Subcutaneous Bortezomib in Combination Regimens in Newly Diagnosed Patients with Myeloma or Systemic AL Amyloidosis: High Response Rates and Minimal Toxicity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2968-2968 ◽  
Author(s):  
Gunjan L Shah ◽  
Esha Kaul ◽  
Shelly Fallo ◽  
Furha I. Cossor ◽  
Hedy Smith ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
High Risk ◽  
Response Rate ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
First Line ◽  
Minimal Toxicity ◽  
Grade 3 ◽  
Combination Regimens ◽  
Dose Reductions

Abstract Abstract 2968 Background: Bortezomib, the first-in-class proteasome inhibitor approved for treatment of all phases of multiple myeloma (MM) and used to treat light-chain amyloidosis (AL), was approved for the subcutaneous route of administration in 2012 based on phase III data in relapsed patients (Lancet Oncology 2011;12:431). We report our experience in a tertiary care center with subcutaneously administered bortezomib in newly diagnosed patients with MM and AL. Patients and Methods: With IRB approval, we performed a retrospective study of all newly diagnosed patients with MM or AL treated at our center between 4/1/11, when the hospital pharmacy approved and implemented the option of subcutaneous administration of bortezomib, and 7/31/12. Patients who received subcutaneous bortezomib as part of the first line of therapy were identified through the pharmacy database. Data was abstracted from the medical records; demographics, disease profiles, toxicities, responses, and survival data were collected. Results: Nineteen newly diagnosed patients with symptomatic MM (n=10) or AL (n=9) received bortezomib as part of first line therapy between 4/1/11 and 7/31/12. Median follow-up was 252 days (25–416). They included 12 men and 7 women with a median age of 70 years (range, 49–80), and a median time from diagnosis to treatment of 21 days (3–130). MM patients were ISS stage I (n=4), II (n=3) and III (n=2), and six AL patients had cardiac involvement, stage II (n=5) and III (n=1), respectively. Four MM patients had high-risk cytogenetics and 1 AL patient had del17p. Treatment regimens included cyclophosphamide, bortezomib and dexamethasone on the 35-day schedule (CyBorD-35) (n=12), CyBorD-28 (n=3), CyBorD-21 (n=1), and weekly BD (n=3). Median initial bortezomib dose was 1.5mg/m2 (1.3–1.5), and patients received a median of 4 cycles of therapy (1–8). With respect to side effects, no patients developed rash or grade 3 or 4 peripheral neuropathy. One patient developed grade 3 diarrhea and two grade 3 thrombocytopenia. The latter were the only patients requiring dose reductions (5%, 2/19). Five patients (MM=3, AL=2) proceeded to consolidation with stem cell transplant (SCT) after a median of 4 cycles (1–5). Overall best hematologic responses, including post-SCT patients, in MM were CR/VGPR/PR/SD in 3, 2, 4 and 1 patient, and in AL as per new consensus criteria (Blood 2010;116:1364a) were CR/VGPR/PR in 2, 5 and 2 patients. One MM patient with high risk disease (del17p, del5q) died 118 days after diagnosis status post 3 cycles of CyBorD with SD. One AL patient with del17p relapsed 6 months after achieving a VGPR. Aggregate hematologic response rate > VGPR (CR 6, VGPR 6) was 63%, and > PR was 95% (18/19). Conclusions: With the use of subcutaneous bortezomib in combination regimens in newly diagnosed patients with MM or AL, there was a high overall response rate and minimal toxicity. Five percent of patients required dose reductions of bortezomib for thrombocytopenia. No patients experienced grade 3 or 4 peripheral neuropathy. These results are consistent with the findings of the phase III study in relapsed patients and provide a basis for further studies comparing new proteasome inhibitors to subcutaneous bortezomib in combination regimens for newly diagnosed patients with MM or AL. Disclosures: Comenzo: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
Author(s):  
Angela Dispenzieri ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Partial Response ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Labeling ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

