Simplified Risk Stratification Model for Patients With Waldenström Macroglobulinemia.

PURPOSE: Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS: We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS: In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively (P < .0001). CONCLUSION: Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Cerebellum/liver index on baseline 18F-FDG PET/CT to improve prognostication in post-transplant lymphoproliferative disorders: a multicenter retrospective study.

BACKGROUND: Besides International Prognostic Index (IPI) score, baseline prognostic factors of post-transplant lymphoproliferative disorders (PTLD) are poorly identified due to the rarity of the disease. New indexes derived from healthy organ uptake in baseline 18F-FDG PET/CT have been studied in immunocompetent lymphoma patients. The aim of this study is to evaluate the performances of the cerebellum-to-liver uptake ratio (denoted as CLIP) as a prognostic factor for PFS and OS. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. The previously published threshold of 3.24 was used for CLIP in these analyses. RESULTS: A total of 97 patients was included with a majority of monomorphic diffuse large B-cell lymphoma subtype (78.3%). Both IPI score (≥ 3) and CLIP (< 3.24) were significant risk factors of PFS with corresponding hazard ratios of 2.0 (1.0-4.0) and 2.4 (1.3-4.5) respectively. For OS, CLIP was not significant and resulted in a hazard ratio of 2.6 (p = 0.059). Neither IPI score or Total Metabolic Tumor Volume reached significance for OS. CONCLUSION: CLIP is a promising predictor of PFS and perhaps OS in PTLD. Further prospective studies are needed to confirm these results.

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network.

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.

ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.

High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.

Advances in Treatment of Waldenström Macroglobulinemia.

PURPOSE OF REVIEW: The discovery of recurring somatic mutations, in particular MYD88 and CXCR4 mutations, in Waldenström macroglobulinemia (WM), a rare B-cell lymphoproliferative disorder, led in the last decade to the development of several therapeutic agents with high efficacy. This review aims to provide an overview of available treatments in WM and novel agents, focusing on studies published over recent years. RECENT FINDINGS: There is no international consensus on the best first-line option in treatment-naïve patients. Randomized clinical trials are rare in WM and there has been no prospective comparison of chemoimmunotherapy and BTK inhibitors in the frontline setting. Chemoimmunotherapy and BTK inhibitors, the two feasible and most widely used treatments in first-line treatment, represent very different options in terms of duration of therapy, route of administration, cost, and adverse effect. In addition to tumor genotype and patient comorbidities, choice of therapy in WM should take into account these parameters. Results of ongoing and future clinical trials evaluating fixed-duration combinations with BTK inhibitors and novel agents are awaited.

Pretreatment CT Texture Parameters as Predictive Biomarkers of Progression-Free Survival in Follicular Lymphoma Treated with Immunochemotherapy and Rituximab Maintenance.

The purpose of this study was to determine whether texture analysis features present on pretreatment unenhanced computed tomography (CT) images, derived from 18F-fluorodeoxyglucose positron emission/computed tomography (18-FDG PET/CT), can predict progression-free survival (PFS), progression-free survival at 24 months (PFS 24), time to next treatment (TTNT), and overall survival in patients with high-tumor-burden follicular lymphoma treated with immunochemotherapy and rituximab maintenance. Seventy-two patients with follicular lymphoma were retrospectively included. Texture analysis was performed on unenhanced CT images extracted from 18-FDG PET/CT examinations that were obtained within one month before treatment. Skewness at a fine texture scale (SSF = 2) was an independent predictor of PFS (hazard ratio = 3.72 (95% CI: 1.15, 12.11), p = 0.028), PFS 24 (hazard ratio = 13.38; 95% CI: 1.29, 138.13; p = 0.029), and TTNT (hazard ratio = 5.11; 95% CI: 1.18, 22.13; p = 0.029). Skewness values above -0.015 at SSF = 2 were significantly associated with lower PFS, PFS 24, and TTNT. Kurtosis without filtration was an independent predictor of PFS (SSF = 0; HR = 1.22 (95% CI: 1.04, 1.44), p = 0.013), and TTNT (SSF = 0; hazard ratio = 1.23; 95% CI: 1.04, 1.46; p = 0.013). This study shows that pretreatment unenhanced CT texture analysis-derived tumor skewness and kurtosis may be used as predictive biomarkers of PFS and TTNT in patients with high-tumor-burden follicular lymphoma treated with immunochemotherapy and rituximab maintenance.

Risk Factors of Progression in Low-tumor Burden Follicular Lymphoma Initially Managed by Watch and Wait in the Era of PET and Rituximab.

Patients (pts) with asymptomatic low-burden follicular lymphoma (FL) are usually observed at diagnosis. Time to lymphoma treatment (TLT) initiation can however be very heterogeneous and risk factors of progression are poorly studied. Our study evaluated 201 pts with grade 1-3a low-tumor burden FL diagnosed in four French centers between 2010 and 2020 and managed by a watch and wait strategy in real-life settings. After a median follow-up of 4.8 years, the median TLT was 4.2 years (95% confidence interval, 3.1-5.5). On multivariate analysis, elevated lactate dehydrogenase (hazard ratio [HR] = 2.2; P = 0.02), more than 4 nodal areas involved (HR = 1.7; P = 0.02) and more than 1 extranodal involvement (HR = 2.7; P = 0.01) were identified as independent predictors of TLT. The median TLT was 5.8 years for pts with no risk factor, 2.4 years for 1 risk factor, and 1.3 years for >1 risk factors (P < 0.01). In a subanalysis of 75 pts staged with positron emission tomography-computed tomography (PET-CT), total metabolic tumor volume (TMTV) ≥14 cm3 and standardized Dmax (reflecting tumor dissemination) >0.32 m-1 were also associated with shorter TLT (HR = 3.4; P = 0.004 and HR = 2.4; P = 0.007, respectively). In multivariate models combining PET-CT parameters and clinical variables, TMTV remained independent predictor of shorter TLT. These simple parameters could help to identify FL patients initially observed at higher risk of early progression. The role of PET-CT (extranodal sites and PET metrics) in low-burden FL appears promising and warrants further assessment in large cohorts.

Evaluation and Management of Disease Transformation in Waldenström Macroglobulinemia.

Histologic transformation (HT) to diffuse large B-cell lymphoma occurs rarely in Waldenström macroglobulinemia, with higher incidence in MYD88 wild-type patients. HT is suspected clinically when rapidly enlarging lymph nodes, elevated lactate dehydrogenase levels, or extranodal disease occur. Histologic assessment is required for diagnosis. HT carries a worse prognosis compared with nontransformed Waldenström macroglobulinemia. A validated prognostic score based on three adverse risk factors stratifies three risk groups. The most common frontline treatment is chemoimmunotherapy, such as R-CHOP. Central nervous system prophylaxis should be considered if feasible and consolidation with autologous transplant should be discussed in fit patients responding to chemoimmunotherapy.

Born in the UK: A registry to improve and broadcast knowledge on Waldenström macroglobulinaemia.

Registries constitute an interesting source of real-world data and bring complementary information to randomised controlled trials. They are of particular importance in rare diseases such as Waldenström macroglobulinaemia (WM), which can present with various clinical and biological features. In their paper Uppal and colleagues describe the development of the Rory Morrison Registry, the UK registry for WM and IgM-related disorders and highlight the profound changes in therapies both at first-line and relapsed settings in the recent years. Commentary on: Uppal E. et al. The WMUK Rory Morrison Registry for Waldenström Macroglobulinaemia: the growth of a national registry for a rare disorder. Br J Haematol. 2023;201:905-912.

Baseline 18F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of immunosuppression. Sequential treatment is commonly proposed, combining induction with rituximab (R-induction) followed by either continuation of treatment or addition of chemotherapy depending on response. Response to R-induction, often assessed by CT scan, is a major predictor of overall survival (OS). The aim of the study was to analyze predictive factors of R-induction response, including total metabolic tumor volume (TMTV), and investigate the role of 18F-FDG PET/CT in response assessment. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. Only patients treated by R-induction with a baseline 18F-FDG PET/CT were included. Response to R-induction was assessed by 18F-FDG PET/CT. The optimal threshold of TMTV for rituximab response was determined using receiver operating characteristic curves. Univariate and multivariate analyses were conducted to identify predictive factors of response. A total of 67 patients were included. Survival characteristics were similar to those previously reported: the complete response rate to R-induction was 30%, the 3-year OS estimate was 66%, and the treatment-related mortality was 4%. The optimal threshold for TMTV to predict R-induction response was 135 cm3. The response rate to R-induction was 38% in the 21 patients with TMTV ≥ 135 cm3 and 72% in the 46 patients with TMTV < 135 cm3. TMTV was a significant predictor of response, both at univariate and multivariate analyses (odd ratios = 3.71, P = 0.022). Baseline TMTV is predictive of response to R-induction. Early assessment of patient response is feasible with 18F-FDG PET/CT.

Comparative analysis of rituximab or obinutuzumab combined with CHOP in first-line treatment of follicular lymphoma.

PURPOSE: Rituximab (R) or obinutuzumab (G) combined with CHOP chemotherapy are used in previously untreated follicular lymphoma (FL). The aim is to compare in real life setting the efficacy and safety of these therapeutic strategies and assess the economic impact of introducing G. METHODS: This retrospective study, performed in 3 centers, included data from all patients who received R-CHOP or G-CHOP for previous untreated FL from June 1st, 2016 to December 31st, 2020. Progression-Free Survival (PFS) were estimated according to the Kaplan-Meier method. A budgetary impact model was performed from the French health care system's perspective. RESULTS: N = 124 patients were included (58 G-CHOP; 66 R-CHOP). Fifty-one and 57 patients achieved a complete response at the end of induction in the G-CHOP and R-CHOP group, respectively. PFS was not significantly longer in the G-CHOP group (HR 0.28; 95% CI 0.08-0.97; p value = 0.14). Hematological toxicity occurred more frequently with G-CHOP than R-CHOP during induction treatment (n = 58; 100% vs. n = 61; 92%), including higher severe neutropenia (grade ≥ 3) (n = 26; 45% vs. n = 23; 35%). Infusion-related reactions during the first infusion occurred more frequently with G-CHOP (n = 19; 33% vs. n = 16; 24%). The introduction of a completed G treatment (induction and maintenance) results in an additional cumulative cost per patient estimated at more than €30,000. CONCLUSION: Similar results were found in the GALLIUM subgroup analysis study, suggesting that at this time there is no absolute benefit to administer G-CHOP instead of R-CHOP in all patients with previously untreated FL and may encourage clinical and economic trials including quality of life data.

Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA group.

Patients with relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) have a poor prognosis. Bendamustine (B) and brentuximab-vedotin (Bv) have shown interesting results in this setting. However, little information is available about their efficacy in combination. This multicenter and retrospective study aimed to evaluate the efficacy and safety of the combination of BBv in patients with noncutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was the overall response rate. A total of 82 patients with R/R PTCL were included. The best overall response rate (ORR) was 68%, with 49% of patients in complete response (CR). In multivariable analysis, only the disease status after the last regimen (relapse vs refractory) was associated with the response with an ORR of 83% vs 57%. Median duration of response was 15.4 months for patients in CR. With a median follow-up of 22 months, the median progression free survival (PFS) and overall survival (OS) were 8.3 and 26.3 months respectively. Moreover, patients in CR, who underwent an allogeneic transplant, had a better outcome than patients who did not with a median PFS and OS of 19.3 vs 4.8 months and not reached vs 12.4 months, respectively. Fifty-nine percent of patients experienced grade 3/4 adverse events that were mainly hematologic. BBv is highly active in patients with R/R PTCL and should be considered as a one of the best options of immunochemotherapy salvage combination in this setting and particularly as a bridge to allogeneic transplant for eligible patients.

Reduced peripheral blood dendritic cell and monocyte subsets in MDS patients with systemic inflammatory or dysimmune diseases.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.

Does early disease progression predict survival after first line-treatment of Waldenström macroglobulinemia?

In symptomatic Waldenström macroglobulinemia (sWM) patients, prognosis is assessed with the international prognostic scoring system (IPSSWM). In follicular lymphoma and other B-cell and T-cell lymphomas, disease progression within 24 months (POD24) or (in patients without POD24) after 24 months has been proposed as the start date for stratifying subsequent survival. In the present report, we assessed in a large series of 472 sWM patients, the prognostic value of this new dynamic endpoint already reported in many other lymphomas subtypes. The 3 year subsequent survival for patients with POD24 was 75% and 93% for patients without POD24. In sWM patients, departure from the proportional hazards assumption complicated this analysis. In patients without POD24, the median subsequent progression-free survival time of 43 months accounted for favorable outcome, whereas survival after progression was not influenced by the time to progression. In addition, sensitivity analysis showed that the baseline IPSSWM score also influenced survival after POD24. In sWM patients, we conclude that the apparent difference in survival after POD24 or the 24 months time-point (in patients without POD24) is mainly explained by the prolonged subsequent progression free survival of latter patients. Indeed, the mortality after progression is not influenced by the time to this event.

Cerebellum/liver index in pretherapeutic 18F-FDG PET/CT as a predictive marker of progression-free survival in follicular lymphoma treated by immunochemotherapy and rituximab maintenance.

ABSTRACT: The purpose of this study was to investigate the value of the "cerebellum/ liver index for prognosis" (CLIP) as a new prognostic marker in pretherapeutic 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) in patients with follicular lymphoma treated by immunochemotherapy and rituximab maintenance, focusing on progression-free survival (PFS).Clinicobiological and imaging data from patients with follicular lymphoma between March 2010 and September 2015 were retrospectively collected and 5-year PFS was determined. The conventional PET parameters (maximum standardized uptake value and total metabolic tumor volume) and the CLIP, corresponding to the ratio of the cerebellum maximum standardized uptake value over the liver SUVmean, were extracted from the pretherapeutic 18F-FDG PET.Forty-six patients were included. Eighteen patients (39%) progressed within the 5 years after treatment initiation. Five-year PFS was 78.6% when CLIP was >4.0 and 42.0% when CLIP was <4.0 (P = .04). CLIP was a significant predictor of PFS on univariate analysis (hazard ratio 3.1, P = .049) and was near-significant on multivariate analysis (hazard ratio 2.8, P = .07) with ECOG PS as a cofactor.The CLIP derived from pretherapeutic 18F-FDG PET seems to be an interesting predictive marker of PFS in follicular lymphoma treated by immunochemotherapy and rituximab maintenance. These results should be evaluated prospectively in a larger cohort.