M J Kersten Utrecht Kite Runner Peer Review

INTRODUCTION

Section:

Waldenström's Macroglobulinemia (WM) is an indolent B-jail cell lymphoma, characterized by bone marrow (BM) infiltration of lymphoplasmacytoid cells and plasma cells (PCs), producing immunoglobulin K (IgM) Yard-protein.ⁱ

CONTEXT

• Key Objective

• What is the efficacy and prophylactic of the novel less neurotoxic oral proteasome inhibitor ixazomib combined with subcutaneous rituximab and dexamethasone (IRD) in patients with relapsed or refractory Waldenström'due south Macroglobulinemia (WM)?

• Knowledge Generated

• Treatment with IRD achieved a major response charge per unit of 51% including 14% very expert partial response (PR) and 37% PR, which improved until month 12 to a major response rate of 61% with fifteen% very practiced PR and 46% PR with manageable toxicity. Use of SC rituximab did not event in infusion-related reactions or immunoglobulin Yard flare. Median progression-complimentary survival and overall survival were not reached, and after median follow-up of 24 months, progression-free survival and overall survival were 56% and 88%, respectively.

• Relevance

• This phase I/Two clinical trial demonstrates that the IRD regimen, with oral ixazomib and SC rituximab, provides an constructive and well-tolerated treatment in patients with heavily pretreated WM. Larger randomized trials demand to compare the efficacy of IRD to other regimens for relapsed or refractory WM.

Anti-CD20 monoclonal antibodies–based combinations are used for the primary therapy of WM; however, management of relapsed or refractory (RR) affliction remains challenging. Several phase Ii studies have shown clinical action of the proteasome inhibitor (PI) bortezomib in WM. However, bortezomib-associated peripheral polyneuropathy (PNP) occurs frequently, leading to treatment discontinuation in approximately 30% of patients with WM.^2-7 The oral PI ixazomib is proven to exist less neurotoxic and well tolerated in multiple myeloma (MM).^8,nine A previous study of ixazomib, rituximab, and dexamethasone (IRD) in treatment-naive WM patients demonstrated an overall response charge per unit (ORR) of 96% and a median progression-gratuitous survival (PFS) of 40 months, with skilful tolerability and 20% incidence of form 1 neuropathy.^x,11 All the same, no data on the activity and toxicity of IRD in RR WM exist. In WM, MYD88 ^L265P and CXCR4 mutations are present in > 90% and upwardly to xl% of patients, respectively.^12-xiv Previous studies have demonstrated that PFS is unaffected past CXCR4 status in patients treated with PIs in offset line.^xi CXCR4 mutations were, even so, associated with lower very good partial response (VGPR) rates and increased fourth dimension to response compared with CXCR4 wild-type patients, but for relapsed patients, no data exist on the impact of CXCR4 on PFS after handling with PIs.^10,xi,xv,xvi Rituximab sensitization is observed in approximately 7% of patients with WM, often leading to treatment discontinuation.¹⁷ The apply of subcutaneous (SC) rather than intravenous (IV) rituximab could consequence in less sensitization.

In this prospective, multicenter, phase I/2 study performed past the Haemato Oncology Foundation for Adults in kingdom of the netherlands and European Consortium for Waldenström's Macroglobulinemia in collaboration with the Greek Myeloma Study Group (HOVON124/ECWM-R2), nosotros establish the effective dose level for ixazomib in combination with SC rituximab and dexamethasone and demonstrate the feasibility and efficacy of this regimen in relapsed WM.

METHODS

Section:

Patients

Patients with progressive or relapsed WM later prior systemic therapy, requiring treatment based on consensus criteria, were enrolled.¹⁸ Patients had to accept measurable disease (divers as IgM level > one g/dL). The Data Supplement (online only) shows the complete inclusion and exclusion criteria. Central pathology review was performed by K.A. and Southward.T.P.

All patients provided written informed consent. The study Protocol (online just) was canonical by the Ethical Review Committee of all participating centers and was carried out in accord with the principles of the Helsinki Declaration.

Report Blueprint and Handling

The HOVON124 study (http://www.trialregister.nl identifier: NL5025 [NTR5171]) is an international, multicenter, prospective, open up-label phase I/2 report conducted at 18 centers: xiv in the Netherlands, 3 in Belgium, and one in Greece. An contained Data Prophylactic Monitoring Board evaluated the general progress and rubber at predefined intervals.

Baseline cess included poly peptide electrophoresis, immunofixation, free light chain measurements, BM biopsy, molecular assay for MYD88 and CXCR4 mutations, and computed tomography (CT) scan of neck, chest, and abdomen. Phase I report pattern is described in the Data Supplement.

