Bortezomib plus Dexamethasone versus Fludarabine plus Cyclophosphamide in initial treatment of patients with Waldenström macroglobulinemia

Abstract Purpose We examined the efficacy of bortezomib plus dexamethasone(BD) versus fludarabine plus cyclophosphamide(FC) in patients with symptomatic, untreated Waldenström macroglobulinemia(WM). Furthermore, to evaluate the toxicity of BD regimen in WM. Patients and methods: 17 untreated WM patients received either bortezomib and dexamethasone(n=7) or fludarabine and cyclophosphamide(n=10). BD group: A cycle of therapy consisted of bortezomib 1.3 mg/m2 intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11. Patients received 4 cycles at least. FC group: A cycle of therapy consisted of fludarabine 25 mg/m2 on days 1-3; cyclophosphamide 250mg/m2 on days 1-3. Patients received 4-6 consecutive cycles for induction therapy. Responses were based on paraprotein levels. Herpes zoster prophylaxis was instituted with using oral valacyclovir. Results: In BD and FC groups, the overall response rates(PR+MR) were 86% versus 70% respectively. There was not complete response in two groups. In BD and FC groups, minor and partial responses occurred at a median of 25 vs. 54 days and 55 vs. 94 days respectively(P<0.05, respectively). The median progression-free survival(PFS) was 27 months, and a median follow-up of 62 months the actuarial 5-year overall survival(OS) rate was 80% in FC group. Because of a short following time, there were not PFS and OS that can be observed in BD group. Hemoglobin and platelet levels increased normally in 83% vs. 50% and 100% vs. 66% patients in BD and FC groups respectively(P<0.05, respectively). In BD group, peripheral neuropathy was the most common toxicity(57% grade 1- 2, no grade 3- 4). Hematologic toxicities included grade 3 to 4 thrombocytopenia in 2/7(28%) and neutropenia in 1/7(14%). 42% patients developed herpes zoster. Conclusions: The results demonstrate that BD produces rapid responses, along with high rates of response in WM, and it was generally well-tolerated in our study. Herpes zoster prophylaxis is necessary with BD, and peripheral neuropathy was the most common toxicity, but not leading to discontinuance of BD. This retrospective analysis confirms that BD therapy is an effective initial treatment in WM. Disclosures: No relevant conflicts of interest to declare.

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A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study

Blood ◽

10.1182/blood.2020006844 ◽

2020 ◽

Vol 136 (18) ◽

pp. 2038-2050 ◽

Cited By ~ 6

Author(s):

Constantine S. Tam ◽

Stephen Opat ◽

Shirley D'Sa ◽

Wojciech Jurczak ◽

Hui-Peng Lee ◽

...

Keyword(s):

Progression Free Survival ◽

Complete Response ◽

Phase 3 ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Significant Difference ◽

Duration Of Response ◽

Btk Inhibitor ◽

Grade 3

Abstract Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

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Final Results Of a Phase II Study Of Lenalidomide In Combination With Rituximab For The Treatment Of Indolent Non Follicular Non Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.4383.4383 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4383-4383 ◽

Cited By ~ 1

Author(s):

Stefano Sacchi ◽

Samantha Pozzi ◽

Marina Cesaretti ◽

Luigi Marcheselli ◽

Gabriele Buda ◽

...

Keyword(s):

Clinical Trial ◽

Informed Consent ◽

Phase Ii ◽

Conflicts Of Interest ◽

Dose Intensity ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Complete Response ◽

