Development of hypogammaglobulinemia in patients treated with imatinib for chronic myeloid leukemia or gastrointestinal stromal tumor

Imatinib mesylate is a tyrosine kinase inhibitor used as first line treatment in chronic myeloid leukemia and gastrointestinal stromal tumor patients. Although several in vitro and animal studies demonstrated that imatinib affects immune response, few immune alterations are described in humans. We retrospectively studied hematologic and immunological parameters in 72 chronic myeloid leukemia and 15 gastrointestinal stromal tumor patients treated with imatinib at standard dosage and in 20 chronic myeloid leukemia patients treated before the introduction of imatinib in clinical practice. Both chronic myeloid leukemia and gastrointestinal stromal tumor patients developed a significant reduction of gammaglobulin and immunoglobulin serum levels. No significant hypogammaglobulinemia was observed in chronic myeloid leukemia patients in the pre-imatinib era. These data demonstrate that imatinib treatment induces hypogammaglobulinemia that can reach a severe entity in 10% of cases, both in chronic myeloid leukemia and in gastrointestinal stromal tumor patients. Prospective studies are needed to evaluate immune humoral alterations and to define the real incidence of infectious events, including viral reactivations

Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation.

ABSTRACT Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients

The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826)

Patients' preferences for chronic lymphocytic leukemia treatment: The CHOICE study

Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W &amp; W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W &amp; W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression-free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options

Role of image-guided fine-needle aspiration biopsy in the management of patients with splenic metastasis

BACKGROUND: Splenic metastases are very rare and are mostly diagnosed at the terminal phase of the disease or at the time of autopsy. The cytohistological diagnosis, when done, is made prevalently by splenectomy. Reports on splenic percutaneous biopsies in the diagnosis of splenic metastasis are fragmentary and very poor. The aims of this study are to analyse retrospectively the accuracy, safety and the clinical impact of ultrasound (US)-guided fine-needle aspiration biopsy (UG-FNAB) in patients with suspected splenic metastasis. METHODS: A retrospective analysis of 1800 percutaneous abdominal biopsies performed at our institute during the period from 1993 to 2003 was done and 160 patients that underwent splenic biopsy were found. Among these 160 patients, 12 cases with the final diagnosis of solitary splenic metastases were encountered and they form the basis of this report. The biopsies were performed under US guidance using a 22-gauge Chiba needle. All the patients underwent laboratory tests, CT examination of the abdomen and chest, US examination of abdomen and pelvis. RESULTS: There were 5 women and 7 men, median age 65 years (range 48–80). Eight patients had a known primary cancer at the time of the diagnosis of splenic metastasis: 3 had breast adenocarcinoma, 2 colon adenocarcinoma, 2 melanoma and 1 lung adenocarcinoma. Four patients were undiagnosed at the time of the appearance of splenic metastasis and subsequent investigations showed adenocarcinoma of the lung in 2 patients and colon adenocarcinoma in the remaining 2. There was a complete correspondence between the US and Computed Tomography (CT) in detecting focal lesions of the spleen. The splenic biopsies allowed a cytological diagnosis of splenic metastasis in all the 12 patients and changed clinical management in all cases. Reviewing the 160 patients that underwent UG-FNAB of the spleen we found no complications related to the biopsies. CONCLUSION: These results indicate that UG-FNAB is a successful technique for diagnosis of splenic metastasis allowing an adequate treatment of the affected patients

Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma

Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy

Benda-BEAM High-Dose Therapy Prior to Auto-SCT is Effective in Resistant/Relapsed DLBCL