Single Agent Bortezomib Is Associated with a High Response Rate in Patients with High Risk Myeloma. A Phase II Study from the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3527-3527 ◽  
Author(s):  
Angela Dispenzieri ◽  
Lijung Zhang ◽  
Rafael Fonseca ◽  
David H. Vesole ◽  
Philip R. Greipp
Keyword(s):  
Peripheral Neuropathy ◽  
High Risk ◽  
Adverse Events ◽  
Response Rate ◽  
Single Agent ◽  
Novel Therapies ◽  
Newly Diagnosed ◽  
Monoclonal Protein ◽  
Grade 3

Abstract Background: MM is an incurable disease with an anticipated overall survival ranging from months to decades. Novel therapies like bortezomib have activity in both the relapsed/refractory and up front settings. There are sparse data on whether novel therapies may overcome high risk features. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients received bortezomib 1.3 mg/m2 every other week indefinitely. Patients relapsing on maintenance schedule resumed full induction schedule. Responses were defined by the EBMT criteria. The primary end-point was the response rate (90% power to detect a response rate of >=50% ). Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled. Among the 43 eligible patients, median age was 63; 51% were male. All had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Response data are available for 37 of the 43 eligible patients. The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patients with CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable). The median progression free survival is 9.4 months. Thirty-three percent of patients completed the 8 cycles of planned induction therapy and moved to maintenance. Reasons for discontinuing therapy have included progression or death (n=18), adverse events (n=6), and other (n=14). Only 12% of patients remain on active therapy: 0% of deletion 13q patients; 25% of t(4:14) and 12% each of high B2M and high PCLI patients. Of the 14 patients who entered the maintenance phase of treatment, 3 have progressed. Of these 3, 2 took re-induction, and neither responded. Median time to progression for those entering maintenance was12.4 months from the time of starting maintenance. The most common adverse events of grade 3 or higher included neutropenia (33%), diarrhea (31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%), fatigue (14%). Grade 1–2 sensory peripheral neuropathy occurred in 53% of patients, with only 2% having grade 3 sensory neuropathy. One patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses of protocol treatment due to heart block and asystole. Updated results on the full study population will be presented at the meeting. Conclusions: In high risk patients, upfront bortezomib appears to result in comparable response rates to those reported for unselected cohorts of newly diagnosed myeloma patients. Continued follow-up of these patients will provide information about whether this will translate into better overall outcomes. Figure Figure

The Combination of the Proteasome Inhibitor Bortezomib with Doxorubicin and Dexamethasone (PAD Regimen) as Front-Line Therapy In Newly Diagnosed, High-Risk Multiple Myeloma: Results of a Phase II Prospective Multicenter Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3052-3052 ◽  
Author(s):  
Ioannis Baltathakis ◽  
Evangelos Terpos ◽  
Sosana Delimpasi ◽  
Konstantinos Liapis ◽  
Fotios Panitsas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Front Line ◽  
Grade 3 ◽  
Cell Harvest

