Persistent cytopenia due to poor graft function (PoGF) is a relatively common complication which may affect up to 20% of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). ...Treatment options for PoGF remain limited, and reinfusion of additional HSC is often the only way to rescue hematopoiesis. Here we describe a retrospective single-center experience with the thrombopoietin-mimetic agent eltrombopag for the treatment of PoGF. Thirteen patients have received eltrombopag for either PoGF (n = 12) or primary graft failure (n = 1). In the 12 PoGF patients eltrombopag was started at the median time of 79 days after HSCT, due to persistent thrombocytopenia, with concomitant anemia and neutropenia in 7 and 3 patients, respectively. The treatment was started at the dose of 50 mg per day, and eventually increased up to 150 mg in case of lack of response. Hematological response was seen in 7 patients, with 6 complete responses. Hematological responses were seen both in patients with evidence of immune-mediated pathophysiology, and with possible infectious/iatrogenic causes. In responding patients, eltrombopag was discontinued in 6/7 patients without further relapse. These results suggest that eltrombopag is safe and possibly effective in the setting of the treatment of PoGF, and pave the way for future prospective studies.
Belantamab-mafodotin is an innovative and selective treatment for multi-refractory/relapsed multiple myeloma (MM) patients; however, available real-life experiences on efficacy and safety are ...limited. In this real-world multicentric retrospective study, we enrolled 28 MM patients treated in four Hematology units of Campania region, Italy, who received a median of six treatment lines prior to belantamab-mafodotin. The overall response rate (ORR) was 40% (complete remission, CR, 11%; very good partial remission, VGPR, 11%; and partial remission, PR, 18%), with a median progression-free survival (PFS) and overall survival (OS) of 3 and 8 months, respectively. One of the most frequent drug-related adverse events was keratopathy observed in nine (32%) patients, leading to therapy discontinuation in only three (11%) of them. Moreover, 22 out of 28 total patients who were treated with at least two administrations achieved an ORR of 50% (CR, 14%; VGPR, 14%; and PR, 22%) with a median PFS and OS of 5 and 11 months, respectively. In conclusion, our multicentric study confirmed efficacy and safety of belantamab-mafodotin in triple-refractory MM patients even in the real-life setting.
Contrast-enhanced ultrasonography (CEUS) use for detecting lymphoma in the spleen was questioned because of the risk of its inadequate diagnostic accuracy. The aim of the present study was to ...validate CEUS exam for the identification of spleen involvement by lymphoma in patients at risk. A total of 260 nodules from the spleens of 77 patients with lymph node biopsy-proven non-Hodgkin lymphoma (NHL; n = 44) or Hodgkin lymphoma (HL; n = 33) at staging (n = 56) or follow-up (n = 21) were collected in a hematology Italian center and retrospectively analyzed. Nodules were classified as malignant lymphoma if ≥0.5 cm (long axis) with arterial phase isoen-hancement and early (onset <60 s after contrast agent injection) wash-out of marked (≤120 s after contrast agent injection) degree. Other perfusional combinations at CEUS scans qualified lesions as benign or inconclusive. Diagnostic reference standard was clinical laboratory imaging monitoring for 230 nodules, and/or histology for 30 nodules. The median nodule size was 1.5 cm (range 0.5−7 cm). According to the reference standard, 204 (78%) nodules were lymphomas (aggressive-NHL (a-NHL), 122; classic-HL (c-HL), 65; indolent (i)-NHL, 17) and 56 (22%) were benign (inflammation, infection, and/or mesenchymal) lesions. Sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy of CEUS for detecting lymphoma in the spleen were 95%, 100%, 100%, 85%, and 96%, respectively. Marked wash-out range of 55−90 s (median, 74 s), 92−120 s (median, 100 s), and 101−120 s (median, 114.5 s) was 100%, 96.6%, and 77% predictive of a-NHL, c-HL, and i-NHL splenic nodular infiltration, respectively. The CEUS perfusional pattern of arterial phase isoenhancement with early wash-out of marked degree was highly accurate for the detection of lymphomatous invasion of spleen in patients at risk, enabling its use for a confident non-invasive diagnosis.
Summary
We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients ...(29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.
The incidence of peripherally inserted central catheter (PICC)-related adverse events has been uncertain in the setting of acute myeloid leukemia (AML) compared with the incidence of centrally ...inserted central catheter (CICC) adverse events.
We conducted a monocentric, randomized trial of patients with previously untreated AML. Of the 93 patients, 46 had received a PICC and 47 had received a CICC as frontline intravascular device. Thereafter, all patients underwent intensive chemotherapy for hematologic remission induction. The primary endpoint was catheter-related (CR)-bloodstream infection (BSI) and venous thrombosis (VT) rate. The secondary endpoints catheter malfunction, catheter removal, and patient overall survival.
The CR-BSI and CR-VT rate in the PICC and CICC groups was 13% and 49%, respectively, with a difference of 36 percentage points (relative risk for CR-BSI or CR-VT, 0.266; P = .0003). The CR-BSI incidence was 1.4 and 7.8 per 1000 catheters daily in the PICC and CICC groups, respectively. Among the CR thromboses, the symptomatic VT rate was 2.1% in the PICC group and 10.6% in the CICC group. In the CICC group, 16 of the 47 patients (34%) had the catheter removed for BSI (n = 5), septic thrombophlebitis (n = 4), VT (n = 2), or malfunction (n = 5) a median of 7 days after insertion. In the PICC group, only 6 of the 46 patients (13%) required catheter removal for VT (n = 2) or malfunction (n = 4). At a median follow-up of 30 days, 6 patients in the CICC group died of CR complications versus none of the patients in the PICC group (P = .012). Using PICCs, the reduction in BSI and symptomatic VT decreased mortality from CR infection and venous thromboembolism. In contrast, the CICC approach led to early catheter removal mostly for difficult-to-treat infectious pathogens.
Our data have confirmed that BSI and symptomatic VT are the major complications affecting frontline central intravascular device-related morbidity in the leukemia setting. The use of a PICC is safer than that of a CICC and maintains the effectiveness for patients with AML undergoing chemotherapy, with an approximate fourfold lower combined risk of infection or thrombosis at 30 days.
Placement of a central venous catheter (CVC) is fundamental for the administration of chemotherapeutic agents and supportive therapy for patients with acute myeloid leukemia (AML). We performed a single-center, randomized trial comparing peripherally inserted central catheter (PICC)-related and centrally inserted central catheter (CICC)-related complications. Among 93 randomized patients, PICC was safer than CICC, with a 36-percentage point reduction in the complication rate, while maintaining effectiveness. We propose PICC as a new frontline central vascular access option for patients with AML.
Introduction. Type I Gaucher disease (GD1) has been associated with increased cancer risk in the International Collaborative Gaucher Group (ICGG) Registry. Particularly, it is well recognized that ...the risk for multiple myeloma (MM) in affected individuals may be about 9 times higher than expected in the general US populations (Rosenbloom et al, 2022). Pathogenetic relationship between GD1 and MM is still unclear. It was hypothesized that accumulation of glucosylceramide in the macrophages leads to their activation and chronic immune stimulation favouring polyclonal gammopathies. In this scenario plasma cell clone selection could be promoted and subsequent MGUS/MM could derive from it. Diagnosis of GD1 is often inaccurate or delayed since symptoms and signs of disease are nonspecific or underhand. We designed a prospective study to investigate the prevalence of GD1 in a large MM patient population to provide substantial evidences to consider GD1 in the pathogenesis and management of MM. Patients and Methods. This is an observational, prospective, cross-sectional, multicentre study. Twenty-five Italian hematologic centers participated in this study. Due to the lack of data on the effective prevalence of GD1 in MM, the sample size has been determined considering clinically relevant a prevalence of the condition > 0.5% for defining as “high risk” the selected population. Considering an alpha error of 5% and a statistical power of 95%, approximately 1000 patients should beenrolled.. All MM patients are screened by Dried Blood Spots (DBS) sampling technique, that was centralized at the Istituto per la Ricerca e l'Innovazione Biomedica CNR-Palermo. All patients with a positive DBS test undergo genetic test to confirm the diagnosis of GD1. Primary end-point of the study is the prevalence of DBS test positivity in MM patients, which measures glucocerebrosidase activity in peripheral blood leukocytes (normal range 0.2-2.5 nMol/h/m). If the observed prevalence had been significantly higher than predicted, we would have tried to identify the population at higher potential risk of associated GD1. Results. We enrolled 902 patients with a median age of 68 years (range 37-90), 60% of which were male. No patients were Jews, 2 were Asian and 10 were Black, all others were Caucasian. Newly diagnosed and relapsed-refractory MM were 65% and 35%, respectively, whereas SMM and MM were 15% and 85%, respectively. Monoclonal component was IgG in 60%, IgA in 25%, light chain in 15%. Median Ferritin was 310 ng/ml (range 17-1236) and median Alkaline Phosphatase was 75 U/L (range 29-355). Descriptive data of DBS test, enzymatic activity and genetic tests are reported in the Table. In summary, DBS test was found positive in 12/902 (1.33%). Genetic test confirms GBA gene mutations, single heterozygous in 11 patients and double heterozygous in 1 patient. N370S and L444P loci accounted for 50% of GBA gene mutations found. Double-heterozygous patient started replacement therapy for GD1 with imiglucerase. Conclusions. After the enrolment of more than three quarter of the planned patients, the prevalence of DBS test positivity was higher than 0.5% (1.3%). Genetic test confirmed involvement of GBA genes, all but one in heterozygosity fashion. This study allowed to identify one patient with MM and GD1 requiring therapy for both diseases at the same time. The results of this study support further investigations on the implication of the GD1 in the pathogenesis and management of MM. More data on MM patient subgroups at higher risk of associated GD1 may be provided.