Open Label ◽

Grade 3

Abstract Background Advanced-stage, relapsed indolent non follicular lymphomas (INFLs) have a relatively poor prognosis, with low complete response to conventional chemotherapy and short survival. Thus, there is a need for innovative treatment with high efficacy and a good safety profile. Lenalidomide (R®) is an immunomodulatory drug with a direct tumoricidal effect and action on T, NK and stromal cells that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab (R). To test the efficacy of R® combined with R (R2), we have conducted a multi center, open label phase II clinical trial in patients (pts) with relapsed INFL. Methods Eligible pts must have indolent non follicular B-cell lymphoma relapsed after at least 2 but less than 4 prior lines of R-containing immuno-chemotherapy with measurable disease. Patients received oral R® 20 mg once daily on days 1-21. R is administered at a dose of 375 mg/m2 at day 14 of every course. Treatment is repeated every 28 days for up to 6 courses. The primary objectives of the study were to evaluate the antitumor activity of oral R® when given in combination with R and to assess the safety of R2 regimen evaluated by standard criteria (CTC-NCI 3.0). The secondary objectives were the evaluation of progression free survival (PFS) and overall survival (OS). Results From July 2010 and March 2013, 44 pts entered the protocol. Six out of 44 pts were excluded from this analysis as 2 withdrew informed consent and 4 refused to start treatment immediately after signing the informed consent. Enrolled pts (38 cases) had: 18 small lymphocytic lymphoma (SLL), 12 lymphoplasmacytic lymphoma (LPL) and 8 marginal zone lymphoma (MZL). Median age was 68 years (51-75) and 58% were male. LDH value was increased in 21% of pts and β-2-microglobulin in 75%; 51% of pts had Hb<12 g/dL and 66% had bone marrow involved (median infiltrating 40%). Of the 38 pts, 7 achieved a complete remission and 14 a partial remission with an ORR of 55%. Seven pts had a stable disease and 5 a lymphoma progression. In general, the regimen R2 was relatively well-tolerated. Grade 3-4 hematological events were observed in 22 pts. The most common adverse events were neutropenia (58%), thrombocytopenia (11%), anemia (10%) and infection (10%). Grade 3-4 non hematological events were fever (5%), dyspnea (3%), allergic reaction to R (3%), renal failure (3%) and erythema (3%). Growth factors were administered in 58% of pts. The median dose intensity was 0.94 for R and 0.98 for R®. With a median follow-up of 19 months (range 1-43), overall 6 pts died, 5 for lymphoma progression and 1 for treatment related toxicity. The 2-years OS and the 2-years PFS were shown in Figure 1. Figure 2 shows the PFS by histology. The percentage of 2-years PFS (71%) for MZL appear impressive. Conclusions The chemo-free R2 scheme as treatment for relapse INFLs produces response in about 50% of pts and remission appear durable in pts with MZL. The toxicity profile of the combination is tolerable with manageable hematologic side effects. These results support the design of clinical trial with this chemo-free combination as first line treatment for INFLs, in particular for MZL. Disclosures: No relevant conflicts of interest to declare.

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Primary Therapy of Waldenström Macroglobulinemia With Bortezomib, Dexamethasone, and Rituximab: WMCTG Clinical Trial 05-180

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.4677 ◽

2009 ◽

Vol 27 (23) ◽

pp. 3830-3835 ◽

Cited By ~ 164

Author(s):

Steven P. Treon ◽

Leukothea Ioakimidis ◽

Jacob D. Soumerai ◽

Christopher J. Patterson ◽

Patricia Sheehy ◽

...

Keyword(s):

Herpes Zoster ◽

Peripheral Neuropathy ◽

Response Rates ◽

Immunoglobulin M ◽

Primary Therapy ◽

Waldenström Macroglobulinemia ◽

Bone Marrow Disease ◽

Waldenstrom Macroglobulinemia ◽

Best Response ◽

Prophylactic Antiviral Therapy

Purpose We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM). Patients and Methods A cycle of therapy consisted of bortezomib 1.3 mg/m2 intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m2 on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment. Results Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade ≤ 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy. Conclusion The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.

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The Combination of Cyclophosphamide, Velcade and Dexamethasone (CVD) Induces High Response Rates with Minimal Toxicity Compared to Velcade Alone (V) and Velcade Plus Dexamethasone (VD).

Blood ◽

10.1182/blood.v108.11.3537.3537 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3537-3537 ◽

Cited By ~ 4

Author(s):

Faith E. Davies ◽

Ping Wu ◽

M. Srikanth ◽

Matthew W. Jenner ◽

Sharon Dines ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Dose Reduction ◽

Synergistic Effects ◽

Progression Free Survival ◽

Response Rates ◽

Complete Response ◽

Chemotherapeutic Agents ◽

Duration Of Treatment ◽

Similar Frequency ◽

Grade 3

Abstract Bortezomib (Velcade®), as the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma. Preclinical and/or clinical studies showed improved activity by combining this agent with a number of conventional chemotherapeutic agents, suggesting synergistic effects. We conducted a retrospective study to assess the efficacy and toxicity profile with Velcade alone and in combination with dexamethasone or cyclophosphamide, and dexamethasone for patients with multiply relapsed myeloma. 11 patients were treated with Velcade alone, 20 with the combination of Velcade and dexamethasone (VD), and 11 with the regimen comprising Velcade, dexamethasone and cyclophosphamide (CVD). Velcade 1.3mg/m2 was given as a single bolus IV on days 1, 4, 8 and 11, dexamethasone 40mg po on the day of Velcade injection and the day thereafter, and cyclophosphamide 500 mg po days 1, 8, 15 of a 21 day cycle for a maximum of 9 cycles of treatment. No patient received prophylactic anticoagulation. Toxicity profiles and response were assessed every 3 weeks. There was no statistical difference of baseline characteristics (age, ISS, number of previous lines of treatment) among the three treatment groups (P>0.05). The overall response rates (CR+PR) within the three groups are 30% (V), 47% (VD), and 64% (CVD) respectively. The CR rate of CVD group is impressive at 27% compared to 5% with VD and 0% with V. The median duration of treatment of three groups (V vs VD vs CVD) are 115 days, 98 days and 116 days respectively (P>0.05). Thrombocytopenia and new/worsening peripheral neuropathy are the most common side effects in each group. Although thrombocytopenia and neutropenia occurred in the CVD group (36% and 27% respectively), it was at a similar frequency as in the groups of VD (50% and 15%) and V (64% and 45%). Grade 3 infection rates were also similar at 18%, 30% and 18% (V vs VD vs CVD). Peripheral neuropathy is the most troublesome side effect, and is the main reason for Velcade dose reduction and/or discontinuation in each group (27% V, 45% VD, 54% CVD). 27% of patients within CVD group required dose reduction of cyclophosphamide due to neutropenia. Median follow up is currently too limited to comment on whether the improved CR rate with CVD translates into an improved progression free survival. In conclusion CVD is a well tolerated regimen producing high overall and complete response rates, with no increase in toxicity compared to VD or V alone, and lacks the toxicity associated with Velcade- melphalan combinations.

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Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results.

Blood ◽

10.1182/blood.v110.11.4494.4494 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4494-4494

Author(s):

Irene M. Ghobrial ◽

Swaminathan Padmanabhan ◽

Ashraf Badros ◽

Marybeth Nelson ◽

Renee Leduc ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Phase Ii ◽

Single Agent ◽

Clinical Activity ◽

Synergistic Activity ◽

Similar Treatment ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Best Response ◽

Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM. METHODS: Patients who had at least one previous therapy for WM, symptomatic, and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15 q 28 days x 6 cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4. RESULTS: 17 pts (10 men and 7 women, median age 62 years, range 43 – 81) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. The median IgM at baseline was 4070 mg/dL (range 1370– 10,800); median M-spike at baseline was 2.48 g/dL (range 1.5 – 4.87); and median hemoglobin was 11.0 g/dL (6.3–15.2). The median follow up was 5 months (range 1 – 11 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. 13 pts are currently evaluable for response, best response to bortezomib and rituximab after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with bortezomib and rituximab. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6 and improved to grade 1 within 2 weeks of holding therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient. One patient discontinued therapy on study after 1 cycle because of inability to travel to study site and completed similar treatment off study and was unevaluable on this study. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates exciting activity achieving CR+ PR + MR in 85%, and/or stabilization of disease in 15% of evaluable patients with relapsed WM. No significant peripheral neuropathy was observed with this regimen. Updated data will be presented at the meeting. Response N=13; ORR (CR+PR+MR)= 85% Median time to best response (months) Complete Response 1 (8%) 6 Partial Response 3 (23%) 3.5 (3–4) Minimal Response 7 (54%) 4 (2–6) Stable Disease 2 (15%) NA Progressive Disease 0

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Safety and Efficacy of Purine Analogs for Treatment of Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood-2020-138750 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Abdul Jabbar Dar ◽

Qasim Khurshid ◽

Muhaddis Ejaz Ahmad ◽

Muhammad Ali Mirza ◽

Farhan Khalid ◽

...

Keyword(s):

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

The United States ◽

Cochrane Library ◽

Waldenström Macroglobulinemia ◽

Overall Response ◽

Waldenstrom Macroglobulinemia ◽

Purine Analogs ◽

Number Of Patients

Introduction: There are about 1500 cases every year in the United States of America and while the disease is incurable but it is treatable. Purine analogs are anti-metabolites that mimic the structure of metabolic purines and are used for the treatment of Waldenstrom macroglobulinemia (WM). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 1995, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 16 studies involving patients with Waldenstrom macroglobulinemia. Results: The total number of patients in the studies involving regimens based on purine analogs were 1211. The doses of Fludarabine ranged from 25-30 mg/m2 and that of Cladribine ranged from 0.1-0.5 mg/kg. The complete response (CR) observed ranged from 2-15% and the partial response (PR) ranged from 11-67%. The overall response rate (ORR) ranged from 38-95%. Fludarabine: In the study Dhodapkar et al., N=231, the highest CR and ORR was observed, 4% and 66% respectively. In the study Zinzani et al., the PR was 41%. Fludarabine and Cyclophasphamide: In the study Dimopoulos et al., the PR was 55% and the progression free survival (PFS) was 24 months. Fludarabine, Cyclophosphamide and ofatumumab: In the study Gavriatopoulou et al., the PR was 67% and very good partial response (VGPR) was 17% and the PFS was 23 months. Fludarabine, rituximab and cyclophosphamide: In the study Tedeschi et al., the CR was 11.60%, ORR was 79% and the PR was 41.8%. Fludarabine and Rituximab: In the study Treon et al., the CR was 4.6%, VGPR was 32.5%, PR was 48%, and ORR was 95.3% with PFS of 51.2 months. Cladribine: In the study Liu et al., the CR was 5% and PR was 50%. In the studies Dimopoulos et al., 1994 the highest CR was observed, 11.5% with an ORR of 85%. The PR was also the highest, 73%. Conclusion: There is limited literature on regimens containing both Fludarabine and Cladribine, which are used for the treatment of WM. Despite heterogenicity in WM patients and various regimens used in literature. Purine analogs containing regimens are a remarkably effective treatment with overall response rates reaching up to 79%. Neutropenia and thrombocytopenia were the main side effects. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing purine analogs. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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Efficacy and safety of once-weekly bortezomib in multiple myeloma patients

Blood ◽

10.1182/blood-2010-07-294983 ◽

2010 ◽

Vol 116 (23) ◽

pp. 4745-4753 ◽

Cited By ~ 265

Author(s):

Sara Bringhen ◽

Alessandra Larocca ◽

Davide Rossi ◽

Maide Cavalli ◽

Mariella Genuardi ◽

...

Keyword(s):

Survival Rate ◽

Peripheral Neuropathy ◽

Progression Free Survival ◽

Complete Response ◽

Recent Phase ◽

Grade 3 ◽

Schedule Change ◽

Post Hoc ◽

The Impact ◽

Weekly Group

AbstractIn a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

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Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8535 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8535-8535

Author(s):

I. M. Ghobrial ◽

J. Matous ◽

S. Padmanabhan ◽

A. Badros ◽

S. Chuma ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Complete Remission ◽

Phase Ii ◽

Median Number ◽

Toxicity Assessment ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Grade 3 ◽

Relapsed Disease

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]

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Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8043 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8043-8043

Author(s):

Irene M. Ghobrial ◽

Morie A. Gertz ◽

Betsy LaPlant ◽

John Kelly Camoriano ◽

Suzanne R. Hayman ◽

...

Keyword(s):

Single Agent ◽

Mammalian Target Of Rapamycin ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Long Term Results ◽

Entire Study ◽

Waldenström Macroglobulinemia ◽

Overall Response ◽

Waldenstrom Macroglobulinemia

8043 Background: The mammalian target of rapamycin (mTOR) signal pathway controls cell proliferation and survival. The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 x 106/L, a neutrophil count ≥1,000 x 106/L. Patients received everolimus 10 mg PO daily. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 60 pts were treated. The median age was 64 years (range, 43-85). The median number of prior therapies was 3 (range, 1-11). All but two patients (97%) had received prior rituximab based therapy and 64% of patients had received prior alkylator based therapies. The overall response rate (complete response CR+ partial response PR+ minimal response MR) was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for the entire study population is 28 months (mos), (95% CI: 18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 55-NR), respectively. The estimated PFS at 12 and 24 months is 62% (95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 patients who achieved a PR responded after a median of 2 months (range, 1-26) of treatment. The median duration of response (DR) for these patients has not yet been reached and 19 of these patients remain in response after a median follow up of 31 months (range, 3-54). All but two patients had a decrease in their serum IgM. Grade 3 or higher related toxicities were observed in 67% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 5% of patients. Dose reductions due to toxicity occurred in 63% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 73% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient population.

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Initial Treatment with Bortezomib (Velcade®), Doxil®, and Dexamethasone (VDD) Is Superior to Thalidomide and Dexamethasone (TD) as Initial Therapy Prior to Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v112.11.3713.3713 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3713-3713

Author(s):

Andrzej Jakubowiak ◽

Tara Kendall ◽

Ammar Al-Zoubi ◽

Yasser Khaled ◽

Shin Mineishi ◽

...

Keyword(s):

Phase Ii ◽

Initial Treatment ◽

Progression Free Survival ◽

Complete Response ◽

Initial Therapy ◽

Cancer Center ◽

Eligibility Criteria ◽

Free Survival ◽

Post Transplant ◽

Grade 3

Abstract A number of novel combinations used in initial therapy of myeloma show improved overall response (OS) and complete and near complete response (CR/nCR) rates. However, it is not clear if improved responses impact the results after the subsequent ASCT and the overall outcome of MM therapy. To address this issue, we performed a retrospective analysis of patients with symptomatic myeloma who were initially treated with TD (N= 31) or VDD (N =30) followed by ASCT, as part of 2 consecutive clinical studies conducted at the University of Michigan Cancer Center. From July 2003 to May 2005, 31 pts were enrolled in a phase II study of treatment of newly diagnosed myeloma with initial therapy using three 5-week cycles of TD. Thalidomide was given daily starting at 50 mg/d up to 400 mg/d and dexamethasone at 40 mg on days 1–4, 9–12, and 17–20. The outcomes were compared with 30 pts who were enrolled from July 2005 to January 2007 in a phase II trial of initial therapy with six 3-week cycles of VDD regimen. VDD included Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg on days 1–4 in the first 10 pts and 40 mg (cycle 1) then 20 mg (cycle 2–6) Dexamethasone on days of Velcade and the day after in the remaining patients. There were no significant differences in eligibility criteria between both studies. The characteristics of pts in the TD vs. VDD trial were as follows: median age 57 (26–65) vs. 58 (38–71), stage III in 23 vs. 27 pts, ch13 del in 12 vs. 13 pts, and median beta2-microglobulin 3.1 vs. 4.6. Best response to initial therapy (≥PR by modified EBMT criteria) was observed in 80% of pts treated with TD vs. 93% with VDD, CR/nCR in 10% treated with TD vs. 40% with VDD, ≥ very good partial response (VGPR) in 29% treated with TD vs. 63% with VDD (P < 0.01). Grade 3–4 toxicities related to TD included DVT/PE in 5 pts, constipation in 2, CHF in 2, and diabetes in 2. Three pts were removed from the TD study due to toxicities, and 1 died of unexplained cause. Grade 3–4 toxicities during VDD therapy included 4 pts with fatigue, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with pneumonia. There was no death on VDD therapy. In the TD group, 27/27 patients collected median 8.8 × 106 CD34+ cell/kg and 27 completed at least a single ASCT (21 tandem, 6 single). In VDD group, 30/30 collected median 7.5 × 106 CD34+ cell/kg and 28 completed at least a single ASCT (17 tandem, 12 single, 1 single then reduced intensity allo). For pts initially treated with TD, 74 % achieved ≥PR, 48% ≥VGPR and 29% CR/nCR at 3 months after the completion of ASCT. For patients initially treated with VDD, response rates at 3 months post transplant were significantly better with ≥PR in 87%, ≥VGPR in 77%, and CR/nCR in 57% of pts (P ≤ 0.01). After a median follow-up of 49.75 (TD) and 23.8 (VDD) months, progression-free survival (PFS) is 27 months in TD group and not reached in VDD group, with 2 year PFS 53% in TD group and 83% in VDD group (P < 0.01). OS is not reached in both groups with 2 year OS slightly better (NS) in VDD (92%) compared to TD (85%). Based on these observations, it appears that high CR/nCR and VGPR rates in response to initial treatment with VDD persist post transplant, resulting in an improved probability of longer progression-free survival and possibly overall survival. Updated survival curves will be presented at the meeting.

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