Patricia Severns

MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival

MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic discrimination can be difficult among suspected wild‐type MYD88 (MYD88WT) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10‐year survival was 73% (95% confidence interval [CI] 52–86%) for MYD88WT versus 90% (95% CI 82–95%) for mutated (MYD88MUT) WM patients (Log‐rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B‐cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88WT and MYD88MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2–233·8; P < 0·001). Overall survival was shorter among MYD88WT patients with an associated DLBCL event (Log‐rank P = 0·08). The findings show that among suspected MYD88WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88MUT disease.

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (nu2009=u200927; 14%), toxicity (nu2009=u200915; 8%), nonresponse (nu2009=u20095; 3%), and other unrelated reasons (nu2009=u20094; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4‐fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; Pu2009=u2009.046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenström Macroglobulinemia

Purpose: Proteasome inhibition is of proven efficacy in patients with Waldenström macroglobulinemia (WM). However, WM remains incurable with standard treatments. Novel agents, safe and effective, are needed. Patients and Methods: We designed a prospective phase II study evaluating the combination of ixazomib, dexamethasone, and rituximab (IDR) as primary therapy in symptomatic patients with WM. Protocol therapy consisted of oral ixazomib, 4 mg, with intravenous or oral dexamethasone, 20 mg, on days 1, 8, and 15 every 4 weeks for induction cycles 1 and 2, and in combination with intravenous rituximab, 375 mg/m2, on day 1, every 4 weeks for cycles 3 to 6. Maintenance therapy followed 8 weeks later with IDR given every 8 weeks for 6 cycles. Results: Twenty-six patients were enrolled. All patients had the MYD88 L265P mutation, and 15 patients (58%) had a CXCR4 mutation. The median time to response was 8 weeks, which was longer (12 weeks) in WM patients with CXCR4 mutations (P = 0.03). The overall response rate was 96%, and the major response rate was 77%. With a median follow-up of 22 months, the median progression-free survival was not reached. Grade ≥2 adverse events reported in >1 patient included infusion-related reactions (19%), rash (8%), and insomnia (8%). Conclusions: IDR offers a highly effective and well tolerated, neuropathy-sparing regimen for primary therapy in patients with WM. This trial is registered at www.clinicaltrials.gov under ID NCT02400437. Clin Cancer Res; 24(14); 3247–52. ©2018 AACR.

Response and survival for primary therapy combination regimens and maintenance rituximab in Waldenström macroglobulinaemia

Waldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Comparative studies evaluating the efficacy of primary therapy in symptomatic WM patients have not been performed. In this study, we compared response and survival outcomes in WM patients who received primary therapy with cyclophosphamide‐dexamethasone‐rituximab (CDR), bortezomib‐dexamethasone‐rituximab (BDR) and bendamustine‐rituximab (Benda‐R), as well as maintenance rituximab following primary therapy. Analyses were adjusted for relevant clinical factors associated with response and survival. Maintenance rituximab was analysed as a time‐varying covariate. Our study included 182 patients, of which 57 (31%) received Benda‐R, 87 (48%) BDR and 38 (21%) CDR; 116 (64%) received maintenance rituximab. The median time to best response was shorter for Benda‐R and BDR than CDR (18, 20 and 30 months, respectively). Benda‐R and BDR were associated with better median progression‐free survival (PFS) than CDR (5·5, 5·8 and 4·8 years, respectively), and better 10‐year overall survival rates (OS; 95%, 96% and 81%, respectively). Maintenance rituximab was associated with higher rates of major response (97% vs. 68%), and better median PFS (6·8 years vs. 2·8 years) and 10‐year OS rate (84% vs. 66%) when compared to not receiving maintenance. Benda‐R, BDR and maintenance rituximab associate with higher response rates and longer survival in WM patients than CDR and no maintenance, respectively.

BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism

Acquired ibrutinib resistance due to BTKCys481 mutations occurs in B-cell malignancies, including those with MYD88 mutations. BTKCys481 mutations are usually subclonal, and their relevance to clinical progression remains unclear. Moreover, the signaling pathways that promote ibrutinib resistance remain to be clarified. We therefore engineered BTKCys481Ser and BTKWT expressing MYD88-mutated Waldenström macroglobulinemia (WM) and activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cells and observed reactivation of BTK-PLCγ2-ERK1/2 signaling in the presence of ibrutinib in only the former. Use of ERK1/2 inhibitors triggered apoptosis in BTKCys481Ser-expressing cells and showed synergistic cytotoxicity with ibrutinib. ERK1/2 reactivation in ibrutinib-treated BTKCys481Ser cells was accompanied by release of many prosurvival and inflammatory cytokines, including interleukin-6 (IL-6) and IL-10 that were also blocked by ERK1/2 inhibition. To clarify if cytokine release by ibrutinib-treated BTKCys481Ser cells could protect BTKWT MYD88-mutated malignant cells, we used a Transwell coculture system and showed that nontransduced BTKWT MYD88-mutated WM or ABC DLBCL cells were rescued from ibrutinib-induced killing when cocultured with BTKCys481Ser but not their BTKWT-expressing counterparts. Use of IL-6 and/or IL-10 blocking antibodies abolished the protective effect conferred on nontransduced BTKWT by coculture with BTKCys481Ser expressing WM or ABC DLBCL cell counterparts. Rebound of IL-6 and IL-10 serum levels also accompanied disease progression in WM patients with acquired BTKCys481 mutations. Our findings show that the BTKCys481Ser mutation drives ibrutinib resistance in MYD88-mutated WM and ABC DLBCL cells through reactivation of ERK1/2 and can confer a protective effect on BTKWT cells through a paracrine mechanism.

Ibrutinib withdrawal symptoms in patients with Waldenström macroglobulinemia

Ibrutinib is the first approved therapy for the treatment of patients with Waldenström macroglobulinemia (WM). The approval was based on results of a study in WM patients that showed overall response rate (ORR) of 91% and median time to response of 4 weeks. Similar results were reported in another multicenter study in rituximabrefractory WM patients and in a study evaluating ibrutinib as primary therapy for WM patients. Temporary interruption of ibrutinib is sometimes needed to manage toxicities or perioperatively to minimize bleeding. We observed that some WM patients developed withdrawal symptoms while holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. We performed a retrospective study that shows that withdrawal symptoms develop in 20% of WM patients who hold ibrutinib therapy. The rate of withdrawal symptoms was lower in patients who started ibrutinib at serum IgM levels ≥4,000 mg/dl and CXCR4 mutated patients, and higher in patients who had achieved a very good partial response (VGPR) on ibrutinib. Symptoms ensue within 2 days of ibrutinib hold and resolve rapidly following reinitiation of therapy. In two thirds of the patients who experience withdrawal, there is no evidence of disease progression during ibrutinib hold. In the patients who progress during the hold, response is regained within 3 months of ibrutinib reinitiation. We identified patients seen at our institution between May 2012 and April 2017 who met diagnostic criteria for WM, met criteria to initiate therapy, and received ibrutinib at 420 mg PO once daily. The Institutional Review Board at the Dana-Farber Cancer Institute approved the study. Medical files were reviewed to identify WM patients who reported new-onset symptoms occurring during a temporary hold of ibrutinib therapy. Patients’ characteristics were compared using c, Fisher exact or rank sum tests as needed. The association of clinical factors with withdrawal symptoms was evaluated by fitting logistic regression models, and reported as odds ratio (OR) with 95% confidence interval (CI). All withdrawal symptoms were graded according to the Common Terminology Criteria for Adverse Events. P-values <0.05 were considered statistically significant. Calculations and graphs were obtained using STATA (StataCorp, College Station, TX, USA). A total of 189 patients with WM who started ibrutinib were identified; 75 patients (40%) did not hold ibrutinib, and 114 (60%) held ibrutinib at some point during therapy. The median time on ibrutinib in patients who held ibrutinib was 22 months (95% CI 18-39 months) and 12 months (95% CI 9-15 months) for those who did not hold ibrutinib. There were no differences in characteristics between patients who held and did not hold ibrutinib (data not shown). From patients who held ibrutinib, 92 (81%) did not experience withdrawal symptoms and 22 (19%) did. Of patients who experienced withdrawal symptoms, 17 (82%) were receiving ibrutinib in the relapsed and 4 (18%) in the frontline setting. All patients were holding ibrutinib for the first time since treatment initiation. The median drug hold length was 7 days (range 3-33 days). Reasons for holding ibrutinib included: procedure/surgery (n=14; 64%), toxicity (n=6; 27%),

Low levels of von Willebrand markers associate with high serum IgM levels and improve with response to therapy, in patients with Waldenström macroglobulinaemia

Waldenstr€ om macroglobulinaemia (WM) is a rare lymphoma characterized by the accumulation of malignant IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs (Swerdlow et al, 2016). Recurrent MYD88 and CXCR4 mutations define the genomic landscape of WM (Hunter et al, 2017). Acquired von Willebrand disease (VWD) has been described in patients with WM (Mazurier et al, 1980), and a retrospective study suggested that high von Willebrand factor (VWF) levels might be prognostic in patients with WM (Hivert et al, 2012). However, the clinical characteristics and outcomes to therapy of WM patients with low levels of VWF antigen (VWF:Ag), VWF activity (Ristocetin cofactor; VWF:RCo) and factor VIII (FVIII) have not been extensively studied. We carried a retrospective study in newly diagnosed WM patients seen at our institution who were tested for VWF:Ag, VWF:RCo and FVIII levels (VW markers). Low VW markers levels were defined as below 50%. Logistic regression models were fitted to evaluate the association of clinical factors and low VW markers. We also evaluated the association of response to therapy on VW markers using linear regression models. Categorical response to therapy was defined using current guidelines (Owen et al, 2013). MYD88 mutation was evaluated using polymerase chain reaction techniques and CXCR4 mutations using Sanger sequencing (Hunter et al, 2014; Xu et al, 2014). MYD88 and CXCR4 genotyping has been routinely performed at our centre since 2013, but it is not available in all patients. A total of 320 WM patients were tested due to reported signs of bleeding or easy bruising, of whom 49 (15%) showed low levels of VW markers. The median serum IgM