A rare case of appendicular skeleton localization in a patient with chronic lymphocytic leukemia successfully treated with salvage radiation therapy

Bone involvements in chronic lymphocytic leukemia (CLL) are considered rare events, and the English-language medical literature describes them only in sporadic case reports. Consequently, robust indications for a rational clinical management are lacking. We report the case of a middle-aged man in clinical follow-up for CLL who experienced pain at the right tibial level that was refractory to nonsteroidal anti-inflammatory drugs and an acute episode of anemia. Instrumental examinations and a bioptic sample surprisingly demonstrated a bone tibial localization by CLL

Prednisone vs high-dose dexamethasone in newly diagnosed adult primary immune thrombocytopenia: a randomized trial

A debate exists regarding which type of corticosteroids (standard-dose prednisone [PDN] or high-dose dexamethasone [HD-DXM]) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged >= 18 but <= 80 years, platelet count of <= 20 or >20 but <50 x 10(9)/L, and bleeding score of >= 8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410

Multiple Myeloma in 2023 Ways: From Trials to Real Life

Multiple myeloma is a chronic hematologic malignancy that obstinately tends to relapse. Basic research has made giant strides in better characterizing the molecular mechanisms of the disease. The results have led to the manufacturing of new, revolutionary drugs which have been widely tested in clinical trials. These drugs have been approved and are now part of the therapeutic armamentarium. As a consequence, it is essential to combine what we know from clinical trials with real-world data in order to improve therapeutic strategies. Starting with this premise, our review aims to describe the currently employed regimens in multiple myeloma and compare clinical trials with real-life experiences. We also intend to put a spotlight on promising therapies such as T-cell engagers and chimeric antigen receptor T-cells (CAR-T) which are proving to be effective in changing the course of advanced-stage disease

Health-related quality of life and burden of fatigue in patients with primary immune thrombocytopenia by phase of disease

The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol., 2016. © 2016 Wiley Periodicals, Inc

Autologous Stem Cell Transplantation Versus Bortezomib-Melphalan-Prednisone for Newly Diagnosed Multiple Myeloma: Second Interim Analysis of the Phase 3 EMN02/HO95 Study

BackgroundThe EMN02/HO95 trial is the largest multicenter, randomized, phase 3 study conducted in the novel agent era and aimed to prospectively compare (randomization 1, R1) autologous stem cell transplantation (ASCT) vs proteasome inhibitor-based intensification therapy, and (randomization 2) consolidation therapy vs no consolidation, followed by lenalidomide maintenance for newly diagnosed MM.MethodsAfter 3 to 4 cycles of bortezomib-based induction therapy and subsequent PBSC collection, patients aged ≤65 years were randomized (R1, stratification by ISS stage) to receive high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT or standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for 4 additional 42-day cycles (each including 8 doses of bortezomib). Progression-free survival (PFS) from R1 was the primary study end point for R1. The preplanned second interim analysis of ASCT vs VMP was performed in July 2017 when at least 66% of required events had occurred, and results are herein reported.ResultsA total of 1503 patients were registered and 1192 were eligible for R1. Based on the allocation ratio for R1 depending on the single (1:1) vs double (1:1:1) HDM policy of each center, 695 patients were randomly assigned to ASCT and 497 patients to VMP. Median age was 58 years in both groups; ISS stage III was 20% in ASCT arm and 21% in VMP arm. FISH analysis of CD138+ bone marrow plasma cells was available in approximately 75% of patients in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto) was detected in 25% of patients in both groups. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population and for each of the two treatment groups. On an intention-to-treat basis, median PFS was not yet reached in the ASCT group and was 44 months in the VMP group; 3-year estimate of PFS was 64% vs 57%, respectively (HR=0.76; 95% CI=0.64-0.91; P=0.002), which represented a 24% reduced risk of progression or death in the ASCT group compared with the VMP group. Prespecified subgroup analyses of PFS confirmed that the benefit associated with ASCT was not influenced by revised ISS (R-ISS) disease stage (stage II: P=0.006; stage III: P&lt;0.001), HiR-cyto (present: P=0.001; absent: P=0.048); LDH values (above and below the upper limits: P=0.030 and P=0.004, respectively); sex (males: P=0.017; females: P=0.038) and age (&gt;55 years: P=0.027; ≤55 years: P=0.038). The probability of achieving ≥ best VGPR was 84% in the ASCT group and was 75% in the VMP group (odds ratio=1.79; CI=1.32-2.35; P&lt;0.001). Minimal residual disease, as assessed by multiparameter flow cytometry (sensitivity: 10-5), was negative in 239 out of 316 evaluable patients who reached ≥VGPR and were treated with either ASCT (n=153, or 64%) or VMP (n=89, or 36%) (Oliva S. et al, 2017 ASCO Annual Meeting, Abstract 8011). In a multivariate Cox regression analysis, randomization to ASCT (HR=0.69; CI=0.56-0.86; P&lt;0.001), best ≥VGPR (HR=0.40; CI=0.32-0.51; P&lt;0.001), R-ISS stage I vs III (HR=0.48; CI=0.31-0.75; P=0.001), absence of HiR-cyto (HR=0.66; CI=0.51-0.85; P=0.001), R-ISS II vs III (HR=0.70; CI=0.51-0.98; P=0.037) and Hb ≥10.5 g/dL (HR=0.78; CI=0.62-0.99, P=0.037) were independent predictors of prolonged PFS. Overall survival (OS) rate (a secondary end point) at 3 years from R1 was 85% in both treatment arms. However, when the analysis was performed in predefined subgroups, a significantly longer OS associated with ASCT-2 vs ASCT-1 was observed for patients with R-ISS stage III (69% vs 47% at 3 years; HR=0.43; CI=0.23-0.81; P=0.009) and HiR-cyto (74 % vs 61%; HR=0.60; CI=0.38-0.94; P=0.027), including those with del(17p) positivity (75% vs 51%; HR=0.47; CI=0.24-0.92; P=0.028).ConclusionsIn comparison with VMP as standard-dose intensification therapy for newly diagnosed MM, HDM plus ASCT significantly increased the rate of high quality responses, ultimately leading to improved PFS. PFS benefit associated with ASCT was retained across predefined subgroups of patients at standard-risk and high-risk. Randomization to ASCT was an independent predictor for improved PFS and significantly prolonged OS in subgroups of patients with poor prognosis, including those with R-ISS stage III and who carried t(4;14) ± t(14;16) ± del(17p), a finding not observed in the first interim analysis.Disclosures Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Oliva: Celgene: Honoraria; Takeda: Honoraria. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Mellqvist: janssen: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: participation advisory board; Sandoz: Other: participation advisory board. Dimopoulos: Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology. Zweegman: Takeda: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation; Celgene: Other: advisory board participation, Research Funding. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Sonneveld: Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.↵* Asterisk with author names denotes non-ASH members. This icon denotes a clinically relevant abstrac

Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial

Background: Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk. Methods: The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18-65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, patients were stratified according to International Staging System stage (I vs II/III) and age (&lt;60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m2 on days 1 and 2 of cycle 1, followed by 36 mg/m2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1-21; cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1-2 and days 15-16, every 28 days for up to 2 years, and lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643. Findings: Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46-56). 4-year progression-free survival was 71% (95% CI 64-78) in patients with zero HRCA, 60% (95% CI 52-69) in patients with one HRCA, and 39% (95% CI 30-50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90-1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74-3·75]); p&lt;0·0001) across the induction-intensification-consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34-2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91-98) in patients with zero HRCA, 83% (95% CI 76-90) in patients with one HRCA, and 63% (95% CI 54-74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22-5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24-13·18]; p&lt;0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53-4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33-42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74-88) in patients with zero HRCA, 68% (95% CI 59-78) in patients with one HRCA, and 53% (95% CI 42-67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01-2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60-4·69], p=0·0003) than in patients with zero HRCA. Interpretation: This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need. Funding: Amgen and Celgene/Bristol Myers Squibb