Kirsten Meid

Ibrutinib in Previously Treated Waldenström's Macroglobulinemia

BACKGROUND MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenströms macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Brutons 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 Waldenströms 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 Waldenströms macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

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 Waldenströms 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.

Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database

Waldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Given that the survival of WM patients can be prolonged, our objective was to describe trends in overall survival (OS) and analyse competing risks of death in patients with WM. The analysis included 5784 patients diagnosed with WM between 1991 and 2010 from the Surveillance, Epidemiology and End Results (SEER) database. Multivariate hazard models for OS and cumulative incidence of death were fitted according to epoch of diagnosis (1991–2000 vs. 2001–10) while adjusting for age, sex, race, histology, site of involvement and registry. Median OS for the 1991–2000 and the 2001–10 cohorts was 6 and 8 years, respectively (P < 0·001). In the multivariate analysis, better OS [hazard ratio (HR) 0·73, 95% confidence interval (CI) 0·67–0·79; P < 0·001] was seen in the 2001–10 cohort. Survival benefits were identified, for the 2001–10 cohort, in almost every stratum analysed, with the exception of patients aged <50 years and blacks. In the multivariate competing‐risk analysis, the 2001–10 cohort experienced lower rates of WM‐related (HR 0·57, 95% CI 0·49–0·66; P < 0·001) and non‐WM‐related deaths (HR 0·72, 95% CI 0·66–0·79; P < 0·001). In conclusion, there have been significant improvements in OS, WM‐related and non‐WM‐related mortality in patients with WM diagnosed in the last decade.

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.

Atrial fibrillation associated with ibrutinib in Waldenström macroglobulinemia.

M. Schimmel, E. Nur and B.J. Biemond had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: MS, EN, LV, BB. Acquisition of data: MS, ROE. (Statistical) analysis and interpretation of data: MS, EN, DB, ROE, LV, BB. Drafting of the manuscript: MS, EN and BB. Critical revision of the manuscript for important intellectual content: all named co-authors.

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.

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.

Incidence of secondary malignancies among patients with Waldenström macroglobulinemia: An analysis of the SEER database

Waldenström macroglobulinemia (WM) is an indolent malignancy that predominantly affects older individuals who are at risk for secondary malignancies (SMs). The objective of this study was to characterize the incidence of SMs after a diagnosis of WM with the Surveillance, Epidemiology, and End Results (SEER) database.

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.

Idelalisib in Waldenström macroglobulinemia: high incidence of hepatotoxicity.

Waldenstr€ om macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the accumulation of IgMsecreting lymphoplasmacytic cells.[1] Despite therapeutic advances, WM remains incurable, and novel treatment options are needed. Over 90% of patients with WM carry the MYD88 L265P gene mutation, which promotes the survival of WM cells through activation of the Bruton tyrosine kinase (BTK) pathway.[2] In a phase II study evaluating the BTK inhibitor ibrutinib in 63 patients with relapsed and/or refractory disease, an overall response rate (ORR) of 90% with acceptable toxicity was observed.[3] These results prompted the approval of ibrutinib by the United States Food and Drug Administration for use in patients with symptomatic WM. MYD88 L265P also promotes activation of the phosphatidylinositol-3-kinase (PI3K) pathway and exposure to the PI3K-delta inhibitor idelalisib induced robust killing in MYD88-mutated WM cells.[4] In a prior phase 2 study, 80% ORR was reported in 10 patients with WM, refractory to anti-CD20 and alkylating agents, treated with idelalisib 150mg twice daily.[5] In addition, a phase 1 study including nine relapsed/refractory WM patients treated with idelalisib reported 56% ORR.[6] Given these results, we initiated a prospective investigator-initiated phase 2 study to evaluate the safety and efficacy of idelalisib in patients with relapsed and/or refractory symptomatic WM (CinicalTrials.Gov identifier NCT02439138). The study was activated on 10 September 2015. All patients provided written informed consent after approval of the study by the Institutional Review Board at the Dana-Farber Cancer Institute. Gilead Sciences provided research funding and study drug. The primary objective was to determine response rates to idelalisib as defined by the 6th International Workshop in WM.[7] Serum IgM level, complete blood count, blood chemistries, liver function tests, bone marrow biopsy, and computed tomography (CT) scans were obtained at the beginning of the study. Eligibility criteria included a clinicopathological diagnosis of WM,[8] need for treatment according to guidelines,[9] at least one prior line of therapy, platelet count 50,000/mm, neutrophil count 1000/mm, creatinine level 2mg/dl, total bilirubin level 1.5mg/dl, aspartate and alanine aminotransferase levels 2.5 times the upper limit of normal, ECOG performance status of 2 or lower, and no active HIV, hepatitis B or C infection. The treatment regimen consisted of idelalisib at 150mg PO twice daily until disease progression or unacceptable toxicity. An allele-specific PCR assay was used to detect the MYD88 L265P mutation. CXCR4 mutational status was determined by Sanger sequencing. A one-stage design was used with alpha level at 0.05 and beta level at 0.20. This assumed a null ORR of 40% and a successful ORR of 70%. Our accrual goal was 30 patients. Five patients were enrolled in the study and received therapy. The median age at study entry was 66 years (range 57–80 years). Two patients met criteria for treatment due to anemia, one due to constitutional symptoms, one due to hyperviscosity, and one for evidence of renal involvement by lymphoplasmacytic lymphoma. The median number of prior therapies was 4 (range 3–9). All the patients were previously exposed to rituximab and bortezomib, four to alkylating agents, two to nucleoside analogs, and one to ibrutinib. The median bone marrow involvement was 40% (range 20–80%), the median IgM level was 4512mg/dl (range 3970–6190mg/dl), and the median hemoglobin level was 11g/dl (range 7.7–12.4g/dl). According to the International Prognostic Scoring System for WM, three patients were intermediate, one was low and one was high risk. The MYD88 L265P gene mutation was identified in all patients and CXCR4 mutations in two. Four patients were evaluable for response and exhibited stable disease on idelalisib. Patient 1 had previously progressed on ibrutinib therapy, and was not evaluable