Publications by authors named "Claudio Cerchione"

71 Publications

Urinary Biomarkers in Tumors: An Overview.

Methods Mol Biol 2021 ;2292:3-15

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Recent reports suggest that urine is a useful noninvasive tool for the identification of urogenital tumors, including bladder, prostate, kidney, and other nonurological cancers. As a liquid biopsy, urine represents an important source for the improvement of new promising biomarkers, a suitable tool to identify indolent cancer and avoid overtreatment. Urine is enriched with DNAs, RNAs, proteins, circulating tumor cells, exosomes, and other small molecules which can be detected with several diagnostic methodologies.We provide an overview of the ongoing state of urinary biomarkers underlying both their potential utilities to improve cancer prognosis, diagnosis, and therapeutic strategy and their limitations.
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http://dx.doi.org/10.1007/978-1-0716-1354-2_1DOI Listing
January 2021

Beyond Andromeda: Improving Therapy for Light Chain Amyloidosis.

Front Oncol 2020 3;10:624573. Epub 2021 Feb 3.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Therapy for light chain amyloidosis (AL) continues to evolve, and a new standard of care for the disease is rapidly forming. The risk of early death however, mainly from cardiac complications, remains an important benchmark yet to be definitively improved upon. This brief review explores recent advances in plasma cell directed therapy for AL, highlighting unique factors specific to these patients and AL biology driving differences in treatment strategies and clinical development compared with multiple myeloma. Improving upon proteasome inhibitor based upfront therapy combinations with the addition of anti-CD38 antibodies has shown promise with improved response rates in the ANDROMEDA (NCT03201965) study. Though depth and kinetics of achieving deep hematologic response as well as rates of biomarker defined organ response were improved with the addition of daratumumab to the combination of bortezomib, cyclophosphamide, and dexamethasone, death rates in each arm remained similar. Evaluation of other targeted and novel therapies in AL is ongoing, and we highlight efforts evaluating B-cell maturation antigen (BCMA) directed therapy, BCL-2 family inhibitors, and other novel agents in the field. We also look ahead to efforts to reimagine the clinical development of anti-fibrillar therapies after late phase study failures. Upcoming anti-amyloid fibril antibody studies explore opportunities to improve outcomes for the sickest AL patients with advanced cardiac disease, focusing on improving overall patient survival and reducing the risk of early death in this uniquely frail population.
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http://dx.doi.org/10.3389/fonc.2020.624573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888257PMC
February 2021

Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia.

PLoS One 2021 16;16(2):e0247093. Epub 2021 Feb 16.

Health Research Institute of Santiago de Compostela (IDIS), Santiago, Spain.

Background: FLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs.

Methods: We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test.

Results: A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants.

Conclusions: We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247093PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886212PMC
February 2021

PET/CT in Multiple Myeloma: Beyond FDG.

Front Oncol 2020 25;10:622501. Epub 2021 Jan 25.

Hematology Unit, Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST) IRCCS, Meldola, Italy.

Recent advances in the diagnosis and treatment of multiple myeloma (MM) have highlighted the importance of imaging methods, not only in the localization and extent of the disease but also in prognostic stratification and assessment of response to therapy. In this context, PET/CT, combining both morphological and functional information, is particularly useful in this pathology. The tracer mostly used is 18F-FDG, a glucose analog, which provides extremely accurate information with a sensitivity ranging from 80 to 100%. However, this tracer has some limitations, mostly related to the physiological uptake of FDG in the bone marrow and brain, which reduce its effectiveness. For this reason, some studies in the literature have evaluated the effectiveness of other PET tracers, which provide information on protein metabolism or the synthesis of metabolic plasma membranes, such as choline and methionine, as well as innovative radiopharmaceuticals, directed against receptors expressed by cells of myeloma, including tracers directed to the chemokine receptor. This review analyzes the characteristics and accuracy of non-FDG tracers in the management of patients with multiple myeloma.
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http://dx.doi.org/10.3389/fonc.2020.622501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868556PMC
January 2021

The molecular pathogenesis of multiple myeloma.

