PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.
It is unclear how treatment advances impacted the population-level survival of patients with lymphoplasmacytic lymphoma/Waldenstr€ om macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first-line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66-75 and >75 years) and four calendar periods. Overall, treatment with anti-neoplastic agents within 1 year post-diagnosis gradually decreased over time, following a broader application of an initial watch-and-wait approach. Approximately 40% of patients received anti-neoplastic therapy during 2011-2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014-2018 revealed that dexamethasonerituximab-cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5-year RS increased significantly over time, particularly since the introduction of rituximab in the early-mid 2000s. The 5-year RS during 1989-1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011-2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab-containing therapy. The lack of survival improvement in the post-rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/ WM.
Introduction In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN. Methods In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström’s Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN). Results NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients. Conclusion Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.
Introduction The management of Waldenström's Macroglobulinemia (WM), a rare and incurable B-cell non-Hodgkin lymphoma, has evolved in recent years. Treatment options are increasing including more modern targeted therapies. Therefore there are currently several effective treatment options available for WM. There is no consensus on a preferred treatment. Widely used treatment options include rituximab combined with chemotherapy, proteasome inhibitors, and the oral BTK inhibitor ibrutinib. These treatments have varying properties in terms of efficacy, toxicity profile, duration (fixed-duration vs long-term maintenance), administration (oral vs intravenous/subcutaneous (IV/SC)), and type of agent (chemotherapy vs targeted therapy). A better understanding of patients' treatment preferences could aid physicians in developing an individualized treatment plan. Also, a better insight in patients' treatment views could help direct future clinical studies in WM. However, treatment preferences of WM patients have not been investigated. We aimed to evaluate treatment preferences of WM patients by means of a discrete choice experiment (DCE) and to assess the importance of different attributes describing the currently available treatment regimens. Methods A mixed-method approach, consisting of a literature review, qualitative interviews and expert discussions was utilized for identification and selection of attributes/levels. A DCE questionnaire was developed in Dutch and included 5 treatment-related attributes: 5-year progression-free survival (PFS), frequency/route of administration(IV/SC or oral)/setting (clinic or home) of treatment, adverse events (nausea & vomiting and fatigue, neuropathy and atrial fibrillation), risk of future secondary malignancies (low vs high), and type of treatment agent (chemotherapy or targeted therapy). Each respondent was presented with 16 choice cards and was asked to choose between two hypothetical but realistic treatment options (see Figure 1 for an example). A pilot DCE study was carried out in 5 patients to evaluate feasibility. Data were collected via a nationwide online questionnaire via the patient organizations' website and via paper-based questionnaires sent to the participants known at the outpatient clinic. An orthogonal design was used to construct the choice tasks and a mixed logit panel data model was used to assess patients' preferences and trade-offs between attributes/levels. Results A total of 330 online questionnaires and 17 paper-based questionnaires were returned. After excluding incomplete survey data, 214 (65%) questionnaires were included for data analysis, respondents characteristics are presented in Table 1. The 5-year PFS followed by the risk of secondary malignancies were the most important attributes for making treatment decisions. The probability of choosing a treatment option increased with 26% and 22% if the 5-year PFS increased from 50% to 70% and if the chance of future secondary malignancies was decreased from "high risk" to "low risk", respectively. Of the adverse events, patients disliked being at risk for neuropathy the most more than nausea, vomiting and extreme fatigue. Patients were willing to give up 7,2% treatment efficacy to avoid risk of neuropathy. The probability of choosing a treatment option increased with 8% for a fixed-duration treatment with IV/SC administration at the hospital compared to an ongoing daily oral regimen at home (Table 2). Socio-demographic characteristics such as age, gender and treatment status did not significantly influence patients' preferences with the exception of educational status. Lower 5-year PFS was more acceptable for patients with higher education (P<0.0001 ) and this subgroup of patients preferred a treatment with targeted therapy and low risk of secondary malignancy (P<0.0001). Conclusion These are the first data on WM patients' preferences on treatment characteristics. We found that Dutch WM patients find efficacy (high 5-year PFS rate) the most important attribute, followed by a low risk of future secondary malignancies. Neuropathy was the adverse event they most wanted to avoid. They preferred a fixed-duration IV/SC treatment over an ongoing oral regimen. These data can be used in discussions with individual patients about their treatment preference, and help direct future clinical trials that optimally connect to WM patients' preferences. Figure 1 Figure 1. Disclosures Minnema: Cilag: Consultancy; Janssen: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy. Kersten: Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Vos: Celgene: Other: Travel reimbursement; Sanofi: Membership on an entity's Board of Directors or advisory committees.
Introduction Since no curative options for Waldenstrom's Macroglobulinemia (WM) are available, novel safe and effective treatments are needed. Several new agents, including BTK inhibitors and proteasome inhibitors (PIs) have shown considerable efficacy. PIs have shown synergy with rituximab in newly diagnosed and relapsed patients, with bortezomib being most extensively used. However, WM patients often have disease-related polyneuropathy (PNP) and there is a considerable risk of bortezomib induced PNP or worsening of existing PNP. Additionally, it requires parenteral administration. In the current study, we aimed to investigate the efficacy and toxicity of the oral and less neurotoxic proteasome inhibitor ixazomib citrate in patients with relapsed WM. Given the fact that WM patients have a tendency to develop rituximab intolerance, we explored the use of subcutaneous rituximab. Methods We conducted a multicenter phase I/II trial of the Ixazomib, Rituximab, Dexamethasone (IRD) combination in patients with relapsed WM. The phase I part of the trial was performed according to a standard '3+3' design with a primary endpoint of dose limiting toxicity, aiming to establish the recommended phase II dose level (RP2D). For the phase II part the primary endpoint was overall response rate (ORR, at least minimal response (MR)) after 8 induction cycles. Treatment consisted of a total of 8 induction cycles q28 days with ixazomib citrate, 4 mg orally on day 1,8,15 and dexamethasone, 20 mg orally on day 1,8,15,22. In cycle 3 rituximab 375 mg/m2 iv on day 1 was added and in cycle 4-8 rituximab was given sc (1400 mg flat dose day 1). Subsequently, patients with at least a PR received 2 years of rituximab maintenance treatment (1400 mg sc q 3 months). Results With 60 patients, enrolment is complete. One patient was ineligible (rituximab refractory). Dose level 1 (ixazomib citrate 4 mg) was feasible and was taken forward as the phase II dose. Of the first 50 eligible patients included in the pre-final analysis and treated at the RP2D, the median age was 69 years (range 46-83) and 72% were male. The median number of prior treatments was 2 (range 1 to 7); 70% had an intermediate or high WM IPSS score. The median hemoglobin level was 10.2 g/dl (range 7.0-15.0) and the median IgM level was 3.4 g/dl (range 1.33-9.1 g/dl). 39/50 patients completed 8 cycles of induction therapy with a median relative dose intensity of 1.0 for all three drugs. Eleven patients went off protocol early (5 progression, 3 toxicity, 2 intercurrent death, 1 insufficient clinical benefit). 74% of patients achieved the primary endpoint (16%≥VGPR, 52%≥PR, 74%≥MR), and best ORR on protocol was 88% (2% CR, 22% VGPR, 44% PR, 20% MR). With a median follow-up of 19.5 months (range 7-49), the median duration of response and median progression free survival were not reached. A rapid and statistically significant decrease in IgM levels was seen already after cycle 2 (before the introduction of rituximab; IgM 3.93 to 2.37 g/dl, p<0.001), accompanied by a rapid increase in Hb levels (Hb 10.5 to 11.5 g/dl, p<0.001), but the depth of response continued to increase until month 12. Two patients had an infusion-related reaction to the first (iv) dose of rituximab; subsequent sc dosing of rituximab was well tolerated in all patients. Grade 3/4 toxicity was seen in 28% and 10% of patients respectively. 21 SAEs were reported in 15 patients, mostly infections. 6 patients died while on the trial (2 progressive disease, 1 progressive multifocal leukencephalopathy (symptoms present already at entry), 2 deaths considered unrelated in elderly patients (>80 years) with multiple pre-existing comorbidities, 1 graft versus host disease after progression and subsequent allogeneic stem cell transplantation. Conclusions Treatment with the combination of ixazomib citrate, sc rituximab and dexamethasone is feasible, easy to administer and shows promising efficacy with manageable toxicity in patients with relapsed or progressive WM. The final analysis for the primary endpoint for all 60 patients will be shown at the conference. Role of the funding source: the study was financially supported by grants from Takeda Oncology, Roche and the Dutch Cancer Society. Acknowledgments: the authors wish to acknowledge the trial coordinators and central datamanagers of HOVON data center and all patients and contributing centers for participation in the trial Figure IgM (A) and Hemoglobin (B) levels during treatment Disclosures Kersten: Gilead: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Kite Pharma: Honoraria, Research Funding; Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding. Minnema:Jansen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Vos:Celgene: Honoraria. Kastritis:Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Chamuleau:Genmab: Research Funding. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. OffLabel Disclosure: Ixazomib in Waldenstrom's Macroglobulinemia
Waldenström’s macroglobulinemia (WM), a rare low-grade B-cell non-Hodgkin lymphoma (NHL), has a distinct clinical presentation and different treatment-related side effects compared with other NHL. Currently, a wide variety of therapeutic agents are available for the treatment of WM but there is no consensus on optimal treatment in first line and/or at relapse. The aim of this survey was to evaluate the current knowledge and perspectives of hematologists on diagnosis and treatment of WM. Also, we compare these results to a similar survey done before the publication of the first Dutch national guideline, in order to evaluate the impact of the implementation of a national guideline. A link to an online survey was sent out to all registered hematologists and hemato-oncologists in the Netherlands with the request to participate. The survey contained questions regarding the preferred diagnostic and treatment methods in patients with WM as well as treatment goals. We also compared physicians preferred treatment goals to those of patients (as studied in a recent nationwide patient questionnaire). Ninety-five responses (30% response rate) were obtained, out of which 82 (86%) surveys were complete. The respondents most commonly used dexamethasone-rituximab-cyclophosphamide as first-line treatment. For second-line treatment, bendamustine with rituximab and ibrutinib monotherapy were the most frequently applied. Compared with the initial survey, serum IgM M-protein was determined in all cases, MYD88 mutation analysis was currently widely implemented, prevention of an IgM “flare” was uniformly managed by the respondents and use of rituximab-cyclophosphamide-vincristine-prednisone was entirely abandoned. Physicians differed somewhat from patients with regard to most important treatment goals. The approach to diagnostic methods and treatment options in WM was more consistent with international guidelines and was more homogeneous after implementation of the national guideline. These data indicate an increase in knowledge on WM diagnosis and treatment. This may have resulted from implementation of a local guideline or the global rise in awareness and attention for WM.
Marginal Zone Lymphoma (MZL) and Waldenström's Macroglobulinemia (WM) are indolent lymphomas that both arise from post germinal center lymphocytes. Both can secrete a monoclonal protein but high levels are mostly only seen in WM. The MYD88 L256P somatic mutation that is present in an estimated 95% of patients with WM has helped greatly in differentiating the two lymphomas. Several large clinical studies with new drugs have been performed that have provided new treatment options for both MZL and WM patients. In this short review we will discuss the recent literature published and provide some recommendations.
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