For phase 2, patients were treated with eight 28-day cycles of ixazomib at the recommended dose level (4 mg apartment dose, orally, day 1, 8, and 15) and dexamethasone (twenty mg orally, solar day 1, 8, 15, and 22). To avoid the risk of IgM flare and to assess the effect of ixazomib only, rituximab was added from bike three onward; the outset dose was given Iv (375 mg/m^two on 24-hour interval 1), and all subsequent doses were given at a apartment dose of one,400 mg SC.

Later cycle 4, patients with progressive disease (PD) went off report. Later bike 8, patients with at least minor response (MR) continued to rituximab maintenance (rituximab SC 1,400 mg every 3 months for 2 years).

Response Evaluation and Finish Points

Responses were adamant using the International Workshop for WM-vi criteria.^xix,20 Definitions of complete response, VGPR, partial response (PR), and MR are provided in the Data Supplement. Cheson criteria were used to asses CT scan results and are summarized in the Data Supplement.²¹ IgM flare is defined as a temporary IgM increase > 25% from baseline (with a minimum of 5 one thousand/L) followed by an MR or improve to handling. Toxicity was reported co-ordinate to the Common Terminology Criteria for Agin Events version four.03.^2,22

The primary terminate point of the study was ORR later on eight cycles of IRD, based on IgM level. Secondary stop points included the rate of complete response, VGPR, PR, and MR separately, the best responses and responses after cycles 2, 4, and 8, the increase in hematocrit and decrease in IgM level, time to start and all-time responses, duration of response (DOR), PFS, and overall survival (Bone). Furthermore, toxicity profile of IRD and patient-reported outcome measures (PROMs) were studied with an emphasis on neurotoxicity, too equally quality of life. All terminate points are described in the Data Supplement. The efficacy analyses are performed in 59 patients, based on intention to treat.

Patient-Reported Outcome Measures

The European Organisation for Inquiry and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire (QLQ-C30) is a cancer-specific multidimensional 30-detail questionnaire containing functional, symptom, global health status (GHS), QOL, and single-item scales. The 30 question scores were converted to a 0-100 score according to the EORTC QLQ-C30 scoring transmission. College scores on the GHS and functional scales stand for better QOL, whereas higher scores on the symptom scales represent to greater degree of symptom brunt.²³ Neurotoxicity was assessed using the EORTC QLQ-CIPN20 questionnaire. This questionnaire is adult to assess chemotherapy-induced PNP and contains three subscales based on sensory, motor, and autonomous neuropathy complaints.²⁴ The subscales were transformed to a 0-100 score, with higher score representing more symptoms. Items 1-nineteen were analyzed. In addition, a neurotoxicity scoring tool direct linking complaints to CTC-AE grading (version 4.0) was used.²⁵

Assessment of Bone Marrow Response and Molecular Analysis

Paraffin-embedded BM biopsies performed at entry and after cycles four and 8 or at early on withdrawal or progression or relapse were centrally reviewed. Infiltration percent of BM biopsies was adamant past immunohistochemical assessment of CD3, CD20, CD79a, CD138, κ, and λ. BM tumor populations were defined as follows: full tumor cells represented by CD79a⁺ cells, malignant B lymphocytes represented by CD20⁺ cells, lymphoplasmacytic cells represented by involved calorie-free chain (κ or λ) positive cells minus the CD138⁺ cells, and PCs by CD138⁺ cells. Two independent observers estimated the infiltration per centum of the populations, blinded for patient biopsy sample and time point.

For molecular analysis, genomic DNA was extracted from BM sections as well every bit BM aspirates of most patients using the QIAamp DNA Micro Kit (Qiagen, Santa Clarita, CA). Library grooming was carried out using the Ion AmpliSeq Library Kit ii.0 according to manufacturer's instructions. An overview of the 64-gene panel kit used and detailed description of sample processing for next-generation sequencing (NGS) is available in the Data Supplement.

Statistical Analysis

The statistical analysis plan for stage I/II is described in the Information Supplement. Using a Simon two-phase min-max design based on a historical response charge per unit of forty% and an predictable response charge per unit of 60%, using an α = .05 and a power of (1-β) 90%, results in a sample size of 54 patients. Considering a putative 10% ineligibility charge per unit, 60 patients were planned to be enrolled. Since 59 eligible patients were enrolled finally, nosotros computed the signal estimate for ORR, 95% CI, and P value for over-running Simon's ii-phase design (Data Supplement). Time-to-event cease points were estimated using the Kaplan-Meier method, and log-rank examination was used to analyze group differences in PFS and OS. PROMs were analyzed with nonparametric statistics. A Wilcoxon matched-pairs signed rank test was used to analyze alter over time. Correlations were carried out by Spearman'south correlation. A P value < .05 was considered statistically significant. All statistical analyses were performed with Stata (v15.1, StataCorp LP, Higher Station, TX) and R (v3.6.1, R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Section:

Patients

Between Jan 2015 and January 2019, sixty patients with RR WM were enrolled (n = vi in stage I at the recommended dose level and n = 54 in phase II). One patient was ineligible (rituximab-refractory) and therefore 59 patients were included in the phase II analysis.

