A Phase II Study of Bortezomib-Dexametason Followed by High-Dose Melphalan Combined with Bortezomib in Patients Relapsing After High-Dose Melphalan with Autologous Stem Cell Support

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3073-3073
Author(s):  
Peter Gimsing ◽  
Oyvind Hjertner ◽  
Niels Abildgaard ◽  
Niels Frost Andersen ◽  
Tobias Gedde Dahl ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Induction Therapy ◽  
Response Rate ◽  
Phase Ii Study ◽  
High Dose ◽  
Stem Cell Support ◽  
First Relapse ◽  
High Dose Melphalan ◽  
Cell Support

Abstract Abstract 3073 Introduction. The prognosis of multiple myeloma has improved significantly during the last three decades especially in the younger patient who are eligible for high-dose chemotherapy with autologous stem cell support (ASCT). However, in spite of prolonged progression free survival (PFS) the patients will eventually experience treatment demanding relapse. As many of the patients still have stored frozen stem cells, it is a widespread routine to offer another ASCT after re-induction therapy or in some cases directly without induction therapy. Only few reports of the results of ASCT in the relapse setting have been published and all have been retrospective analyses. It is well known that the time from first ASCT to relapse has an impact on both PFS and on overall survival (OS) after second-line treatment (Alegre et al, 2002, Alvares et al, 2005, Lenhoff et al, 2006). New drugs like bortezomib and lenalidomide have improved the PFS and OS at relapse also in some of the bad-risk patients. Therefore, we decided to determine the effect of induction therapy with bortezomib and dexamethasone and including bortezomib in the conditioning regimen with high-dose melphalan (HDM) in the relapse setting, which has also been addressed by the French group (Roussel et al, 2011). Inclusion criteria. Patients formerly treated for multiple myeloma with HDM with stem cell support as first line treatment and who had first symptomatic relapse and had stored more than 2.0 × 106 CD34+ stem cell/ kg body weight. Exclusion criteria. Former treatment with bortezomib. Study design. Prospective non-randomised phase II study. Study treatment. Three courses of bortezomib 1.3 mg/m2 (Velcade®) days 1, 4, 8 and 11 and dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11 and 12 (btz-dex) followed by Melphalan (200 mg/m2) on day –2 with bortezomib 1.3 mg/m2 days –5 and –2, and reinfusion of more than 2.0 × 106 CD34+ stem cells/kg body weight on day 0. Prophylactic treatment for herpes zoster was giving according to local routine. Primary end-point: Comparison of PFS after the first ASCT and the second ASCT with bortezomib included in induction and conditioning at first relapse. Secondary end-points: Toxicity of bortezomib as part of the high-dose melphalan conditioning, response rate of the second ASCT and comparison of time schedule for marrow regeneration (neutrophil- and platelet recovery) in the first and second ASCT. Pre-planned exploratory subgroup analysis of patients with early relapse (within first year) vs. later relapse, different types of relapse. Results. 53 patients relapsing from 3.5 to 112.3 months after initial ASCT (7 patients had received initial tandem ASCT) were included. Four included patients never went forward to ASCT after relapse: one patient died from septicemia shortly after one bortezomib injection, one patient developed respiratory insufficiency after the second btz-dex course and two patients had aggressive progression after the third btz-dex course. The table summarises the results of the 49 patients who completed the ASCT after first relapse. The ratios between the second and first PFS (Hermansen & Gimsing, 2008) were calculated and showed median: 0.9 (range: 0 – 1.77). Detailed safety data will be presented. Conclusion: Salvage high-dose melphalan with bortezomib and stem cell support after reinduction with btz-dex at first relapse after high-dose therapy with saved frozen stem cells is a safe treatment with high response rate and reasonable long PFS compared to the initial treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thalidomide Maintenance Following High-Dose Melphalan with Autologous Stem Cell Support in Myeloma

2008 ◽  
Vol 8 (3) ◽  
pp. 153-158 ◽  
Author(s):  
Julie E. Chang ◽  
Mark B. Juckett ◽  
Natalie S. Callander ◽  
Brad S. Kahl ◽  
Ronald E. Gangnon ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Dose ◽  
Stem Cell Support ◽  
High Dose Melphalan ◽  
Cell Support