While vast majority of patients achieve robust engraftment within a few weeks after allogeneic hematopoietic stem cell transplantation (HSCT), some patients may experience persistent cytopenias, ...mostly thrombocytopenia, which are usually referred to as poor graft function (PGF). Unfortunately, treatment options for PGF remain limited, because except the possible treatment of the cause (which is often missing, and not always treatable) the only therapy is a boost of HSCT from the same donor. Eltrombopag is a thrombopoietin-mimetic agent which is approved for the treatment of idiopathic thrombocytopenia; more recently, it has been shown effective for the treatment of aplastic anemia. Between January 2011 and April 2018, 66 patients suffering from different malignant or non-malignant hematological diseases underwent an HSCT at the Federico II University of Naples. We report on a retrospective analysis of 13 transplanted patients who have consistently received eltrombopag for the treatment of post-HSCT persistent cytopenia. Patients were selected according the following criteria: lack of neutrophil engraftment at day +28 (primary graft failure), or persistent unilineage or multilineage cytopenia at anytime after HSCT (PGF; demonstration of impaired hematopoiesis by bone marrow analysis). All but one patients (who had severe aplastic anemia) were transplanted for a malignant disease, after a fully myelo-ablative conditioning regimen. There was a female prevalence (9 out 13); the median Sorror comorbidity index was 0 (range 0-2) while the median EBMT score was 4 (range 2-7). The most common HSC source was bone marrow (BM) (10 out 13 patients, 83,3%), and the median dose of CD34+ was 2.24 x 106/kg (range 0.68-7.2), with 4 out of the 13 patients (33%) who have received <2 x 106 CD34+/kg (but only 1 <1.5 x 106 CD34+/kg). Major ABO-incompatibility was present in 4/13 cases (25%); these patients underwent 2-3 sessions of plasmapheresis before receiving an unmanipulated BM. The vast majority of patients (9 out 13, 75%) were transplanted from a haploidentical donor, while 2 and 2 patient were grafted from unrelated or sibling HLA-matched donor. Considering patients evaluable for engraftment (alive at day +35, n=52) the incidence of PGF was not increased in haplo-identical HSCT (Fisher two-tailed exact test, p=0.32). All but one patients had ANC engraftment (median 18 days, range 14-34), with donor engraftment confirmed by full donor chimerism on bulk BM specimen. The patient suffering from primary graft failure underwent a second HSCT from the same donor, eventually dying from acute GvHD. Indeed, 11/12 patients were classified as having PGF based on low platelet counts; 6 of them were considered primary PGF because they have never reached platelets >20000/µL after HSCT. In most patients, PGF was not limited to the megakaryocytic lineage, since anemia and neutropenia affected respectively 6 and 2 patients. At the time of PGF, 6/12 patients had grade II-IV acute GvHD. Among the 12 patients with PGF, 5 patients achieved a complete response and 2 patient a partial response; among the 5 non-responders, 2 suffered from early deaths due to infectious complications and were not evaluable for response. Among the 6 responders, 3 of them have discontinued eltrombopag, while retaining their hematological response. The long-term outcome of this cohort was good, since only 3 deaths were observed (the 2 infections and one grade IV aGvHD). No patient experienced relapse of his underlying disease, eventually suggesting that eltrombopag should not preferentially stimulate possible residual malignant cells. In conclusion, our study suggest that eltrombopag is safe and can be hypothesized as etiologic treatment of PGF; indeed, eltrombopag may be considered in post-HSCT prolonged cytopenia due to PGF when other etiologic treatments are elusive or ineffective. Not all PGF share the same cause and pathogenic mechanism; in our preliminary experience eltrombopag seems more effective when additional specific causes can be identified (e.g., immune mechanism associated with GvHD, or infectious complications and their treatments). Future studies are needed to better understand the pathogenic events underlying PGF in individual patients, and to identify the setting of PGF patients who may best benefit from eltrombopag treatment.
Pane:BMS: Speakers Bureau; AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Risitano:Amyndas Pharmaceuticals: Consultancy; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.
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