Abstract Abstract 3052 The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has shown efficacy in both relapsed/refractory and untreated, symptomatic multiple myeloma (MM). The activity of this regimen is largely attributed to the recognized synergy between bortezomib and doxorubicin. Bortezomib is capable of reversing resistance to chemotherapy in MM with adverse prognostic features (high-risk myeloma), which has an unfavorable outcome with conventional chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT). In addition, disease status prior to ASCT has prognostic significance for survival, underscoring the need for highly efficient remission induction strategies. In a prospectively designed phase II trial, we focused on the efficacy and safety of the PAD combination as front-line treatment for high-risk myeloma. The study recruited patients aged ≤70 years with newly diagnosed, symptomatic MM with high-risk features (defined by at least one of the following criteria: ISS stage II/III according to serum albumin and beta2-microglobulin, and/or detection of 13q deletion by FISH or conventional karyotyping). Between 2005 and 2008, 40 patients were enrolled in the protocol. The median age of patients was 59 years (range: 41–70 years), and 27 (67.5%) were male. Each 21-day cycle of PAD included bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 on days 1–4, and dexamethasone 40 mg on days 1–4 and 8–11. According to protocol, patients received 4 induction cycles of PAD before proceeding to stem cell harvest and ASCT. Acyclovir and ciprofloxacin prophylaxis were routinely used. Patients were evaluated for toxicity at each cycle and for response after the end of the fourth cycle. The primary study endpoint was the response rate at the end of induction (assessed by the International Myeloma Working Group uniform response criteria, 2006). Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), ability to mobilize stem cells, and response after ASCT. ISS stage was I in 2 patients (5%), II in 18 (45%), and III in 20 (50%). Nine out of 40 patients (22.5%) presented with renal failure (creatinine >2mg/dl) due to myeloma at diagnosis. Deletion 13q was detected in 19 patients. Bone disease was present in 30 patients (75%) at diagnosis, and 19 (47.5%) had ≥3 lytic lesions on plain skeleton radiograms. Median patient follow-up time was 28.3 months (range, 1.4–49.3). All patients completed the 4 cycles of PAD, with the exception of one who died during the 2nd cycle. The overall response rate assessed after the 4th cycle of PAD was 95%. Complete remission (CR) was achieved in 12/39 (31%), very good partial remission (VGPR) in 15/39 (38.5%), and PR in 10/39 (25.5%). Thirty-one patients were considered eligible for ASCT, and an adequate stem cell harvest was achieved in all. Following ASCT, CR rate reached 52% (16/31) with a CR+VGPR rate of 84% (26/31). PFS was 67% at 2.1 years, and calculated OS was 81.4% at 4 years (Figures 1 and 2). Factors associated with shorter OS were beta2-microglobulin ≥5.5 mg/L (p=0.03), and ISS stage III (p=0.03). By assessment of the glomerular filtration rate (GFR), a significant improvement in renal function was demonstrated after induction with PAD (median GFR pre- and post-induction: 59.7 versus 82.1 ml/min, respectively; p<0.001). Improvement in kidney function was observed irrespective of the type of response. There was only one treatment-related death secondary to infection. Toxicities were manageable in general, and included grade 3–4 neutropenia in 8/40 patients (20%), grade 3–4 thrombocytopenia in 4/40 (10%), and grade 3 peripheral neuropathy in 4/40 (10%). No grade 4 peripheral neuropathy was encountered. We conclude that the PAD regimen is very effective, and produces high-quality responses in a substantial proportion of patients with newly diagnosed, high-risk MM (CR+VGPR: 69.5%). PAD is well tolerated and does not compromise stem cell mobilization and harvest. Upfront treatment with 4 cycles of PAD followed by ASCT resulted in notable PFS and OS rates in this patient group with adverse-prognosis MM. PAD was shown to be particularly beneficial in patients with renal impairment at diagnosis due to myeloma. Disclosures: Baltathakis: Janssen-Cilag: Research Funding. Terpos:Janssen-Cilag: Honoraria. Delimpasi:Janssen-Cilag: Research Funding. Dimopoulos:Janssen-Cilag: Honoraria. Harhalakis:Janssen-Cilag: Research Funding.

A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Versus Bortezomib, Melphalan and Prednisone (VMP) in Elderly Newly Diagnosed Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 652-652 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Davide Rossi ◽  
Valeria Magarotto ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Gastrointestinal Complications ◽  
Free Survival ◽  
Weekly Infusion ◽  
Grade 3

Abstract Background: In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Methods: Newly diagnosed myeloma patients (N=393) older than 65 years, from 58 centers in Italy, were randomly assigned to receive VMPT (N=193) or VMP (N=200). Initially, patients were treated with nine 6-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42, followed by bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (bortezomib 1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Primary end-point was progression-free survival (PFS). Results: Patient characteristics were similar in both groups: median age was 71 years, 23% of patients were aged > 75 years. Patients who received at least 1 cycle were evaluated: 152 patients for VMPT (62 received bortezomib bi-weekly infusion and 90 weekly infusion) and 152 patients for VMP (62 received bortezomib bi-weekly infusion and 90 weekly infusion). Data were analyzed in intention-to-treat. The very good partial response (VGPR) rate was higher in the VMPT group (55% versus 42%, p=0.02), including a CR rate of 31% in the VMPT group and 16% in the VMP group (p=0.003). In the subgroup treated with weekly infusion of bortezomib, VGPR was 59% for VMPT and 37% for VMP (p=0.004), including 28% CR for VMPT and 10% for VMP (p=0.004). Subgroup analyses did not show any statistical difference between responses and either age, B2-microglobulin or chromosomal abnormalities, such as del13, t(4;14), t(14;16) and del17. After a median follow-up of 13.6 months, the 2-year PFS was 83.9% in the VMPT group and 75.7% in the VMP group (HR=0.73, 95% CI 0.38–1.42, p=0.35). In patients who received weekly infusion of bortezomib, the 2-year PFS was 86.8% in the VMPT group and 78.1% in the VMP group (HR=0.65, 95% CI 0.24–1.8, p=0.41). In patients who achieved CR after induction, the 2-year PFS was 100% for VMPT and 79% for VMP (p=0.02). The 3-year overall survival (OS) was 89.5% in the VMPT group and 88.7% in the VMP group (HR=1.02, 95% CI 0.43–2.46, p=0.96). The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%), infections (14% vs 10%), and gastrointestinal complications (7% vs 8%), respectively. The weekly infusion of bortezomib significantly decreased the incidence of grade 3–4 peripheral neuropathy (9% for VMPT and 3% for VMP). Conclusion: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. The weekly infusion of bortezomib significantly reduced the incidence of grade 3–4 peripheral neuropathy without influencing outcome. Table. Complete responses, progression-free survival and peripheral neuropathy in all patients and in those who received weekly infusion of bortezomib VMPT group (n=152) VMP group (n=152) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) CR rate (%) 31 28 16 10 2-year PFS (%) 84 87 76 78 Grade 3–4 peripheral neuropathy (%) 18 9 12 3

A phase II study of combination of bortezomib, liposomal doxorubin, and dexamethasone (VDD) as first line therapy for multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17504-17504 ◽  
Author(s):  
A. J. Jakubowiak ◽  
J. Friedman ◽  
T. Kendall ◽  
A. Al-Zoubi ◽  
M. S. Kaminski
Keyword(s):  
Peripheral Neuropathy ◽  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Cell Transplant ◽  
First Line ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

17504 Background: We have recently reported that a combination of bortezomib (Velcade), liposomal doxorubicin (Doxil), and dexamethasone (VDD) is very active and well tolerated in relapsed/refractory myeloma (MM) producing 83% overall response rate and 33% of complete (CR) or near complete (nCR) response rate. In the current study, we evaluated the activity of VDD as first line therapy in newly diagnosed patients with MM. The primary objective of this study was to determine the efficacy of this regimen. Methods: This is a phase II, single institution trial which opened in July 2005 with target accrual of 30 patients. EBMT criteria were used for evaluation of responses. The regimen was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone for a total of 160 mg per cycle, initially at 40 mg on days 1–4 and then 20 mg on days of Velcade and the day after. VDD was repeated every 3 weeks for a total of 6 cycles. Results: To date, 19 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 4.7 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 58 (range 39–83), chromosome 13 deletion in 4 patients, beta2-microglobulin 4.4 (61% > 4.0). CR + nCR have been observed in 2 patients (11%), very good partial response (VGPR) in 5 patients (28%), partial response (PR) in 9 patients (50%) and minor response (MR) in 1 patients (5%) for an overall response (≥ MR) of 94%, ≥ PR of 89% and ≥ VGPR of 39%. All patients who proceeded to stem cell transplant collected without any problems. The regimen was very well tolerated. Most surprisingly, only 1 patient developed peripheral neuropathy grade 1. One patient developed pneumonia and PE and one patient grade 3 diarrhea, which was found to be secondary to cryptosporidium. Grade 3 or 4 neutropenia was observed in 6 patients and grade 3 thrombocytopenia in 1 patient. The most common grade 1 and 2 toxicities were thrombocytopenia and fatigue, both significantly less common than in relapsed patients treated with the same regimen. One patient developed grade 2 DVT and 1 grade 2 PPE. Conclusions: VDD combination shows high overall activity of 94% and ≥ 90% disease reduction of 39%. The regimen is very well tolerated and has a surprisingly low incidence of peripheral neuropathy. [Table: see text]