Feasability of High Dose Melphalan and Peripheral Blood Stem Cell Support(IPC-LAM 2000) for Patients over 60 Years with Acute Myeloid Leukemia(AML) in First Remission(CR1):Final Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2922-2922
Author(s):  
Anne-Marie Stoppa ◽  
Norbert Vey ◽  
Reda Bouabdallah ◽  
Catherine Faucher ◽  
Diane Coso ◽  
...  
Keyword(s):  
Stem Cell ◽  
Blood Cell ◽  
Peripheral Blood Stem Cell ◽  
Red Blood Cell Transfusion ◽  
High Dose ◽  
Secondary Leukemia ◽  
Stem Cell Support ◽  
Cd34 Cells ◽  
High Dose Melphalan ◽  
Cell Support

Abstract The optimal post remission treatment of AML patients(pts) > 60 y is controversial and disappointing with less than 20 % of pts cured. High dose of alkylating agents (BuMel-CyTBI)with peripheral blood stem cell support (PBSC) is recognized as a standard consolidation therapy for pts in AML CR1 younger than 60 y. Moreover, high dose Melphalan (HDMel)is reported as safe and efficient in patients with myeloma up to 75 y.The objective of the IPC-AML2000 study is to assess the feasability of HdMEL and PBSC support for AML CR1 patients > 60 y. From 01/2000 to 06/2004, 74/142 pts obtained CR1 after DNR/ARAC induction. They were offered a 1st consolidation with reduced DNR/ARAC dose and a 2nd consolidation (priming course) with Cyclophosphamide 3000mg/m2, VP16 300mg/m2 followed by lenograstim 263mcg/d and PBSC collection then a final intensification with HDMel 140 mg/m2. Median age of the 74 pts was 67 y(61–79).There were 37m/37f; 17 pts (23%) had secondary leukemia following antecedent of hematologic disorder(n=12) or exposure to radiochemotherapy for cancer(n=5),30% had leucocytosis>30.10*9/ at diagnosis. Cytogenetic analysis revealed favorable risk karyotype in 10% of the pts, intermediate risk in 73% and unfavorable risk in 16%.Thirty four pts(46%)underwent a med of 2 (2–5) apheresis in a med of 15(10–36) days after the priming course, for a med of 8(2,5–23) 10*6/kg CD34+ cells collected. All the 34 patients collected underwent HDMel in a med of 2,5(2–5) months after CR1. Reasons for not receiving HDMel in 40 pts were equally divided in: refusal(27%,n=11)early relapse(25%,n=10)contra indication because of organ dysfonction or poor performance status(27%,n=11) or low CD34 counts (17%,n=7) The med age of the transplanted pts was 67 years(61–71);78% of de novo leukemia pts underwent HDMel compared to 22% of secondary leukemia pts (p=0,02) Following reinfusion of cryopreserved PBSC at Day0 and lenograstim 263mcg/day begining at Day 4,neutrophil reconstitution>0,5 and 1 .10*9/l was observed at Day 11(9–15) and Day12(9–18) respectively.Platelet reconstitution > 25,50,100.10*9/l was observed at Day 13(8–20),Day 14(11–35)and Day 19(13–100) respectively; med platelet and red blood cell transfusion were 0 unit(0–2) and 2 units (0–6) respectively;67% and 32% of the patients did not received any platelet or red blood cell transfusion respectively;20% of patients did not received antibiotherapy. Extra hematological toxicity was limited to mucositis (grade 0/1=57%,gr 2=12%,gr 3=26%,gr 4=5%) Median Day of hospital discharge was Day 14(0–24).No toxic death was observed. With a med follow up of 30(14–68) mths for pts alive, 2 year disease free survival of the 74CR patients and the 34 who received HDMel is 20%[12–31] and 25%[14–42] respectively with a med CR duration of 8 mths(2–68). DFS risk factor analysis for the transplanted pts did not show impact of age, secondary leukemia,hyperleucocytosis,caryotype,but a trend(p=0,003)for shorter DFS in pts receiving high doses of CD34 + cells (<=9.10*6/kg:14 mths,>9:6 mths)These data suggest that consolidation with HDMel and PBSC support is feasible in half of the AML pts > 60 y and can be incorporated safely in the treatment stategy of such pts. Giving the high relapse rate observed, alternative treatment should be considered.

