering applications. The hot embossing technique (HE) allows the ...obtainment of PCL scaffolds with a regular array of micro pillars on their surface. The main drawback affecting this kind of micro fabrication process is that such structural superficial details can be damaged when detaching the replica from the mold. Therefore, the present study has focused on the optimization of the HE processes through the development of an analytical model for the prediction of the demolding force as a function of temperature. This model allowed calculating the minimum demolding force to obtain regular micropillars without defects. We demonstrated that the results obtained by the analytical model agree with the experimental data. To address the importance of controlling accurately the fabricated microstructures, we seeded on the PCL scaffolds human stromal cell line (HS-5) and monocytic leukemia cell line (THP-1) to evaluate how the presence of regular or deformed pillars affect cells viability.
viability results, scanning electron and fluorescence microscope imaging analysis show that the HS-5 preferentially grows on regular microstructured surfaces, while the THP-1 on irregular microstructured ones.
Bevacizumab, is a humanized monoclonal antibody to vasculo-endothelial-growth-factor, with anticancer activity in non-small-cell-lung cancer (NSCLC) patients. Our previous results from a dose/finding ...phase I trial in NSCLC patients, demonstrated the anti-angiogenic effects and toxicity of a newest bevacizumab-based combination with fractioned cisplatin and daily oral etoposide. We designed a phase II trial to evaluate in advanced NSCLC patients the antitumor activity and the safety of this novel regimen. In particular, 45 patients (36 males and 9 females), with a mean age of 54 years, an ECOG ≤ 2, stage IIIB/IV and NSCLC (28 adenocarcinomas, 11 squamous-cell carcinomas, 2 large-cell carcinomas, 4 undifferentiated carcinomas), were enrolled. They received cisplatin (30 mg/sqm, days 1-3), oral etoposide (50 mg, days 1-15) and bevacizumab (5 mg/kg, day 3) every three weeks (mPEBev regimen). Patients who achieved an objective response or stable disease received maintenance treatment with bevacizumab in combination with erlotinib until progression. Grade I-II hematological, mucosal toxicity and alopecia were the most common adverse events. The occurrence of infections (17%), thromboembolic events (4.4%) and severe mood depression (6.7%) was also recorded. A partial response was achieved in 31 (68.8%) patients, disease remained stable in 8 (17.8%), and disease progressed in 6 (13.3%) with a progression-free-survival of 9.53 months (95%CI, 7.7-11.46). Our bio-chemotherapy regimen resulted very active in advanced NSCLC, however, the toxicity associated with the treatment requires strict selection of the patients to enroll in future studies.
The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of ...tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall survival.
Abstract
Background and Aims
Immunoglobulin light-chain (AL)amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the kidneys. New therapeutic ...strategies with bortezomib and lenalidomide have improved the prognosis. The aim of our study was to evaluate the long term efficacy of therapeutic protocol utilizing bortezomib in induction and in conditioning with lenalidomide for PRR (partial renal response) AL renal Amyloidosis transplant-ineligible patients.
Method
This is a prospective analysis of 16 transplant-ineligible patients with histological diagnosis of renal amyloidosis admitted to our Nephrology Department from 01/2010 to 01/10/2020. All patients have overt nephrotic syndrome at the diagnosis. Two/thirds of them have renal failure. The diagnosis of amyloid is based on the kidney biopsy finding, by light microscopic examination, of amorphous extracellular Congo red positive deposits, which display characteristic dichroism and apple green birefringence under polarised light. Bortezomib-based (BD) regimen is used (Bortezomib 1.3mg/m2 subcutaneously; Cyclophosphamide 200mg/m2 and Dexamethasone 40mg) for 9 cycles. Hematological and organ response were evaluated according to the novel criteria of the International Society of Amyloidosis. The patients with partial renal response (PRR: decreased of 24 hour urine protein and serum creatinine > 50% over baseline) were treated with cycles of Lenalidomide (dose adjustments for renal function, orally on days 1 trough 21 of each 28-days cycle) in combination with dexamethasone and prophylactic anti-thrombotic treatment.