Hematol Rep 2020 Dec 18;12(3):9054. Epub 2020 Dec 18.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Multiple Myeloma (MM) is characterized by uncontrolled proliferation and accumulation of clonal plasma cells within the bone marrow. However, the cell of origin is a B-lymphocyte acquiring aberrant genomic events in the germinal center of a lymph node as off-target events during somatichypermutation and class-switch recombination driven by activation-induced-deaminase. Whether pre-germinal center events are also required for transformation, and which additional events are required for disease progression is still matter of debate. As early treatment in asymptomatic phases is gaining traction in the clinic, a better understanding of the molecular pathogenesis of myeloma progression would allow stratification of patients based on their risk of progression, thus rationalizing efficacy and cost of clinical interventions. In this review, we will discuss the development of MM, from the cell of origin through asymptomatic stages such as monoclonal gammopathy of undetermined significance and smoldering MM, to the development of symptomatic disease. We will explain the genetic heterogeneity of MM, one of the major drivers of disease recurrence. In this context, moreover, we will propose how this knowledge may influence future diagnostic and therapeutic interventions.
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http://dx.doi.org/10.4081/hr.2020.9054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772755PMC
December 2020

Hydroxychloroquine as Prophylaxis for COVID-19: A Review.

Front Pharmacol 2020 3;11:605185. Epub 2020 Dec 3.

Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy.

The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.605185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744418PMC
December 2020

Novel Insights in Anti-CD38 Therapy Based on CD38-Receptor Expression and Function: The Multiple Myeloma Model.

Cells 2020 12 11;9(12). Epub 2020 Dec 11.

Hematology Unit and Romagna Transplant Network, Ravenna Hospital, 48121 Ravenna, Italy.

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look atCD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.
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http://dx.doi.org/10.3390/cells9122666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764337PMC
December 2020

Radiology imaging management in an Italian cancer center (IRST IRCCS) during the COVID-19 pandemic.

Insights Imaging 2020 Dec 3;11(1):129. Epub 2020 Dec 3.

Radiology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

In Italy, the first case of the coronavirus disease 2019 (COVID-19) was officially reported on 20.02.2020. The disease has since rapidly evolved, causing a public health emergency throughout the country but especially in our region, one of the most widely affected areas. We reorganized the daily routine of our cancer center to reduce the risk of contagion. A temporary tensile structure was set up as an entry-point triage, and a COVID-19 route was created with a dedicated CT scanner. A pre-access telephonic triage was performed the day before a patient was scheduled to come in for an examination. At the time of writing (May 4), 4053 patients had been to our center since the emergency officially began (9.03.2020) and the COVID-19 route had been activated for only 9 paucisymptomatic outpatients and 7 symptomatic inpatients. We also re-evaluated patient radiology examination lists and rescheduled non-urgent tests in consensus with the referring oncologist. Out of a total of 1438 patients scheduled for radiological examinations, 456 were postponed for a total volume reduction of 29.1%. Nine asymptomatic patients with typical CT findings of COVID-19 were identified during routine CTs, but none were RT-PCR-positive for SARS-CoV-2. We guaranteed all urgent and semi-urgent examinations, including those to stage newly diagnosed cancers and to evaluate response to treatment, ensuring the continuation of the diagnostic and therapeutic pathway of our patients. The measures we took were instrumental in keeping the institute COVID-19-free. We also describe the planned measures to resume normal clinical practice at the center.
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http://dx.doi.org/10.1186/s13244-020-00935-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711054PMC
December 2020

Multiple Myeloma Outpatient Transplant Program in the Era of Novel Agents: State-of-the-Art.

Front Oncol 2020 11;10:592487. Epub 2020 Nov 11.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Multiple myeloma (MM) is the most common indication for autologous stem cell transplantation (ASCT), and outpatient models have been widely developed in this setting. Although numerous studies have demonstrated the safety and feasibility of outpatient ASCT, it is not a routine procedure. Stringent guidelines for patient selection and clinical management, including functional status, caregiver support, and psychological aspects, are essential to identify eligible patients. However, there is still no general agreement on these criteria. Quality of life data are limited and contradictory. There is considerable variability in outpatient transplant models, and there are no randomised studies supporting the use of one over the other. Studies evaluating results in terms of long-term survival, transplant toxicity in comparison with a standard approach are lacking. The procedure is cost-effective within the context of a hospital budget, but an in-depth analysis of the real cost of these programmes has yet to be performed.
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http://dx.doi.org/10.3389/fonc.2020.592487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686536PMC
November 2020

Correspondence in reference to previously published manuscript: "Faouzi Djebbari et al. Efficacy and infection morbidity of front-line immuno-chemotherapy in follicular lymphoma. Eur J Haematol. 2020; 105: 667-671".

