Median Treatment-free Survival Research Articles

Vitamin D supplement for patients with early-stage chronic lymphocytic leukemia is associated with a longer time to first treatment

AbstractLow levels of vitamin D are associated with a shorter time to first treatment (TTFT) and inferior overall survival in patients with chronic lymphocytic leukemia (CLL). But whether vitamin D supplement affects the clinical course of patients with CLL, remains an open question. In this study, we aimed to retrospectively explore the clinical benefit of vitamin D supplement or one of its analogs, on TTFT and treatment-free survival (TFS) in a large cohort of patients with asymptomatic CLL, who were under watch-and-wait approach. Among the 3474 patients included in the study, 931 patients (26.8%) received either vitamin D supplement or its analog, for a minimum of 6 months. We found that vitamin D supplement was statistically significant for longer TTFT in the young cohort (age ≤65) and was associated with a longer TFS for all ages (P = .004). Among non–vitamin-D users, the median TFS was found to be 84 months, whereas among vitamin D supplement users the median TFS extended to 169 months. In conclusion, our long-term retrospective study demonstrates that the administration of vitamin D to patients with CLL in a watch-and-wait active surveillance is significantly associated with a longer TFS (in any age) and a longer TTFT among young patients (age ≤65). A prospective clinical trial is needed to validate results.

Outcomes of Patients with Small Lymphocytic Lymphoma (SLL) Receiving First Line Treatment

INTRODUCTION Chronic lymphocytic leukemia (CLL) and SLL represent a single entity in current classifications per the WHO-HAEM5 and ICC. Both are characterized by malignant B cells with an identical immunophenotype, but they are distinguished by the predominant site of disease burden, such as peripheral blood for CLL and nodal compartments for SLL. Most clinical trials and retrospective studies involving CLL/SLL do not separate out SLL patients. In this study, we report reasons for treatment initiation and outcomes in a cohort of SLL patients seen at our institution. METHODS Using the Mayo Clinic CLL Database, we retrospectively identified patients with SLL who received first line therapy between 12/1995 and 2/2023. Patients were classified as having SLL if they met at least one of the following criteria for diagnosis: 1) presence of lymphadenopathy or splenomegaly (either by exam or scans) and an absolute clonal B cell count of < 5 x 109/L; or 2) presence of lymphadenopathy or splenomegaly (either by exam or scans) and an absolute lymphocyte count of < 11 x 109/L (if absolute clonal B cell count was not available). Although the presence of anemia (hemoglobin < 11 g/dL) and thrombocytopenia (platelets < 100 x 109/L) are considered as exclusion criteria for a diagnosis of SLL, patients were included if these cytopenia were due to autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP) with < 50% bone marrow involvement by SLL (bone marrow biopsy confirmed). Patients treated for SLL with extranodal involvement were also included. Indications for SLL treatment were abstracted by chart review and included one of the following: 1) symptomatic or progressive lymphadenopathy and/or splenomegaly, 2) autoimmune cytopenias, 3) extranodal/direct organ infiltration; and 4) other (e.g., cryoglobulinemia, paraneoplastic, non-infiltrative renal disease such as minimal change disease). Overall survival (OS) was defined as the time from treatment start until date of death or last known to be alive. Treatment-free survival (TFS) was defined as the time from treatment start until the earliest of date of next treatment, or death. Kaplan-Meier method was used to display OS and TFS. Cox proportional hazards regression models were used to estimate associations of factors with time-to-event outcomes. RESULTS We identified 182 patients with SLL who received first line treatment. The median age at treatment start was 66 years, and 132 (73%) were male. Unmutated IGHV was identified in 60/82 (73%) patients and peripheral blood fluorescent in situ hybridization (FISH) assessed pre-treatment start showed del13q in 10%, trisomy 12 in 43%, del11q in 7%, del17p in 8%, and no abnormalities in 33%. TP53 disruption (del17p and/or TP53 mutation) was present in 7/89 (8%) patients prior to first therapy. The median follow-up after diagnosis was 6.9 years. The indications for treatment were grouped as follows: symptomatic or progressive lymphadenopathy/splenomegaly (n=130), extranodal/direct organ infiltration (n=30), AIHA/ITP (n=10), and other (n=12). For the entire cohort, the median TFS was 2.9 years and the median OS was 12.3 years. The median TFS by the treatment indication groups were 3.3, 5.1, 1.6, and 5.3 years, respectively (Figure 1). The median OS by treatment indication groups were 11.1, 10.5, 8.8, and 19.9 years, respectively. Among the 160 patients with symptomatic or progressive lymphadenopathy/splenomegaly or extranodal disease, the treatments administered include: mAb alone (n=35), chemotherapy alone (n=33), chemoimmunotherapy (n=57), targeted agent (n=33; Bruton tyrosine kinase inhibitor [BTKi] based n=28; venetoclax-based n=3, BTKi + venetoclax n=2), and other (n=2). The median TFS by treatment groups were 2.4, 2.0, 3.8, and 6.0 years (Figure 2), respectively (excluding the small “other” subgroup of 2 patients). The median OS for these groups were 9.5, 9.7, 15.0, and not evaluable, respectively. Only older age at treatment start predicted for shorter TFS (HR 1.02; 95%CI 1.002-1.038; p=0.03) and shorter OS (HR 1.05; 95%CI 1.03-1.07; p<0.01). CONCLUSIONS In this study of patients with SLL who received therapy, the most frequent indications for treatment included symptomatic lymphadenopathy and/or splenomegaly, followed by extranodal disease. Trisomy 12 was the most frequently detected abnormality on peripheral blood FISH testing. Treatment with novel agents achieved durable TFS and OS.

