Beyond Chemotherapy: Present and Future Perspectives in the Treatment of Lymphoproliferative Disorders.

Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective.

Age-related changes in human bone marrow mesenchymal stromal cells: morphology, gene expression profile, immunomodulatory activity and miRNA expression.

Introduction: Mesenchymal stromal cells (MSC) are one of the main cellular components of bone marrow (BM) microenvironment. MSC play a key role in tissue regeneration, but they are also capable of immunomodulating activity. With host aging, MSC undergo age-related changes, which alter these functions, contributing to the set-up of "inflammaging", which is known to be the basis for the development of several diseases of the elderly, including cancer. However, there's few data investigating this facet of MSC, mainly obtained using murine models or replicative senescence. The aim of this research was to identify morphological, molecular and functional alterations of human bone marrow-derived MSC from young (yBM-MSC) and old (oBM-MSC) healthy donors. Methods: MSC were identified by analysis of cell-surface markers according to the ISCT criteria. To evaluate response to inflammatory status, MSC were incubated for 24h in the presence of IL-1ß, IFN-α, IFN-É£ and TNF-α. Macrophages were obtained by differentiation of THP-1 cells through PMA exposure. For M1 polarization experiments, a 24h incubation with LPS and IFN-É£ was performed. MSC were plated at the bottom of the co-culture transwell system for all the time of cytokine exposure. Gene expression was evaluated by real-time PCR after RNA extraction from BM-MSC or THP-1 culture. Secreted cytokines levels were quantitated through ELISA assays. Results: Aging MSC display changes in size, morphology and granularity. Higher levels of ß-Gal, reactive oxygen species (ROS), IL-6 and IL-8 and impaired colony-forming and cell cycle progression abilities were found in oBM-MSC. Gene expression profile seems to vary according to subjects' age and particularly in oBM-MSC seem to be characterized by an impaired immunomodulating activity, with a reduced inhibition of macrophage M1 status. The comparative analysis of microRNA (miRNA) expression in yBM-MSC and oBM-MSC revealed a significant difference for miRNA known to be involved in macrophage polarization and particularly miR-193b-3p expression is strongly increased after co-culture of macrophages with yBM-MSC. Conclusion: There are profound differences in terms of morphology, gene and miRNA expression and immunomodulating properties among yBM-MSC and oBM-MSC, supporting the critical role of aging BM microenvironment on senescence, immune-mediated disorders and cancer pathogenesis.

Supportive Care in Older Lymphoma Patients to Reduce Toxicity and Preserve Quality of Life.

The treatment paradigm in older patients with malignant hemopathies is the choice between an effective conservative treatment that preserves quality of life and an intensive, potentially curative treatment with more toxicities. For each patient, it is important to determine the risk/benefit ratio. The patient should be involved in the discussion, sufficiently informed and able to express himself and his expectations in terms of quality of life. However, this informed consent is conditioned by the ability of the patient to understand the risks and benefits of the treatment. Decline in quality of life is an important parameter for older patients with cancer and many prospective trials have now confirmed the impact of different side effects of treatment, such as recurrent hospitalization, loss of autonomy in daily activities, loss of contact with grandchildren and loss of cognitive functions. Interventions oriented to vulnerabilities detected in the older patients (by comprehensive geriatric assessment) and an optimal approach, including preventive measures to reduce treatment-related toxicity and mortality, are directly correlated to improvement in quality of life.

Syringomyelia Associated with Chiari 1 Malformation in Adults: Positive Outcome Predictors after Posterior Fossa Decompression with Duraplasty.

