Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult ...population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve telomere maintenance, DNA repair, biogenesis of ribosomes, control of proliferation and others. The increased knowledge on the genes involved in MDS pathogenesis and the wider availability of molecular diagnostic assessment have led to an improvement in the detection of IBMFS genetic predisposition in MDS patients. A punctual recognition of these disorders implies a strict surveillance of the patient in order to detect early signs of progression and promptly offer allogeneic hematopoietic stem cell transplantation, which is the only curative treatment. Moreover, identifying an inherited mutation allows the screening and counseling of family members and directs the choice of donors in case of need for transplantation. Here we provide an overview of the most recent data on MDS with genetic predisposition highlighting the main steps of the diagnostic and therapeutic management. In order to highlight the pitfalls of detecting IBMFS in adults, we report the case of a 27-year-old man affected by MDS with an underlying telomeropathy.
Digital health tools are increasingly being used in cancer care and may include electronic patient-reported outcome (ePRO) monitoring systems. We examined physicians' perceptions of usability and ...clinical utility of a digital health tool (GIMEMA-ALLIANCE platform) for ePRO monitoring in the real-life practice of patients with hematologic malignancies. This tool allows for the collection and assessment of ePROs with real-time graphical presentation of results to medical staff. Based on a predefined algorithm, automated alerts are sent to medical staff. Participating hematologists completed an online survey on their experience with the platform. Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) agreed to enter the platform and had a median age of 57 years. Twenty-three hematologists with a median age of 42 years and an average of 17 years of experience in clinical practice were surveyed. All hematologists agreed or strongly agreed that the platform was easy to use, and 87%, agreed or strongly agreed that ePROs data were useful to enhance communication with their patients. The majority of physicians (78%) accessed the platform at least once per month to consult the symptom and health status profile of their patients. The frequency of access was independent of physician sex (
=0.393) and years of experience in clinical practice (
=0.404). In conclusion, our preliminary results support the clinical utility, from the perspective of the treating hematologist, of integrating ePROs into the routine cancer care of patients with hematologic malignancies.
A total of 63 myeloproliferative neoplasms MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF) underwent spleen stiffness (SS) measurement by ...vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (
p
=0.035), with hemoglobin level <10 g/dl (
p
=0.014) and with white blood cells ≥10,000/μl (
p
=0.008). Median SS was significantly higher in MF patients compared to ET and PV (
p
=0.015). SS also correlated with higher
JAK2
variant allele frequency (
p
=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN.
The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was ...defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (
clinicaltrial.gov
identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with
IGHV
unmutated (
IGHV
unmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and
NOTCH1
mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ
2
= 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and
IGHV
mutational status in the training and validation cohorts,
IGHV
unmut and LDT>12months group showed a predominant prognostic role over
IGHV
mut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.
Patients with B‐lineage acute lymphoblastic leukemia treated with pegasparaginase‐containing regimens can develop hepatotoxicity related to it. The systemic hyperbilirubinemia due to hepatotoxicity ...can lead to the development of CSF xanthochromia.
Key Clinical Message
Patients with B‐lineage acute lymphoblastic leukemia treated with pegasparaginase‐containing regimens can develop hepatotoxicity related to it. The systemic hyperbilirubinemia due to hepatotoxicity can lead to the development of CSF xanthochromia.
Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring. TP53 disruption is the strongest predictor of chemo-refractoriness and its ...assessment is the first decisional node in the disease treatment algorithm.
The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options for TP53 disrupted patients are described, including: i) agents circumventing TP53 disruption; ii) targeted therapies restoring the physiological function of mutant p53; and iii) medicines potentiating p53 function.
The key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, however TP53 disrupted patients still have a less favorable outcome than wild type cases, possibly because these novel drugs do not directly target p53 and do not restore the function of the disrupted p53 pathway. Emerging innovative molecules in cancer are able to restore the p53 mutant protein and/or potentiate the activity of the p53 wild type protein. If these compounds were confirmed as efficacious also for CLL, they would represent another step forward in the care of high risk CLL patients with TP53 abnormalities.