Table ane summarizes patient's characteristics. A summary of prior treatments is included in the Data Supplement. The median age was 69 years (range, 46-91 years), 68% were males, and 21 (36%) patients were high risk based on the International Prognostic Scoring System for WM. Central pathology review confirmed the diagnosis of WM in all patients.

Table one. Patient Characteristics

Dose level.

During stage I, no dose-limiting toxicity during cycle i occurred and no serious agin events (SAEs) were reported. Thus, the iv mg dose was accounted feasible and the six patients treated during phase I were included in the interim efficacy analysis of phase II.

Efficacy

At the interim analysis, 24 of 29 (83%) patients treated in the phase II part (stage ane) achieved a response, which led to a positive advice from the Data Safety Monitoring Board to proceed to stage 2. Based on intention-to-treat, the ORR afterward eight IRD cycles was 71% (42 of 59; 95% CI, 60 to 79), including VGPR in eight (14%), PR in 22 (37%), and MR in 12 (xx%) patients. Two (3%) patients had stable disease and one (2%) had PD after eight cycles (Fig 1A ). Responses connected to improve with therapy until month 12, with best ORR of 85% (50 of 59) with 15% (9 of 59) VGPR, 46% (27 of 59) PR, and 24% (14 of 59) MR. Median time to outset and best responses was 4 and 5 months, respectively. Median DOR was 36 months. Average hematocrit level increased from 0.33 L/L at baseline to 0.37 L/L later four cycles (P < .001) and further increased to 0.38 L/L afterwards eight cycles (P < .001; Fig 2A ). After the beginning two cycles of single-agent ixazomib, IgM level decreased significantly (median 3,700-2,700 mg/dL, P < .0001), decreasing farther to one,200 mg/dL after viii cycles (P < .001; Fig 2B ). In total, 48 of 59 patients (81%) completed at least vi cycles of IRD. Reasons for before discontinuation of 14 patients were progression (n = 6), toxicity (due north = 3), unrelated intercurrent death (n = two), incompliance (n = 1), and other reasons (n = 2; Fig 3 ). Amidst the 14 patients who did not complete eight cycles of IRD, one had VGPR, four had a PR, ii had an MR, three had stable illness, and four had a PD between cycles ii and 7.

FIG 1. (A) Responses during induction wheel 1-8 of 59 enrolled patients and (B) responses during consecration wheel 1-8 by mutation status. C, wheel; MR, pocket-sized response; NA, not available; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

FIG 2. (A) Ht (L/L) contour over the first eight induction cycles for the included patients and (B) total serum IgM (g/50) profile over the first eight consecration cycles for the included patients. Ht, hematocrit; IgM, immunoglobulin M.

FIG iii. Menstruation diagram: number of patients going through the protocol treatment including reasons for exclusion. ^aPatients who for any reason do non tolerate the SC assistants of rituximab can be treated with rituximab Four at the regular dose of 375 mg/m². CR, complete response; Iv, intravenous; MR, minor response; PD, progressive disease; PR, partial response; RP2D, recommended phase II dose; SC, subcutaneous; SD, stable disease; VGPR, very good partial response.

CT-confirmed lymphadenopathy and hepatosplenomegaly at baseline was present in 32 of 59 (54%) and 10 of 59 (17%) patients, respectively. On follow-up CT browse, lymphadenopathy and hepatosplenomegaly decreased or resolved in 14 of 32 (44%) and 5 of 10 (50%) patients and remained stable in 10 of 32 (31%) and two of 10 (xx%) patients, respectively. Progression of lymphadenopathy occurred in 2 of 32 (6%) patients.

Survival

Median PFS and Os were not reached, and afterward a median follow-up of 24 months (range, 7.4-54.iii months), PFS was 56% (95% CI, 40 to 67; events = 23 out of 59) and Os was 88% (95% CI, 75 to 95; events = 6 out of 59; Figs 4A and 4B ). Six patients died during the report period: two died of PD, one of progressive multifocal leukoencephalopathy, one of graft-versus–host-illness following subsequent allogenic stem-jail cell transplantation afterward PD, and 2 patients with cardiac comorbidities died of sudden death. These were all considered unrelated to report treatment (the patient with progressive multifocal leukoencephalopathy, in hindsight, already had symptoms at baseline).

