Three-Way Translocation t(12;15;17) (p13;q24;q21) Found in Acute Promyelocytic Leukemia with Basophilic Differentiation.

Acute promyelocytic leukemia is a rare form of acute myeloid leukemia in which immature promyelocytes abnormally proliferate in the bone marrow. In most cases, the disease is characterised by the translocation t(15;17) (q24;q21), which causes the formation of PML::RARA, an oncogenic fusion protein responsible for blocking myeloid differentiation and survival advantage. Here, we present a case of acute promyelocytic leukemia with two unusual features: basophilic differentiation and a three-way translocation involving chromosomes 12, 15 and 17. In the few cases reported, basophilic differentiation was associated with a poor prognosis. In contrast, our patient responded promptly to the standard treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) and obtained complete remission. To our knowledge, this is the first report of basophilic acute promyelocytic leukemia with the three-way translocation t(12;17;15) (p13; q24;q21).

A real-life study of daratumumab combinations in newly diagnosed patients with light chain (AL) amyloidosis.

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.

Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4dim/CD5bright proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4dim/CD5bright PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of a multicenter, retrospective real-world experience with 321 cases outside of controlled clinical trials.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Daratumumab-based regimens for patients with multiple myeloma plus extramedullary plasmacytomas or paraskeletal plasmacytomas: initial follow-up of an Italian multicenter observational clinical experience.

Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients.

Monocyte-to-platelets ratio (MPR) at diagnosis is associated with inferior progression-free survival in patients with mantle cell lymphoma: a multi-center real-life survey.

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR). We reviewed the clinical features of 165 consecutive MCL patients newly diagnosed and not eligible for autologous stem cell transplantation (both for age or comorbidities) who accessed two Italian Centers between 2006 and 2020. MPR was calculated using data obtained from the complete blood cell count at diagnosis before any cytotoxic treatment and correlated with PFS. Univariate analysis showed that MPR ≥ 3 was associated with inferior PFS (p = 0.02). Multivariate analysis confirmed that MPR ≥ 3, LDH > 2.5 ULN, and bone marrow involvement were significant independent variables in predicting PFS. For these reasons, MPR ≥ 3 seems the most promising prognostic factor in patients with MCL, and it could be considered a variable in new predictive models.

Baseline IgM Amounts Can Identify Patients with Poor Outcomes: Results from a Real-Life Single-Center Study on Classical Hodgkin Lymphoma.

Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an immunoregulatory role. Therefore, we investigated if, as a surrogate of defective B cell function, it could have any clinical impact on prognosis. In this retrospective, observational, single-center study, we evaluated 212 newly diagnosed HL patients, including 132 advanced-stage. A 50 mg/dL level of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity for predicting a complete response in the whole cohort (area under curve (AUC) = 0.62, p = 0.013). In multivariate analysis, baseline IgM ≤ 50 mg/dL and the presence of a large nodal mass (<7 cm) were independent variables able to predict the clinical outcome, while, after two cycles of treatment, IgM ≤ 50 mg/dL at baseline and PET-2 status were independent predictors of PFS. The amount of IgM at diagnosis is a valuable prognostic factor much earlier than PET-2, and it can also provide information for PET-2-negative patients. This can help to identify different HL classes at risk of treatment failure at baseline.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Efficacy and safety of tixagevimab-cilgavimab versus SARS-CoV-2 breakthrough infection in the hematological conditions.

BACKGROUND: Managing SARS-CoV-2 infection in frail and immunosuppressed patients still represents an open challenge, but, starting from the phase 3 PROVENT study, prophylaxis with tixagevimab-cilgavimab has improved the approach in this category of patients, guaranteeing a better outcome and inferior mortality. Real-life data in a heterogeneous cohort are few. METHODS: The aim of this study is to evaluate the benefit of prophylaxis with tixagevimab-cilgavimab in a cohort of 202 patients affected by different hematological diseases (lymphoproliferative, myeloproliferative, autoimmune, patients recently receiving a bone marrow transplant), active (with ongoing treatment), or in watch-and-wait strategy, followed in our center, during a median follow-up of 249 (45-325) days. RESULTS: An incidence of 44 breakthrough infections (21.8%) is reported, with no treatment-related adverse effects. Age ≥70 years, ongoing treatment (above all with monoclonal antibodies), baseline lymphoproliferative disorders, and prior virus exposure are identified as risk factors related to subsequent infection (p < 0.05). Moreover, the incidence is higher in low/nonresponse to prior vaccination (p = .002). Patients treated with tixagevimab-cilgavimab had a mild course of the infection and a reduction of the duration compared with preprophylaxis infection (11 vs. 15 days, p < .001). The concurrent treatment with anti-CD20 monoclonal antibodies and B-non-Hodgkin lymphoma still confers a higher duration of infection despite prophylaxis. No deaths attributable to the infection occurred. CONCLUSION: Prophylaxis treatment seems to be a valid and safe strategy, although not preventing breakthrough infection, but the severe complications associated with the infection and the possible delays in administering lifesaving therapies from long positivity.