BACKGROUND: Syringomyelia (Syr) in patients with Chiari 1 malformation (CM1) may be attributable to abnormal dynamics of cerebrospinal fluid (CSF) in the upper cervical segment; fourth ventricle enlargement has been reported in association with a worse clinical and radiological presentation, independently of the posterior fossa volume. In this study, we analyzed presurgery hydrodynamic markers to evaluate if their changes could be associated with clinical and radiological improvement after posterior fossa decompression and duraplasty (PFDD). As a primary endpoint, we aimed to correlate improvement in the fourth ventricle area with positive clinical outcomes. METHODS: In total, in this study, we enrolled 36 consecutive adults with Syr and CM1 who were followed by a multidisciplinary team. All the patients were prospectively evaluated with clinical scales and neuroimaging, including CSF flow, the fourth ventricle area, and the Vaquero Index by using a phase-contrast MRI before (T0) and after surgical treatment (T1-Tlast, with a range of 12-108 months). The CSF flow at the craniocervical junction (CCJ), the fourth ventricle area, and the Vaquero Index changes were statistically analyzed and compared to the clinical and quality of life improvement after surgery. The good outcome prediction ability of presurgical radiological variables was tested. RESULTS: Surgery was associated with positive clinical and radiological outcomes in more than 90% of cases. The fourth ventricle area significantly reduced after surgery (T0-Tlast, p = 0.0093), but no significant associations with clinical improvement were found. The presurgical presence of CSF flow at the CCJ was able to predict a good outcome (AUC = 0.68, 95% CI 0.50-0.87 and LH+ = 2.1, IC 95% 1.16-3.07) and was also significantly associated with post-surgical pain relief (rho = 0.61 and p = 0.0144). CONCLUSIONS: Presurgery CSF flow at the CCJ is proposed as a radiological marker with the ability to predict a positive outcome after PFDD in adults with syringomyelia and CM1. Measurements of the fourth ventricle area could be useful additional information for evaluating surgical long-term follow-up; further experience on larger cohorts is required to better define the prognostic yield of this radiological parameter.

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy.

For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.

Brentuximab Vedotin and Pembrolizumab Combination in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Single-Centre Retrospective Analysis.

Classical Hodgkin lymphoma (HL) patients presenting a relapsed/refractory (R/R) disease are currently managed with salvage chemotherapy followed by autologous stem cell transplantation (ASCT). However, almost 25-30% of these patients fail to achieve a complete response (CR) with standard salvage regimens. In this retrospective study, we evaluated the efficacy of a combination of brentuximab vedotin (BV) and pembrolizumab in a series of HL patients presenting with a high-risk, multi-refractory disease. Patients achieving a Deauville score ≤4 proceeded to ASCT consolidation. After ASCT, patients received BV as maintenance for a total of 16 administrations. We collected data from 10 patients with a median age of 30.7 years. At a median follow-up of 16.5 months, we reported a complete metabolic remission (CMR) in eight patients (80%), with seven patients (70%) directly proceeding to ASCT (the other two patients in CMR are still undergoing treatment). BV consolidation was started in six patients and completed by three patients (one ongoing, two interruption). Two patients (20%) presented a progressive disease (PD) and subsequently died, while the others are still in CMR. The BV and pembrolizumab combination is a very effective bridge treatment to ASCT for high-risk R/R HL patients.

Brentuximab vedotin consolidation after autologous stem cell transplantation for Hodgkin lymphoma: A Fondazione Italiana Linfomi real-life experience.

The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post-ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression-free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post-ASCT BV maintenance in the real-life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow-up was 20 months. Patients presented a median of two lines of treatment pre-ASCT, with 51% receiving BV. Twenty-nine percent of patients had at least two high-risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET-CT, a Deauville score (DS) of 1-3 was reported in 75% and 78% of pre- and post-ASCT evaluations, respectively. Grade 3-4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three-year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3-year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post-ASCT DS 4-5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post-ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV.

Diagnosis and treatment of Chiari malformation and syringomyelia in adults: international consensus document.

BACKGROUND: Syringomyelia and Chiari malformation are classified as rare diseases on Orphanet, but international guidelines on diagnostic criteria and case definition are missing. AIM OF THE STUDY: to reach a consensus among international experts on controversial issues in diagnosis and treatment of Chiari 1 malformation and syringomyelia in adults. METHODS: A multidisciplinary panel of the Chiari and Syringomyelia Consortium (4 neurosurgeons, 2 neurologists, 1 neuroradiologist, 1 pediatric neurologist) appointed an international Jury of experts to elaborate a consensus document. After an evidence-based review and further discussions, 63 draft statements grouped in 4 domains (definition and classification/planning/surgery/isolated syringomyelia) were formulated. A Jury of 32 experts in the field of diagnosis and treatment of Chiari and syringomyelia and patient representatives were invited to take part in a three-round Delphi process. The Jury received a structured questionnaire containing the 63 statements, each to be voted on a 4-point Likert-type scale and commented. Statements with agreement <75% were revised and entered round 2. Round 3 was face-to-face, during the Chiari Consensus Conference (Milan, November 2019). RESULTS: Thirty-one out of 32 Jury members (6 neurologists, 4 neuroradiologists, 19 neurosurgeons, and 2 patient association representatives) participated in the consensus. After round 2, a consensus was reached on 57/63 statements (90.5%). The six difficult statements were revised and voted in round 3, and the whole set of statements was further discussed and approved. CONCLUSIONS: The consensus document consists of 63 statements which benefited from expert discussion and fine-tuning, serving clinicians and researchers following adults with Chiari and syringomyelia.