Results
The mean age was 63±7 years and 7/16 (43.7%) were males. By immunohistochemistry the protein composition of the amyloid deposits was FLC k in 6/16 and FLC lambda in 10/16. Periombelical fat aspirate was positive in 5 patients (31.2%). At onset the mean proteinuria was 13.1 ± 3.6 gr/24h with average MDRD of 37.2 ml/min (III stage CKD), average pro-BNP 420.1 and SIV 12.5 mm. At onset three patients (18.7%) had confirmed multiple myeloma (Clone of plasma cells proliferation > 30% in the bone marrow). 3/16 patients died for cardiac arrhythmia at 3 and 4 months after CyBorD cycles initiation. Therefore CyBorD regimen was completed in 13/16 patients. After 9 CyBorD cycles: 3/13 patients showed a complete renal response (CRR: MDRD > 90 ml/min, proteinuria/24h< 300 mg) and CHR (normal serum FLC ratio); 10/13(76.9%) showed a PRR and PHR (dFLC decrease >50% compared to baseline), one patient died for Sepsis, All patients with CRR or PRR showed a complete cardiological response (normal BNP and SIV). Adverse events during therapy: HZV nevralgy in 3. The 9 patients in PRR were treated with Lenalidomide. After median 6 treatment cycles 7/9 (77.7%) patients showed a CRR and CHR. Haemodialysis was started in 2/9 (22.2%) patients. We decided to discontinue the therapy for adverse events in 3 patients: breast cancer in one, transient troponin I increase and angina in an other patient, pneumonia events in one. The pneumoniae infectious and anginal episodes regressed with drug discontinuation. Median follow-up time from diagnosis of Renal Amyloidosis was 46 months. Median follow-up from the start of Lenalidomide was 36 months. One patients died for breast cancer, but in CRR. All the others patients with CRR (9/13, 69.2%), including the two who suspended Lenalidomide for its toxic effects have been in remission for 30 months on average.
Conclusion
We conclude the following Lenalidomide therapy is very effective at increasing the number of CRR. In addition, the two treatment regimens (induction therapy with CyBorD and conditioning with Lenalidomide) kept patients in remission for more than 30 months on average. Further studies on larger samples are needed to validate the data.
A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic ...abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies.
Abstract Background Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Gemcitabine is the mainstay treatment for advanced disease. However, almost all up-to-date trials, ...that evaluated the benefit of gemcitabine-combination schedules, failed to demonstrate an improvement in overall survival (OS). In this study, we performed a systematic review and a meta-analysis of randomised clinical trials (RCTs) to investigate the efficacy and safety of gemcitabine-based combination regimens as compared to gemcitabine alone in the management of pancreatic cancer. Methods Clinical trials were collected by searching different databases (PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library) and abstracts from major cancer meetings. We considered period ranging from January 1997 to January 2012. Primary end-point was OS, secondary end-points were response rate (RR), disease control rate (DCR) and safety. Hazard ratios (HRs) of OS, odds-ratios (ORs) of RR, DCR and risk ratios of grade 3–4 toxicity rates (TRs), were extracted as presented in retrieved studies and used for statistical analysis. Meta-analytic estimates were derived using random-effects model. Findings Thirty-four trials for a total of 10,660 patients were selected and included in the final analysis. The analysis showed that combination chemotherapy confers benefit in terms of OS (HR: 0.93; 95% confidence interval (CI): 0.89–0.97; p = 0.001). ORs for both RR and DCR demonstrated a significant advantage for combination therapy (OR for RR: 0.60, 95%CI: 0.47–0.76, p < 0.001; OR for DCR: 0.79; 95%CI: 0.66–0.93; p = 0.006). Toxicities were more frequent with the combination treatment and significance in terms of risk ratio was reached for diarrhoea (0.53, 95%CI: 0.36–0.79), nausea (0.74, 95%CI: 0.56–0.96), neutropenia (0.71, 95%CI: 0.59–0.85) and thrombocytopenia (0.57, 95%CI: 0.43–0.75). Interpretation The combination chemotherapy as compared to gemcitabine alone significantly improves OS in advanced pancreatic cancer (APC). However, this advantage is marginal whereas the treatment-related toxicity is increased, suggesting the use of gemcitabine-based combination regimens only in selected patient populations. New prospective trials, based on translational approaches and innovative validated biomarkers, are eagerly awaited on this topic.
Myeloproliferative neoplasms (MPN) are traditionally regarded as a disease of older adults, though a not negligible fraction of cases occurs at a younger age, including women of childbearing ...potential.
MPN in younger patients, indeed, offer several challenges for the clinical hematologist, that goes from difficulties in reaching a timely and accurate diagnosis to a peculiar thrombotic risk, with a relatively high incidence of thromboses in unusual sites (as the splanchnic veins or the cerebral ones). Moreover, the issue of pregnancy is recently gaining more attention as maternal age is rising and molecular screening are widely implemented, leading to a better recognition of these cases, both before and during pregnancy.
In the present work we aim at discussing four clinical topic that we identified as areas of uncertainty or true unmet medical needs in the management of younger patients with MPN, with a particular focus on the topic of pregnancy. For each of these topics, we critically reviewed the available evidence that support treatment decisions, though acknowledging that recommendations in this field are mostly based on expert opinion or derived from guidelines of other clinical conditions that share with MPN a high vascular risk, as antiphospholipid syndrome.
Taking into consideration both the lack of evidence-based data and the clinical heterogeneity of MPN, we support an individualized strategy of counseling and management for both young patients and for expectant mother with MPN.
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