Sildenafil citrate suppresses disease progression in patients with Waldenstrom’s macroglobulinemia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7556-7556 ◽  
Author(s):  
C. J. Patterson ◽  
J. Soumerai ◽  
Z. Hunter ◽  
X. Leleu ◽  
I. Ghobrial ◽  
...  
Keyword(s):  
Disease Progression ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Response To Therapy ◽  
Sildenafil Citrate ◽  
Waldenström’S Macroglobulinemia ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

7556 Background: Responses to sildenafil citrate (Viagra), a phosphodiesterase-5 inhibitor used to treat erectile dysfunction, have been observed in patients with Waldenstrom’s Macroglobulinemia (WM). Moreover, sildenafil citrate induces apoptosis of WM lymphoplasmacytic cells (Clin Lymphoma 5:205, 2004). We therefore conducted a prospective phase II study of sildenafil citrate in patients with slowly progressing WM who did not meet consensus eligibility for active therapy (Semin Oncol 2003; 30:116). Intended therapy was as follows: Week 1 25 mg po qD Week 2 50 mg po qD Week 3 75 mg po qD Week 4, then Months 2–24 100mg po qD or Maximum Tolerated Dose Methods: Thirty patients were enrolled, 18 of whom were previously untreated. All patients demonstrated progressing disease prior to enrollment. Median age was 66 (range 43–85 yrs), baseline BM involvement was 30% (range 5–90%), serum IgM was 3,640 (range 790–6,720 mg/dL), hematocrit was 37.1% (range 32.7–58.5%), and B2M was 2.3 (range 1.5–8.9 mg/dL). Patients were evaluable for response after 3 months of therapy. Results: At a median of 3 months, serum IgM levels declined in 19/30 (63%) patients from a median of 3,640 (range 790–6,720 mg/dL) to 2,965 (range 1,170–6,110 mg/dL). 5/30 patients (17%) demonstrated at least a minor response (≥25% IgM decrease). Two patients were taken off study for non-response to therapy. Toxicities were mild and included headaches, sinus congestion, facial flushing, dyspepsia, and generally resolved on their own with prolonged sildenafil citrate usage. Only two patients required dose modification to 25 mg and 75 mg po qD, respectively. Corollary studies to determine putative mechanisms of action for sildenafil citrate in WM were also performed and will be updated at the meeting. Conclusions: This prospective clinical trial provides preliminary evidence for activity of sildenafil citrate in patients with advancing WM. With minimal toxicity, sildenafil citrate appears to have suppressed disease progression in more than half of patients and has resulted in objective responses, thus warranting further investigation in WM and possibly other B-cell disorders. No significant financial relationships to disclose.

Clinical Characteristics of Rituximab Intolerance in Patients with Waldenstrom's Macroglobulinemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2610-2610
Author(s):  
Sandra Kanan ◽  
Kirsten Meid ◽  
Steven P Treon ◽  
Jorge J. Castillo
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow Involvement ◽  
Single Agent ◽  
Response To Therapy ◽  
Waldenström’S Macroglobulinemia ◽  
Facial Swelling ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Anti Cd20 ◽  
Waldenström's Macroglobulinemia

Abstract Introduction: Rituximab is a chimeric anti-CD20 monoclonal antibody used for the treatment of both untreated and previously treated patients with Waldenström’s Macroglobulinemia (WM). Rituximab is often associated with infusion-related reactions (IRR) during the first infusion which is associated with a well described cytokine release syndrome. Rituximab is also associated with depletion of uninvolved immunoglobulins leading to symptomatic hypogammaglobulinemia associated with recurring infections in many patients. IRRs and hypogammaglobulinemia are common reasons for rituximab dicontinuation in patients with WM. In this study, we present data on WM patients who developed intolerance to rituximab defined as cessation of rituximab therapy outside of infusion related first-cycle IRRs, and symptomatic hypogammaglobulinemia. Methods: We performed a retrospective chart review within the clinical database of our center for patients with the consensus clinicopathological diagnosis of WM between 1996 and 2013, and for whom rituximab therapy was prematurely truncated. We excluded patients who experienced first-cycle IRRs and patients in whom rituximab was stopped due to symptomatic hypogammaglobulinemia. Clinical and laboratory data were collected and tabulated, and are presented using descriptive statistics. Results: From a database of 1,600 patients with WM, we have so far identified 40 WM patients who were considered intolerant to rituximab. The median age at WM diagnosis for these patients was 60.5 years (range 35-83 years). There was a male predominance of 2:1. The median number of therapies prior to becoming rituximab intolerant was 1 (range 0-5 lines). Fifty percent of patients were not previously exposed to rituximab. Fifty-three percent of patients became rituximab intolerant while receiving single agent rituximab, 18% while receiving bortezomib-based therapy, 15% while receiving cyclophosphamide-based therapy and 8% while receiving bendamustine-based therapy. Forty percent of patients developed rituximab intolerance while undergoing induction therapy, and the remaining 60% became intolerant during the maintenance phase. The most common reasons for stopping rituximab were fever, chills, facial swelling, shortness of breath, hypotension, back pain, hives, chest pain, and serum sickness-like symptoms. The median serum IgM prior to development of rituximab intolerance was 3,053 mg/dl (range 550-9,000 mg/dl), the median hemoglobin was 10.4 g/dl (8.2-14.5 g/dl), the median platelet count was 300 x 109/L (range 93-913 x 109/L), and the median bone marrow involvement was 35% (range 5-90%). Twenty-one percent of patients had familial WM, and 65% of patients were responding torituximab-based therapy at the time of intolerance. Importantly, 20% percent (n=8) of patients received ofatumumab, a fully human anti-CD20 monoclonal antibody, after developing rituximab intolerance, of whom 7 (87%) subsequently tolerated ofatumumab without incidence. Conclusions: We present data on 40 WM patients who became intolerant to rituximab outside of the context of first-cycle IRRs, and symptomatic hypogammaglobulinemia. Our study shows that rituximab can be associated with a variety of symptoms that prompt cessation of therapy, and that most patients show a response to therapy despite intolerance. The use of ofatumumab is feasible and well tolerated in WM patients intolerant to rituximab. Additional research is needed to better understand the pathophysiology behind rituximab intolerance in this patient population. Data collection continues. Disclosures No relevant conflicts of interest to declare.

Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8513-8513
Author(s):  
M. A. Gertz ◽  
R. Abonour ◽  
L. T. Heffner ◽  
P. R. Greipp ◽  
H. Uno ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Waldenström’S Macroglobulinemia ◽  
Minor Response ◽  
Free Survival ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

scholarly journals Waldenström's macroglobulinemia - a review

2014 ◽  
Vol 60 (5) ◽  
pp. 490-499 ◽  
Author(s):  
Susana Coimbra ◽  
Rafael Neves ◽  
Margarida Lima ◽  
Luís Belo ◽  
Alice Santos-Silva
Keyword(s):  
Bone Marrow ◽  
Autologous Transplantation ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Response To Therapy ◽  
Lymphoid Cells ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Waldenström's macroglobulinemia (WM) is a lymphoproliferative disease of B lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone marrow and by IgM monoclonal hypergammaglobulinemia. It was first described in 1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and serum viscosity, normal radiography and bone marrow infiltrated by lymphoid cells. The WM is a rare disease with a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. Most patients have clinical signs and symptoms related to hyperviscosity resulting from IgM monoclonal gammopathy, and/or cytopenias resulting from bone marrow infiltration by lymphoma. The differential diagnosis with other lymphomas is essential for the assessment of prognosis and therapeutic approach. Treatment of patients with asymptomatic WM does not improve the quality of life of patients, or increase their survival, being recommended, therefore, their follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used. However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising results with bortezomib, an inhibitor of proteasomes, and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may be indicated. The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical manifestations, diagnosis, prognosis and treatment.

scholarly journals In Waldenstrom's macroglobulinemia the quantity of detectable circulating monoclonal B lymphocytes correlates with clinical course

Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 911-914 ◽  
Author(s):  
BR Smith ◽  
NJ Robert ◽  
KA Ault
Keyword(s):  
B Lymphocytes ◽  
Response To Therapy ◽  
Clinical Activity ◽  
Waldenström’S Macroglobulinemia ◽  
Abnormal Cells ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Subsequent Regeneration ◽  
Waldenström's Macroglobulinemia ◽  
Overnight Culture

Using a sensitive flow-cytometer-based method of detecting small numbers of morphologically normal monoclonal B lymphocytes, we have investigated the presence and quantity of these cells in the blood of 12 patients with Waldenstrom's macroglobulinemia. All 12 patients, including 6 at the time of asymptomatic presentation, had such circulating monoclonal cells. By comparison, 2 of 7 patients with multiple myeloma had such cells, and prior studies have shown that 80% of patients with non-Hodgkin's lymphoma exhibit blood involvement by these criteria. Enzymatic removal of surface immunoglobulin (lg) with subsequent regeneration by the cells after overnight culture established that the monoclonal surface lg being studied was of intrinsic cell membrane origin and not passively adsorbed serum lg. Serial studies were performed in 7 patients. In the 4 cases where a clinical response to therapy and a decrease in serum IgM level was seen, there was a corresponding decrease in the estimated number of abnormal cells. In the 3 cases where there was neither clinical nor serum M-component evidence of response, the estimated percent abnormal cells likewise increased or remained constant. We conclude that patients with Waldenstrom's macroglobulinemia have a significant number of peripheral blood monoclonal B lymphocytes, even early in their disease, and that for a given patient, serial determinations of the number of these cells as estimated by flow cytometry reflects the clinical activity of the disease.

Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2727-2727
Author(s):  
Irene M. Ghobrial ◽  
Fangxin Hong ◽  
Swaminathan Padmanabhan ◽  
Ashraf Z. Badros ◽  
Meghan Rourke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Significant Activity ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Grade 3 ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 2727 Poster Board II-703 INTRODUCTION: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenstrom's Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response. RESULTS: Thirty-seven patients were treated. Majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI: [65,92]) with 2 patients (5%) in complete remission (CR)/near CR, 17 (46%) in partial response (PR), and 11(30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4–21.1). Death occurred in 1 patient due to viral pneumonia. The most common grade 3 and 4 therapy related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade-3 peripheral neuropathy occurred in only 2 patients (5%). The median event-free survival (EFS) is 12 months (95% CI, 11–20) with estimated 12 month and 18 month EFS of 49% (95% CI: [31, 67%]) and 38% (95% CI: [20, 56%]). The median overall survival has not been reached. CONCLUSIONS: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with relapsed WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Combining Ixazomib With Subcutaneous Rituximab and Dexamethasone in Relapsed or Refractory Waldenström's Macroglobulinemia: Final Analysis of the Phase I/II HOVON124/ECWM-R2 Study

2021 ◽  
pp. JCO.21.00105
Author(s):  
Marie José Kersten ◽  
Karima Amaador ◽  
Monique C. Minnema ◽  
Josephine M. I. Vos ◽  
Kazem Nasserinejad ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Progression Free Survival ◽  
Immunoglobulin M ◽  
Waldenström’S Macroglobulinemia ◽  
Minor Response ◽  
Free Survival ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

scholarly journals In Waldenstrom's macroglobulinemia the quantity of detectable circulating monoclonal B lymphocytes correlates with clinical course

Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 911-914 ◽  
Author(s):  
BR Smith ◽  
NJ Robert ◽  
KA Ault
Keyword(s):  
B Lymphocytes ◽  
Response To Therapy ◽  
Clinical Activity ◽  
Waldenström’S Macroglobulinemia ◽  
Abnormal Cells ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Subsequent Regeneration ◽  
Waldenström's Macroglobulinemia ◽  
Overnight Culture

Abstract Using a sensitive flow-cytometer-based method of detecting small numbers of morphologically normal monoclonal B lymphocytes, we have investigated the presence and quantity of these cells in the blood of 12 patients with Waldenstrom's macroglobulinemia. All 12 patients, including 6 at the time of asymptomatic presentation, had such circulating monoclonal cells. By comparison, 2 of 7 patients with multiple myeloma had such cells, and prior studies have shown that 80% of patients with non-Hodgkin's lymphoma exhibit blood involvement by these criteria. Enzymatic removal of surface immunoglobulin (lg) with subsequent regeneration by the cells after overnight culture established that the monoclonal surface lg being studied was of intrinsic cell membrane origin and not passively adsorbed serum lg. Serial studies were performed in 7 patients. In the 4 cases where a clinical response to therapy and a decrease in serum IgM level was seen, there was a corresponding decrease in the estimated number of abnormal cells. In the 3 cases where there was neither clinical nor serum M-component evidence of response, the estimated percent abnormal cells likewise increased or remained constant. We conclude that patients with Waldenstrom's macroglobulinemia have a significant number of peripheral blood monoclonal B lymphocytes, even early in their disease, and that for a given patient, serial determinations of the number of these cells as estimated by flow cytometry reflects the clinical activity of the disease.

scholarly journals BTKCys481Ser Mutation Drives Ibrutinib Resistance through ERK1/2 Hyperactivation, and Can Confer a Protective Effect on Bystander Waldenstrom's Macroglobulinemia and ABC DLBCL Cells through Paracrine Mediated Pro-Survival Signaling

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 803-803
Author(s):  
Jiaji Chen ◽  
Xia Liu ◽  
Manit Munshi ◽  
Lian Xu ◽  
Nickolas Tsakmaklis ◽  
...  
Keyword(s):  
Protective Effect ◽  
Disease Progression ◽  
Tumor Cells ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Survival Signaling ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Ibrutinib Resistance ◽  
Waldenström's Macroglobulinemia

Abstract Activating mutations in MYD88 promote NF-kB survival signaling in WM and ABC DLBCL cells through BTK and HCK, both targets of ibrutinib (Yang et al, Blood 2013; 2016). These findings likely explain the high rates of response observed in MYD88 mutated WM and ABC DLBCL patients (Treon et al, NEJM 2015; Wilson et al, Nature Med 2015). Resistance to ibrutinib is increasingly being recognized with prolonged therapy in patients with various B-cell malignancies. Mutations at the BTKCys481 site are observed in half of WM patients with disease progression following initial response (Xu et al, Blood 2017), and are also associated with clinical resistance in patients with CLL and MCL. However, in many WM and CLL cases, BTKCys481 mutations are subclonal and their relevance to clinical disease progression remains unclear. Moreover, the signaling mechanisms that promote ibrutinib resistance remain to be clarified. We therefore performed lentiviral transduction studies in MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD-8, HBL-1) cells with vector alone, wild-type BTK (BTKWT), and the BTK variant most frequently observed in ibrutinib resistant WM and CLL cases (BTKCys481Ser). BTKCys481Ser but not BTKWT or vector only transduced WM and ABC DLBCL cells uniformly demonstrated persistent BTK and PLCγ2 activation in the presence of ibrutinib (100, 500 nM), along with a 1-3 log fold increase in EC50 to ibrutinib. Western blot analysis showed persistent BTK signaling in BTKCys481Ser expressing cells that was accompanied by ERK1/2 hyperactivation. Use of highly selective and potent ERK1/2 inhibitors (ulixertinib, GDC-0994) induced apoptosis of BTKCys481Ser expressing WM and ABC DLBCL cells, and showed synergistic tumor cell killing with ibrutinib by CellTiter-Glo® Luminescent Cell Viability Assays using Calcasyn, as well as enhanced apoptosis by Annexin V staining. Using a multiplex cytokine assay and confirmed by TaqMan® quantitative RT-PCR assay for cytokine mRNA levels, we identified that ERK1/2 activation in ibrutinib treated BTKCys481Ser WM and ABC DLBCL cells was accompanied by persistent release of pro-inflammatory and growth enhancing cytokines including CXCL13, IL-2R, IL-6, IL-10, IL-12p40, and TNF-a that was blocked by ulixertinib. In contrast, ibrutinib blocked their release in BTKWT WM and ABC DLBCL cells. We next sought to clarify if cytokine release by ibrutinib treated BTKCys481Ser WM and ABC DLBCL could impact survival of bystander tumor cells. We performed experiments using a Transwell system in which BTKCys481Ser or BTKWT transduced WM or ABC DLBCL cells were co-cultured with their native counterpart cells in the presence or absence of ibrutinib (Figures 1A, B). These studies showed that native WM or ABC DLBCL cells were rescued in the presence of ibrutinib when co-cultured with their BTKCys481Ser but not BTKWT transduced counterparts. Finally, use of IL-6 and IL-10 blocking antibodies abolished the protective effect on native tumor cells conferred by co-culture with BTKCys481Ser expressing cells in the presence of ibrutinib (Figures 1C, D). Our findings show that BTKCys481Ser mutation drives ibrutinib resistance through hyperactivation of ERK1/2, and that paracrine mediated ERK1/2 dependent pro-survival signaling by BTKCys481Ser expressing cells can confer a protective effect on bystander Waldenstrom's Macroglobulinemia and ABC DLBCL cells in the presence of ibrutinib. Figure 1 Figure 1. Disclosures Castillo: Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding. Treon: Pharmacyclics: Consultancy, Research Funding.

Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: Responses in multiple myeloma and Waldenstrom’s macroglobulinemia at well-tolerated doses

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8003-8003 ◽  
Author(s):  
K. A. Stewart ◽  
O. A. O’Connor ◽  
M. Alsina ◽  
S. Trudel ◽  
P. R. Urquilla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Stable Disease ◽  
Proteasome Inhibition ◽  
Maximum Tolerated Dose ◽  
Symptomatic Improvement ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

8003 Background: Carfilzomib is a novel, irreversible tetrapeptide proteasome inhibitor derived from the natural product epoxomicin. Carfilzomib was well tolerated in preclinical animal studies when administered on a two-week cycle, QDx5; proteasome inhibition one hour after dosing at the MTD was >80%. Two Phase I dose-escalation studies are ongoing, aimed at determining the safety, tolerability, and biological response to carfilzomib. Methods: Carfilzomib was administered according to two different dose-intensive schedules. In PX-171–001, carfilzomib was administered on a two week cycle, QDx5 with nine days rest; in PX-171–002, carfilzomib was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. Eligible patients have multiple myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), or Waldenström's Macroglobulinemia (WM). Results: Thus far, a total of 54 subjects have been enrolled. Although the maximum tolerated dose (MTD) has not yet been identified on either study, responses seen on both protocols have established 11 and 15 mg/m2 as the minimal effective doses (MEDs) on PX-171–001 and 002, respectively. Of 3 patients with MM or WM treated on the 001 protocol, one MM patient has had a Partial Response (PR) and one WM patient had a Minimal Response (MR). Of 8 patients with MM treated on the 002 protocol, 3 patients have had PRs. 6 additional patients have had Stable Disease lasting longer than 6 months and symptomatic improvement has been seen in patients on both protocols. 11 subjects remain on study with stable disease or better. Proteasome inhibition in whole blood at the highest dose levels exceeded 80% one hour after the first dose. Carfilzomib has been well tolerated at doses at and above the MED thus far. There has been no incidence of painful peripheral neuropathy on either study. No dose-limiting toxicities (DLTs) have occurred on PX-171–001; one DLT (Gr 4 anemia and thrombocytopenia) was observed at 27 mg/m2 on PX-171–002. Conclusions: Thus far, intensive dosing with carfilzomib is well-tolerated at proteasome inhibition levels of more than 80%. Five responses have been observed, and several subjects have achieved long lasting SD and/or symptomatic improvement. No significant financial relationships to disclose.

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