FIG 4. Kaplan-Meier curves for all 59 patients in the intention-to-treat analysis for (A) PFS and (B) Os measured from enrollment. Os, overall survival; PFS, progression-free survival.

No statistically significant differences were institute for PFS in the univariable analysis for baseline risk factors (ie, International Prognostic Scoring Organization for WM score; Data Supplement).

Safety

During consecration, none of the patients experienced an IgM flare. In 34 patients, a cycle of IRD was delayed because of hematologic toxicity (northward = vi), infusion-related reactions (IRRs) to Iv rituximab (n = 2), neurotoxicity (due north = five), or other toxicity (n = 21). Grade 1 neurotoxicity and course ii infections, gastrointestinal disorders, and local reactions were mutual. Anemia grade 3 (n = iv), thrombocytopenia class two (n = 11), grade three (n = iv), and grade 4 (n = 3), and neutropenia grade three (north = 7) and grade 4 (n = iv) were seen. SAEs occurring in ≥ 4% of patients were infections (n = 8) and other conditions (n = 7) like dehydration, subarachnoid haemorrhage (because of trauma), and secondary malignancy. A consummate overview of agin events and SAEs is provided in the Data Supplement.

Patient-Reported Event Measures

Neuropathy.

The QLQCIPN20 and Common Terminology Criteria for Adverse Events grading were obtained at baseline (n = 57), after cycle 4 (n = 46), and subsequently cycle 8 (due north = 47). Outcomes for the EORTC QLQ-CIPN20 are summarized in the Data Supplement. Mean scores at baseline were 10.two, nine.2, and 14.7 for the sensory, motor, and autonomic domains, respectively. When compared to scores at the stop of consecration for all subscales, the boilerplate change in means was not statistically meaning (P > .05 for sensory, motor, and autonomic scales), demonstrating no increment in neuropathy-associated symptom burden during treatment.

Quality of life.

A full of 57, 46, and 41 patients completed the EORTC QLQ-C30 questionnaire at baseline, later on cycle 4, and afterward cycle 8, respectively. The mean scores from the EORTC QLQ-C30 scales and items are summarized in the Data Supplement. Patients reported a pregnant improvement in all items of the functional scales (P < .05 for role, emotional, and social performance) at the end of induction except for physical and cognitive functioning when compared with baseline. Overall, GHS significantly increased at the end of induction (P = .01), suggesting improvement in QOL.

Mail service Hoc Analyses: Assessment of BM Response and Molecular Analysis

Median BM involvement at baseline was 35% and after 8 cycles decreased significantly to 12% (P < .001; Tabular array 2 and Information Supplement). NGS was performed on BM biopsies and BM aspirates of 23 and 24 patients, respectively. In the BM biopsies, NGS demonstrated a MYD88^L265P in 23 of 26 patients (88%), with a median variant allele frequency (VAF) of xx.four% (range, ane.4%-46.5%) at baseline. In BM aspirates, a MYD88^L265P was nowadays in 39 of 42 patients (93%) with a median VAF of 5.seven% (range, 0.iii-43.6%) at baseline. In the whole report group, MYD88 and CXCR4 mutations were present in 51 of 55 (93%) and 14 of 52 (27%) patients, respectively. MYD88 and CXCR4 mutation status was undetermined in four and seven patients, respectively. Median BM involvement in MYD88^WT versus MYD88^L265P patients was 10% versus 35%.

Table 2. Immunohistochemical Assessment of Bone Marrow Biopsies

Later on eight cycles of IRD, the MYD88^L265P median VAF decreased from 20.iv% to 8.0% (P = .03) and from 5.7% to 0% (P = .05) for BM biopsies and BM aspirates, respectively (Table 3). MYD88^L265P VAF determined past NGS on BM biopsies correlated strongly with the immunohistochemically estimated BM interest (CD79⁺) at baseline (r = 0.85; P < .001), after bicycle 4 (r = 0.93; P < .001), and later cycle eight (r = 0.97, P < .001; Data Supplement). Patients with MYD88^L256P /CXCR4^WT and MYD88^WT /CXCR4^WT had the highest rates of VGPR and PR (47% and 33%) while no patient with MYD88^L256P /CXCR4^MUT achieved VGPR (Fig 1B ). Median PFS was non reached in both MYD88^L265P /CXCR4^WT and MYD88^WT /CXCR4^WT patients and was 36 months in MYD88^L265P /CXCR4^MUT patients. At 24 months, the PFS for the MYD88^L265P /CXCR4^WT , MYD88^L265P /CXCR4^MUT , and MYD88^WT /CXCR4^WT patients was 75% (95% CI, 61 to 92), 57% (95% CI, 36 to 90), and 67% (95% CI, 30 to 100), of which 9 (26.5%), 8 (57%), and one patients progressed, respectively (log-rank P = .19; Data Supplement). Although these results suggest an inferior outcome for CXCR4^MUT patients, statistical significant difference was not reached since the written report was underpowered to detect such a divergence.

