Impact of minimal residual disease response and of status of disease on survival after blinatumomab in B-cell acute lymphoblastic leukemia: results from a real-life study.

Blinatumomab is a bispecific T-cell engager approved for relapsed/refractory and minimal residual disease positive B-cell Acute Lymphoblastic Leukemia. We conducted a retrospective study evaluating the outcome of Blinatumomab. The impact of clinical and treatment-related variables on cumulative incidence of relapse/progression (CIRP), event-free (EFS) and overall survival (OS) was analyzed. From January 2016 to December 2022 50 Ph'- (37) and Ph+ (13) B-ALL patients received Blinatumomab. The median age was 37. Indications to blinatumomab were relapsed/refractory B-ALL in 29 and MRD-positive in 21 patients. Blinatumomab was the 2nd and 3rd line in 40 and in 10 patients, respectively. Twenty patients were treated pre-transplantation, ten were treated for relapse after transplant, twenty were not eligible for transplant. Out of 29 patients treated for relapsed/refractory disease, 16 (55%) achieved complete response and 12 achieved MRD-negativity. Out of 21 patients treated for MRD, 16 (76%) achieved MRD-negativity. At a median follow-up of 46 months the median EFS and OS were 11.5 and 16.2 months. The CIRP was 50%. In univariate analysis age, disease-status (overt vs. minimal disease) at blinatumomab, bridging to transplant after blinatumomab and MRD-response resulted significant for EFS and OS. In multivariate analysis only disease-status and MRD-response retained significance both for EFS and OS. Disease-status and MRD-response resulted significant for EFS and OS also after censoring at HSCT. This retrospective study on B-ALL patients treated with blinatumomab confirms a superior outcome for MRD-responsive over MRD non-responsive patients. Survival depends also on the disease-status prior treatment.

Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year followup of the GIMEMA CML 0307 study.

We report the final analysis, with a 10-year follow-up, of the phase II study GIMEMA CML 0307 (NCT00481052), which enrolled 73 adult patients (median age 51 years; range, 18-83) with newly diagnosed chronic-phase chronic myeloid leukemia to investigate the efficacy and the toxicity of front-line treatment with nilotinib. The initial dose was 400 mg twice daily; the dose was reduced to 300 mg twice daily as soon as this dose was approved and registered. The 10-year overall survival and progression- free survival were 94.5%. At the last contact, 36 (49.3%) patients were continuing nilotinib (22 patients at 300 mg twice daily, 14 at lower doses), 18 (24.7%) patients were in treatment-free remission, 14 (19.2%) were receiving other tyrosinekinase inhibitors and four (5.5%) patients have died. The rates of major and deep molecular responses by 10 years were 96% and 83%, respectively. The median times to major and deep molecular response were 6 and 18 months, respectively. After a median duration of nilotinib treatment of 88 months, 24 (32.9%) patients discontinued nilotinib while in stable deep molecular response. In these patients, the 2-year estimated treatment-free survival was 72.6%. The overall treatment-free remission rate, calculated on all enrolled patients, was 24.7% (18/73 patients). Seventeen patients (23.3%), at a median age of 69 years, had at least one arterial obstructive event. In conclusion, the use of nilotinib front-line in chronic phase chronic myeloid leukemia can induce a stable treatment-free remission in a relevant number of patients, although cardiovascular toxicity remains of concern.

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study.

OBJECTIVE AND METHODS: In order to assess the efficacy of brentuximab vedotin (Bv) in combination with bendamustine (B) in multiple relapsed or refractory (RR) classic Hodgkin lymphoma (cHL), medical records of 47 patients treated with BvB in second relapse or beyond were reviewed. RESULTS: The median number of previous treatments was 2 (1-4). Bv was given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m2 on days 1 and 2 of a 21-day cycle. The median number of BvB cycles was 4 (2-7), and all patients were evaluable for efficacy. The CR and OR rates were 49% and 79%, respectively; 67% of responding patients and 2 in stable disease proceeded to a SCT procedure. After a median follow-up of 19 months (5-47), median PFS was 18 months (95%CI: 23-29), and the 2-year OS was 72%. Significantly longer PFS and OS were observed in patients attaining a major clinical response to treatment and in those who received consolidation with SCT. Fifteen (32%) patients experienced severe (G > 2) toxicity. The main toxicities were neutropenia (23%), gastrointestinal (10%), peripheral sensory neuropathy (11%), and infection (4%). CONCLUSION: Our real-world results suggest that BvB is an effective third-line rescue and bridge-to-transplant regimen for RR-cHL patients.

