Physicians' Perceptions of Clinical Utility of a Digital Health Tool for Electronic Patient-Reported Outcome Monitoring in Real-Life Hematology Practice. Evidence From the GIMEMA-ALLIANCE Platform.

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 (p=0.393) and years of experience in clinical practice (p=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.

Genetic screening of children with marrow failure. The role of primary Immunodeficiencies.

The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with single-lineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multi-lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant.

Treatment and prognosis of primary pulmonary lymphoma: A long-term follow-up study.

Primary pulmonary lymphoma (PPL) is a rare disease with not well-defined optimal treatment. Outcomes and follow-up are variable in published data. OBJECTIVES: To define the outcome and optimal treatment strategies in PPL. METHODS: We reviewed the medical records of 49 patients with PPL treated in three Italian Hematological Institutions between 2002 and 2018. RESULTS: Thirty-eight (77.5%) cases were indolent PPL, and 11 (22.5%) cases were aggressive PPL. The majority of patients were asymptomatic at diagnosis, early stages (stages IE-IIE), normal serum LDH, no bone marrow involvement, and low or low-intermediate risks of IPI. Local therapy ± immunotherapy or immuno-chemotherapy was possible in 18/49 (37%) patients. Twenty-eight (57%) patients were treated with immuno-chemotherapy after biopsy. Waiting and watching were reported in 3 (6%) patients. Overall, the CR and ORR were 83.7% and 95.9%. With a median follow-up of 62.5 months (range 0.8-199 months), the estimated 5- and 10-year OS rates were 85% and 72.3% for all patients, 89.2% and 80.3% for indolent PPL, and 70.7% and 47.1% for aggressive PPL. Aggressive PPL tended to have a high risk of progression in the first months (P = .056). No advantages were found for indolent PPL who received immuno-chemotherapy or more conservative approaches. CONCLUSION: Our studies confirm the epidemiological and favorable survival of patients with PPL, suggesting a very conservative approach, particularly in indolent subtypes.

Myelodysplasia as assessed by multiparameter flow cytometry refines prognostic stratification provided by genotypic risk in systemic mastocytosis.

Systemic mastocytosis (SM) is characterized by extreme heterogeneity of manifestations and prognosis. Several disease-related biomarkers, including clinical, hematological and molecular variables, have been correlated with prognosis. Although relevant, the mutation profile closely reflects the WHO classification that has per se prognostic value. High-risk mutations (HRM) are largely confined to advanced forms, and thus fail in providing information regarding progression and outcome in the not-advanced variants. In this work, we studied hematopoietic cells by multi-parameter flow cytometry (MFC) in order to highlight dysplastic traits that might provide insights into outcome. A score previously validated for myelodysplastic syndromes, with high reproducibility in standard diagnostics, was used. The application of an MFC score to a cohort of 71 SM cases, concurrently genotyped for configuring a HRM category, resulted in the identification of two separate patients' categories (MFC+ and MFC-) characterized by significantly different clinical and laboratory features at presentation. The extent of dysplasia by MFC tended to parallel WHO-category and genotype-related stratification. MFC+ patients had shorter survival compared to MFC- ones, for whom the incidence of progression and/or death was virtually null. Of note, MFC score remained prognostically informative in unadvanced subsets. Furthermore, the integration of MFC and HRM was an independent predictor for outcome, also overcoming WHO-categories in multivariate analysis for EFS. Our results support the use of MFC analysis in the evaluation of patients with SM, alone and in combination with HRM, for refinement of prognosis assessment.

Real-Life Management of Children and Adolescents with Chronic Myeloid Leukemia: The Italian Experience.

BACKGROUND: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. METHODS: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. RESULTS: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines' recommendations. CONCLUSIONS: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

Gaucher Disease and Myelofibrosis: A Combined Disease or a Misdiagnosis?

BACKGROUND: Gaucher disease (GD) and primary myelofibrosis (PMF) share similar clinical and laboratory features, such as cytopenia, hepatosplenomegaly, and marrow fibrosis, often resulting in a misdiagnosis. CASE REPORT: We report here the case of a young woman with hepatosplenomegaly, leukopenia, and thrombocytopenia. Based on bone marrow (BM) findings and on liver biopsy showing extramedullary hematopoiesis, an initial diagnosis of PMF was formulated. The patient refused stem cell transplantation from an HLA-identical sibling. Low-dose melphalan was given, without any improvement. Two years later, a BM evaluation showed Gaucher cells. Low glucocerebrosidase and high chitotriosidase levels were indicative for GD. Molecular analysis revealed N370S/complex I mutations. Enzyme replacement therapy with imiglucerase was commenced, resulting in clinical and hematological improvements. Due to an unexpected and persistent organomegaly, PMF combined with GD were suspected. JAK2V617F, JAK2 exon 12, MPL, calreticulin, and exon 9 mutations were negative, and BM examination showed no marrow fibrosis. PMF was excluded. Twenty years after starting treatment, the peripheral cell count and liver size were normal, whereas splenomegaly persisted. CONCLUSION: In order to avoid a misdiagnosis, a diagnostic algorithm for patients with hepatosplenomegaly combined with cytopenia is suggested.

Mast Cell Disorders, Melanoma and Pancreatic Carcinoma: From a Clinical Observation to a Brief Review of the Literature.

Mastocytosis can be associated with other clonal or non-clonal hematologic diseases as well as a variety of non-hematologic malignancies. A 75-year-old Caucasian male patient was referred to us with a 5-month history of neutrophilic leukocytosis and mild splenomegaly. He had developed a cutaneous melanoma sixteen years ago. According to the clinical and pathological features, a final diagnosis of systemic mastocytosis was established. The patient started treatment with interferon-α at a dose of 3 MIU/day, combined with low doses of prednisone. We observed a rapid disappearance of symptoms. Unfortunately, after 3 months a diagnosis of pancreatic adenocarcinoma was established. A review of the literature suggests that mastocytes could have a pivotal role in several malignancies. Different chemokines, mitogenic factors, chemical mediators of inflammation, and specific gene mutations could explain the association between mastocytosis and other hematologic and non-hematologic disorders.

Can chronic myeloid leukaemia in children and adolescents be successfully treated without haematopoietic stem cell transplant? A single centre experience.

We analysed the long-term outcome of 35 children and adolescents (<20 years at diagnosis) with chronic myeloid leukaemia (CML) in chronic phase: 20 patients had received interferon-alpha and/or tyrosine kinase inhibitors (TKIs), and 15 underwent a haematopoietic stem cell transplant. The 10-year survival probabilities were similar in transplanted and non-transplanted patients (73·3% vs. 72·1%, respectively), whereas the survival probability was significantly lower in patients diagnosed before 1999 compared to those diagnosed afterwards (62·1% vs. 100%, P = 0·0384). The availability of TKIs and the standardized molecular monitoring have significantly improved treatment, management and outcome in children and adolescents with CML.

Successful Management of a Chronic Refractory Leg Ulcer in an Adolescent with Sickle Cell Anemia.

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by a wide range of clinical manifestations. Chronic leg ulcers are a disabling complication with repercussions on the quality of life. We report the case of a 14-year-old girl with a diagnosis of SCD who developed a chronic leg ulcer that was successfully treated with a multi-disciplinary approach, including local and systemic therapies. The role of different treatments, in particular low molecular weight heparin, in the refractory chronic leg ulcer healing process will be discussed.

Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib.

In patients with chronic myeloid leukemia (CML) responsive to imatinib, it is still unknown whether the long-lasting treatment could induce the appearance of a persistent/late chronic anemia. To highlight this issue, we revised 128 patients with CML (M/F 64/64, median age at diagnosis 56.9 years, interquartile range 43.0-69.3) treated at our Institution with 1st line imatinib for at least 36 months and in stable complete cytogenetic response. At the 36th month of imatinib, a chronic anemia (Hb < 12 g/dl for > 6 months) was present in 38/128 patients (29.6%): the anemia was moderate (Hb > 8 ≤ 10 g/dl) in 12 patients (9.3%) and mild (Hb > 10 < 12 g/dl) in 26 patients (20.3%). All patients with persistent/late chronic anemia had a low reticulocyte count and 8/38 a condition of iron deficiency without clinical and instrumental signs of chronic blood loss. Four out of 38 patients (10.5%) needed red cell transfusions during the follow-up. At a landmark analysis from the 36th month of imatinib treatment, cumulative 4-year overall survival (OS) for patients with chronic anemia was 94.4% (CI 95% 83.8-100) compared to 93.5% (CI 95% 87.2-99.8) for patients without chronic anemia (P = 0.617). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in about 30% of our responsive patients: its occurrence does not seem to affect OS, but its real impact should be evaluated on a larger cohort of patients.

Complete clearance of Ph+ metaphases after 3 months is a very early indicator of good response to imatinib as front-line treatment in chronic myelogenous leukemia.

AIM: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable). METHODS: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. RESULTS: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). CONCLUSIONS: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.