Clinical Outcomes with Venetoclax-Based Treatment Regimens in Patients with Chronic Lymphocytic Leukemia (CLL)

INTRODUCTION We aim to identify factors that impact outcomes of venetoclax for patients with CLL treated in routine practice at a tertiary center. We report on the use of venetoclax in the most frequently encountered disease scenarios: first-line, relapsed/Bruton tyrosine kinase inhibitor (BTKi)-naïve, and relapsed/BTKi-exposed. METHODS We identified patients who received venetoclax therapy for CLL (between 4/2012-4/2023) from the Mayo Clinic CLL Database. Undetectable measurable residual disease (uMRD) was defined as <1 CLL cell per 10,000 leukocytes using 8-color flow cytometry on peripheral blood (PB) or bone marrow (BM). Overall survival (OS) was defined as the time from venetoclax start until date of death or last known to be alive. Treatment-free survival (TFS) after venetoclax was defined as the time from venetoclax start until the earliest of date of next treatment, or death. Kaplan-Meier was used to display OS and TFS. Multivariable Cox proportional hazards regression models were used to estimate associations of factors with time-to-event outcomes. RESULTS A total of 155 patients received venetoclax: firstline therapy (in combination with obinutuzumab, n=55) and relapsed CLL (n=100; 17 had relapsed/BTKi-naïve CLL, and 83 had previously received BTKi [55 with progression after BTKi], relapsed/BTKi-exposed). The median follow-up for the cohorts of first-line therapy, relapsed/BTKi-naïve, and relapsed/BTKi-exposed was 12.9 months, 37.0 months, and 27.6 months, respectively. Baseline characteristics at the time of venetoclax initiation for all patients are shown in Table 1. The median TFS for the overall cohort was 39.0 months. The median OS was 54.6 months. Among patients treated with venetoclax as first-line therapy (n=55), the 2-year TFS ( Figure 1) and 2-year OS rates were both 91%. MRD testing was performed in 28 patients and was uMRD in 23 (82%) patients (only PB assessed, n=7; only BM assessed, n=2; PB and BM assessed, n=14). Detectable MRD was identified in 3 patients, and 2 patients had discordant results (PB uMRD and BM detectable disease). Among patients treated with venetoclax in the relapsed/BTKi-naïve setting (n=17), the 2-year TFS rate was 73% ( Figure 1) and the 2-year OS rate was 100%. MRD testing was performed in 7 patients and was uMRD in all 7 (100%) (only PB assessed, n=3; only BM assessed, n=2; PB and BM assessed, n=2). The median time to first uMRD result was 14.1 months. Among relapsed/BTKi-exposed venetoclax-treated patients (n=83), the median TFS was 26.9 months ( Figure 1), and the median OS was 39.4 months.In this subgroup, the median TFS for patients with (n=55) and without (n=28) prior disease progression on prior BTKi were 22.3 and 42.3 months, respectively. Median TFS with venetoclax monotherapy (n=30) was 24.0 months, venetoclax in combination with rituximab (n=37) was 26.9 months, and venetoclax in combination with obinutuzumab (n=16) was 39.0 months. BTKi-exposed patients that were chemotherapy-naïve (n=27) and chemotherapy-exposed (n=56) had median TFS of 29.1 and 24.0 months, respectively. MRD testing was performed in 28 patients and was uMRD in 16 (57%) patients (only PB assessed, n=9; only BM assessed, n=2; PB and BM assessed, n=5). Detectable MRD was identified in 11 patients, and 1 had discordant results (PB uMRD and BM detectable disease). The median time to first uMRD result was 11.5 months. TP53 disruption, unmutated IGHV genes, older age, complex karyotype (CK; defined as more than 3 chromosomal aberrations on CpG stimulated karyotype), and disease progression on prior BTKi were associated with shorter TFS in the overall cohort on univariate analysis. TP53 disruption, older age, CK, and disease progression on prior BTKi were associated with shorter OS in the overall cohort on univariate analysis. Multivariable analysis was performed by including only those patients where all variables significant in univariable analysis were available (OS model n=65, TFS model n=53). In these models, only CK was significantly associated with shorter TFS (HR 8.5; 95%CI 2.5-29.1; P<0.001) and shorter OS (HR 4.1; 95%CI 1.2-14; P=0.03). CONCLUSIONS Patients with BTKi-exposed CLL, particularly those with prior disease progression on BTKi, had worse outcomes. Our study identified CK as one of the most important baseline predictors of adverse TFS and OS in the overall cohort of patients, supporting karyotype assessment for prognostication prior to venetoclax treatment.

High Responses Rates with Single Agent Belantamab Mafodotin in Relapsed Systemic AL Amyloidosis

Introduction: Systemic AL amyloidosis, a rare incurable plasma cell disorder, has no approved treatments at relapse. Belantamab mafodotin is an antibody-drug conjugate which targets BCMA antigen approved for relapsed refractory myeloma. We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those traditionally excluded from clinical trials (eGFR<30 ml/min/1.73m 2 and cardiac Mayo stage IIIb disease). Methods: All patients treated with belantamab mafodotin monotherapy at standard dose (2.5 mg/kg) or dose reduction between April 2021 - July 2023. Standardised assessments including measurement of cardiac biomarkers, clonal parameters and imaging were performed and disease assessment was reported as per International Society of Amyloidosis consensus criteria. Results: Twenty-seven patients were included. The median age at was 65 years (range 41-76) and eight (30%) patients were aged >70 years. Eighteen (67%) had λ AL-type and nine (33%) κ AL-type. A median of two organs were involved at baseline (range 1-4) with renal and cardiac involvement in 20 (74%) and 15 (56%) respectively (3 each for Mayo stage IIIa and stage IIIb). The median time from AL amyloidosis diagnosis to first administration of belantamab mafodotin was 69 (range 5-174) months (~6 years) with a median of 3 prior lines of treatment (range 2-6). Prior drug class exposure included proteasome inhibitors (100%), immunomodulatory drugs (81%) and anti-CD38 antibody (81%) therapy. Ten patients (37%) had undergone prior melphalan-conditioned autologous stem cell transplantation. At the time of first belantamab mafodotin dose, the median involved free light chain concentration was 118mg/l (range 31-1778), eGFR was 40 ml/min (range 7 - 120) and a third (9/27) with an eGFR <30 ml/min/1.73m 2. NT-proBNP was 845 ng/l (range 99-70,000). At data cut-off, a median of 5 (range 1-11) doses of belantamab mafodotin were delivered. Of those with evaluable disease, best haematological overall response rate (partial response or better) was 80% (20/25) at a median time to best haematological response of 2 months (95% CI 1-4, range 1-17). Complete response (CR) or very good partial response (VGPR) was achieved in 64% (16/25). Two patients have only had 1 cycle and too early to perform response assessment. Reasons for treatment discontinuation (n=12) were: inadequate response/progression (n=7), keratopathy (n=1), grade 3 thrombocytopenia (n=1), physician choice (n=3: discontinued due to treatment for unrelated metastatic squamous cell carcinoma but remains in CR; facilitation of renal transplant; prior to BCMA-directed CAR-T in VGPR). At a median follow-up of 13 months follow-up (95% CI 4-18, range 1-27) from belantamab mafodotin initiation, 15 patients (56%) remain on therapy. Two patients died (1 due to progressive disease, 1 unrelated) and seven patients progressed and had subsequent line of therapy at a median time of 6 months (95% CI 2-4) in those that had a next line of therapy. Median treatment-free survival or death was 27 months (10-NR), and 1-year treatment-free survival/death was 69% (95% CI 41-86). Median overall survival (OS) is not reached. 1-year OS is 88% (95% CI 59-97). Bilateral microcystic corneal keratopathy, the most frequent adverse event, was seen in 19 (70%) patients (5%; 1/19 grade 4).Ocular adverse events improved in all patients after treatment delay. Only one patient required treatment cessation due to ocular toxicity (despite achieving PR after one dose). Thrombocytopenia was reported in 3 (11%) (grade 3: 1; grade 2: 1). Only two patients remained on the standard dose of 2.5mg/kg for >3 cycles. Nine patients had eGFR <30ml/min and 6/9 started at a dose of 1.25mg/kg with no unexpected side effects (1 patient had grade 3 keratopathy). One patient post-renal transplantation (on tacrolimus and mycophenolate) had no significant toxicity and achieved a CR after cycle 3. No treatment-related deaths, cardiac or renal toxicities observed in our cohort. Conclusion: Belantamab mafadotin has high efficacy and good tolerability in multiply relapsed AL amyloidosis including efficacy in patients otherwise excluded from clinical trials. Treatment-emergent adverse events (especially keratopathy) do not preclude delivery of drug with appropriate dose reductions.