Background Digital health tools are increasingly being used in oncology practice to better monitor patients' health status. They may include electronic-patient-reported outcome (ePRO) monitoring ...systems, with automated alerts triggered to the physician depending on specific conditions (e.g., when patients report clinically relevant problems). Although implementation of these tools in real-life practice may offer valuable benefits, it is important to assess their usability and utility from the users' standpoint. Objective The aim of this study was to evaluate the patients' perception of usability and utility of a digital health tool for ePRO monitoring of patients with hematologic malignancies in real-life practice. Methods In December 2020, the GIMEMA Group developed a digital health platform for adult patients with hematologic malignancies (GIMEMA-ALLIANCE platform) with the goal of facilitating patient-centered care. The platform was open to enrollment until December 2022 and involved 26 hospitals. After providing written informed consent, patients received a personal password to access the secure patient portal and complete ePRO questionnaires assessing health-related quality of life (HRQoL) and symptoms (EORTC QLQ-C30 and selected items from the EORTC Item Library). Real-time graphical presentation of PRO results is displayed for both patients and physicians. The platform allows hematologists to receive real-time alerts in the presence of clinically important problems and symptoms. For the purpose of this study, a dedicated section in the patient portal was developed to evaluate the usability and utility of the platform. In this section, patients had the possibility to complete the System Usability Scale (SUS). The SUS is a 10-item widely used questionnaire to evaluate users' perceived system satisfaction. Its score ranges from 0 to 100 and a score ≥70 is considered a threshold for an acceptable usability. Analyses were performed overall and by age group category, based on the median age of the patient population. Patients also completed an ad-hoc survey consisting of 6 items covering aspects on the utility of the platform, for example in favoring shared decision-making or improving the communication with the treating hematologist. Only patients who have completed the ePRO questionnaires at least twice, i.e. those who had the possibility to sufficiently test its functionalities, were considered eligible for completing the survey on usability and utility of the platform. Results Out of the 362 eligible patients, a total of 161 (44%) completed the survey. No difference in age and sex was found between patients who completed or not the survey. The median age of patients who completed the survey was 59 years (IQR: 51 - 67) and 53 (34%) were women. The most prevalent diagnosis was multiple myeloma (n=40, 25%). At the time of survey completion, 69% of the patients were receiving a treatment for their disease. The mean SUS score of the overall population was 80.8 (SD 15.5) and the majority of patients (n=131, 81%) gave a rating ≥70 (the prespecified threshold for the acceptable usability). The mean SUS score for the younger and the older groups was 80.5 (SD 14.9) and 81.4 (SD 16), respectively. Eighty-eight percent of patients agreed or strongly agreed that the platform was easy to use, 83% felt very confident in using the platform, and 72% found the various functionalities offered by the platform well integrated (Figure 1). Positive feedbacks on the utility of the platform were also collected. For example, 71% of patients considered the ePRO questionnaires useful for their health conditions and 63% would recommend its use to other patients. However, amongst the patients who had visits at the clinic (n=127), only 39% reported that their doctor discussed ePRO results with them, and this may explain the lower agreement for some items (Figure 2). For example, 38% of the patients strongly agreed/agreed that the platform helped them to improve the communication with their doctor, while 44% neither agreed or disagreed and 18% strongly disagreed/disagreed. Conclusion This study showed a good usability and utility of the GIMEMA-ALLIANCE platform from the patients' perspective, and this was true for younger and older patients. Future areas of improvement should include actions to facilitate physicians in discussing ePRO results during the clinical encounter with their patients.
Summary
The inducible T‐cell co‐stimulator (ICOS) is a T‐cell receptor that, once bound to ICOS ligand (ICOSL) expressed on several cell types including the B‐cell lineage, plays a decisive role in ...adaptive immunity by regulating the interplay between B and T cells. In addition to its immunomodulatory functions, we have shown that ICOS/ICOSL signalling can inhibit the activity of osteoclasts, unveiling a novel mechanism of lymphocyte–bone cells interactions. ICOS and ICOSL can also be found as soluble forms, namely sICOS and sICOSL. Here we show that: (i) levels of sICOS and sICOSL are increased in multiple myeloma (MM) compared to monoclonal gammopathy of undetermined significance and smouldering MM; (ii) levels of sICOS and sICOSL variably correlate with several markers of tumour burden; and (iii) sICOS levels tend to be higher in Durie–Salmon stage II/III versus stage I MM and correlate with overall survival as an independent variable. Moreover, surface ICOS and ICOSL are expressed in both myeloma cells and normal plasma cells, where they probably regulate different functional stages. Finally, ICOSL triggering inhibits the migration of myeloma cell lines in vitro and the growth of ICOSL+ MOPC‐21 myeloma cells in vivo. These results suggest that ICOS and ICOSL represent novel markers and therapeutic targets for MM.
Summary
Richter syndrome (RS) is mostly due to the direct transformation of the chronic lymphocytic leukaemia (CLL) clone, as documented by the same immunoglobulin heavy‐chain variable region (IGHV) ...rearrangement in both CLL and RS cells. In rare cases characterized by a better outcome, the RS clone harbours a different IGHV rearrangement compared to the CLL phase. We investigated the CLL phase of clonally unrelated RS to test whether the RS clone was already identifiable prior to clinicopathologic transformation, albeit undetectable by conventional approaches. CLL cells of eight patients with unrelated RS were subjected to an ultra‐deep next‐generation sequencing (NGS) approach with a sensitivity of 10−6. In 7/8 cases, the RS rearrangement was not identified in the CLL phase. In one case, the RS clone was identified at a very low frequency in the CLL phase, conceivably due to the concomitance of CLL sampling and RS diagnosis. Targeted resequencing revealed that clonally unrelated RS carries genetic lesions primarily affecting the TP53, MYC, ATM and NOTCH1 genes. Conversely, mutations frequently involved in de novo diffuse large B‐cell lymphoma (DLBCL) without a history of CLL were absent. These results suggest that clonally unrelated RS is a truly de novo lymphoma with a mutational profile reminiscent, at least in part, of clonally related RS.
Background: Since its introduction ponatinib has proved great efficacy among patients (pts) with chronic myeloid leukemia (CML), representing in some settings like the T315I mutation the only ...therapeutical choice due to its unique conformation. Its use both in the cohort of heavily pretreated CML and frontline has led to promising results in terms of overall survival (OS) and progression free survival (PFS), as demonstrated in the PACE study (Cortes JE, Blood 2018) and in the single center experience of the MD Anderson (Jain P, Lancet Haematol 2015). The cardiovascular toxicity associated with treatment has been addressed both in protocols and real-life experiences: it is clear that the benefits of ponatinib in terms of molecular response have to be balanced with the possibility of adverse events such as arterial and venous thromboembolism, dyslipidemia and hypertension which have to be managed and, whenever possible, prevented (Dorer JD, Leuk Res 2016; Caocci G, Int J Cardiol 2019). Before the final registration of the drug by AIFA, ponatinib has been available in Italy since October 2011 to March 2015 in compassionate regimen: the results collected here represent a real-life experience on ponatinib use in a cohort of Italian patients mostly heavily pre-treated.
Methods: Italian chronic-phase (CP) CML pts treated with ponatinib in compassionate regimen since October 2011 were collected in the GIMEMA retrospective multicenter protocol CML1214 (clinicaltrials.gov NCT02448095). Primary objective of the study was the assessment of the tolerability and safety profile; secondary objectives were the assessment of the OS, PFS, best response, mutational status, rate of dose reductions. Data were collected following the rules of retrospective studies in Italy and all patients signed an informed consent.
Results: 34 pts with CP-CML were enrolled. Accelerated phase or blastic phase were considered as exclusion criteria. There were 17 males and 17 females, with a median age of 62 (25-84) years at ponatinib initiation. Sokal score was high in 7 (23.33%), intermediate in 17 (56.67%), low in 6 (20%) and unknown in 4 pts. Regarding previous TKIs, 22 (64.7%) pts had three previous lines of therapy, 10 (29.41%) two lines, 2 (5.8%) only one TKI before ponatinib. Two patients experienced a previous stem cell transplant (SCT) and other 10 (29.4%) harbored a T315I mutation before ponatinib initiation. At baseline none of the 34 patients were in major molecular remission (MMR). The median follow-up on ponatinib was 46.6 months (range 15.2-74.5). Cumulative incidence of MMR was 14.7% at three months, 20.6% at six months, 29.4% at nine months, and 55.5% at 36 months. Rate of OS at 36 months was 80% (Figure 1); the presence of T315I did not affect survival. At last follow-up 17 pts were still on treatment with ponatinib; eight pts died, 3 after SCT, 1 for cardiovascular toxicity, 3 for disease progression; one for unknown reason. The treatment-related vascular adverse events (AEs) represented 20.6% of total AEs reported: 6 of them were cardiovascular, 2 cerebrovascular, 2 peripheral, 3 new-onset hypertension, 2 cardiac failures. Non cardiovascular AEs were mostly due to hematological intolerance, with 43 events of neutropenia/thrombocytopenia out of 73 total collateral effects, followed by 9 reported skin problems (which varied from simple rash or desquamation to one episode of ichthyosis).
Conclusions: After a median follow up of 46.6 months, ponatinib provided substantial benefits in a cohort of pts in a timeframe where, after failing 2nd generation TKIs, no other chances were available except transplantation, and T315I positive patients were practically orphan of treatment before ponatinib. Aside from the large prospective PACE trial, results from GIMEMA CML1214 pair with other real-life experiences like the French PEARL (Heiblig M, Exp Hematol 2018) or the Spanish GELMC (Garcia-Gutierrez V, EHA 2016) reports, thus confirming the manageability and the effectiveness of this therapy in challenging clinical situations.
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Fava:Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy. Elena:Pfizer: Consultancy; Novartis: Consultancy. Iurlo:Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.
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