Christina Hanzis

Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia.

We report the treatment outcome for 30 relapsed/refractory Waldenströms macroglobulinemia (WM) patients following bendamustine-containing therapy. Treatment consisted of bendamustine (90 mg/m2 I.V. on days 1, 2) and rituximab (375 mg/m2 I.V. on either day 1 or 2) for 24 patients. Six rituximab-intolerant patients received bendamustine alone (n=4) or with ofatumumab (1000 mg I.V. on day 1; n=2). Each cycle was 4 weeks, and median number of treatment cycles was 5. At best response, median serum IgM declined from 3980 to 698 mg/dL (P<.0001), and hematocrit rose from 31.9% to 36.6% (P=.0002). Overall response rate was 83.3%, with 5 VGPR and 20 PR. The median estimated progression-free survival for all patients was 13.2 months. Overall therapy was well tolerated. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues. Bendamustine is active and produces durable responses in previously treated WM, both as monotherapy and with CD20-directed monoclonal antibodies.

Maintenance Rituximab is associated with improved clinical outcome in rituximab naïve patients with Waldenstrom Macroglobulinaemia who respond to a rituximab-containing regimen

This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab‐naïve patients who responded to a rituximab‐containing regimen. Eighty‐six patients (35%) subsequently received maintenance rituximab (M‐Rituximab). No differences in baseline characteristics, and post‐induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2‐year period for patients receiving M‐Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41·8%) of M‐Rituximab patients respectively, following induction therapy (P < 0·0001). Both progression‐free (56·3 vs. 28·6 months; P = 0·0001) and overall survival (Not reached versus 116 months; P = 0·0095) were longer in patients who received M‐Rituximab. Improved progression‐free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P ≤ 0·0001). Best serum IgM response was lower (P < 0·0001), and haematocrit higher (P = 0·001) for patients receiving M‐Rituximab. Among patients receiving M‐Rituximab, an increased number of infectious events were observed, but were mainly ≤grade 2 (P = 0·008). The findings of this observational study suggest improved clinical outcomes following M‐Rituximab in WM patients who respond to induction with a rituximab‐containing regimen. Prospective studies aimed at clarifying the role of M‐Rituximab therapy in WM patients are needed to confirm these findings.

Hepcidin Is Produced by Lymphoplasmacytic Cells and Is Associated With Anemia in Waldenström's Macroglobulinemia

Waldenströms macroglobulinemia (WM) patients often present with anemia as their primary disease manifestation that may be related to hepcidin, an important regulator of iron homeostasis. We therefore determined hepcidin levels in 53 WM patients, and 20 age-matched healthy patient donors by hepcidin-25 ELISA. Serum hepcidin levels were elevated in WM patients versus healthy patients (P=.04), and correlated with BM disease involvement (P=.004), beta-2-microglobulin levels (P=.029), and inversely with hemoglobin (P=.05). No correlation with serum iron indices was observed, though in patients with high hepcidin levels, increased iron deposition in bone marrow macrophages was observed. Importantly, hepcidin transcripts and protein were produced by primary WM cells. Hepcidin levels correlated with serum IL-6 (P<.001) and C-Reactive Protein (P=.033) levels. The results of this study implicate hepcidin as a contributor to anemia in WM, and suggest that an iron re-utilization defect accompanies hepcidin overproduction leading to its sequestration in WM patients.

Associated Malignancies in Patients with Waldenström's Macroglobulinemia and Their Kin

We examined the incidence of other malignancies in 924 Waldenströms Macroglobulinemia (WM) patients and their kin. A total of 225 (24.3%) patients had ≥1 additional malignancy, with 63% predating the WM diagnosis. The most common gender-adjusted malignancies were prostate (9.4%), breast (8.0%), non-melanoma skin (7.1%), hematologic (2.8%), melanoma (2.2%), lung (1.4%) and thyroid 1.1%). Among hematologic malignancies, all 13 cases of diffuse large B-cell lymphoma and 4 cases of acute myelogenous leukemia were diagnosed after WM, and were therapy-related. Familial WM subgroup analysis showed a higher incidence of prostate cancer (P=.046) in sporadic WM patients, while patients with familial WM had a higher incidence of lung cancer (P=.0043). An increased incidence of myeloid leukemias (P<.0001) was reported among kin of familial WM patients. These data reveal specific cancer associations with WM, and provide a basis for exploratory studies aimed at delineating a common genetic basis. Additionally, these studies suggest specific cancer clustering based on familial predisposition to WM.

Familial Disease Predisposition Impacts Treatment Outcome in Patients With Waldenström Macroglobulinemia

UNLABELLED Familial disease is common in Waldenström macroglobulinemia (WM). We examined the impact of familial disease status on treatment outcome in WM and observed that familial disease was associated with inferior outcomes. However patients with familial WM receiving a bortezomib-containing regimen showed improved treatment outcomes vs. those receiving non–bortezomib-containing regimens. Bortezomib-containing regimens may therefore represent a more optimal treatment approach for patients with familial WM. BACKGROUND We examined the impact of familial predisposition on treatment outcome in 135 patients with Waldenström macroglobulinemia (WM), 26.7% of whom had first- or second-degree relatives with a B-cell lymphoproliferative disorder. PATIENTS AND METHODS All patients were rituximab naive and received a rituximab-containing regimen. There were no significant differences in baseline characteristics between cohorts. RESULTS Overall response (93.9% vs. 75.0%; P = .029) and complete response/very good partial response (CR/VGPR) (23.2% vs. 16.7%; P < .0001), time to progression (TTP) (45.5 vs. 21 months; P = .015) and time to next therapy (TTNT) (50.0 vs. 33.0 months; P = .024) favored patients with sporadic WM. By multivariate analysis, familial predisposition was an independent marker for disease progression (hazard ratio, 0.554). Patients with familial but not sporadic disease exhibited better responses, including CR/VGPR attainment (P = .0006) and a trend for longer progression-free survival (> 33 vs. 20.6 months; P = .08), with bortezomib-containing therapy. CONCLUSION The findings convey that familial predisposition is an important determinant of treatment outcome in WM. Prospective studies to confirm these observations are needed.

Family history of non-hematologic cancers among Waldenstrom macroglobulinemia patients: A preliminary study

BACKGROUND Little is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM. METHODS All probands aged 20-79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype. RESULTS Family history of prostate cancer had the largest overall rate ratio (RR=1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR=1.3, 95% CL: 1.1, 1.7; breast: RR=1.3, 95% CL: 1.2, 1.6). CONCLUSION Our study suggests that it may be worthwhile to pursue these associations in a case-control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history.