Patients with Chronic Lymphocytic Leukemia Carrying t(14;19) Display a Distinctive Transcriptomic Profile and Adverse Outcome, Which Might be Overcome Continuous Therapy with BTK Inhibitors. an Italian Campus CLL and Eric Study

Introduction Rearrangements of the BCL3 gene due to the translocation t(14;19)(q32;q13) can be identified in up to 1% of chronic lymphocytic leukemias (CLL) with stimulated karyotype and is associated with an adverse outcome. In this study, we aimed at unraveling the clinico-molecular features of CLL harboring t(14;19), including the response to novel therapies. Methods CLL with t(14;19) were collected within databases from the Italian Campus CLL , European Research Initiative on CLL, German CLL study group and Ohio State University. Treatment-free survival (TFS), time to next treatment (TTNT), overall survival (OS) curves were compared with the Log-rank tests. For RNA sequencing (RNA-seq), RNA was extracted from 10 6 purified B-cells, processed by TruSeq Stranded Total RNA Ribo-Zero Gold, sequenced by Illumina at an average read depth of 120x10 6 per sample. Linear and circular RNAs (circRNA) were identified and quantified with CirComPara2 software. Differential expression analysis was conducted imposing a 0.01 Benjamini-Hochberg adjusted p value threshold by using the DESeq2 and limma-voom R/Bioconductor packages for gene and circRNA expression, respectively. Pathway enrichment was conducted using the gene set enrichment analysis (GSEA) method from the clusterProfiler R. Results We gathered data from 88 patients with t(14;19) CLL from 16 centers, 52% were males, the median age at diagnosis was 58±13years, 93% (68/73) had an unmutated IGHV status [U-IGHV, including 25% stereotyped subset #8], 60% carried trisomy 12 (+12), 52% a complex karyotype (CK, 52% ≥3 aberration, 19% ≥5), 39% atypical phenotype (22/57, Matutes score <3) and 15% TP53 abnormality (abn, deletion and/or mutation). To dissect the role of t(14;19) in CLL pathobiology, we analyzed the transcriptomes of 25 t(14;19) samples (comparable in terms of TFS and OS to the whole cohort), 22 control CLL without t(14;19) (11 with +12 and 11 with both normal FISH and karyotype, 10 being U-IGHV) and B cells from 9 healthy donors. Among the differentially expressed genes between t(14;19) cases and control CLL, 708 were upregulated and 1230 downregulated. In particular, among the top upregulated genes we found BCL3, CD79b (confirming their atypical phenotype), CDKN2A, U2, TP63 and LAG3 whereas among the downregulated CD274 and TIGIT. Of note, the t(14;19) cases displayed a significant enrichment (p-adjusted<0.01) of distinct Gene Ontology pathways, primarily downregulation of leukocyte chemotaxis, immune effector process and cytokine-mediated signaling. Further, we detected over 23000 circRNAs expressed from 7024 genes. Most circRNAs were backspliced from known exons (97%), whereas 1.8% and 1.2% involved intronic and intergenic regions, respectively. We found 60 circRNA upregulated and 197 downregulated circRNAs in t(14;19) cases compared to control CLL, including 28 also differentially expressed against normal B cells, such as circCDK14, not annotated and generated by antisense gene. After a median follow-up of 7.6 years, the median TFS and OS were 2 and 12.6 years, respectively. In univariate analysis, no clinic-biological variables correlated with TFS and OS. The poor outcome of t(14;19) patients was similar to CLL cases without t(14;19) but harboring TP53 abn or CK5, and even shorter than CK3 or +12 patients (historic data from the Italian Campus CLL). By analyzing the first-line therapy, 28 patients received FCR/BR, 6 venetoclax-based (VEN) therapy (5 within the CLL13 trial), 12 BTK inhibitor (BTKi, 10 ibrutinib and 2 acalabrutinib), 34 other therapies. TTNT was longer with BTKi (p<0.001, Figure 1). At 3-year 59%, 67%, 100% and 35% for patients treated with FCR/BR, VEN, BTKi and others did not need a further line of therapy. In the relapse setting, 11 patients received VEN and 29 BTKi; a trend for a longer TTNT was observed with BTKi (3-year, 16% vs 64%, p=0.09) Discussion In this international retrospective study we report that t(14;19) i) is recurrent in young CLL with sterotyped #8; ii) portends a negative prognostic impact superimposable to CK5 or TP53 cases; iii) display by a distinct gene expression profile characterized by the deregulation of immune checkpoints, offering a hint for innovative therapeutic approaches, and of circRNAs, whose pathogenetic role in CLL is still unknown and deserves further investigation. Finally, for this aggressive subset of CLL, a continuous therapy with a BTKi resulted in improved treatment outcomes

Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease?

BackgroundUpfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. ObjectiveTo investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design, setting, and participantsThis was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysisWe measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitationsAt median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. ConclusionsCN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summaryIn our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

Safety and efficiency of repeat salvage lymph node dissection for recurrence of prostate cancer using PSMA-radioguided surgery (RGS) after prior salvage lymph node dissection with or without initial RGS support.

Metastasis-directed therapy is a feasible option for low PSA, recurrent locoregional metastatic prostate cancer. After initial salvage surgery, patients with good response might consider a repeat salvage surgery in case of recurrent, isolated, and PSMA-positive metastases. This analysis aimed to evaluate the oncological outcome and safety of repeat PSMA-targeted radioguided surgery (RGS) after either prior RGS or "standard" salvage lymph node dissection (SLND). We identified 37 patients undergoing repeat RGS after prior SLND (n = 21) (SLND-RGS) or prior RGS (n = 16) (RGS-RGS) between 2014 and 2021 after initial radical prostatectomy with or without pelvic radiation therapy at two German tertiary referral centers. Kaplan-Meier analyses and uni-/multivariable Cox regression models were used to investigate factors associated with biochemical recurrence-free survival (BRFS) and treatment-free survival (TFS) after repeat salvage surgery. Complete Biochemical Response (cBR, PSA < 0.2ng/ml) was observed in 20/32 patients (5 NA). Median overall BRFS [95% confidence interval (CI)] after repeat salvage surgery was 10.8months (mo) (5.3-22). On multivariable regression, only age (HR 1.09, 95% CI 1.01-1.17) and preoperative PSA (HR 1.23, 95% CI 1.01-1.50) were associated with shorter BRFS, although PSA (HR 1.16, 95% CI 0.99-1.36) did not achieve significant predictor status in univariable analysis before (p value = 0.07). Overall, one year after second salvage surgery, 89% of the patients (number at risk: 19) did not receive additional treatment and median TFS was not reached. Clavien-Dindo grade > 3a complications were observed in 8% (3/37 patients). Limitations are the retrospective evaluation, heterogeneous SLND procedures, lack of long-term follow-up data, and small cohort size. In this study, repeat RGS was safe and provided clinically meaningful biochemical recurrence- and treatment-free intervals for selected cases. Patients having low preoperative PSA seemed to benefit most of repeat RGS, irrespective of prior SLND or RGS or the time from initial RP/first salvage surgery.

Chronic Lymphocytic Leukemia With Two B-Cell Populations of Discordant Light Chain Restrictions in Individual Patients: Parallel Development of Biclonal B-Cell Neoplasms or Clonal Evolution With Isotype Switch?

To evaluate clinicopathologic characteristics of biclonal chronic lymphocytic leukemia (CLL). Retrospectively analyze clinical data and pathologic features. Ten cases were identified in which flow cytometry demonstrated an abnormal B-cell population with a CLL-like immunophenotype but showed no definitive light chain restriction. All had cytogenetic abnormalities detected, including seven with two CLL-related abnormalities. Four of these showed features suggestive of clonal evolution, all having del(13q) as a "stem-line" abnormality and three showing del(11q) as a "side-line" abnormality. Five (50%) cases demonstrated deleterious NOTCH1 mutations, in contrast to 11.8% in a control group of monoclonal CLL (P < .05). Of the 10 patients, 5 received treatment, with good/partial response in three cases and therapeutic resistance in one case. The median treatment-free survival was estimated at 68 months. Despite a polytypic pattern of light chain expression, the neoplastic nature of biclonal CLL is suggested by a characteristic CLL phenotype and can be confirmed by cytogenetic and genomic analyses. The two clones with discordant light chain isotypes may share a "stem-line" cytogenetic abnormality, suggesting possible clonal evolution. Biclonal CLL is associated with NOTCH1 mutations, which may occur in a small subclone and gradually evolve in clonal size. Genomic analysis on light chain-sorted and/or chronologically collected samples may provide insight into clonal evolution in CLL.

Prognostic Role of Revised International Prognostic Score for Waldenstrom Macroglobulinemia (rIPSSWM) in Newly Diagnosed Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Report from the NF10 International, Prospective, Observational Study of the Fondazione Italiana Linfomi

Background: Revised international prognostic score for Waldenstrom macroglobulinemia (rIPSSWM) has been recently validated for symptomatic WM patients in need of treatment and was built on the independent prognostic role of Age, LDH, Serum Albumin and Beta2microglobulin. In 2010 the NF10 study was started by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of, Indolent non follicular B-Cell Lymphomas (INFL) including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) and marginal zone lymphomas (MZL). Methods: We aimed to assess the prognostic role of RIPSSWM (ref) on an unselected population of treatment naïve patients with LPL/WM enrolled in the NF10 registry. Main study endpoint was Overall Survival. Secondary endpoint was treatment free survival (TFS). Results: From July 2010 to January 2020, 1535 INFL cases were registered and 1328 validated. Three hundred and seventeen cases were LPL/WM. Median age was 69 years (range 60-76); 6% had ECOG performance status > 1, median hemoglobin concentration was 12 g/dl (IQR 10 - 13.6), median serum albumin was 4 g/dl (IQR 3.6 - 4.3); serum CM was present in 254 patients with median concentration of 1.6 g/dl (IQR 0.74 - 2.4). Lactate dehydrogenase and b2-microglobulin were elevated in 21% and 59% of cases, respectively. Overall, 191 patient received systemic therapy. Immediate systemic therapy was planned in 133 (42%) patients. Additionally 58 patients required systemic treatment due to progressive disease from watch and wait. Median time to treatment for WW patients was 18 months (95% CI 15 to 28). When systemic therapy was prescribed rituximab (R) was used in 82% and was combined with cytotoxic therapy in 76% of cases. Regarding immunochemotherapy regimens, R was combined with bendamustine in 34%, alkylating agents in 30%, fludarabine in 8%, and CHOP like in 4%. With 58 months of median follow up (1 - 114), 5-year overall survival (OS) was 83% (95%CI: 78-88). In univariate analysis of OS, Age (>75years), elevated LDH, elevated B2M, and low serum albumin (<3.5) were associated with a different risk of death; the initial choice of deferring therapy did not impact on OS. Revised IPSSWM score could be calculated for 228 patients: 34(15%), 55(24%), 63(28%), 60(26%), and 16(7%) patients had 0,1,2,3, or 4-5 risk factors, respectively. Five-year OS was 100%, 98%, 79%, 83%, and 29% by risk group (p<0.001; c-Harrel 0.792: Figure1). The risk of dying due to lymphoma progression or due to other causes was similarly low for low risk patients (0-1 risk factors). Intermediate (2-3 RF) and high risk patients (4-5 RF) had a three-fold higher risk of dying due to causes unrelated to lymphoma compared to lymphoma related deaths. rIPSSWM was also correlated with a different TFS among patients initially observed (Figure 1: median TFS not reached for 0 RF, vs 15 months for 1-3 RF, vs 1.5 months for 4-5 RF p <0.001). Conclusions: We were able to validate the prognostic role of rIPSSWM in an unselected population of newly diagnosed patients with LPL/WM thus extending the usefulness of this score to asymptomatic patients. The rIPSSWM was particularly able to identify a small group of patients at very high risk of death within few months from the diagnosis. Moreover the rIPSSWM was also able to predict the time to initial treatment for patients who were initially observed. The NF10 study confirms that a web-based world-wide cooperation allows the collection of a relevant and complete data set, providing a platform for future prognostic and pathobiological studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Unsupervised Machine Learning Method Stratifies Chronic Lymphocytic Leukemia Patients in Novel Categories with Different Risk of Early Treatment

Novel scoring systems have been developed in recent years to improve the accuracy of prognostication from historical clinical staging systems (Rai, Binet) for chronic lymphocytic leukemia (CLL). Most of them, however, rely on discretized and dichotomic values of the various biomarkers to infer prognosis. Here we analyzed the immunophenotypic and (immuno)genetic profiles in a wide CLL cohort by applying unsupervised machine learning methods elaborating prognostic factors as continuous variables, to identify novel relationships and interactions likely missed in conventional models. The study included 989 CLL patients with Rai stages 0-I-II (50, 36, 14% respectively), 420 (42.4%) treated, analyzed between 2003 and 2020. Treatment-free survival (TFS) was calculated from sampling (median TFS, 46 months). Median time of sampling from diagnosis was 7.2 months (~60% cases within 12 months). The studied laboratory-based markers were: CD20, FMC7, CD49d, CD49c, CD38, CD23, CD43, CD22, ZAP-70 expression by flow cytometry (reported as % of positive cells); del13, tris12, del11 and del17 cytogenetic abnormalities detected by FISH, reported as % of nuclei with abnormal signal; mutational status of TP53 by deep NGS, reported as % variant allele fraction (VAF); IGHV gene mutational status, reported as % mutations. By applying Cox proportional hazard model to estimate TFS on this pool of features, we selected the features with a fit p-value<0.05, i.e. del11, tris12, TP53 mutations, % IGHV mutation, expression of CD38 and CD49d. Then we grouped similar profiles with an unsupervised k-means algorithm, optimized by the Elbow method, to partition observations into 6 clusters (C1-C6). Clustering confidence for each patient was estimated through leave-one-out procedure and the average normalized score was 0.83 (0.85, 0.86, 0.79, 0.91, 0.73, 0.84, for C1 through C6, respectively). Centroid analysis was employed to evaluate which features mostly defined each cluster, as detailed below. C1 (n=220): all cases with <4.1% IGHV mutations, mostly (70%) IGHV-unmutated (UM, <2% cut-off), low CD49d expression (<30% of positive cells) in 90% of cases, low representation of other features (tris12, del11, CD38, TP53 mutations); C2 (n=210): high CD49d expression (99% of cases), equally balanced IGHV status (52% UM), low representation of other features; C3 (n=147): tri12 cases (100%; >10% of nuclei), concurrent high expression of CD49d (95%) and CD38 (67%), slightly enriched in UM IGHV cases (60%); C4 (n=303): cases heavily mutated in IGHV genes (mutation range 4.1-22.0%), low representation of all the other features; C5 (n=52): TP53 mutated cases with high mutation burden (VAF 35-97%), skewed towards UM IGHV (70%), irrelevant all the other features; C6 (n=57): highly clonal del11q cases (range 50-98%) mutually exclusive with TP53 mutations (2 mutated cases only), mostly UM IGHV (89%), low representation of all other features. Notably, in C1-C4, cases bearing TP53 mutations were present, although representing a minority (5-10%), mostly with low-VAF (median 6.7%, range 5-39%). Kaplan-Meier analysis revealed heterogeneous behaviors: C2, C3, C5, C6 presented a 50% TFS of 59, 25, 5, 9 months respectively, whereas TFS was not reached for C1 and C4 (Figure, A). Hierarchical agglomerative clustering identified 3 major risk classes (Figure, B). The high risk class (n=109) comprised C5 and C6 (TP53 mutations and del11q); the intermediate risk class (n=577) stratified on C1-2-3; the low risk class (n=303) was made by C4 only (CLL with highly mutated IGHV). The 50% TFS for high-intermediate-low risk was 7, 50 and not reached, respectively. In conclusion, we present here a novel machine-learning-driven, laboratory-based classification for predicting the risk of early treatment in CLL. Our approach identifies clusters at different risk with some novelties: i) a high IGHV mutational burden (i.e >4%) in the absence of other markers (e.g. CD49d) identifies patients with a particularly benign clinical course; ii) TP53 mutations and del11q associate with high risk of early treatment only if present in the vast majority of the CLL clone; iii) a IGHV status with low burden of mutations (i.e. <4%) along with CD49d expression or tris12 identifies patients at intermediate risk. These novel stratifications should be incorporated in risk algorithms for treatment prediction of CLL patients. Validation in additional independent cohorts is needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Throughput Proteomics Identifies THEMIS2 As Biomarker of Inferior Treatment-Free Survival in Chronic Lymphocytic Leukemia

Background Notwithstanding advances in the prognostication of chronic lymphocytic leukemia (CLL), it remains challenging to distinguish between patients with favorable and unfavorable treatment-free survival (TFS). In addition, the downstream protein correlates of well-known genomic features of CLL are not always clear. To address this, we performed large-scale, unbiased characterization of global intracellular protein expression in a cohort of previously untreated CLL patients. Materials and methods We selected 40 CLL cases (patients in need of treatment within 24 months of sampling) and 40 age- and sex-matched CLL controls (patients without need for treatment for at least 24 months since sampling) from the Dutch natural history CLL cohort. In this cohort, we characterized global intracellular protein expression of magnetically purified B cells using tandem-mass-tagging, followed by high-performance liquid chromatography and triple tandem mass-spectrometry. In addition, recurrent cytogenetic aberrations (del13q, del11q, del17p and trisomy 12), IGHV mutational status and TP53 mutations were characterized using targeted fluorescence in situ hybridization (FISH), Sanger sequencing and next-generation sequencing, respectively. Results Expression of 3268 proteins was quantified in the cohort, allowing for a comprehensive characterization of the CLL proteome. CLL with unmutated IGHV (U-CLL) was associated with significant overexpression of 32 proteins, including ZAP70 and proteins involved in B-cell receptor signaling, such as CD79b and immunoglobulin constant regions mu and delta (adjusted P-value <0.05). CLL with mutated IGHV (M-CLL) was associated with higher intracellular expression of 7 proteins, including both subunits of ferritin (FTH1 and FTL, adjusted P-value <0.05). Trisomy 12 was associated with increased intracellular expression of 32 proteins, 13 (40%) of which are encoded by genes on chromosome 12, and decreased expression of 8 proteins. Many of these hits are concordant with the results of independently performed mass-spectrometry screens. Interestingly, the intracellular concentration of THEMIS2 was significantly higher in cases, compared to controls. THEMIS2 is an protein that is constitutively bound to Grb2, Lyn and PLCγ2 and lowers the threshold for B-cell receptor activation by low-avidity antigens. THEMIS2 protein levels were higher in both U-CLL cases (mean fold change 2, P-value <0.0001) and M-CLL cases (mean fold change 1.7, P-value <0.01), compared to controls. Concordantly, Cox proportional hazards modelling demonstrated that higher concentration of THEMIS2 was significantly associated with shorter TTFT, independent of IGHV mutational status and TP53 aberrations (standardized HR 2.79 [95%CI 1.71-4.54], P<0.0001). ROC analysis indicated a good discriminatory capacity of elevated THEMIS2 concentration, with an AUC of 0.83. THEMIS2 protein quantification by ELISA in a cohort of 40 patients confirmed that higher expression of THEMIS2 was associated with inferior TTFT (median TTFT for patients with THEMIS2 levels above versus below the mean 11 months versus 66 months, P=0.04). Gene expression analysis by qPCR confirmed higher expression of THEMIS2 in cases, compared to controls (mean fold change of 3, P<0.01). Analysis of a publicly available, independently generated mass-spectrometry dataset of 68 CLL patients confirmed the association of elevated intracellular THEMIS2 expression and TFS (median TFS 3 months versus not reached, P<0.0001). Conclusions We present a comprehensive characterization of the proteome of untreated CLL. Of note, we identify elevated gene and protein expression of THEMIS2 as putative biomarker of inferior TTFT, independent of IGHV mutational status and TP53 aberrations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CLL-506 Clinical Outcomes Beyond Progression on Ibrutinib in Patients With Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. To analyze survival estimates of patients with CLL following true disease progression (per iwCLL 2018 criteria) on ibrutinib. Retrospective. Academic. Patients with CLL who received ibrutinib therapy for CLL at a Mayo Clinic Cancer Center site (Arizona, Florida, Minnesota) between 4/2012-6/2021. Treatment-free survival (TFS) was analyzed as the duration from the start of treatment immediately after ibrutinib failure to the start of the subsequent line of therapy or death, whichever occurred earlier. Overall survival (OS) was analyzed as the time from date of progression while on ibrutinib and from subsequent therapy start date until date of death or last known to be alive. OS was analyzed using the Kaplan-Meier method (with comparisons of OS by characteristics analyzed by the log rank test). Among 144 patients with CLL identified to have disease progression on ibrutinib, the median age was 68 years and 74% were male. Unmutated IGHV (90%) and TP53 disruption (50%) were common in evaluable patients at the time of progression on ibrutinib. The median OS for the entire cohort following progression on ibrutinib was 25.5 months; 29.8 months and 8.3 months following CLL progression (n=104) and Richter's transformation (n=38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline (n=23) compared to relapsed/refractory setting (not reached versus 28.5 months; p=0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p=0.24). Among patients with CLL disease progression on ibrutinib, next-line treatment with chimeric antigen receptor T-cell therapy or venetoclax-based treatment was associated with significantly longer median OS and TFS compared to other approved treatments (OS: not-reached, 29.8 months, and 9.1 months, respectively, p=0.034; TFS: 30.4 months, 20.1 months, and 4.4 months, respectively, p<0.001) Conclusions: These findings suggest an unmet need for this growing patient population while supporting the current practice of next-line venetoclax and participation in clinical trials.

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia.

Patients with chronic lymphocytic leukaemia (CLL) disease progression on ibrutinib or after sequential ibrutinib and venetoclax-based treatments (double-refractory) have poor outcomes. In this retrospective study, we analysed outcomes with combined ibrutinib and venetoclax treatment in these groups of patients. The median treatment-free and overall survival for 22 patients with prior progression on ibrutinib (venetoclax-naïve) were 23.7 and 47.1 months respectively. In 11 patients with double-refractory CLL, the median treatment-free and overall survival were 11.2 and 27.0 months respectively. The combination of ibrutinib and venetoclax may help bridge the current gap in options for patients with disease refractory to the most commonly used novel agents.

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

Active surveillance in prostate cancer is possible for Afro-Caribbean population: Comparison of oncological outcomes with a Caucasian cohort

Prostate cancer is supposedly more aggressive among Afro-Caribbean men. There is a lack of data in this population for active surveillance. Published series are retrospective or have small samples and results are discordant. The objective was to determinate whether actual active surveillance modalities can be applied for Afro-Caribbean men by comparing their oncological outcomes with Caucasian men. A total of 449 consecutive patients who underwent active surveillance for favorable-risk prostate cancer in two French University-Medical-Centers between 2005 and 2018: 261 in Guadeloupe, French West Indies, and 188 in Bordeaux, metropolitan France. Median follow-up was 56 months, (95% CI [32-81]) and 52 months (95% CI [30-75]), respectively (P=0.07). Curative treatment was given in case of histological, biological, or imaging progression, or upon patient demand. Primary endpoints were treatment-free, overall and specific survival. Secondary outcomes were reasons of discontinuating active surveillance, histological poor prognosis factors after prostatectomy, CAPRA-S score, biochemical-recurrence-free after treatment and metastasis-free survival. Kaplan-Meier method was used. Median treatment free survival was 58.4 months (CI 95% [48.6-83.1]) for ACM and not reached at 120 months for CM (P=0.002). Overall survival (P=0.53), and specific survival (P=0.21) were similar in the two groups. CM were likely to have poor prognosis factor on prostatecomy piece (57 vs 30%, P=0.01). No difference for repartition of the CAPRA-S score (P=0.86), biochemical-recurrence-free (P=0.92) and metastasis-free (P=0.44) survival. Oncological outcomes for active surveillance of Afro-Caribbean and Caucasian men were similar in terms of mortality, recurrence and metastasis in our bicentric study, showing usability of current criteria for Afro-Caribbean. The higher rate of disease progression in the Afro-Caribbean population requires close monitoring. 3.

A randomized phase III trial of secondary cytoreductive surgery in later recurrent ovarian cancer: SOC1/SGOG-OV2.

6001 Background: In China, secondary cytoreductive surgery (SCR) has been standard of care in some high volume cancer centers for ovarian cancer (OC) and most pts prefer surgery over the past two decades. Although GOG213 showed no OS benefit, the debate on selected pts and the conflict with certain local clinical care is still open. Methods: Pts with 1st relapsed OC after 6m+ platinum-free interval (PFI) were eligible if predicted to be a potential R0 by iMODEL score combined with PET-CT image and were randomized to SCR followed by chemotherapy (surgery arm) vs 2nd line chemotherapy alone (no surgery arm). Co-primary endpoint is PFS and OS. The 2nd endpoint is accumulated treatment-free survival (TFSa), which was defined as the overall survival time minus the time of surgery and chemotherapy after randomization. We report analysis of PFS and interim analysis of TFSa. Results: 357 pts were randomized 2012-2019. 6.3% of 175 pts were operated in no surgery arm and cross-over rate was 36.9% in 2nd+ relapsed pts of no surgery arm. 97% and 96% of pts received a platinum-containing 2nd line therapy. Complete resection (R0) rate was 76.7% in overall and 61.1% in pts with iMODEL&gt; 4.7. 60 d mortality rates were 0 % in both surgery and no surgery arm. Postoperative 30 d complication rate with ≥ grade 3 was 5.2%. The median follow-up was 36.0 m. Median PFS was 17.4 m and 11.9 m in surgery and no surgery arm, respectively (HR 0.58, 95% CI 0.45-0.74, p &lt; 0.001). Median time to start of first subsequent therapy (TFST) was 18.1 m vs 13.6 m in favor of the surgery arm (HR 0.59, 95%CI 0.46-0.76). 1.1% and 10.1% of pts underwent Bevacizumab and PARPi maintenance in the 2nd line therapy. The OS and TFSa was immatured. The median TFSa was unreached and 39.5 m in R0 subgroup and no surgery arm, respectively (HR0.59, 95%CI 0.38-0.91). TFSa in surgery arm showed a better long-term survival than that in no surgery group (restricted mean survival time from 60 to 72m: 6.2m vs 4.2m). Conclusions: SCR in selected pts resulted in a dramatically significant extension of PFS. The interim analysis of TFSa indicate that SCR might contribute to long-term survival.

Possible hampered effectiveness of second-line treatment with rituximab-containing chemotherapy without signs of rituximab resistance: a population-based study among patients with chronic lymphocytic leukemia.

Rituximab-containing chemotherapy remains a viable frontline treatment option for patients with chronic lymphocytic leukemia (CLL) in the era of novel agents. However, its effectiveness in the second-line setting-in relation to previous rituximab exposure in first-line-has hardly been evaluated in a population-based setting. Therefore, in this comprehensive, population-based study, we assessed the impact of first-line treatment with rituximab-containing chemotherapy on the effectiveness of second-line treatment with rituximab-containing chemotherapy. We selected all 1735 patients diagnosed with CLL between 2004 and 2010 from the Dutch Population-based HAematological Registry for Observational Studies (PHAROS). The primary endpoint was treatment-free survival (TFS). First- and second-line treatment was instituted in 663 (38%) and 284 (43%) patients, respectively. In first line, the median TFS was 19.7 and 67.1months for chemotherapy without (n = 445; 67%) and with rituximab (n = 218; 33%), respectively (adjusted hazard ratio [HRadjusted], 0.83; P= 0.031). The median TFS among recipients of second-line chemotherapy without (n = 165; 57%) and with rituximab (n = 121; 42%) was 15.0 and 15.3months, respectively (HRadjusted, 0.93; P= 0.614). Of the 121 patients who received rituximab-containing chemotherapy in second-line, 89 (74%) and 32 (26%) received first-line chemotherapy without and with rituximab, respectively. Median TFS in these two treatment groups was 18.3 and 12.1months, respectively (HRadjusted, 1.71; P= 0.060). Collectively, in this population-based study, the effectiveness of first-line treatment with rituximab-containing chemotherapy was less pronounced in second-line treatment. The hampered effectiveness of rituximab-containing chemotherapy in second-line could not be explained by previous rituximab exposure.

Treatment-free survival after discontinuation of immuno-checkpoint therapy, and outcome of subsequent molecular targeted therapy: Retrospective study of Japanese metastatic renal cell carcinoma patients (after I-O study).

677 Background: Guidelines for treatment of metastatic renal cell carcinoma (mRCC) recommend nivolumab monotherapy (NIVO) for treated mRCC, and nivolumab + ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor risk mRCC patients. Though molecular targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their impact is still unclear. Methods: Japanese mRCC patients treated with TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator assessed ORR of the first TT after NIVO, and after NIVO+IPI. Secondary endpoints included treatment-free survival (TFS) after discontinuation of NIVO and NIVO+IPI, and progression-free survival (PFS) and safety of the first subsequent TT after NIVO and NIVO+IPI. Results: Twenty-six patients of CheckMate 025 and 19 patients of CheckMate 214 from 20 centers in Japan were analyzed. Median TFS after ICI discontinuation was 1.0m and 2.5m for CheckMate 025 and CheckMate 214 patients, respectively. Median follow-up period from the start of TT after ICI discontinuation to date of analysis or death was 22.1m for CheckMate 025, and 20.3m for CheckMate 214 patients. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most treated therapy for both CheckMate 025 (53.8%) and CheckMate 214 (47.4%) patients. ORR of TT after NIVO and NIVO+IPI was 26.9% and 31.6%, and median PFS was 8.9m and 16.3m, respectively. During the treatment of first TT after NIVO and NIVO+IPI, 98% percent experienced treated-related adverse events, 51% experienced grade 3-4, but no treatment related death. Conclusions: TTs have favorable antitumor activity for mRCC after NIVO and NIVO+IPI, possibly by changing the mode of action. Safety signals of TTs after ICI were similar to the previous reports. These results indicate sequential TTs after ICI may contribute for durable survival benefit.

Oral Fludarabine and Intravenous Rituximab (FR) for Chronic Lymphocytic Leukemia (CLL): Long Term Outcomes and Secondary Malignancies in 673 Patients Treated in British Columbia (BC)

Oral Fludarabine and Intravenous Rituximab (FR) for Chronic Lymphocytic Leukemia (CLL): Long Term Outcomes and Secondary Malignancies in 673 Patients Treated in British Columbia (BC)

Waldenström Macroglobulinemia in Young Patients Treated in the Modern Era: A Multi-Institutional Italian Study

Background. Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma typical of the elderly population, with a median age at diagnosis of 65-70 years and median overall survival of approximately 10 years. Age is the most important prognostic factor in WM, and unrelated mortality significantly impacts survival in elderly patients. The past two decades have witnessed important treatment advances in WM, with the introduction of anti-CD20 monoclonal antibodies in the early 2000s and of ibrutinib in more recent years. Less than 10% of WM patients are diagnosed at young age, and few studies have addressed their characteristics and outcome in the era of immunotherapy and targeted therapies. Here we report the presenting features, treatment and outcome of WM patients younger than 55 years diagnosed in 12 Hematologic Centers across Italy between 2000 and 2018. Patients and Methods. Diagnostic criteria were those established during the second International Workshop on WM (Owen et al, 2003) and were retrospectively applied to patients diagnosed before 2003. The overall survival (OS) observed in the study cohort was compared with the expected survival of the general Italian population matched by sex, age and calendar year. The expected survival estimates were derived from Italian life tables (Istituto Nazionale di Statistica, ISTAT). Results. The median age of patients included in the study was 50 years (interquartile range, IQR: 46-52). Their clinical characteristics at diagnosis are reported in Table 1. With a median follow-up of 5.6 years (IQR 3.1-9.1), 76 of 129 patients (59%) have been treated, at diagnosis (n=31, 41%) or after initial observation (n=45, 59%). The median treatment-free survival was 39 months. According to ISS-WM prognostic score, 58% were classified as low risk, 30% as intermediate risk and 12% as high risk. Frontline therapy included Rituximab in 71/76 patients (93%). Rituximab was associated with chemotherapy in 62 patients (82%), whereas 9 patients (12%) received a chemo-free induction. Five patients (7%) received chemotherapy only as first-line therapy (Table 2). The overall response rate (ORR) to induction therapy was 85%, including 39% CR+VGPR. Two patients received Rituximab maintenance for 2 years. The median progression-free survival (PFS) after first-line therapy was 76 months. Four of 76 patients (5%) received an autologous stem cell transplantation at relapse/progression. Overall, 14/76 patients (18%) received ibrutinib as first (n=2) or as subsequent line of therapy (n=12). During follow-up, 4/76 patients (5%) developed a solid cancer (bladder n=2, breast n=1, prostate n=1) and 2 a second hematologic cancer (chronic myelomonocytic leukemia n=1, secondary MDS n=1). Using a competing-risk model, accounting for death from any cause as the competing event, the cumulative incidence of second cancers was 2% at 5 years and 5.8% at 10 years. Three patients have died, 2 due to WM and 1 due to acute myeloid leukemia. The 5-and 10-year OS from diagnosis were 99% and 96% respectively. In a time-dependent survival analysis, considering therapy as a time-dependent covariate, the OS of treated and untreated WM patients was not significantly different (P = 0.162) (Figure 1). Among treated patients, the OS was significantly shorter in high-risk patients as compared with low- and intermediate-risk patients (5-year OS 85.7% versus 100%, P=0.018) (Figure 2). The OS of young WM patients was not significantly reduced as compared with age-, sex- and calendar year- matched general population (P &amp;gt; 0.05) (Figure 3). Conclusions. The presenting features of young WM patients resemble those typically described in the elderly WM population. Among treated patients, more than half are low-risk according to ISS-WM, confirming age as the most important prognostic factor. More than 90% of patients received Rituximab as part of the upfront treatment, mainly in combination with chemotherapy. Ibrutinib seems to be preferred over autologous stem cell transplantation in the relapsed/refractory setting. The outcome of young WM patients treated in Italy in the contemporary era was excellent in terms of both PFS and OS, with a life expectancy not significantly reduced as compared with the general population. Figure 1 Disclosures Varettoni: Gilead: Other: travel expenses; Janssen: Consultancy; Roche: Consultancy; ABBVIE: Other: travel expenses. Tedeschi:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Benevolo:Novartis Pharmaceuticals: Consultancy. Del Fabro:Janssen: Consultancy. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor &amp; Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Arcaini:Gilead Sciences: Research Funding; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy.