Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.

ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Dose reductions in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5-74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55-3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41-3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow-up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects.

The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.

Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy.

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Bone marrow involvement and subclonal diversity impairs detection of mutated CXCR4 by diagnostic next-generation sequencing in Waldenström macroglobulinaemia.

CXCR4 mutations impact disease presentation and treatment outcomes in Waldenström macroglobulinaemia (WM). Non-uniform testing for CXCR4 mutations may account for discordant findings in WM clinical trials. We compared two approaches used in these trials for detection of the most common CXCR4 (S338X) variant: targeted next-generation sequencing (NGS) using unselected bone marrow (BM) samples, and combined allele-specific polymerase chain reaction (AS-PCR) and Sanger sequencing with unselected and CD19-selected BM samples. Our findings showed that targeted NGS frequently yielded false-negative results. Both CD19 selection and AS-PCR markedly improved detection of CXCR4S338X mutations. Sensitivity was adversely impacted by low BM involvement and CXCR4 mutation clonality.

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.

Deepening of response after completing rituximab-containing therapy in patients with Waldenstrom macroglobulinemia.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI.

TP53 mutations are associated with mutated MYD88 and CXCR4, and confer an adverse outcome in Waldenström macroglobulinaemia.

Little is known about TP53 mutations in Waldenström Macroglobulinaemia (WM). We evaluated 265 WM patients for TP53 mutations by next-generation sequencing, and validated the findings by Sanger sequencing. TP53 mutations were identified and validated in 6 (2·6%) patients that impacted the DNA-binding domain. All six were MYD88- and CXCR4-mutated. Ibrutinib showed activity in patients carrying all three mutations. With a median follow-up of 18 months, 2 (33%) with biallelic TP53 inactivation died of progressive disease. TP53 mutations are rare in WM, and associate with MYD88 and CXCR4 mutations. WM patients with TP53 mutations show response to ibrutinib.

CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4FS ) and nonsense (CXCR4NS ) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4FS and CXCR4NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4NS and 19 (11%) had CXCR4FS mutations. In multivariate models, patients with CXCR4NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12-0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95-8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4NS and CXCR4FS , and advocate in favour of CXCR4 mutational testing as well as CXCR4-directed therapy.

Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia.

Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4WHIM mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD19+ lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease. Targeted next-generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 had BTKCys481 variants that included BTKCys481Ser(c.1635G>C and c.1634T>A) and BTKCys481Arg(c.1634T>C) Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identified BTKCys481 mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTKCys481 mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTKCys481 mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additional BTKCys481Tyr(c.1634G>A) mutation in the 2 patients with multiple other BTKCys481 mutations, as well as CARD11Leu878Phe(c.2632C>T) and PLCγ2Tyr495His(c.1483T>C) mutations. Four of the 5 patients with BTKC481 variants were CXCR4 mutated. BTKCys481 mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4.

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.

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 in previously treated Waldenström's macroglobulinemia.

BACKGROUND: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib. METHODS: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. RESULTS: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). CONCLUSIONS: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

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 (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 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; P = .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.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia.

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8 g/l (range 31-124 g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60 g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3 months, whereas the median time for patients with serum IgM level of 50·01-60 g/l was approximately 3 years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival (P = 0·12). The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Renal disease related to Waldenström macroglobulinaemia: incidence, pathology and clinical outcomes.

The incidence and prognostic impact of nephropathy related to Waldenström macroglobulinaemia (WM) is currently unknown. We performed a retrospective study to assess biopsy-confirmed WM-related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5·1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis (n = 11, 25%), monoclonal-IgM deposition disease/cryoglobulinaemia (n = 10, 23%), lymphoplasmacytic lymphoma infiltration (n = 8, 18%), light-chain deposition disease (n = 4, 9%) and light-chain cast nephropathy (n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy (TMA) (n = 3, 7%), minimal change disease (n = 2, 5%), membranous nephropathy (n = 1, 2%) and crystal-storing tubulopathy (n = 1, 2%). The median overall survival in patients with biopsy-confirmed WM-related nephropathy was 11·5 years, shorter than for the rest of the cohort (16 years, P = 0·03). Survival was better in patients with stable or improved renal function after treatment (P = 0·05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome.

Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia.

Bortezomib frequently produces severe treatment-related peripheral neuropathy (PN) in Waldenström's macroglobulinemia (WM). Carfilzomib is a neuropathy-sparing proteasome inhibitor. We examined carfilzomib, rituximab, and dexamethasone (CaRD) in symptomatic WM patients naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m(2) (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m(2), on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m(2), and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m(2), on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88(L265P) or CXCR4(WHIM) mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. CaRD offers a neuropathy-sparing approach for proteasome inhibitor-based therapy in WM. This trial is registered at www.clinicaltrials.gov as #NCT01470196.

Histological transformation to diffuse large B-cell lymphoma in patients with Waldenström macroglobulinemia.

Histological transformation to diffuse large B-cell lymphoma (DLBCL) rarely occurs in patients with Waldenström Macroglobulinemia (WM). We identified 20 patients out of a cohort of 1,466 WM patients who experienced histologic transformation. The 5, 10, and 15-year cumulative incidence rates were 1, 2.4, and 3.8%, respectively. Approximately half of the patients were naive to nucleoside analogues, and a quarter were previously untreated for WM at the time of transformation. More than 80% of patients presented with extranodal involvement, 65% with high IPI scores. DLBCL cells did not express CD10 but expressed BCL6 and BCL2. All patients were treated with chemoimmunotherapy. The median survival from histological transformation was 2.7 years. The median overall survival was shorter for transformed patients versus those who did not transform (estimated 9 vs. 16 years; P = 0.09). Histological transformation to DLBCL is rare, and is associated with inferior survival in WM. Am. J. Hematol. 91:1032-1035, 2016. © 2016 Wiley Periodicals, Inc.