Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs

First-line therapy with either bortezomib-melphalan-prednisone or lenalidomide-dexamethasone followed by lenalidomide for transplant-ineligible multiple myeloma patients: A pooled analysis of two randomized trials

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger ( 6475 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196)

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis

We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage

P134 | BEYOND SUPPORTIVE CARE: THROMBOPOIETIN RECEPTOR AGONISTS AS THERAPEUTIC ENABLERS IN SOLID TUMORS WITH THROMBOCYTOPENIA. A SINGLE-CENTER EXPERIENCE

Introduction: Thrombocytopenia is a frequent hematologic complication in patients with solid tumors, arising from bone marrow infiltration, immune-mediated destruction, or treatment-related toxicity. Chemotherapeutic agents—especially platinum compounds, taxanes, and antiangiogenic drugs—are commonly implicated. Targeted therapies and immune checkpoint inhibitors have also been associated with immune thrombocytopenia. This condition may limit treatment intensity, increase bleeding risk, and negatively impact prognosis. Thrombopoietin receptor agonists (TPO-RAs) represent a valuable option to restore platelet counts and support the continuation of oncologic therapy in selected patients. Patients and Methods: We retrospectively analyzed 13 patients with solid tumors and thrombocytopenia, either at diagnosis or during anticancer therapy. Data were collected from 2017 to 2024. Median age was 76 years; the cohort included 6 females and 7 males. Bone marrow biopsy was performed in 12 cases, including cytogenetic and molecular analyses. Three patients harbored TP53 mutations, and one showed myelophthisis. Tumor types included breast, ovarian, prostate, bladder, lung, pancreatic and neuroendocrine carcinoma, renal cancer, and Hodgkin lymphoma. Clinical data included tumor histology, hematologic parameters, treatments, and responses to supportive therapy. Results: Four patients initially received corticosteroids or intravenous immunoglobulins, with limited or partial responses. Subsequently, 11 patients were treated with eltrombopag, 6 with romiplostim, and 1 with avatrombopag. Four patients required a switch to a second TPO-RA, and one a third as well. All achieved complete platelet responses, enabling continuation of oncologic therapy. TPO-RA dosing was individualized based on each patient’s treatment phase and platelet trend, with weekly complete blood counts submitted remotely by patients or referring oncologists. At the time of analysis, 10 patients were alive. Three patients died, including the one with myelophthisis, who continued breast cancer treatment for three years before death. (Tab. 1) Conclusion: Our experience supports the use of TPO-RAs in thrombocytopenic patients with solid tumors. These agents may enable full oncologic treatment delivery and improve clinical outcomes. In selected patients, restoring platelet counts is not just supportive care—it is a therapeutic bridge to maintaining oncologic intent and potentially prolonging survival

SP06 | EFFICACY OF ZANUBRUTINIB IN COMBINATION WITH ROMIPLOSTIM FOR EVANS SYNDROME IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA DURING VENETOCLAX TREATMENT

Introduction: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in Western countries, with age-related incidence and clinical heterogeneity. Evans Syndrome (ES), defined by the concurrent occurrence of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA), is a rare immune disorder often associated with lymphoproliferative diseases and potentially fatal outcomes. Management relies on expert consensus due to the lack of randomized trials. Standard CLL therapies include BTK inhibitors (BTKi) and the BCL2 inhibitor Venetoclax, often with anti-CD20 antibodies. When CLL progression is associated with immune cytopenias, immunosuppressive therapy is used, with CLL-directed treatment in refractory cases. To date, no reports have described ITP onset following Venetoclax in a patient with prior AIHA successfully treated with Zanubrutinib. Patients and Methods: We report the case of a 75-year-old man diagnosed in 2019 with asymptomatic CLL who, in 2021, developed steroid- and IVIG-refractory warm AIHA, treated with Bendamustine-Rituximab, achieving partial response. In July 2024, he showed rapid lymphocytosis progression (DT <2 months), splenomegaly (23 cm), thrombocytopenia (PLT 86×10⁹/L), and constitutional symptoms (Rai IV/Binet C). FISH was negative; IGHV unmutated, TP53 wild-type, CLL-IPI 6. Venetoclax-Rituximab (Murano protocol) was started. In week 2 of ramp-up, the patient developed spontaneous ecchymoses and gingival bleeding. Labs showed PLT 0×10⁹/L, Coombs-positive tests, Hb 10.7 g/dL, and a positive SARS-CoV-2 swab. Steroids and IVIG were ineffective. After swab negativization, Rituximab 375 mg/m² was administered weekly ×4 without response. He was referred to our ITP hub. Results: Romiplostim (Rom) was initiated at 3 μg/kg/week and increased by 2 μg/kg/week; Zanubrutinib (Zanu) 160 mg BID was added in week 2. Platelet and hemoglobin normalization occurred within 4 weeks. After 6 months, BTKi was continued at full dose and Rom reduced to 5 μg/kg/week. A 10-day BTKi interruption led to PLT drop (11×10⁹/L), reversed after Zanu reintroduction. The patient has since maintained a complete hematologic response with no adverse events (fig.1). Conclusion: TPO-RAs are effective in ITP. However, when ITP is secondary to CLL, targeting the underlying disease is crucial. BTKi have shown efficacy in ITP, as highlighted in the LUNA3 trial. This case supports the safety and efficacy of combining BTKi and TPO-RAs in refractory secondary ITP.