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Palonosetron (Aloxi) and dexamethasone for the prevention of acute and delayed nausea and vomiting in patients receiving multiple-day chemotherapy.

OBJECTIVE: The objective of this study was to determine the efficacy of palonosetron combined with dexamethasone in prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving multiple-day chemotherapy and the efficacy of a second dose of palonosetron in treating breakthrough emesis. MATERIALS AND METHODS: Forty-six patients treated with multiple-day chemotherapy for hematologic malignancies received palonosetron as prophylaxis for CINV on the first day of chemotherapy and dexamethasone throughout the entire period of chemotherapy. If breakthrough emesis occurred, a second dose of palonosetron was administered after 72 h following the first administration. The results were retrospectively compared to group of patients with similar clinical characteristics undergoing similar multiple-day chemotherapy. This group had received single-dose ondansetron as CINV prophylaxis on the first day of chemotherapy plus dexamethasone throughout the entire period of chemotherapy and metoclopramide for breakthrough emesis. RESULTS: One hundred eighty and 173 chemotherapy cycles were administered in the palonosetron and ondansetron groups, respectively. Nausea and vomiting were absent in 80% of patients of the palonosetron group and 60% of the control group (p < 0.05). In the palonosetron group, 67% of patients who experienced CINV were successfully rescued by a second dose of palonosetron, while in the ondansetron group, only 22% showed a no CINV after metoclopramide treatment (p = 0.04). CONCLUSIONS: The present results appear to be encouraging in terms of complete prophylaxis of CINV and treatment of breakthrough emesis in the setting of multiple-day chemotherapy.

Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

BACKGROUND: Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. DESIGN AND METHODS: One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients' characteristics and the clinical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. RESULTS: The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. CONCLUSIONS: We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.

Haematopoietic stem cell transplantation for vasculitis including Behcet's disease and polychondritis: a retrospective analysis of patients recorded in the European Bone Marrow Transplantation and European League Against Rheumatism databases and a review of the literature.

OBJECTIVE: To evaluate the feasibility of haematopoietic stem cell transplantation (HSCT) in vasculitis. METHODS: This is a retrospective analysis of patients who had received HSCT for vasculitic diseases and have been reported to the European League Against Rheumatism autoimmune disease or European Bone Marrow Transplantation ProMISe databases. Information about the disease and outcome was obtained by a questionnaire sent to the referring centres. Response of the disease to HSCT was defined as partial or complete responses according to the ability to reduce immunosuppression after HSCT. In addition, the Medline database was searched for reports on HSCT in patients with vasculitis. RESULTS: Detailed information was obtained for 15 patients, whose median age at HSCT was 37 years. The diagnoses were cryoglobulinaemia in four patients, Behçet's disease in three patients, Wegener's granulomatosis in three patients, and undifferentiated vasculitis, Churg-Strauss angiitis, polychondritis, Takayasu arteritis and polyarteritis nodosa in one patient each. 14 patients received autologous HSCT and 1 an allogeneic HSCT as the first transplant. In three patients, further transplantation was given because of relapse. The overall response, including all consecutive transplantations (HSCT/patient, n = 1-3, median 1.3) to HSCT, was 93%, with 46% complete responses and 46% partial responses; median (range) duration of response at the time of reporting was 45 (16-84) months. Three patients died, one from advanced disease, one from cancer and one from graft-versus-host disease. The Medline search showed five other patients who were effectively treated with HSCT for vasculitic diseases. CONCLUSION: This retrospective study suggests that autologous HSCT is feasible for vasculitis. Its value remains to be tested in prospective controlled studies.

Polymorphonuclear leukocyte integrins in chronic renal failure.