Prognostic Impact of Muscle Quantity and Quality and Fat Distribution in Diffuse Large B-Cell Lymphoma Patients.

Baseline CT scans of 116 patients (48% female, median 64 years) with diffuse large B-cell lymphoma (DLBCL) were retrospectively reviewed to investigate the prognostic role of sarcopenia and fat compartment distributions on overall survival (OS), progression-free survival (PFS), and early therapy termination. Skeletal muscle index (SMI), skeletal muscle density (SMD), and intermuscular adipose tissue (IMAT) were quantified at the level of the third lumbar vertebra (L3) and proximal thigh (PT). Low L3-SMD, but not low L3-SMI, was associated with early therapy termination (p = 0.028), shorter OS (HR = 6.29; 95% CI = 2.17-18.26; p < 0.001), and shorter PFS (HR = 2.42; 95% CI = 1.26-4.65; p = 0.008). After correction for sex, International Prognostic Index (IPI), BMI, and R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), low L3-SMD remained associated with poor OS (HR = 3.54; 95% CI = 1.10-11.40; p = 0.034) but not with PFS. Increased PT-IMAT was prognostic for poor OS and PFS after correction for sex, IPI, BMI, and R-CHOP therapy (HR = 1.35; CI = 1.03-1.7; p = 0.03, and HR = 1.30; CI = 1.04-1.64; p = 0.024, respectively). Reduced muscle quality (SMD) and increased intermuscular fat (IMAT), rather than low muscle quantity (SMI), are associated with poor prognosis in DLBCL, when measured at the L3 level, and particularly at the level of the proximal thigh. The proximal thigh represents a novel radiological landmark to study body composition.

Long-term results of the MCL01 phase II trial of rituximab plus HyperCVAD alternating with high-dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma.

Mantle cell lymphoma is a rare and incurable lymphoproliferative disorder. In the MCL01 trial, patients were treated with the R-HCVAD regimen [rituximab plus HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-CVAD) alternating with high-dose methotrexate and cytarabine (AM)] for four cycles followed by autologous stem cell transplantation (ASCT) for those who reached only a partial response. After a median follow-up of 10·5 years, we reported 10-year progression-free and overall survival rates of 35% and 61% respectively, with a 10-years cumulative incidence rate of second malignancies of 10·6%. Mature results of the MCL01 trial confirmed the efficacy of HyperCVAD-AM as a frontline regimen for younger patients (≤65 years).

Hodgkin's lymphoma: post- autologous transplantation consolidation therapy.

A first-line chemotherapy program based on the ABVD regimen is currently considered the golden standard by most hematologists, being able to achieve a cure without any need of subsequent therapies in >70% of patients with advanced-stage Hodgkin's lymphoma (HL). To increase this percentage, efforts in recent decades focused on the development of new therapeutic strategies. A first major effort was the introduction of the BEACOPP chemotherapy regimen, which is able to increase the response rate and to reduce the need of salvage therapies. However, this result did not demonstrate an advantage in terms of overall survival compared to ABVD, mainly due to an excess of non lymphoma-related events in the follow-up phase. Here we describe three clinical cases of young HL patients who had relapsed/refractory disease after the induction chemotherapy. These three clinical cases provide practical and real world evidence in favor of the use of BV in monotherapy as consolidation treatment after autologous stem cells transplantation in patients with relapsed/refractory HL.

Germinotropic lymphoproliferative disorder: a systematic review.

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers.

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

Management of Extramedullary Intradural Spinal Tumors: The Impact of Clinical Status, Intraoperative Neurophysiological Monitoring and Surgical Approach on Outcomes in a 12-Year Double-Center Experience.

