A rescue approach in refractory diffuse large B-cell lymphoma with obinutuzumab-redirected cytokine-induced killer cells: a first-in-human case report.

Not available.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study.

Treatment of diffuse large B-cell lymphoma (DLBCL) in older patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a 2-stage single-arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2) in ≥70-year-old untreated frail patients with DLBCL. Frailty was prospectively defined using a simplified geriatric assessment tool. Patients were administered a maximum of 6 28-day cycles of 20 mg oral lenalidomide from days 2 to 22 and IV rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients with partial response or complete response (CR) at cycle 6 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary end point was the overall response rate (ORR) after cycle 6; the coprimary end point was the rate of grade 3 or 4 extrahematological toxicity. The ORR was 50.8%, with 27.7% CR. After a median follow-up of 24 months, the median progression-free survival was 14 months, and the 2-year duration of response was 64%. Thirty-four patients experienced extrahematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥3. The activity of the R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach in frail older patients with DLBCL. This trial was registered at EudraCT as #2015-003371-29 and clinicaltrials.gov as #NCT02955823.

Long-term follow-up of rituximab plus bendamustine and cytarabine in older patients with newly diagnosed MCL.

The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi (RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with a complete remission rate of 91% and 2-year progression-free survival (PFS) of 81% (95% confidence interval [CI], 68-89). Here, we report the long-term survival outcomes, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (range, 57-107 months), the median overall survival (OS) and PFS were not reached. The 7-year PFS and OS rates were 55% (95% CI, 41-67), and 63% (95% CI, 49-74), respectively. Patients who responded (n = 53) had a 7-year PFS of 59% (95% CI, 44-71), with no relapse or progression registered after the sixth year. In the multivariate analysis, blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (P = .04). Patients with an end of treatment negative MRD had better, but not significant, outcomes for both PFS and OS than patients with MRD-positive (P = 0.148 and P = 0.162, respectively). There was no signal of late toxicity or an increase in secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in older patients with MCL. Survival outcomes compare favorably with those of other immunochemotherapy regimens (with or without maintenance), including combinations of BTK inhibitors upfront. This study was registered with EudraCT as 2011-005739-23 and at www.clinicaltrials.gov as #NCT01662050.

Impact of SARS-CoV-2 vaccination and monoclonal antibodies on outcome post-CD19-directed CAR T-cell therapy: an EPICOVIDEHA survey.

Patients with previous CD19-directed chimeric antigen receptor (CAR) T-cell therapy have a prolonged vulnerability to viral infections. Coronavirus disease 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real-world data on the impact of vaccination and treatment on patients with COVID-19 after CD19-directed CAR T-cell therapy are lacking. Therefore, this multicenter, retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared with patients infected with previous variants (7% vs 58% [P = .012]). Twenty-six patients were vaccinated at the time of the COVID-19 diagnosis. Two vaccinations showed a marked but unsignificant reduction in the risk of COVID-19-caused mortality (33.3% vs 14.2% [P = .379]). In addition, the course of the disease appears milder with less frequent intensive care unit admissions (39% vs 14% [P = .054]) and a shorter duration of hospitalization (7 vs 27.5 days [P = .022]). Of the available treatment options, only monoclonal antibodies seemed to be effective at reducing mortality from 32% to 0% (P = .036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death. This trial was registered at www.clinicaltrials.gov as #NCT04733729.

SARS-CoV-2 infection in patients with chronic lymphocytic leukemia: The Italian Hematology Alliance on COVID-19 cohort.

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38-94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24-96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020-22 June 2020) and second wave (23 June 2020-1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03-3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23-4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04-2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62-12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93-36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters.

SARS-CoV-2 infection and vaccination in patients with hairy-cell leukaemia.

Little is known of the course of COVID-19 and the antibody response to infection or vaccination in patients with hairy-cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti-leukaemic treatment, developed COVID-19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti-CD20 or venetoclax therapy, correlating with perivaccine B-cell count. Vaccination appeared to protect from severe COVID-19 in 11 patients with breakthrough infection.