Patients with chronic renal failure (CRF), in comparison with general population, show a higher cardiovascular mortality, not fully explained by the "traditional" risk factors. Among the new factors that have been hypothesized, leukocytes might play an important role. In a group of patients with mild CRF we determined, at baseline and after in vitro activation with 4-phorbol-12-myristate-13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (fMLP), the polymorphonuclear leukocytes (PMN) beta2-integrin pattern (CD11a, CD11b, CD11c and CD18) by using indirect immunofluorescence with a flow cytometer. At baseline we observed an increase in the phenotypical expression of CD11b, CD11c and CD18 in CRF patients. In normal subjects, after activation with both agents, we noted an increase of all adhesion molecules, while in CRF patients we found an increase in the expression of CD11b, CD11c and CD18 but not of CD11a. The altered behaviour of the PMN integrin pattern in mild CRF patients, likely reflecting a state of PMN activation, might have a pathophysiological significance, considering the high incidence of cardiovascular events in CRF.

Polymorphonuclear leukocyte integrin profile in vascular atherosclerotic disease.

Leukocyte-endothelial interactions could have a pathogenic role in atherogenesis. Adhesion molecules expressed by endothelial cells, such as intercellular adhesion molecule 1 (ICAM-1), interact with leukocyte integrins mediating the firm adhesion of leukocytes to endothelium which is followed by their transendothelial migration. The aim of our research was to evaluate polymorphonuclear leukocyte (PMN) integrin expression, at baseline and after activation, in a group of subjects with chronic vascular atherosclerotic disease (VAD). In 27 subjects with VAD we examined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate (PMA), the PMN integrin pattern (CD11a, CD11b, CD11c, CD18) using indirect immunofluorescence and a flow cytometer. At baseline VAD subjects showed an increase of CD11a and CD18 and a decrease of Cd11b and Cd11c as compared to normal subjects. After activation, in normal subjects, we found an increase in the expression of all integrins, while in VAD subjects we observed an increase of CD11b and Cd11c and a decrease of Cd11a and CD18. In VAD subjects, at baseline, the upregulation of Cd11a and CD18 may reflect PMN in vivo activation; after in vitro activation, the decrease of CD11a may be related to the lack of cytoplasmic deposits of this molecule, while CD18 might be internalized. The integrin behaviour pattern in chronic VAD deserves further investigation, considering that integrins are potential targets of therapeutical strategies, with the aim of preventing the atherosclerotic plaque progression and acute ischaemic events.

Phase I-II parallel study of docetaxel on a bimonthly schedule in refractory metastatic breast carcinoma.

BACKGROUND: The 3-week schedule with docetaxel (DTC) 75-100 mg/2 is associated with severe neutropenia, gastro-intestinal side-effects and fluid retention in a significant proportion of patients, which may be of concern in more elderly or poor performance status patients. A phase I-II trial was carried out to test the feasibility and the activity of a new bimonthly schedule of DCT. PATIENTS AND METHODS: The trial included a phase I study which aimed at the identification of dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a bimonthly schedule. The first group of three patients received DCT 40 mg/m2, and in absence of DLT, DCT dosage was escalated by 10 mg/m2/cycle until DLT was reached. In the phase II study, patients were randomized to receive: (a) standard 3-weekly DCT at the dose of 75 mg/m2 (calibration arm); or (b) bimonthly schedule with DCT at the dose recommended in the phase I study. All patients were pretreated with chemotherapy, mostly anthracycline-based regimens, for advanced/metastatic disease. Analysis of response rates, toxicity, and dose-intensity were the main aims of the study. RESULTS: The DLT was represented by severe myelosuppression which was recorded in all patients treated at 70 mg/m2 dose level. Therefore, the MTD was 60 mg/m2 on a bimonthly schedule. However, the dose recommended for the phase II trial was 50 mg/m2, because no difference in delivered dose-intesity was seen between the 50 and 60 mg/m2 dose levels, and the latter dosage was still associated with grade 3 neutropenia in most patients. The parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m2) allows to deliver the same dose-intensity of DCT 75 mg/m2 every 3 weeks. Grade 3-4 side-effects were rather infrequent in patients treated with the bimonthly schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m2 bimonthly and the DCT 75 mg/m2 every 3 weeks, respectively. CONCLUSIONS: Data achieved in the phase I part of the study showed that DCT 50 mg/m2 every 15 days is the recommended dose for phase II studies, while results achieved in the phase II trial suggest that DCT 50 mg/m2 in a bimonthly schedule is active as second-line chemotherapy for MBC being able to induce an ORR in the range reported for DCT 75-100 mg/m2 every 3 weeks. The bimonthly schedule is, however, associated with relatively low toxicity. This characteristic may render the bimonthly schedule particularly attractive for future phase II trials of DCT in combination with other antineoplastic agents.