Objective: Intradural Extramedullary (IDEM) tumors are usually treated with surgical excision. The aim of this study was to investigate the impact on clinical outcomes of pre-surgical clinical conditions, intraoperative neurophysiological monitoring (IONM), surgical access to the spinal canal, histology, degree of resection and intra/postoperative complications. Methods: This is a retrospective observational study analyzing data of patients suffering from IDEM tumors who underwent surgical treatment over a 12 year period in a double-center experience. Data were extracted from a prospectively maintained database and included: sex, age at diagnosis, clinical status according to the modified McCormick Scale (Grades I-V) at admission, discharge, and follow-up, tumor histology, type of surgical access to the spinal canal (bilateral laminectomy vs. monolateral laminectomy vs. laminoplasty), degree of surgical removal, use and type of IONM, occurrence and type of intraoperative complications, use of Ultrasonic Aspirator (CUSA), radiological follow-up. Results: A total number of 249 patients was included with a mean follow-up of 48.3 months. Gross total resection was achieved in 210 patients (84.3%) mostly in Schwannomas (45.2%) and Meningiomas (40.4%). IONM was performed in 162 procedures (65%) and D-wave was recorded in 64.2% of all cervical and thoracic locations (99 patients). The linear regression diagram for McCormick grades before and after surgery (follow-up) showed a correlation between preoperative and postoperative clinical status. A statistically significant correlation was found between absence of worsening of clinical condition at follow-up and use of IONM at follow-up (p = 0.01) but not at discharge. No associations were found between the choice of surgical approach and the extent of resection (p = 0.79), the presence of recurrence or residual tumor (p = 0.14) or CSF leakage (p = 0.25). The extent of resection was not associated with the use of IONM (p = 0.91) or CUSA (p = 0.19). Conclusion: A reliable prediction of clinical improvement could be made based on pre-operative clinical status. The use of IONM resulted in better clinical outcomes at follow-up (not at discharge), but no associations were found with the extent of resection. The use of minimally invasive approaches such as monolateral laminectomy showed to be effective and not associated with worse outcomes or increased complications.

Incidence of Clinically Significant (≤10 g/dL) Late Anemia in Elderly Patients with Newly Diagnosed Chronic Myeloid Leukemia Treated with Imatinib.

BACKGROUND: In elderly patients with chronic myeloid leukemia (CML) responsive to imatinib, the incidence of clinically significant (CS) late chronic anemia is still unknown. MATERIALS AND METHODS: To highlight this issue, we revised retrospectively 81 CML patients aged >60 years treated at our Institution with front-line imatinib for at least 24 months in durable complete cytogenetic response (CCyR). CS late chronic anemia was defined as the presence of persistent (>6 months) and otherwise unexplained Hb levels ≤10 g/dL, which occurred >6 months from imatinib start. RESULTS: A condition of CS late chronic anemia occurred in 22 out of 81 patients (27.2%) at different intervals from imatinib start. Seven out of 22 patients (31.8%) needed packed red cell transfusions during the follow-up. At diagnosis, patients who developed CS late chronic anemia were significantly older and had a lower Hb median level. Six out of 22 patients with CS late chronic anemia received subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 IU weekly: all 6 patients achieved an erythroid response. A significantly worse event-free survival (EFS) in patients with untreated CS late chronic anemia was observed (p = 0.012). CONCLUSIONS: CS late chronic anemia during long-term treatment with imatinib is a common complication in responsive elderly patients, with worse EFS if untreated. Results with EPO are encouraging, but larger studies are warranted to define its role.

Atypical cutaneous lesions in advanced-stage Hodgkin lymphoma: A case report.

BACKGROUND: Cutaneous involvement in Hodgkin lymphoma (HL) is a rare finding. Few cases have been reported in literature, most describing paraneoplastic manifestations. Only very few papers have described primary HL skin infiltration, reporting a wide range of clinical presentations that frequently include ulcers; plaques, nodules and papules have also been noticed. CASE SUMMARY: We report the case of a 56-year-old man who presented fever, multiple adenomegalies of neck and axilla and thick serpiginous skin lesions involving bilateral pectoral regions. After an initial diagnostic workup for a suspected active infectious disease, a lymph node biopsy was performed, which showed a neoplastic invasion from a mixed cellularity classical HL. The same histological pattern was described in a cutaneous biopsy of the chest lesions. The other staging procedures performed revealed an advanced disease, with unfavourable clinical prognostic features. The patient was prescribed 6 cycles of ABVD chemotherapy scheme (doxorubicin, bleomycin, vinblastine, dacarbazine), a regiment that requires demonstration of metabolic response achievement at the interim PET/CT scan to confirm continuation or to change therapeutic strategy. CONCLUSION: Skin involvement in HL is a rare finding and may represent a challenging clinical presentation due to extremely various types of lesions observed.

Clinical diagnosis-part I: what is really caused by Chiari I.