P136 | CLINICAL BENEFITS OF EARLY USE OF AVATROMBOPAG AS FIRST-LINE TPO-RA IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC IMMUNE THROMBOCYTOPENIA: THE EARLIER YOU START, THE LESS YOU NEED? A SINGLE-CENTER EXPERIENCE.

Introduction: Immune thrombocytopenia (ITP) is a rare autoimmune disorder caused by immune-mediated platelet destruction. After initial treatment with corticosteroids and/or immunoglobulins, second-line therapies for chronic or refractory ITP include thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag, romiplostim, and avatrombopag (Ava), and immunosuppressants like rituximab and fostamatinib. Splenectomy is now rarely performed. Treatment is individualized based on disease severity, comorbidities, and prior response. Patients and Aim: We report our single-center experience with Ava, emphasizing that early use as the first TPO-RA leads to better responses, lower doses, excellent compliance, and cost savings. Ava became available in Sicily in October 2023; from then to December 2024, 24 adult cITP patients (18 females, 5 males) were enrolled (median age 67.5 years, range 28–84). Median disease duration was 11.5 years (range 1–46), with a median of 2 prior treatment lines (range 1–8); three had undergone splenectomy. Baseline median platelet count was 11.5 × 10⁹/L (range 1–28). Results: Among 24 patients, 11 (45.83%) achieved complete response (CR), 9 (37.5%) partial response (PR), and 4 (16.67%) were refractory, with half discontinuing treatment. Notably, 9 achieved CR with very low Ava doses (mean 27.78 mg/week ±17.87; range 10–60 mg), 7 of whom were naïve to TPO-RAs or immunosuppressants. In high responders, thrombocytosis requiring temporary discontinuation and dose reduction occurred, followed by platelet stabilization without thrombosis or toxicities. None had undergone splenectomy. Median baseline platelet counts were higher in high responders (20 × 10⁹/L) than in poor responders (10 × 10⁹/L). Median time from ITP diagnosis was 8 years (range 1–24) vs 13 years (range 1–47), respectively. Among 15 patients requiring higher doses (mean 270.67 mg/week ±24.63; range 210–280 mg), 4 (16.67%) developed deep vein thromboses, leading to permanent Ava discontinuation (Tab. 1). Conclusion: Our findings suggest that significantly lower Ava doses were sufficient for high responders compared to poor responders (p < 0.001), likely reflecting differences in disease severity, prior treatments, and platelet counts. Early Ava use, preferably as first TPO-RA, may achieve better responses with lower doses, improving compliance and reducing thrombosis rate and long-term costs, which can be regarded as an oral alternative to romiplostim.

SP08 | FEASIBILITY OF FIXED-DURATION IBRUTINIB PLUS VENETOCLAX COMBINATION AS TREATMENT IN A VERY FRAIL, COMORBID AND BEDRIDDEN PATIENT WITH PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA

Introduction: Chronic Lymphocytic Leukemia (CLL) accounts for ~1–1.5% of all malignancies and is the most common adult leukemia in Europe and North America. It shows considerable heterogeneity in outcomes, with 50–70% of patients requiring treatment during the disease course. Standard therapies include BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and the BCL2 inhibitor venetoclax, alone or in combination with anti-CD20 antibodies. Since March 2024, the ibrutinib-venetoclax combination has been reimbursed in Italy as first-line therapy, with proven benefits in Progression Free Survival (PFS) and Time To Next Treatment (TTNT) in the GLOW and CAPTIVATE trials. Case Report: We present a 61-year-old man, heavy smoker, with chronic obstructive pulmonary disease (COPD), type 2 diabetes, ischemic-hypertensive cardiomyopathy, prior myocardial infarction, and multiple strokes (cerebellum, midbrain, pons) resulting in bedridden status, right hemiparesis, and dysphagia. Diagnosed with asymptomatic CLL in 2022, he developed symptomatic progression in Feb 2024, with anemia (Hb 9.6 g/dL), rapid lymphocytosis, bulky lymphadenopathy (7–10 cm), splenomegaly (26 cm), and constitutional symptoms (Rai III/Binet C). Beta-2 microglobulin and LDH were >3× ULN. PET/CT ruled out Richter transformation (SUVmax 6.6). FISH showed trisomy 12 and del(13q); del(17p) and TP53 mutation were negative, IGHV was unmutated. CLL-IPI was 5, ECOG PS 4, CIRS 22. Treatment and Outcome: Liver and kidney function were normal; cardiac evaluation was unremarkable. Given high TLS risk, fixed-duration therapy was started (Tab. 1): ibrutinib for 3 months, associating venetoclax from month 4 (WBC <50 × 10⁹/L), with standard 5-week ramp-up. Continuing his antiplatelet therapy, the patient achieved complete hematologic and radiologic response, is completing therapy without dose reductions or interruptions. No bleeding, TLS, or cardiovascular complications were observed, and MRD assessment in peripheral blood is planned. Conclusion: The ibrutinib-venetoclax combination has shown high efficacy across all CLL patient groups in registration trials. Despite safety concerns limiting its recommendation in the US, this case highlights the feasibility and tolerability of ibrutinib-venetoclax even in highly frail, comorbid patients when carefully managed, supporting its use as a best available first-line option in CLL.

La terapia chirurgica delle metastasi polmonari da osteosarcoma (Considerazioni preliminari su 30 casi osservati)

Si esaminano 30 casi di metastasi polmonare da osteosarcoma per valutare le indicazioni per un’escissione localizzata, e anche per presentare i risultati ottenuti. Questo gruppo è messo a confronto con altri 42 casi analoghi in cui le metastasi non erano state trattate chirurgicamente. I risultati della chirurgia polmonare si sono dimostrati efficaci nel trattamento multidisciplinare dell’osteosarcoma con metastasi polmonare

P135 | CLONAL EVOLUTION IN IMMUNE THROMBOCYTOPENIA (ITP): THREE CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA DURING TREATMENT WITH THROMBOPOIETIN RECEPTOR AGONISTS FOR ITP

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune cytopenia generally benign, though its long-term outcomes remain uncertain. While no clear evidence links ITP to increased risk of myeloid neoplasms (myelodysplastic syndromes or chronic myelomonocytic leukemia, CMML), rare co-occurrences suggest possible clonal hematopoiesis. We report three cases of long-standing ITP evolving into CMML during thrombopoietin receptor agonist (TPO-RA) therapy. Patients and Methods: Three patients (pts) (2 females, 1 male) were diagnosed with ITP at ages 52, 50, and 57, with disease durations of 23, 4, and 15 years, respectively. Initial bone marrow evaluations confirmed ITP. All received corticosteroids as first-line therapy. Second-line treatments included rituximab (n=2) and azacitidine with prednisone (n=1). Due to refractoriness, third-line TPO-RAs were introduced: romiplostim (n=2) and eltrombopag (n=1), with partial responses. Sequential switches followed, and all pts eventually received avatrombopag (Ava). During this therapy, progressive monocytosis and anemia developed, despite partial (n=2) or complete (n=1) platelet responses. In the male patient, monocytosis and leukocytosis had previously occurred under eltrombopag and romiplostim but regressed after their discontinuation. One patient developed an ischemic stroke due to aortic arch thrombosis and middle cerebral artery stenosis, requiring Ava withdrawal. All pts underwent repeat bone marrow evaluations including histology, cytogenetics, and next-generation sequencing (NGS). Results: Bone marrow histology confirmed CMML in all cases, with grade 1–2 reticulin fibrosis and 2–10% myeloid blasts. Cytogenetic analysis was normal. NGS for AML-related mutations was negative. Two patients carried TET2 and ASXL1 mutations, one also had SRSF2. The third patient had SRSF2, NRAS, and RUNX1 mutations. No other pathogenic variants were detected. All patients discontinued TPO-RA therapy. Two remain under follow-up with intermittent corticosteroids or IVIG for persistent thrombocytopenia. The oldest patient died at 76 from cardiovascular complications during SARS-CoV-2 infection (Tab. 1 ). Conclusions: These cases suggest that long-standing ITP may evolve into CMML, particularly during TPO-RA therapy. Early bone marrow evaluation and NGS at diagnosis may help detect clonal hematopoiesis before TPO-RA initiation, especially in patients with additional cytopenias or morphologic/numeric abnormalities