Eur J Haematol 2020 Nov 30. Epub 2020 Nov 30.

Department of Clinical Medicine and Surgery, Hematology Unit, Federico II University Medical School, Naples, Italy.

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http://dx.doi.org/10.1111/ejh.13558DOI Listing
November 2020

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients.

Cell Transplant 2020 Jan-Dec;29:963689720968749

Department of Clinical and Experimental oncology and hematology, Biosciences Laboratory, 124882Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2.Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein.The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%.The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients.Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19.
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http://dx.doi.org/10.1177/0963689720968749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593730PMC
November 2020

How I manage frontline transplant-ineligible multiple myeloma.

Hematol Rep 2020 Sep 21;12(Suppl 1):8956. Epub 2020 Sep 21.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.

The Multiple Myeloma (MM) is a plasma cells hematological malignancy with a median age of 69 years at diagnosis. The autologous stem cell transplantation is the standard of care for this disease but less than half of newly diagnosed patients are assessed for this treatment due to comorbidities or complications of disease. The management of transplant ineligible MM patients is based on the balance safety and efficacy of the new available regimen and a careful assessment of the frailty status is mandatory to define the goals. In this review we discuss of the clinical dilemmas in the management and define how to manage them based on the evidence from clinical trials and "real life" experience.
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http://dx.doi.org/10.4081/hr.2020.8956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520858PMC
September 2020

How I treat relapsed and/or refractory multiple myeloma.

Hematol Rep 2020 Sep 21;12(Suppl 1):8955. Epub 2020 Sep 21.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti- CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.
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http://dx.doi.org/10.4081/hr.2020.8955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520845PMC
September 2020

How I manage frontline transplant-eligible multiple myeloma in Italy.

Hematol Rep 2020 Sep 21;12(Suppl 1):8954. Epub 2020 Sep 21.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.

The treatment of transplant-eligible multiple myeloma patients in Italy consists in an induction phase based on bortezomib plus thalidomide plus dexamethasone (VTd), followed by a single or tandem autologous stem cell transplantation (ASCT), followed by lenalidomide maintenance. This approach offers an overall response rate of 93% and a CR rate of 58% with acceptable toxicity. Lenalidomide maintenance adds a significant increase in disease control, with a progression free survival after ASCT of 53 months, and an overall survival of 86 months. Second primary malignancies represent the most concerning toxicity of lenalidomide maintenance with a 6.9% incidence. However, the benefit in terms of increased myeloma control largely outweigh this complication. The incorporation of daratumumab in this treatment schema will further improve these clinical results.
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http://dx.doi.org/10.4081/hr.2020.8954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520856PMC
September 2020

How we manage smoldering multiple myeloma.

Hematol Rep 2020 Sep 21;12(Suppl 1):8951. Epub 2020 Sep 21.

Dipartimento di Chirurgia e Specialità Medico-Chirurgiche, Sezione di Ematologia, Università degli Studi di Catania.

Smoldering myeloma (SMM) is an asymptomatic stage characterized by bone marrow plasma cells infiltration between 10-60% in absence of myeloma-defining events and organ damage. Until the revision of criteria of MM to require treatment, two main prognostic models, not overlapping each other, were proposed and used differently in Europe and in US. Novel manageable drugs, like lenalidomide and monoclonal antibodies, with high efficacy and limited toxicity, improvement in imaging and prognostication, challenge physicians to offer early treatment to highrisk SMM. Taking advantage from the debates offered by SOHO Italy, in this review we will update the evidence and consequent clinical practices in US and Europe to offer readers a uniform view of clinical approach at diagnosis, follow-up and supportive care in the SMM setting.
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http://dx.doi.org/10.4081/hr.2020.8951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520850PMC
September 2020

Treatment free remission in chronic myeloid leukemia: Lights and shadows.

Hematol Rep 2020 Sep 21;12(Suppl 1):8950. Epub 2020 Sep 21.

Neuro Onco-hematology Unit, Santa Lucia Foundation, I.R.C.C.S. Rome.