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers.

Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Once a malignant event occurs, the BMME acquires cellular, molecular, and epigenetic abnormalities affecting tumor growth and progression. In this context, MSC behavior is affected by signals coming from cancer cells. Furthermore, it has been shown that stromal cells themselves play a major role in several hematological malignancies' pathogenesis. This bidirectional crosstalk creates a functional tumor niche unit wherein tumor cells acquire a selective advantage over their normal counterparts and are protected from drug treatment. It is therefore of critical importance to unveil the underlying mechanisms which activate a protumor phenotype of MSCs for defining the unmasked vulnerabilities of hematological cancer cells which could be pharmacologically exploited to disrupt tumor/MSC coupling. The present review focuses on the current knowledge about MSC dysfunction mechanisms in the BMME of hematological cancers, sustaining tumor growth, immune escape, and cancer progression.

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.

High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.

Purpose: Chronic Myeloid Leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by expression of the BCR::ABL1 oncoprotein. High BCR::ABL1 levels have been associated to proliferative advantage of leukemic cells, blast crisis progression and tyrosine kinase inhibitors (TKIs) inefficacy. We have previously shown that high BCR::ABL1/GUSIS transcripts measured at diagnosis are associated with inferior responses to standard dose Imatinib (IM). However, the mechanisms underlying the higher rates of disease progression and development of TKIs resistance dependent on elevated BCR::ABL1 levels remain unclear. Methods: Leukemic cells were collected from CML patients showing, at diagnosis, high or low BCR::ABL1/GUSIS. BCR::ABL1 expression levels were measured using real-time PCR. Short-term culture and long-term culture-initiating cells assays were employed to investigate the role of BCR::ABL1 gene-expression levels on proliferation, clonogenicity, signal transduction, TKIs responsiveness and self-renewal ability. Cell division was performed by carboxyfluorescein-succinimidyl ester (CFSE) assay. Results: We found that BCR::ABL1 oncogene expression levels correlate in both PMNs and CD34+ cells. Furthermore, high oncogene levels increased both proliferation and anti-apoptotic signaling via ERK and AKT phosphorylation. Moreover, high BCR::ABL1 expression reduced the clonogenicity of leukemic CD34+ cells and increased their sensitivity to high doses IM but not to those of dasatinib. Furthermore, we observed that high BCR::ABL1 levels are associated with a reduced self-renewal of primitive leukemic cells and, also, that these cells showed comparable TKIs responsiveness with cells expressing lower BCR::ABL1 levels. Interestingly, we found a direct correlation between high BCR::ABL1 levels and reduced number of quiescent leukemic cells caused by increasing their cycling. Conclusion: Higher BCR::ABL1 levels improving the proliferation, anti-apoptotic signaling and reducing self-renewal properties cause an increased expansion of leukemic clone.

Potential clinical impact of T-cell lymphocyte kinetics monitoring in patients with B cell precursors acute lymphoblastic leukemia treated with blinatumomab: a single-center experience.

Blinatumomab is a bispecific anti-CD3 and anti-CD19 antibody that acts as a T-cell engager: by binding CD19+ lymphoblasts, blinatumomab recruits cytotoxic CD3+ T-lymphocytes to target the cancer cells. Here we describe seven different patients affected by B-cell precursor acute lymphoblastic leukemia (Bcp-ALL) and treated with blinatumomab, on which we evaluated the potential association between the amount of different T-cells subsets and deep molecular response after the first cycle, identified as a complete remission in the absence of minimal residual disease (CR/MRD). The immune-system effector cells studied were CD3+, CD4+ effector memory (T4-EM), CD8+ effector memory (T8-EM), and T-regulatory (T-reg) lymphocytes, and myeloid-derived suppressor cells (MDSC). Measurements were performed in the peripheral blood using flow cytometry of the peripheral blood at baseline and after the first cycle of blinatumomab. The first results show that patients with a higher proportion of baseline T-lymphocytes achieved MRD negativity more frequently with no statistically significant difference (p=0.06) and without differences in the subpopulation count following the first treatment. These extremely preliminary data could potentially pave the way for future studies, including larger and less heterogeneous cohorts, in order to assess the T-cell kinetics in a specific set of patients with potential synergy effects in targeting myeloid-derived suppressor cells (MDSC), commonly known to have an immune evasion mechanism in Bcp-ALL.