Tabular array 3. Molecular Analysis of Bone Marrow Biopsies and Bone Marrow Aspirates

DISCUSSION

Department:

In this international, prospective phase I/2 written report, nosotros investigated the efficacy and safe of the IRD regimen in patients with RR WM. The current study is the first reporting on the use of ixazomib in RR WM and SC rituximab in WM. We observed a high ORR of 71% afterward 8 cycles of IRD, with further comeback of response until month 12 (best ORR 85%) and a median DOR of 36 months. Median fourth dimension to pocket-sized and major response was 4 and 5 months, respectively. In a previous phase II study of IRD in treatment-naive WM patients, a college ORR of 96% was accomplished, just with similar VGPR rates and DOR.^10,11 The study design also permitted evaluation of unmarried-agent activity of ixazomib, an oral drug, being able to reduce IgM levels significantly after just two cycles, peradventure contributing to the depression rates of IgM flare after rituximab introduction.

We observed a two-year PFS rate of 56% (95% CI, 41 to 69) and an Os of 88% (95% CI, 75 to 95), in a previously treated population with a median of 2 prior lines of therapy. Interestingly, 2-year PFS and Bone rates were only slightly lower compared with the results of IRD in treatment-naive WM patients. Similar to that study, we also establish that PFS was not affected by CXCR4 mutational status.¹⁰ Maintenance with ixazomib could be a promising approach to increase PFS, equally indicated by a median PFS of xl months after six IRD maintenance cycles in the aforementioned study.^xi

Previous studies evaluating ixazomib in MM take shown low rates of PNP (12%-xx%).^eight,26 In our study, new onset or worsening of pre-existing PNP occurred in thirteen (22%) and iii (v%) patients, respectively (Information Supplement), and recovered in most patients during follow-upward. Using PROMs with a validated PNP-specific questionnaire, no increase in PNP-related symptoms was observed and thus ixazomib appears to compare favorably to bortezomib (incidence between 30% and 64%).^2-7 We observed a relatively high incidence of course i PNP, which was probably because of thorough and systematic evaluation of PNP using two dissimilar questionnaires at dissimilar time points. Still, in dissimilarity to bortezomib PNP, it did non lead to discontinuation of therapy or increase in symptom burden. The comeback of QOL besides underscores the tolerability of IRD. Nonetheless, the low rate of severe PNP-related symptom burden and improvement in QOL could potentially be biased considering of patient selection as only 68% (xl of 59) and 69% (41 of 59) of patients completed the PNP and QOL questionnaires after eight cycles, respectively.

Patients with WM have a higher risk of sensitization to rituximab (up to seven%) than other lymphoma patients.¹⁷ In our study, two IRRs occurred subsequently IV rituximab. During subsequent cycles, all patients received SC rituximab without IRRs. In addition, no patient adult rituximab intolerance. Thus, IRD proves a well-tolerated, convenient regimen for patients with RR WM every bit 81% of the patients completed at least 6 cycles.

Bruton's tyrosine kinase inhibitors have revolutionized the handling of WM because of loftier response rates in both treatment-naive and RR WM.^27,28 However, in patients at risk for bleeding or cardiac complications, they may be poorly tolerated; long-term follow-upward data of one of the pivotal studies demonstrated a 12.seven% incidence of atrial fibrillation in relapsed WM.²⁹ Other retrospective studies exterior clinical trials setting too indicated discontinuation rates for toxicity of about xv%.³⁰ Furthermore, 5-year PFS rate for all patients was 54%.²⁹ Therefore, there is a need for alternative chemotherapy-free fixed-duration regimens such equally IRD.