Simultaneous Onset of Haematological Malignancy and COVID: An Epicovideha Survey.

Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

Real-world Outcomes of Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated With Polatuzumab Vedotin-based Therapy.

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy.

Impact of severe acute respiratory syndrome coronavirus-2 infection on the outcome of primary central nervous system lymphoma treatment: A study of the International PCNSL Collaborative Group.

To optimise management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection identifying high-risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS-CoV-2 infection. SARS-CoV-2 was diagnosed before/during first-line treatment in 64 patients, during follow-up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first-line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high-dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID-19). Vaccination was associated with lower pneumonia incidence and in-hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6-month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow-up died from COVID-19, requiring similar measures as infected subjects in the general population.

Obinutuzumab does not improve complete methabolic response but does not compromise mobilization or engraftment of autologous peripheral blood stem cells in diffuse large B cell lymphoma: Results from a fondazione italiana linfomi prospective phase II study (the GIOTTO study).

Salvage immunochemotherapy and transplant consolidation is the standard treatment for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We tested a combination of Obinutuzumab and DHAP for treating R/R DLBCL. The primary end point was the rate of complete metabolic response (CMR). Secondary end points were stem cell mobilization, stem cell engraftment, overall survival, and feasibility. In this prospective, phase-2, single-arm trial (EudraCT 2014-004014-17) patients received the standard three doses of Obinutuzumab for the first cycle, and then one dose. Patients with CMR were consolidated with an autologous stem cell transplantation (ASCT). An interim analysis was provided after the first 29 patients to confirm the initial null hypothesis that at least 10/29 patients would achieve CMR. Among the 29 patients evaluated for the first stage only six patients (6/29, 21%) achieved CMR, thus, study enrollment was stopped. Nine patients exhibited extra-hematologic toxicities ≥ grade 3. Among the 19 patients that started stem cell mobilization, one failed (5%) and 18 achieved mobilization (95%). Of these 18 patients, nine were reinfused. Mobilization was observed in 16 patients (89%) after one or two apheresis rounds. The mean number of CD34 + cells mobilized was 5.8 × 106 /Kg (median: 5.5, IQR: 5-6.75). The mean number of reinfused CD34 + cells in the nine patients was 4.1 × 106 /Kg (median: 4.1, IQR: 3.5-5). Obinutuzumab combined with DHAP did not compromise stem cell mobilization or engraftment after ASCT in patients with DLBCL. However, Obinutuzumab + DHAP provided a lower CMR rate than expected.

Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study.

Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years-mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)-were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice.

Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey.

BACKGROUND: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy. RESULTS: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p < .033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate. CONCLUSION: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.

A prognostic model for patients with lymphoma and COVID-19: a multicentre cohort study.

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin's lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Use of a maturity model for facilitating the introduction of CAR T-cell therapy-Results of the START CAR-T project.

Introduction: Chimeric antigen receptor (CAR) T-cell therapies are novel immunotherapies for the treatment of hematologic malignancies. They are administered in specialized centers by a multidisciplinary team and require the careful coordination of all steps involved in manufacturing and using cellular therapies. The Maturity Model (MM) is a tool developed and used for assessing the effectiveness of a variety of activities. In healthcare, it may assist clinicians in the gradual improvement of patient management with CAR T-cell therapy and other complex treatments. Methods: The START CAR-T project was initiated to investigate the potential of a MM in the setting of CAR T-cell therapy. Four Italian clinics participated in the creation of a dedicated MM. Following the development and test of this MM, its validity and generalizability were further tested with a questionnaire submitted to 18 Italian centers. Results: The START CAR-T MM assessed the maturity level of clinical sites, with a focus on organization, process, and digital support. For each area, the model defined four maturity steps, and indicated the actions required to evolve from a basic to an advanced status. The application of the MM to 18 clinical sites provided a description of the maturity level of Italian centers with regard to the introduction of CAR T-cell therapy. Conclusion: The START CAR-T MM appears to be a useful and widely applicable tool. It may help centers optimize many aspects of CAR T-cell therapy and improve patient access to this novel treatment option.