Barry Turnbull

Polymorphisms in FcγRIIIA (CD16) Receptor Expression Are Associated With Clinical Response to Rituximab in Waldenström’s Macroglobulinemia

6556 Background: Polymorphisms in FcγRIIIA (CD16) receptor expression modulate human IgG1 binding, and antibody dependent cell mediated cytotoxicity, and may therefore impact responses to rituximab in patients with WM. METHODS We therefore performed sequencing of all DNA coding regions for FcγRIIIA in 58 patients with Waldenstroms macroglobulinemia (WM) treated with rituximab. Two distinct, but linked polymorphisms (FcγRIIIA-48 and -158) were commonly observed. All patients with FcγRIIIA-158F/F were always FcγRIIIA-48L/L, and patients with either FcγRIIIA-L/R or -L/H always expressed at least one valine at FcγRIIIA-158 (p≤0.001). RESULTS Major responses were higher in patients with FcγRIIIA-48L/H or -L/R (35%) versus -48L/L (22.0%) (p=NS), and among patients with FcγRIIIA-158V/V or -V/F (36%) versus -158F/F (9.0%) (p=0.03). Major responses for FcγRIIIA-48L/L patients were higher (36.8 vs. 9.0%; p=0.05) when at least one valine was present at FcγRIIIA-158, and were on par with FcγRIIIA-48L/R or -L/H patients (35.3%; p=NS) who always were FcγRIIIA-158V/V or -V/F, thereby supporting a primary role for FcγRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, time to disease progression was 13 and 8 months for patients with FcγRIIIA-158V/V or V/F and -158F/F, respectively (p=NS). CONCLUSIONS The results of these studies therefore support a predictive role for FcγRIIIA-158 polymorphisms and major responses to rituximab inWM. No significant financial relationships to disclose.

Long term outcomes to Fludarabine and Rituximab in Waldenström macroglobulinemia.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

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.

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.

Comparative Outcomes Following CP-R, CVP-R, and CHOP-R in Waldenström's Macroglobulinemia

Since the adoption of rituximab, the importance of doxorubicin and vincristine as treatment components remains to be clarified in Waldenströms macroglobulinemia (WM). We therefore examined the outcomes of symptomatic patients with WM who received CHOP-R (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab; n = 23), CVP-R (cyclophosphamide/vincristine/ prednisone plus rituximab; n = 16), or CP-R (cyclophosphamide/prednisone plus rituximab; n = 19) at our institution. Baseline characteristics for all 3 cohorts were similar for age, previous therapies, bone marrow involvement, hematocrit, platelet count, and serum beta2-microglobulin, though serum immunoglobulin M levels were higher in patients treated with CHOP-R (P < or= .015). The overall response rates (ORR) and complete response (CR) rates to therapy were as follows: CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR 88%; CR 12%); CP-R (ORR, 95%; CR, 0%); P = not significant. Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment-related neuropathy for CHOP-R and CVP-R versus CPR (P < .03). The results of this study demonstrate comparable responses among patients with WM receiving CHOP-R, CVP-R, or CP-R, though a significantly higher incidence of treatment-related neuropathy and febrile neutropenia was observed among patients treated with CVP-R and CHOP-R versus CP-R. The use of CP-R might provide analogous treatment responses to more intense cyclophosphamide-based regimens while minimizing treatment-related complications in patients with WM.

Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenstrom macroglobulinaemia

The incorporation of rituximab into various regimens has improved depth of response in Waldenstrom macroglobulinaemia (WM), though the impact of achieving better responses remains to be determined. We examined response depth on progression‐free survival (PFS) in 159 rituximab‐naïve WM patients who received rituximab‐based therapy. The median follow‐up was 33·5 months, and categorical responses were as follows: complete response (CR, 8·8%); very good partial response (VGPR, 13·2%); partial response (50%); minor response (18·9%); Non‐Responders (8·8%). Sequencing for polymorphic variants of FCGR2A, FCGR2B, and FCGR3A was performed, and impact on response depth determined. Achievement of better categorical responses was incrementally associated with improved PFS (P < 0·0001). No separation was observed between CR and VGPR, and attainment of at least a VGPR was associated with improved time‐to‐progression. Neither age, serum IgM, haematocrit, platelet count, serum β2microglobulin, WM International Prognostic Scoring System score, and treatment group predicted for CR/VGPR. Polymorphisms at FCGR3A‐48 and ‐158 were associated with improved categorical responses, particularly attainment of CR/VGPR (P ≤ 0·03). The attainment of CR/VGPR was associated with significantly longer PFS in rituximab‐naïve WM patients undergoing rituximab‐based therapy, and was predicted by polymorphisms in FCGR3A.

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.

Comparative Response Assessment by Serum Immunoglobulin M M-Protein and Total Serum Immunoglobulin M After Treatment of Patients With Waldenström Macroglobulinemia

Serum immunoglobulin (Ig) M monoclonal protein determined by electrophoresis (sIgM-MP) and total serum IgM (sIgM) by nephelometry are widely used for response assessment in Waldenström macroglobulinemia (WM), although have not been compared for predicting changes in underlying disease burden. We, therefore, compared these serum markers with changes in bone marrow (BM) and extramedullary disease for 73 patients who were rituximab naive and treated with a rituximab-containing regimen. By linear regression analysis, reductions in sIgM-MP and sIgM showed moderate correlation with BM disease involvement (r = 0.4051 and r = 0.4490, respectively), and did not differ from one another as estimators of BM disease response (P = .3745). Neither sIgM-MP nor sIgM showed a strong correlation with BM disease response in patients with low (<1000 mg/dL) or high (>5000 mg/dL) IgM levels and extramedullary disease response. sIgM-MP and sIgM, therefore, are comparable response markers in WM. Development of newer, more accurate surrogate response markers are needed to better delineate treatment outcomes in patients with WM and with low or high IgM levels, and extramedullary disease.

The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Association of familial disease status with inferior treatment outcome in patients with Waldenstrom’s macroglobulinemia.

8073 Background: Previous studies by us and others support a familial predisposition in certain patients with Waldenstroms Macroglobulinemia (WM). The incidence, as well as clinical implications for familial WM disease need to be clarified. METHODS We sought to delineate the relative incidence of familial and sporadic WM in a large population of WM patients, as well as treatment outcomes resulting from the presence of familial disease. As part of these efforts, we examined the impact of familial disease status on a well defined WM patient population whose treatment outcome was previously reported, and who were rituximab-naïve, and received a rituximab containing regimen. WM patients with familial disease were defined as those individuals who had a first or second degree relative with a B-cell disorder. RESULTS Among 924 consecutive patients seen at our center, 254 (27.4%) reported having a first or second degree relative with a B-cell disorder, including 45 (4.9%) patients with > 1 case of WM in their family. One-hundred-thirty-five patients were rituximab-naïve, and received a rituximab containing regimen with either cyclophosphamide, fludarabine, IMID, or bortezomib. Of these patients, 36 (26.7%) and 99 (73.3%) had familial and sporadic WM disease, respectively. No differences in age, baseline IgM, hemoglobin, platelet count, serum B2M, WM IPSS score, or treatment regimen received was observed amog these patients. Overall (74.8% vs. 55.6%; p=0.032) and CR/VGPR (23.2% vs. 16.7%; p<0.0001) responses, time to progression (45.5 vs. 21 months; p=0.015), as well as time to next therapy (50.0 vs. 33.0 months; p=0.024) were greater among sporadic versus familial WM patients. CONCLUSIONS Familial predisposition is common in WM, and associated with an inferior treatment outcome. Prospective studies examining the impact of familial disease status on treatment outcome in WM are warranted.