Abstract Background: The most important drawback of clinical trials of high-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) in lymphomas is the high heterogeneity of histological entities. Therefore, the statistical power is reduced, and data are not conclusive. We previously demonstrated the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to ASCT in resistant/relapsed lymphoma patients. This combination of drugs was able to induce a high CR rate in a population that did not have an opportunity of being cured with other therapies. However, that study enrolled both Hodgkin and non-Hodgkin lymphoma patients. Aims: We designed a phase II study to evaluate the efficacy of the BeEAM conditioning in resistant/relapsed diffuse large B-cell non-Hodgkin lymphoma (DLBCL) patients. Patients and methods: The study was registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2011-001246-14. Until now, 61 patients (median age 54 years, range 19-69) with resistant/relapsed DLBCL were enrolled. The primary end-point of the study is to evaluate the 1-year complete remission rate. Results: Briefly, 46/61 patients had advanced stage disease (III-IV); 20 were primary refractory and 41 had relapsed after a median number of 2 lines of therapy (range: 1-3). Twenty-one patients had 1 or more relevant comorbidities (range: 1- 5). 30 patients were in II or subsequent CR after salvage therapy, whereas 27 were in PR and 4 had stable or progressive disease. A median number of 5.72x106 CD34+/kg cells (range 2.21-10.60) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5x109/l of 10 days. Median times to achieve a platelet count >20x109/l and >50x109/l were 12 and 17 days respectively. Twenty-two out of 61 patients presented a fever of unknown origin (36%), whereas 24 patients (39%) presented a clinically documented infection. All patients received G-CSF after transplant for a median time of 8 days (range: 8-13). One patient died due to an incomplete hematological recovery after transplant, producing an overall transplant related mortality of 2.7%. Fifty-seven patients are evaluable for response: 48/57 (84%) obtained a CR, 3/57 (5%) a PR, whereas 6/57 (11%) did not respond to therapy. After a median follow-up of 10.5 months after transplant (range 3-37), 6/57 (11%) patients were refractory, 12/57 (21%) relapsed and 39/57 (68%) are still alive, in continuous CR. Conclusion: Our clinical trial was designed to closely resemble real-world treatment for these patients. During the study, we transplanted a similar proportion of the patients that would have received ASCT in a real-world scenario. While we cannot make sound comparisons without head-to-head trials, results from previous studies using HDT regimens in DLCBL have not been as encouraging as ours. Accordingly, our data preliminary provide the evidence that the Benda-BEAM regimen is safe and has promising high efficacy in resistant-relapsed aggressive DLBCL patients. Acknowledgments: The study was supported in part by AIL Pesaro Onlus. Mundipharma Italy is grateful acknowledged for providing Bendamustine free of charge. Disclosures Patriarca: Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Zinzani:Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial

BACKGROUND Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). METHODS We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0-9.6; High→Int, HR: 2.3, 95% CI: 1.5-4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential

Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients

Therapeutic approach for chronic myeloid leukemia (CML) patients has undergone a revolutionary change with the introduction of tyrosine kinase inhibitors, which improved overall survival and quality of life. Optimal therapy adherence has become of paramount importance to maximize the benefits in the long-term outcome. Several evidences have been reported that personal factors, such as social support, psychological and subjective perceptions about the drug used and the future, could influence adherence. We here report the results of a questionnaire specifically designed to evaluate factors influencing adherence and perceptions about the future, distributed to patients during regional Italian meetings. Overall, 1133 patients compiled the questionnaire: median age was 57 years. High rate of adherence was reported, but 42% of interviewed patients admitted that they had occasionally postponed a dose and 58% had discontinued therapy mainly for forgetfulness. The majority of patients discussed with personal physician about the importance of adherence and received sufficient information about illness and treatment, but would like to have discussed more about discomfort, anxiety and fear of the future. Summarizing personal drug compliance and estimating how many days a month, on average, the patients did not take the drug, the majority answered that it was less than 3 days (55%) and only a minority (4%) admitted that it was more than 7 days. Interviewed about discontinuation, 49% of patients answered that wouldn't interrupt because of fear of losing all the results achieved so far. This study suggests a higher level of satisfaction with more information received but the need of improving communication about possible future treatment free remission

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial

SIMPLE SUMMARY: The interest in using Machine-Learning (ML) techniques in clinical research is growing. We applied ML to build up a novel prognostic model from patients affected with Mantle Cell Lymphoma (MCL) enrolled in a phase III open-labeled, randomized clinical trial from the Fondazione Italiana Linfomi (FIL)—MCL0208. This is the first application of ML in a prospective clinical trial on MCL lymphoma. We applied a novel ML pipeline to a large cohort of patients for which several clinical variables have been collected at baseline, and assessed their prognostic value based on overall survival. We validated it on two independent data series provided by European MCL Network. Due to its flexibility, we believe that ML would be of tremendous help in the development of a novel MCL prognostic score aimed at re-defining risk stratification. ABSTRACT: Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0–9.6; High→Int, HR: 2.3, 95% CI: 1.5–4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential