Castillo, Jorge J.

AbstractPlasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1–196), the 3‐year progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3‐year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper‐CVAD or auto‐SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient’s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment regimens for patients with WM, and the choice of therapy should be made in a personalized fashion considering the patient’s symptoms, comorbidities, and genomic profile. Bruton tyrosine kinase (BTK) inhibitors are a new option to treat patients with WM. Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors. This review summarizes the pharmacokinetic and pharmacodynamic properties of zanubrutinib as well as safety and efficacy findings. Then, it explores the health economic and outcomes research associated with the costs of treating patients with WM and the reasons why zanubrutinib may be a more cost-effective treatment option compared with ibrutinib, a first-generation BTK inhibitor. Future directions for the treatment of WM focus on the use of zanubrutinib in combination therapy. Combinations based on effective ibrutinib or acalabrutinib treatments may be effectively applied with zanubrutinib given the similar mechanism of action for these BTK inhibitors. Combination therapies could also help prevent the development of disease resistance, minimize toxicity, and support treatment regimens of finite duration.

Histological transformation (HT) to an aggressive lymphoma results from a rare evolution of Waldenström macroglobulinemia (WM). A higher incidence of transformation events has been reported in MYD88 wild-type WM patients. HT in WM can be histologically heterogeneous, although the diffuse large B-cell lymphoma of activated B-cell subtype is the predominant pathologic entity. The pathophysiology of HT is largely unknown. The clinical suspicion of HT is based on physical deterioration and the rapid enlargement of the lymph nodes in WM patients. Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) and extranodal disease. A histologic confirmation regarding the transformation to a higher-grade lymphoma is mandatory for the diagnosis of HT, and the choice of the biopsy site may be dictated by the findings of the 18fluorodeoxyglucose-positron emission tomography/computed tomography. The prognosis of HT in WM is unfavorable, with a significantly inferior outcome compared to WM patients without HT. A validated prognostic score based on 3 adverse risk factors (elevated LDH, platelet count < 100 × 109/L and any previous treatment for WM) stratifies patients into 3 risk groups. The most common initial treatment used is a chemo-immunotherapy (CIT), such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The response duration is short and central nervous system relapses are frequent. Whether autologous stem cell transplantation could benefit fit patients responding to CIT remains to be studied.

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Abstract Introduction: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common PTCL subtype, accounting for approximately 25% of all PTCL cases. The median age at diagnosis is 60 years and is more prevalent among males. Currently, most epidemiological data on T- and NK-cell lymphomas come from developed countries. Thus, very few data are available regarding this condition in Latin American countries, especially in those aged 60 years and older. The Latin American Group of Lymphoproliferative Disorders (GELL) has previously reported on the impact of serum albumin level in survival outcomes in PTCL-NOS. Therefore, we aim to evaluate the clinical, demographic, and outcome patterns of elderly patients with PTCL-NOS. Methods: We conducted an observational, retrospective study of newly diagnosed PTCL-NOS between January 2000 and December 2020. Patient must be aged 60 years and older. All clinical data were retrieved from clinical records at the different participating institutions. The study outcomes were overall survival (OS) and progression-free survival (PFS). The International Prognostic Index (IPI), the Prognostic Index for T-cell lymphoma (PIT), and the NCCN IPI scores were used for risk stratification. Kaplan-Meier and log-rank test were used for survival analysis. Univariate and multivariate Cox regression analysis were used to estimate hazard ratios (HR) with a 95% confidence interval (CI). Outcomes with a p-value &lt;0.05 were considered statistically significant. Results: A total of 107 patients were included; median age at diagnosis was 72 years (range 60-92), 61% were male, 46% had an ECOG ≥2, 70% had stage III-IV, and 15% had more than one extranodal site. The IPI, PIT and NCCN-IPI scores stratified 51%, 69%, and 74% of patients as high- / high-intermediate risk, respectively. Seventy-four (69%) patients received first-line systemic therapy. Most patients (53%) were managed with CHOP/CHOP-like regimen, followed by CHOEP (19%). The overall response (OR) rate to first-line therapy was 61% (complete response, CR 41%). Salvage therapy was given to only 9 patients; the OR rate was 44% (CR 11%). With a median follow-up of 29 months (95% CI 13-45 months), the 2-year OS was 46% (95% CI 36-59), with median survival time of 16 months (95% CI 10-NR). In the multivariate analysis, patients with serum albumin levels &lt;3.5 g/dL had median survival of 7 months (95% CI 3-20) and 2-year OS rate of 24% (95% CI 13-46%), while patients with albumin ≥3.5 g/dL did not reach the median survival time and had a 2-yOS rate of 67% (95% CI 36-65%) (p&lt;0.0001) (Table 1, Figure 1). Patients with a lymphocyte-to-monocyte ratio (LMR) &gt;7.6 had a median OS of 8 months (95% CI 6-NR) and a 2-year OS of 10% (95% CI 2-65), while patients with a LMR ≤7.6 did not reach the median OS and had a 2-year OS of 57% (95% CI 45-72) (p = 0.0108) (Table 1, Figure 1). Conclusions: This large cohort of Latin American PTCL-NOS patients aged ≥60 years showed overall response rates comparable to previously published data. However, survival rates were shorter compared to those reported in developed countries. In this study, we again confirmed low serum albumin level (&lt;3.5 g/dL) as an adverse prognostic factor for OS in PTCL-NOS, and independent from the IPI, PIT and NCCN-IP scores. Additionally, we describe for first time in a Latin American cohort the impact of the LMR on survival, demonstrating poor outcomes in those with LMR &gt;7.6. We are currently validating our findings in a prospective cohort of Latin American PTCL patients and to improve clinical decision-making in those deemed at high-risk for early mortality. Figure 1 Figure 1. Disclosures Otero: Astra Zeneca: Current Employment. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Abstract INTRODUCTION Central nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM. METHODS This international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR). RESULTS Baseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94). Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47). CONCLUSION CNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.