Effectiveness and Safety of Eliglustat Treatment in Gaucher Disease: Real-life Unicentric Experience.

PURPOSE: The therapy and management of Gaucher disease (GD) have radically changed with the use of substrate reduction therapy, of which eliglustat is the most widely known drug, allowing it to overcome the limits of enzyme replacement therapy (ERT). The rarity of GD and the limited use of eliglustat outside clinical trials require further study of its strengths and weaknesses. METHODS: In this study, we evaluated the effectiveness and safety of eliglustat in a cohort of 12 patients with GD followed up in our center, reporting a reduction in both chitotriosidase (394.3 vs 181.1 nmol/h/mL, P = 0.027) and glucosylsphingosine values (45.1 vs 18.9 ng/mL, P <0.001) after at least 12 months of therapy compared with baseline, regardless of patient demographic characteristics and GD characteristics. FINDINGS: There were no drug-related serious adverse effects and no drug-related cardiac events. Most adverse events were mild and transient, mainly dyspepsia and abdominal pain. Of interest, we reported an absence of statistical difference in terms of response regarding glucosylsphingosine reduction in relation to naive or prior exposure to ERT (P = 0.296), which was confirmed also when patients were placed in naive and treated groups for <5 vs >5 years (P = 0.667). IMPLICATIONS: The use of eliglustat immediately after diagnosis may guarantee the best treatment for patients with milder phenotypes or with aggressive disease after an initial stabilization with ERT compared with ERT, which cannot adequately remove the disease burden despite the apparent response, thus potentially reducing future complications caused by substrate deposits.

Gaucher disease prevalence in 600 patients affected by monoclonal gammopathy of undetermined significance.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive inherited disorder caused by the lysosomal enzyme acid ß-glucosidase deficiency. Many patients experience a critical delay in the diagnosis of up to 8-10 years due to its rarity and variability in signs and symptoms, with the consultation of several specialists. PATIENTS AND METHODS: This prospective observational study analyzed the prevalence of GD in 600 patients with monoclonal gammopathy of uncertain significance (MGUS) from January 2018 until February 2022. RESULTS: The mean age of participants was 66 years, with a mean monoclonal component of 0.58 g/dL. In 433 MGUS patients with available data, anemia (hemoglobin level < 10 g/dL) was present in 31 patients (7%), and thrombocytopenia (platelet count <100.000/mm3 ) in 24 (5.5%). Of 600 MGUS patients tested for acid ß-glucosidase enzyme activity, 7 patients (1.2%) had activity below 2.5 nmol/h/mL. In comparison, GBA gene analysis was executed in 110 patients. It revealed 4 patients (0.7%) affected by GD (3 patients with compound heterozygous mutation and 1 with homozygous mutation), with a prevalence of 1 every 150 MGUS patients. Furthermore, 12 out of the remaining 106 evaluated patients (11%) were carriers of a single heterozygous mutation while having regular enzyme activity. CONCLUSIONS: The clinical heterogeneity of GD and frequent lack of awareness among physicians often lead to diagnostic delays and severe clinical manifestations. The role of MGUS in the presence of at least one clinical sign, such as low platelet count, organomegaly, bone pain, or bleeding tendency, could aid in initiating GD screening with DBS, thus reducing the period between symptom onset and the diagnosis of this rare disease.

Lenalidomide plus Dexamethasone Combination as First-Line Oral Therapy of Multiple Myeloma Patients: A Unicentric Real-Life Study.

Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.2%) were alive, and 22 were still in treatment with Len/Dex. Among 73 evaluable patients who received at least two cycles, the overall response rate was 71% (N = 52). The disease control rate, defined as any level of clinical response to therapy, occurred in 71 patients (97%). We reported one or more adverse events of grade 3 or 4 (G3/4) in 65.2% (N = 58) of patients, with a prevalence of hematological toxicity (24 patients), leading to an overall discontinuation of treatment in two cases. In univariate analysis, high ISS, high serum ß2-microglobulin, and creatinine clearance <30 mL/min negatively impact OS, while the depth of response positively impacts OS. Moreover, G3-4 anemia, ISS, frailty score, and ECOG negatively impacts PFS. In conclusion, elderly and more frail patients benefit from the Len/Dex combination also in the era of monoclonal antibodies, ensuring an increased PFS and OS in patients where the therapeutic choice is often limited and usually not very effective.