In addition to the best possible overall survival, discontinuation of the tyrosine kinase-inhibitor (TKI) treatment [treatment free remission (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Worldwide, more than 2000 patients with CML have attempted TFR, and very rare instances of disease transformation have been reported. Several studies in the last decade have demonstrated the feasibility and safety of TKI discontinuation in selected patients with CML who achieve deep and sustained molecular response with TKI. This has moved prime-time into clinical practice although open questions remain in terms of understanding the disease biology that leads to successful TKI cessation in some patients while not in others. Despite the remaining questions regarding which factors may be considered predictive for TFR, treatment interruption is a safe option provided that adequate molecular monitoring is available, with prompt re-initiation of TKIs as soon as major molecular response has been lost. Data from ongoing trials should help refine decisions as to which patients are the best candidates to attempt TKI discontinuation, frequency of a safe monitoring, optimal strategies to sustain ongoing TFR and increase the number of patients who can access to discontinuation programs.
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http://dx.doi.org/10.4081/hr.2020.8950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520857PMC
September 2020

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.

J Hematol Oncol 2020 09 21;13(1):126. Epub 2020 Sep 21.

Biosciences Laboratory (Onco-hematology Unit), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, FC, Italy.

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.
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http://dx.doi.org/10.1186/s13045-020-00959-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507691PMC
September 2020

Multiple myeloma in 2020: state of the art.

Panminerva Med 2020 Dec 22;62(4):191-192. Epub 2020 Sep 22.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

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http://dx.doi.org/10.23736/S0031-0808.20.04159-2DOI Listing
December 2020

Old and new generation proteasome inhibitors in multiple myeloma.

Panminerva Med 2020 Dec 22;62(4):193-206. Epub 2020 Sep 22.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitin-proteasome system, thus interfering with the intracellular machinery who has the duty of misfolded proteins disposal. Myeloma plasma cells are structurally aimed at the production of large quantities of immunoglobulins. This explains their vulnerability to any perturbation of intracellular protein homeostasis. Bortezomib is the first-in-class PI and nowadays, in combination with other compounds, is the cornerstone of multiple myeloma (MM) treatment in several settings. Bortezomib has several attractive features for its inclusion in the induction phase of therapy: high efficacy, rapid cytoreduction, absence of nephrotoxicity, fast reduction of plasmacytomas, and fast pain control. However, the safety profile of bortezomib is characterized by a not negligible peripheral neuropathy. Newer PIs, such as carfilzomib and ixazomib, have been developed and each offers specific advantages. Carfilzomib is extremely efficient in proteasome inhibition. This results in high efficacy but suffers from a significant cardiotoxicity. Ixazomib is the first oral PI with a proteasome inhibition profile similar to bortezomib, with lower neurotoxicity. PIs mechanism of action is complementary with other drug classes, and this explains the synergism between PIs and other drugs, in particular steroids and immunomodulators. PIs are frequently used in doublets and triplets. Also, they can be associated with anti-CD38 monoclonal antibodies. This review summarizes the principal biological and clinical features of PIs in the MM treatment.
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http://dx.doi.org/10.23736/S0031-0808.20.04148-8DOI Listing
December 2020

Acute leukemias in 2020: state of the art.

Minerva Med 2020 Oct 22;111(5):384-385. Epub 2020 Sep 22.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

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http://dx.doi.org/10.23736/S0026-4806.20.07049-4DOI Listing
October 2020

New monoclonal antibodies and tyrosine kinase inhibitors in B-cell acute lymphoblastic leukemia.

Minerva Med 2020 Oct 21;111(5):478-490. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Patients with acute lymphoblastic leukemia (ALL) are characterized by an unfavorable outcome in the majority of adult cases. Several clinical trials have confirmed the usefulness of a pediatric-type therapy applied to adult patients. Adults present with higher risk features at diagnosis that predispose them to chemotherapy resistance and disease relapse after an initial achievement of complete remission. The recent introduction of novel immune-targeted therapies, including monoclonal antibodies (MoAbs) targeting B cell-associated antigens such as CD19 (blinatumumab) and CD22 (inotuzumab), tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, bispecific antibodies and chimeric antigen receptor T- cell therapy (CAR-T), circumvent B-ALL cell chemo-refractoriness through novel mechanisms of action, potentially eradicating minimal residual disease (MRD) and enabling more patients to receive allogeneic hematopoietic stem cell transplantation and to achieve a better clinical outcome.
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http://dx.doi.org/10.23736/S0026-4806.20.07031-7DOI Listing
October 2020

Enasidenib and ivosidenib in AML.