The post hoc analyses comprised immunohistochemical and molecular evaluation. Using immunohistochemistry, we demonstrated that the PC population persisted in almost patients at the terminate of induction, whereas the CD20⁺ B-prison cell population had essentially decreased. Role of this subtract could, yet, be a issue of epitope masking by rituximab or internalization of the CD20:anti-CD20 complex.^31,32 These findings are remarkable since PCs have been shown to exist sensitive to ixazomib and other PIs.³³ A possible explanation for the lesser sensitivity of WM PC population, compared with MM PCs, is that WM PCs might have greater resemblance to normal B lymphocytes. This is supported by gene-expression studies indicating differences in WM PCs compared with MM and marginal zone lymphoma.^34,35

Our molecular assay identified MYD88^L256P in 89% with a coexisting CXCR4 mutation in 26%, consistent with previous reports. We did not perform this analysis on CD19-selected cells only in DNA extracted from unabridged BM biopsies or aspirates.³⁶ The MYD88 VAFs determined from analyzing BM biopsy extracted Deoxyribonucleic acid strongly correlated with the CD79a⁺ BM tumor infiltration simply not when Dna derived from BM aspirates was used, presumably because of the varying limerick of the aspirate. Our findings advocate for the use of DNA extracted from whole BM biopsies for mutational analysis in WM since it yields quantitative information concerning tumor load. This arroyo is more practical and viable for nearly laboratories equally it avoids the need for CD19 selection, which can only be done on fresh samples. Yet, a consistent decalcification method that is non impairing Dna quality of BM biopsies is imperative.

In conclusion, the IRD regimen with oral ixazomib and SC rituximab provides a patient-friendly and efficient treatment in patients with heavily pretreated WM, inducing high rates of response and respectable PFS with very good OS and, thus, could exist an additional handling option for patients with RR WM.

© 2021 past American Social club of Clinical Oncology

DISCLAIMER

Report medication was provided by Takeda (ixaxomib citrate), and Roche (rituximab). Takeda and Roche did not accept any influence on the assay of the information or the interpretation of the results.

Back up

Supported by the Dutch Cancer Lodge (grant number EMCR 2013-6414), Takeda, and Roche.

The authors confirm that parts of the data supporting the findings of this study are available within the supplementary materials (eg, Study Protocol and Statistical Analysis Program). The participant information that underlie the results reported in this study are available on request from the corresponding writer, One thousand.J.K. The information are not publicly bachelor because of restrictions, for example, their containing data that could compromise the privacy of research participants.

Formulation and design: Marie José Kersten, Monique C. Minnema, Josephine M. I. Vos, Efstathios Kastritis, Meletios A. Dimopoulos

Administrative support: Marcel Kap

Provision of written report materials or patients: All authors

Collection and assembly of data: Marie José Kersten, Karima Amaador, Monique C. Minnema, Josephine M. I. Vos, Marcel Kap, Efstathios Kastritis, Maria Gavriatopoulou, Willem Kraan, Dries Deeren, Lidwine W. Tick, Jeanette K. Doorduijn, Fritz Offner, Lara H. Böhmer, Roberto D. Liu, Steven T. Pals, Meletios A. Dimopoulos

Information assay and estimation: All authors

Manuscript writing: All authors

Last approval of manuscript: All authors

Accountable for all aspects of the piece of work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Combining Ixazomib With Subcutaneous Rituximab and Dexamethasone in Relapsed or Refractory Waldenström'due south Macroglobulinemia: Final Analysis of the Phase I/Ii HOVON124/ECWM-R2 Written report

The post-obit represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are cocky-held unless noted. I = Immediate Family Member, Inst = My Establishment. Relationships may not chronicle to the bailiwick thing of this manuscript. For more than information nigh ASCO's conflict of interest policy, please refer to world wide web.asco.org/rwc or ascopubs.org/jco/authors/author-middle.

Open up Payments is a public database containing data reported by companies about payments made to The states-licensed physicians (Open Payments).

Marie José Kersten

Honoraria: Novartis, Kite, a Gilead Company, Roche

Consulting or Advisory Role: Novartis, Kite, a Gilead Visitor, Miltenyi Biotec, Takeda

Inquiry Funding: Kite, a Gilead Company

Travel, Accommodations, Expenses: Novartis, Kite, a Gilead Company, Roche, Celgene

Monique C. Minnema

Consulting or Advisory Office: Janssen-Cilag, Alnylam, Gilead Sciences

Speakers' Bureau: Celgene/Bristol Myers Squibb

Travel, Accommodations, Expenses: Celgene

Josephine M. I. Vos

Consulting or Advisory Office: Sanofi Pasteur

Travel, Accommodations, Expenses: Celgene

Efstathios Kastritis

Honoraria: Amgen, Genesis Pharma, Janssen Oncology, Takeda, Prothena, Pfizer

Consulting or Advisory Role: Amgen, Janssen Oncology, Takeda, Genesis Pharma, Prothena, Pfizer

Research Funding: Janssen Oncology, Amgen

Travel, Accommodations, Expenses: Janssen Oncology, Genesis Pharma, Takeda, Pfizer

Maria Gavriatopoulou

Honoraria: Amgen, Janssen, Celgene, Takeda

Consulting or Advisory Function: Amgen, Karyopharm Therapeutics

Enquiry Funding: Novartis

Travel, Accommodations, Expenses: Takeda, Genesis Pharma, Janssen

Martine Chamuleau

Research Funding: BMS, Gilead Sciences, Genmab

Dries Deeren

Consulting or Advisory Role: Celgene, Alexion Pharmaceuticals, Amgen, Janssen-Cilag, Roche, Takeda, Sanofi

Travel, Accommodations, Expenses: Gilead Sciences

Jeanette Thousand. Doorduijn

Consulting or Advisory Role: Lilly

Travel, Accommodations, Expenses: Celgene

Lara H. Böhmer

Travel, Accommodations, Expenses: Servier

Meletios A. Dimopoulos

Honoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, Beigene

Consulting or Advisory Function: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene

No other potential conflicts of involvement were reported.

Acknowledgment

The authors would similar to give thanks all patients who participated in the trial, the HOVON information center (Henk Hofwegen, Robby Sewsaran, and Danny Buitenhuis), and the members of the Data Safety and Monitoring Board. The authors thank all the local data managers, trial nurses, and laboratory and chemist's personnel for their essential aid with collecting and managing the study data.

REFERENCES

Section:

1.	Swerdlow SH , Campo E , Pileri SA , et al: The 2016 revision of the Earth Health Organization classification of lymphoid neoplasms. Blood 127:2375-2390, 2016 Crossref, Medline, Google Scholar
2.	Dimopoulos MA , García-Sanz R , Gavriatopoulou Yard , et al: Master therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): Long-term results of a stage 2 study of the European Myeloma Network (EMN). Blood 122:3276-3282, 2013 Crossref, Medline, Google Scholar
3.	Gavriatopoulou M , García-Sanz R , Kastritis E , et al: BDR in newly diagnosed patients with WM: Concluding analysis of a stage 2 study after a minimum follow-up of 6 years. Blood 129:456-459, 2017 Crossref, Medline, Google Scholar
4.	Meid K , Dubeau T , Severns P , et al: Long-term follow-up of a prospective clinical trial of carfilzomib, rituximab and dexamethasone (Carte) in Waldenstrom'due south macroglobulinemia. Blood 130:2772, 2017 Google Scholar
5.	Treon SP , Ioakimidis Fifty , Soumerai JD , et al: Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol 27:3830-3835, 2009 Link, Google Scholar
6.	Treon SP , Meid Grand , Gustine J , et al: Long-term event of a prospective report of bortezomib, dexamethasone and rituximab (BDR) in previously untreated, symptomatic patients with Waldenstrom's macroglobulinemia. Claret 126:1833, 2015 Crossref, Google Scholar
7.	Treon SP , Tripsas CK , Meid One thousand , et al: Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Claret 124:503-510, 2014 Crossref, Medline, Google Scholar
8.	Kumar SK , Berdeja JG , Niesvizky R , et al: Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: An open up-label phase 1/2 study. Lancet Oncol 15:1503-1512, 2014 Crossref, Medline, Google Scholar
9.	Offidani M , Corvatta L , Caraffa P , et al: An bear witness-based review of ixazomib citrate and its potential in the handling of newly diagnosed multiple myeloma. Onco Targets Ther vii:1793-1800, 2014 Crossref, Medline, Google Scholar
x.	Castillo JJ , Meid Yard , Gustine JN , et al: Prospective clinical trial of ixazomib, dexamethasone, and rituximab equally primary therapy in Waldenström macroglobulinemia. Clin Cancer Res 24:3247-3252, 2018 Crossref, Medline, Google Scholar
eleven.	Castillo JJ , Meid K , Flynn CA , et al: Ixazomib, dexamethasone, and rituximab in handling-naive patients with Waldenström macroglobulinemia: Long-term follow-upward. Claret Adv 4:3952-3959, 2020 Crossref, Medline, Google Scholar
12.	Castillo JJ , Moreno DF , Arbelaez MI , et al: CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review. Expert Rev Hematol 12:873-881, 2019 Crossref, Medline, Google Scholar
xiii.	Poulain S , Roumier C , Venet-Caillault A , et al: Genomic landscape of CXCR4 mutations in Waldenström macroglobulinemia. Clin Cancer Res 22:1480-1488, 2016 Crossref, Medline, Google Scholar
fourteen.	Kaiser LM , Hunter ZR , Treon SP , et al: CXCR4 in Waldenström'southward macroglobulinema: Chances and challenges. Leukemia 35:333-345, 2020 Crossref, Medline, Google Scholar
15.	Castillo JJ , Gustine JN , Meid Thou , et al: CXCR4 mutational status does not touch on outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors. Am J Hematol 95:E95-E98, 2020 Crossref, Medline, Google Scholar
16.	Sklavenitis-Pistofidis R , Capelletti M , Liu C-J , et al: Bortezomib overcomes the negative affect of CXCR4 mutations on survival of Waldenstrom macroglobulinemia patients. Blood 132:2608-2612, 2018 Crossref, Medline, Google Scholar
17.	Castillo JJ , Kanan S , Meid K , et al: Rituximab intolerance in patients with Waldenström macroglobulinaemia. Br J Haematol 174:645-648, 2016 Crossref, Medline, Google Scholar
eighteen.	Dimopoulos MA , Kastritis E , Owen RG , et al: Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood 124:1404-1411, 2014 Crossref, Medline, Google Scholar
19.	Owen RG , Kyle RA , Rock MJ , et al: Response assessment in Waldenström macroglobulinaemia: Update from the VIth International Workshop. Br J Haematol 160:171-176, 2013 Crossref, Medline, Google Scholar
twenty.	Kimby Due east , Treon SP , Anagnostopoulos A , et al: Update on recommendations for assessing response from the Third International Workshop on Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma 6:380-383, 2006 Crossref, Medline, Google Scholar
21.	Cheson BD , Pfistner B , Juweid ME , et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-586, 2007 Link, Google Scholar
22.	Trotti A , Colevas AD , Setser A , et al: Patient-reported outcomes and the evolution of adverse event reporting in oncology. J Clin Oncol 25:5121-5127, 2007 Link, Google Scholar
23.	Fayers P , Aaronson NK , Bjordal K , et al: The EORTC QLQ-C30 Scoring Manual (ed 3). Brussels, Belgium, European Organisation for Research and Treatment of Cancer, 2001 Google Scholar
24.	Postma TJ , Aaronson NK , Heimans JJ , et al: The development of an EORTC quality of life questionnaire to appraise chemotherapy-induced peripheral neuropathy: The QLQ-CIPN20. Eur J Cancer 41:1135-1139, 2005 Crossref, Medline, Google Scholar
25.	Le-Rademacher J , Kanwar R , Seisler D , et al: Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Brotherhood clinical trials. Support Care Cancer 25:3537-3544, 2017 Crossref, Medline, Google Scholar
26.	Kumar SK , Bensinger WI , Zimmerman TM , et al: Stage 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 124:1047-1055, 2014 Crossref, Medline, Google Scholar
27.	Treon SP , Gustine J , Meid K , et al: Ibrutinib monotherapy in symptomatic, treatment-naive patients with Waldenström macroglobulinemia. J Clin Oncol 36:2755-2761, 2018 Link, Google Scholar
28.	Treon SP , Tripsas CK , Meid K , et al: Ibrutinib in previously treated Waldenström's macroglobulinemia. Due north Engl J Med 372:1430-1440, 2015 Crossref, Medline, Google Scholar
29.	Treon SP , Meid K , Gustine J , et al: Long-term follow-upwardly of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol 39:565-575, 2020 Link, Google Scholar
xxx.	Abeykoon JP , Zanwar Due south , Ansell SM , et al: Ibrutinib monotherapy exterior of clinical trial setting in Waldenström macroglobulinaemia: Practice patterns, toxicities and outcomes. Br J Haematol 188:394-403, 2020 Crossref, Medline, Google Scholar
31.	Crickx E , Chappert P , Weller S , et al: A reservoir of rituximab-resistant splenic retentivity B cells contributes to relapses later B-jail cell depletion therapy. bioRxiv ten.1101/833343 Google Scholar
32.	Lim SH , Vaughan AT , Ashton-Key G , et al: Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood 118:2530-2540, 2011 Crossref, Medline, Google Scholar
33.	Neubert K , Meister South , Moser Thou , et al: The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 14:748-755, 2008 Crossref, Medline, Google Scholar
34.	Roberts MJ , Chadburn A , Ma South , et al: Nuclear protein dysregulation in lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia. Am J Clin Pathol 139:210-219, 2013 Crossref, Medline, Google Scholar
35.	Gutiérrez NC , Ocio EM , de las Rivas J , et al: Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: Comparison with expression patterns of the aforementioned cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 21:541-549, 2007 Crossref, Medline, Google Scholar
36.	Xu L , Hunter ZR , Tsakmaklis Northward , et al: Clonal architecture of CXCR4 WHIM-like mutations in Waldenström macroglobulinaemia. Br J Haematol 172:735-744, 2016 Crossref, Medline, Google Scholar

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Source: https://ascopubs.org/doi/10.1200/JCO.21.00105

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