AIPSS-MF machine learning prognostic score validation in a cohort of myelofibrosis patients treated with ruxolitinib.

BACKGROUND: In myelofibrosis (MF), new model scores are continuously proposed to improve the ability to better identify patients with the worst outcomes. In this context, the Artificial Intelligence Prognostic Scoring System for Myelofibrosis (AIPSS-MF), and the Response to Ruxolitinib after 6 months (RR6) during the ruxolitinib (RUX) treatment, could play a pivotal role in stratifying these patients. AIMS: We aimed to validate AIPSS-MF in patients with MF who started RUX treatment, compared to the standard prognostic scores at the diagnosis and the RR6 scores after 6 months of treatment. METHODS AND RESULTS: At diagnosis, the AIPSS-MF performs better than the widely used IPSS for primary myelofibrosis (C-index 0.636 vs. 0.596) and MYSEC-PM for secondary (C-index 0.616 vs. 0.593). During RUX treatment, we confirmed the leading role of RR6 in predicting an inadequate response by these patients to JAKi therapy compared to AIPSS-MF (0.682 vs. 0.571). CONCLUSION: The new AIPSS-MF prognostic score confirms that it can adequately stratify this subgroup of patients already at diagnosis better than standard models, laying the foundations for new prognostic models developed tailored to the patient based on artificial intelligence.

A case of high-risk AML in a patient with advanced systemic mastocytosis.

Aggressive SM + AML has limited therapeutic options. Even a strong combination of decitabine-venetoclax-midostaurin has a transient effect on AML and a mitigated effect on SM. Larger series are required to identify the best therapeutic strategy.

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data.

Gilteritinib has been approved as monotherapy in adults with acute myeloid leukemia (AML) FLT3 mutated with relapsed or refractory disease, in light of its advantages in terms of survival and the favorable safety profile. Hepatobiliary disorders and musculoskeletal and connective tissue disorders represent the most frequent adverse reactions associated with gilteritinib, whereas the most frequent serious adverse reaction is acute kidney injury. In the summary of product characteristics, gastrointestinal (GI) events are indicated as very common, in particular diarrhea, nausea and stypsis. Furthermore, serious GI disorders have been observed with gilteritinib in clinical trials, including GI hemorrhage, GI perforation and GI obstruction. However, the association with the FLT3 inhibitor has not been confirmed. Nevertheless, serious GI AEs have been recognized as an important potential risk to be monitored in postmarketing surveillance. We present three cases of serious self-limiting GI events observed in patients on gilteritinib treatment for AML, and an analysis of relevant available postmarketing surveillance data.

Clinical outcome of SARS-CoV-2 infections occurring in multiple myeloma patients after vaccination and prophylaxis with tixagevimab/cilgavimab.

Introduction: Patients with multiple myeloma (MM) frequently reported immune impairment with an increased risk for infection-related mortality. We aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during active treatment. Methods: We enrolled 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects. All subjects received 2 or 3 doses of the BNT162b2 (Pfizer/BioNTech) vaccine, and the anti-spike IgG values were evaluated after every dose. We applied the Propensity Score Matching (PSM) as a consequence of the limited sample size and its heterogeneity to adjust for differences in baseline clinical variables between MM patients who achieved or not a vaccine response after 2 or 3 doses. Results: At 30 days from the second dose, the median antibodies level in MM was 25.2 AU/mL, lower than in SMM and in the control group. The same results were confirmed after the third dose, with lower median anti-spike IgG levels in MM, compared to SMM and control group. Following PSM, lack of response to SARS-CoV-2 complete vaccination plus boost was associated with age more than 70 years old and use of high-dose of steroids. We failed to identify an association between specific treatment types and reduced vaccine response. The use of prophylaxis with tixagevimab/cilgavimab for 40 non-responder patients after 3 doses of vaccine has proven to be an effective and safe approach in reducing the risk of serious illness in the event of a breakthrough SARS-CoV-2 infection, faced with a mild symptomatic course, and in providing protection instead of long-term humoral immune vaccine responses. Following PSM, only the high-risk cytogenetic abnormalities were associated with an increased risk of developing a breakthrough SARS-CoV-2 infection. Conclusion: Monitoring the immune response is fundamental in MM patients that remain highly vulnerable to SARS-CoV-2 despite the vaccine. The use of prophylaxis with tixagevimab/cilgavimab can guarantee better protection from the severe form of the disease.