PURPOSE: Chiari malformation is a group of congenital malformations involving the brainstem, cerebellum, and upper spinal cord, frequently identified in both young adults and in children. Chiari I malformation (CM1), classically defined as a caudal displacement of the cerebellar tonsils through the foramen magnum into the spinal cord, is the most common clinical type. A syringomyelia can be associated at the time of the diagnosis or appear secondarily and manifest with medullary symptoms. The aim of this paper is to update the knowledge on clinical manifestations specifically related to Chiari I malformation with or without syringomyelia in the pediatric population. METHODS: Current literature with focus on relevant clinical pediatric issues is reviewed and discussed, comparing with those related to adults; we include the results of a 10-year single-center experience on 600 CM1 patients. RESULTS AND CONCLUSIONS: Herniation of the cerebellar tonsils may lead to significant clinical symptoms, including neck and cervical pain, short-lasting occipital "cough" headache, dizziness, and gait impairment; in children younger than 3 years, oropharyngeal symptoms are prevalent (sleep apnea, feeding problems) whereas in those older than 3 years, a higher incidence of cough headache and scoliosis is reported. CM1 clinical features, both in children and in adults, have in common the presence of anatomical deformities of the brainstem and cerebellum. Clinical myelopathy (sensory/autonomic disorders, motor weakness) can result from direct compression of the cervical spinal cord by the herniated cerebellar tonsils or can be due to the presence of a syrinx, reported in association with Chiari I between 35 and 75% of pediatric patients. Similarly, in our series (440 females, 160 males, 98% > 18 years), syringomyelia associated with Chiari I was ranging from 40 to 60% (respectively in asymptomatic and symptomatic groups); headache was reported in 65%. Sensory disturbances (48%), cranial nerve deficits (45%), motor weakness (32%), and autonomic disorders (35%) were the most frequent neurological signs in our cohort. In Chiari I malformation, cervical pain and occipital cough headache are the most characteristic presenting symptoms, both in old children and in adults; however, headache is often multifactorial, and CM1 patients can report a wide variety of non-specific symptoms and signs. Clinical diagnostic CM1 criteria, shared at the national and international level, are recommended with the aim to avoid consequent controversies on diagnosis and on surgical decision making.

Clinical results according to age in patients with chronic myeloid leukemia receiving imatinib frontline: The younger, the later, the worse?

OBJECTIVES: To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). METHODS: 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20 < 45 years) (YA), middle-aged adults (≥45 < 65 years) (MA) and elderly (≥65 years) (EL). RESULTS: Cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were significantly higher in MA compared with YA and EL (P < .001 for CCyR and P = .001 for MMolR). Number of total events was lower in MA (8 [11.1%] vs 21 [34.4%] in YA and 28 [37.8%] in EL, P = .001): no difference was observed for blastic evolution (P = .478). Number of deaths was higher in the EL (12 [16.2%] vs 2 [3.2%] in YA and 0 in MA, P < .001): however, 11/12 deaths in EL were not related to CML. The PFS curve in MA was significantly longer than in YA and in EL (P = .02). The OS curve in EL was significantly shorter than in YA and in MA (P < .001). CONCLUSIONS: Age at diagnosis influences significantly the course of CML patients treated with imatinib: a possible explanation of the counterintuitive worse course in YA is the delayed diagnosis compared to elderly.

Changes in estimated glomerular filtration rate in chronic myeloid leukemia patients treated front line with available TKIs and correlation with cardiovascular events.

We investigated the median estimated glomerular filtration rate (eGFR) changes in chronic myeloid leukemia (CML) patients treated front line with tyrosine kinase inhibitors (TKIs). A large cohort of 397 patients-320 treated front line with imatinib, 25 with dasatinib, and 53 with nilotinib-was retrospectively analyzed at a single institution. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation for all patients at baseline and then at 6 and 12 months, and at the last follow-up. Taking into account eGFR changes during the first year of treatment and excluding other possible cardiovascular risk factors, we considered also the percentage of cardiovascular events in patients with modifications of this single parameter. Imatinib induced a decrease in median eGFR (p = 0.01): 42 patients treated with imatinib had a cardiovascular event, related to modification of eGFR, in the absence of other cardiovascular risk factors. In patients treated with nilotinib, the median eGFR did not decline from baseline: only 1 patient experienced an ischemic event, but the eGFR remained unchanged. In patients treated with dasatinib, the mean eGFR did not change significantly: 3 patients experienced a cardiac ischemic event, but in all patients the eGFR remained unchanged over time, while advanced age and metabolic alterations contributed to the ischemic events. This long-term follow-up has documented that imatinib may induce changes in the eGFR, which may contribute to the onset of ischemic events. Further analyses on larger series of CML patients are required to conclusively define the potential renal toxicity of second generation TKIs and the consequent risk of developing ischemic events.