A topotecan-containing induction regimen for treatment of high risk neuroblastoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9013-9013 ◽  
Author(s):  
J. R. Park ◽  
C. F. Stewart ◽  
W. B. London ◽  
V. M. Santana ◽  
P. J. Shaw ◽  
...  
Keyword(s):  
High Risk ◽  
Systemic Exposure ◽  
Dose Intensity ◽  
Phase Iii ◽  
Mycn Amplification ◽  
Newly Diagnosed ◽  
C Cycle ◽  
Induction Regimen ◽  
Grade 3 ◽  
Chemotherapy Agents

9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and cyclophosphamide to a multi-agent chemotherapy induction regimen for treatment of newly diagnosed high-risk neuroblastoma. Methods: Patients received 2 cycles of topotecan (starting dose 1.2 mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) followed by an additional 4 cycles of chemotherapy; cisplatin, etoposide alternating with vincristine, doxorubicin, cyclophosphamide. Pharmacokinetically guided topotecan dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone levels) was performed. Chemotherapy cycles were scheduled every 21 days, PBSC harvest occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5. Results: Thirty-one patients, 3 with INSS Stage 3 and 28 with Stage 4, were enrolled between April 2004 and November 2005. Median age at diagnosis was 2.5 years (range 0.9 - 9.35 years). Ten of 25 patients had tumor cell MYCN amplification and 21 of 22 tumors were classified as unfavorable Shimada histology by central review. Targeted topotecan systemic exposure was achieved in 87% (27/31) of patients during T/C cycle 1 and in 85% (23/27) of patients during T/C cycle 2. PBSC collections occurred as intended in 95% of patients (21/22 patients), median harvest 30.8 × 106 CD34+cells cell/kg (range 2.24 - 542). No dose limiting toxicities occurred. All patients experienced Grade 3 or 4 hematopoietic toxicity. Febrile neutropenia occurred in 79% (19/24) of patients during T/C cycles and 78% (18/23) of patients during subsequent cycles of induction therapy. Documented infection occurred in 12.5% (3/24) patients during T/C cycles and 26% (6/23) during subsequent induction cycles. Dose intensity of all chemotherapy agents was maintained in 95.8% (23/24) of patients. Conclusions: This pilot induction regimen was well tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy agents was not limited by the addition of dose-intensive topotecan. These data support investigation of efficacy in a Phase III clinical trial for newly diagnosed high-risk neuroblastoma. [Table: see text]

Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group

2006 ◽  
Vol 24 (3) ◽  
pp. 431-436 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Philip R. Greipp
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Response Rate ◽  
Eastern Cooperative Oncology Group ◽  
Response Rates ◽  
Incidence Rates ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Monoclonal Protein ◽  
Grade 3

Purpose To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. Patients and Methods Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. Results Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). Conclusion Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

scholarly journals Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4077-4077 ◽  
Author(s):  
Deborah A. Katz ◽  
Michael P. Chu ◽  
Kevin A. David ◽  
Catherine Thieblemont ◽  
Nicholas J. Morley ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Metabolic Response ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Randomized Comparison of Imatinib Versus Imatinib Combination Therapies in Newly Diagnosed Chronic Myeloid Leukaemia (CML) Patients in Chronic Phase (CP): First Results of the Phase III (SPIRIT) Trial from the French CML Group (FI LMC)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 183-183 ◽  
Author(s):  
Francois Guilhot ◽  
François-Xavier Mahon ◽  
Joelle Guilhot ◽  
Francoise Rigual-Huguet ◽  
Frederic Maloisel ◽  
...  
Keyword(s):  
Response Rate ◽  
Liver Toxicity ◽  
Phase Iii ◽  
Complete Analysis ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Muscle Cramps ◽  
Log Reduction ◽  
Grade 3

Abstract Imatinib (IM) at 400 mg daily is the first line therapy for newly diagnosed CML patients (pts); however, less than 50% of major molecular responses (MMR) are obtained at 12 months. To improve these results, we designed a phase III, multicenter, open-label, prospective randomized trial. The reference arm was IM 400 mg daily (n=159). The 3 experimental arms were IM 600 mg daily (n=160), IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles)(n=158) and IM 400mg in combination with Peg-IFN alfa-2a (Peg-IFN2a, 90 μg weekly) (n=159). Treatment was delivered at least 12 months or until treatment failure (disease progression) or major toxicity. The primary endpoint is the overall survival. Other endpoints are: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response (major molecular response ie MMR) and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization was stratified according to Sokal risk groups. The current interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization was planned in order to select the best experimental arm for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months was centralized, blinded and calculated according to International score (IS). Pts were recruited between 9/2003 and 10/2007.[median age 51 yrs (18–82), 62% of pts were male; Sokal distribution was low risk 33%, intermediate risk 41% and 27% high risk]. Median follow-up is 36 months (range 8–57) at the time of analysis. Overall, at 3 months 86 % of pts achieved complete hematologic response. The MCyR, CCyR and MMR rates at 6 and 12 months are: IM-400 IM-600 IM-Ara-c IM-PegIFN *p&lt; 10−2 (overall); ** p&lt;10−2 (overall) At 6 months (636 pts, ITT) MCyR 74% 79% 68% 74% CCyR * 48% 67% 55% 56% At 12months (562 evaluable pts) MCyR 64% 76% 77% 74% CCyR 57% 65% 66% 71% MMR at 6 months** 21% 33% 27% 39% MMR at 12 months 40% 52% 51% 61% Interestingly the rate of MMR at 6 months was significantly higher for IM-PegIFN as compared with IM-400 (p&lt;10−3). The 4-log reduction rate in the BCR-ABL/ABL transcript were 18%, 21%, 22%, 34%, for the IM-400, IM-600, IM-Ara-c and IM-PegIFN arms respectively. The corresponding numbers of undetectable (complete molecular response) pts were 2%, 2%, 3% and 9% at 12 months respectively. Grade 3/4 neutropenia and/or thrombocytopenia occurred in 8% of IM-400 pts, in 14% of IM-600 pts, in 41% of IMAra- c pts and in 40% of IM-PegIFN pts respectively. Grade 3/4 non hematological events were reported in 19% of IM-400 pts, in 30% of IM-600 pts, in 27% of IM Ara-c pts and in 31% of IM-PegIFN pts. Among them a relationship between treatment and event was suspected for 21 pts (13%) with IM-400 (7 liver toxicity; 7 oedema+muscle cramps), for 31 pts (19%) with IM-600 (7 liver toxicity, 11 oedema+ muscle cramps) for 36 pts (23%) with IM-Ara-c (2 liver toxicity; 10 gut side effect) and for 47 pts (29%) with IM-PegIFN (6 liver toxicity, 13 skin rash). Discontinuation of experimental treatment occurred within the first 6 and 12 months in 26% and 18% of IM-Ara-c pts and in 35% and 11% pts of IM-PegIFN pts respectively. Within the first 12 months 36% of 600-IM pts reduced their dosage. Although a substantial number of pts stopped PegIFN, this first analysis indicates the usefulness of a combination of IM-PegIFN for the initial treatment of pts with CML CP with a significant molecular response rate improvement. Complete analysis of the 636 pts with a follow-up of 12 months will be presented.

scholarly journals Randomized Comparison of Rituximab Versus Bortezomib Plus Cyclophosphamide and Dexamethasone in Newly Diagnosed Waldenstrom Macroglobulinemia Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4003-4003
Author(s):  
Shuhua Yi ◽  
Wenjie Xiong ◽  
Yi Wang ◽  
Rui Lv ◽  
Li Zengjun ◽  
...  
Keyword(s):  
Adverse Event ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Response Rate ◽  
Routine Practice ◽  
Newly Diagnosed ◽  
Minor Response ◽  
Overall Response ◽  
Good Response Rate ◽  
Grade 3

Background:Waldenstrom's macroglobulinemia (WM) is one type of lymphoma that had the characteristic of both lymphocytes and plasma cells. Rituximab-based or bortezomib-based regiments are commonly used treatment approaches in routine practice in previously untreated patients with LPL/WM. However, which regiment is better still unknown. The purpose of this study is to compare the efficacy of RCD (Rituximab,cyclophosphamide and dexamethasone) and BCD (Bortezomib, cyclophosphamide and dexamethasone)in newly diagnosed WM patients. Methods:30 newly diagnosed WM patients were randomly assigned to BCD or RCD group for introduction chemotherapy. Chemotherapeutic response was evaluated after 3 cycles. If a minor response (MR) or better response achieves, addition 3 cycles will be given. If not, patients will be crossed to control group for another 3 cycles. If a MR or better response comes out, addition 3 cycles will be given, otherwise, the patients will quit this study. Results: Finally, 15 patients were assigned to each treatment group. The basic characteristics of the two groups were similar. The median time to response in RCD and BCD group were 4 months and 3 months, respectively. The CR rate in RCD and BCD group was 20% and 26.7% respectively, with VGPR rate 26.7% and 6.7%, PR rate 46.7% and 40% in each group respectively. Additional 20% minor response was observed in BCD group. The overall response was 86.7% in both groups. However, RCD group had higher good response rate (≥VGPR) compared to BCD ( 46.7% vs 33.4%, p=0.05). The rate of major response (≥PR) in RCD group was higher than that in BCD group (86.7% vs 66.7%, p=0.195). The median follow-up time was 29 months. The median duration of response in RCD and BCD group was 35 months and 30 months, respectively. The 3-year progression-free rate of RCD group was significantly higher than that of the BCD group (87.5% vs 39.2%,p=0.045). The 3-year overall survival rate was 100% with RCD group versus 70% with BCD group (100% vs 70%, p=0.127)The most common adverse events of any grade with RCD and BCD were hematological toxicity. 3 patients in the RCD group had grade 3 or higher granulocytopenia.4 patients in the BCD group occurred grade 3 or higher hypocytosis. Other adverse event in the RCD group included pneumonia (40%), non-infectious fever (26.7%), hyperglycemia (13.3%) and rash (6.7%).The most common non-hematological adverse event in BCD group were peripheral neuropathy (40%), pneumonia (26.7%), herpes zoster (13.3%) and ventosity(6.7%). Events of non-infectious fever occurred more frequently in the RCD group (26.7% vs 0%, p=0.032). However, peripheral neuropathy was more common in the BCD group (40% vs 6.7%, p=0.031). There was no serious non-hematological grade 3 or higher adverse events occurred in the both groups. Conclusion: The RCD and BCD regimens have similar overall response in newly diagnosed WM. RCD regimen has higher good response rate and longer PFS time compared to BCD regimen. Both regimens have good tolerance. Disclosures No relevant conflicts of interest to declare.

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