Minerva Med 2020 Oct 21;111(5):411-426. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.
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http://dx.doi.org/10.23736/S0026-4806.20.07024-XDOI Listing
October 2020

Gemtuzumab ozogamicin in acute myeloid leukemia: past, present and future.

Minerva Med 2020 Oct 21;111(5):395-410. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33+ acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.
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http://dx.doi.org/10.23736/S0026-4806.20.07019-6DOI Listing
October 2020

Tagraxofusp and anti-CD123 in blastic plasmacytoid dendritic cell neoplasm: a new hope.

Minerva Med 2020 Oct 21;111(5):467-477. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy -

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy, characterized by poor prognosis if treated with conventional therapy. Allogenic hematologic stem cell transplant can improve survival and can be curative, but it is available in a small percentage of patients given that the median age at diagnosis is 70 years. In this scenario it is assumed that only the development of precision medicine-driven therapy will change BPDCN patient prognosis. CD123 (the α-subunit of interleukin (IL)-3 receptor) is over-expressed on BPDCN cells surface and seems to be the ideal marker to develop antibody-based therapies. Tagraxofusp (Elzonris®), a recombinant immunotoxin consisting of human interleukin-3 fused to a truncated diphtheria toxin, has been approved by FDA in December 2018 for the treatment of BPDCN in adult and pediatric patients. tagraxofusp has shown promising clinical activity, with a high overall response rate and quite manageable safety profile even in elderly patients. It seems to improve overall survival too, but comparative trials are necessary to confirm this. Adverse events are commonly reported and the most important are transaminitis, thrombocytopenia and capillary leak syndrome (CLS). Therefore, to prevent the onset of severe CLS is recommended to reserve tagraxofusp for patients with preserved hepatic and cardiac functions, and to strictly observe serum albumin level. Further studies are required to resolve many several unanswered questions about tagraxofusp. In this review, we will resume and discuss pharmacological characteristic of tagraxofusp, results of clinical trials leading to its approval by FDA in 2018 and future perspectives about its use in BPDCN and other hematological malignancies.
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http://dx.doi.org/10.23736/S0026-4806.20.07018-4DOI Listing
October 2020

CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia.

Minerva Med 2020 Oct 21;111(5):455-466. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy -

Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.
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http://dx.doi.org/10.23736/S0026-4806.20.07017-2DOI Listing
October 2020

Current strategies for detection and approach to measurable residual disease in acute myeloid leukemia.

Minerva Med 2020 Oct 21;111(5):386-394. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Baseline cytogenetic/genetic features have been widely recognized to play a critical prognostic role in acute myeloid leukemia (AML) and have proven useful in designing risk-adapted treatment strategies. Nevertheless, to improve further the outcome of AML patients we are still in need of accurate methods to explore the quality of response and to adequately discriminate patients who are likely to relapse over time from those who are in deep and stable remission. In this view, is it well established that measurement of leukemic cells surviving chemotherapy (called measurable residual disease, MRD) during the course of treatment may be a reliable biomarker in predicting relapse. Detection of MRD relies on highly sensitive techniques, such as quantitative polymerase chain reaction and multiparametric flow cytometry, which, due to their levels of specificity and sensitivity, are increasingly included in the decision-making process of AML treatment. In the present manuscript, we will review the current techniques of MRD investigation and their clinical contribution to AML management.
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http://dx.doi.org/10.23736/S0026-4806.20.07016-0DOI Listing
October 2020

FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives.

Minerva Med 2020 Oct 21;111(5):427-442. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.
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http://dx.doi.org/10.23736/S0026-4806.20.06989-XDOI Listing
October 2020

Monoclonal antibodies in multiple myeloma.

Panminerva Med 2021 Mar 21;63(1):21-27. Epub 2020 Sep 21.

Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Treatment of multiple myeloma (MM) patients has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivative (IMiDs). In the last years, one further therapeutic option for MM patients is represented by monoclonal antibodies (MoAbs), that seem to change the paradigm of MM treatment, particularly for heavily pretreated or double refractory to a PI and IMiDs patients. Antibodies have an immune-based mechanism, induce durable responses with limited toxicity and combine well with existing therapies. The therapeutic effects are prevalently obtained by means of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) and concurrently by the induction of signals on cell effectors. Immunotherapeutic strategies offer a new and exciting approach to target key molecular pathways that continue to be implicated in the survival of malignant plasma cells. These targets include cell surface proteins (CD38, CD138 [SDC1], B cell maturation antigen [BCMA, TNFRSF17]), cytokines that play a role in plasma cell survival and proliferation (interleukin 6 [IL6] and B cell activating factor), signal regulators of bone metabolism (RANKL [TNFSF11], DKK1) and regulators of the immune system (PD-1[PDCD1], PD-L1[CD274]). This article focuses on new MoAbs and related innovative immunotherapeutic modalities currently under investigation in the treatment landscape of MM.
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http://dx.doi.org/10.23736/S0031-0808.20.04149-XDOI Listing
March 2021

CAR T cells targeting options in the fight against multiple myeloma.

Panminerva Med 2021 Mar 21;63(1):37-45. Epub 2020 Sep 21.

IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Introduction: Multiple myeloma (MM) is a hematological malignancy in which patients present with bone marrow infiltration of clonal terminally-differentiated plasma cells. Monoclonal protein in the serum and/or urine is frequently detected. Over the past decade, important progress has been made in the comprehension of disease biology and treatment personalization. Much work has been put into the development of chimeric antigen receptor (CAR) gene-modified T-cell therapy thought to be a promising therapeutic option for pluritreated patients with refractory MM.

Evidence Acquisition: We performed an analysis of clinical trials registered at the international repository clinicaltrials.gov using "CAR" OR "CAR T" AND "multiple myeloma" as search terms to understand what were the antigens targeted by CAR T strategies and what was the trade-off of their exploitation. The search retrieved a list of 103 trials that was manually filtered to eliminate follow-up and observational or not-pertinent trials.

Evidence Synthesis: Most studies employed anti-BCMA targeting either alone (62/94; 66%), or in combination with a second target (12/94; 13%). The second target most studied was SLAMF7 (CD319) explored by 4/94 (4%) clinical trials. Other antigens investigated and described here include: CD44v6, CD38, CD138, MUC1, CD56, CD19, Igk light chain, Lewis Y, CD229 and GPRC5D.

Conclusions: Targeting an appropriate antigen(s) is the key to both safety and efficacy of CAR T approaches in MM as there is dearth of tumor-specific antigens. Most antigens tested are merely enriched on MM cells. Working with tumor-enriched antigens requires careful assessment of the balance between harm (toxicity) and benefit (disease eradication) to the patient. This review provides an up-to-date overview of the avenues that are being explored.
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http://dx.doi.org/10.23736/S0031-0808.20.04146-4DOI Listing
March 2021

Chemotherapy-based regimens in multiple myeloma in 2020.

Panminerva Med 2021 Mar 21;63(1):7-12. Epub 2020 Sep 21.

Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy.

Multiple myeloma (MM) represents the second-most common hematologic malignancy. In the 1980s, induction therapy with alkylating agents, such as anthracyclines and steroids, as well as high-dose chemotherapy followed by autologous stem cell transplantation were the main therapeutic approaches for MM. Since the introduction of more effective drugs, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and histone deacetylase inhibitor, the new therapeutic algorithm allows of achieving a significantly improvement of prognosis. Numerous regimens, which differently combine these new agents, have been developed and tested in clinical trials. The results of these new regimens are reported each year. In this variegated new contest, old chemotherapeutic drugs still maintain an overriding weight, especially when beneficially combined with new drugs. Also, this is particular true in specific situations, such as extramedullary manifestations, in which tumor mass reduction becomes an urgent clinical need, or in case of chemotherapy-induced stem-cell mobilization. Moreover, melphalan represents the gold standard conditioning regimen since 2002, either alone or, possibly in the next future, in combination with busulfan. Finally, new chemotherapeutic agents with new mechanisms of action, such as melflufen, are in early experimental phase.
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http://dx.doi.org/10.23736/S0031-0808.20.04145-2DOI Listing
March 2021