High-Dose Myeloablative Zevalin Radioimmunotherapy with Tandem Stem-Cell Autografting Has Minimal Toxicity and Full Feasibility in an Outpatient Setting.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2737-2737 ◽  
Author(s):  
Liliana Devizzi ◽  
Ettore Seregni ◽  
Anna Guidetti ◽  
Chiara Forni ◽  
Angela Coliva ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Patient Population ◽  
Outpatient Setting ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Antibiotic Administration ◽  
Hematopoietic Stem ◽  
Stem Cell Support ◽  
Cell Support

Abstract Background : High dose chemotherapy has an established, albeit limited role, in the management of non-Hodgkin lymphoma (NHL). In fact, because of its toxicity, in particular mucositis, neutropenia and thrombocytopenia, myeloablative regimens with autologous stem cell support can be safely delivered only to clinically fit and younger pts, require prolonged hospitalization, and have a restricted impact in the therapy of NHL. With the primary aim of widening the applicability of myeloablative regimens, we designed a pilot study using high-dose Zevalin with tandem stem-cell support in a prospective cohort of 13 refractory or relapsed NHL patients, unable to safely undergo a BEAM chemotherapy course. Methods : Prior to Zevalin, all pts received one cycle of high-dose cyclophosphamide plus rituximab, and one cycle of high-dose cytarabine and rituximab, at patient-adapted doses. Hematopoietic stem cells were harvested from the peripheral blood during the post-cyclophosphamide and/or the post-cytarabine recovery phase, and tested for MRD. Zevalin was administered at twice the MTD (0.8 mCi/kg), and followed by tandem autografting of a small amount of CD34+ (0.8–2 x 106/kg) on day +7, and an optimal amount (>=5 x 106 CD34+ cells/kg) on day +14, respectively. The former reinfusion (supportive autografting) was done still in the presence of potentially myelotoxic doses of circulating radioactivity, and its aim was solely to achieve an immediate albeit transient hematopoietic recovery. At the time of the second reinfusion (reconstituting autografting) the calculated radiation dose to the reinfused stem cells was less than 5 cGy, in order to ensure a complete and long lasting hematopoietic reconstitution. Results: From July 2004 through March 2005, 13 overall NHL patients entered into the study (DLBCL 5, follicular 3, mantle cell 2, marginal zone nodal 1, small lymphocytic 1, lymphoplasmacytoid 1). Median age was 60 yrs (29–69). The number of prior chemotherapy regimes was 1 (4 pts), 2 (5 pts), 3 (3 pts) and 4 (1 pt), respectively. Neutropenia grade 1 or higher was documented in all but 1 patient, and lasted a median of 7 days (1–15), while grade 4 neutropenia was observed in 8 pts, in which lasted a median of 3.5 days only (1–10). Grade >=1 thrombocytopenia was observed in all patients (median 16 days, range 7–30), while grade 4 thrombocytopenia occurred in 10 pts for a median duration (in the thrombocytopenic pts) of 6 days (1–13). Eight patients required platelet transfusions (median 2, range 1–6), and 9 pts received 1 RBC transfusion each. No extra-hematologic toxicity was observed, and all but 4 patients were cared for as outpatients. The 4 hospital admissions lasted 2 (2 pts) and 4 days (2 pts) respectively, and were required for FUO that rapidly resolved upon antibiotic administration. After a median follow-up of 6 months (1–11), 11 pts are alive, of which 10 in continuous CR. Conclusions : High-dose Zevalin with tandem stem-cell transplantation was minimally toxic in this heavily pretreated patient population, and fully applicable in an outpatient setting. Its administration at 0.8 mCi/kg (and possibly up to 1.2 mCi/kg) as a final consolidation step, warrants prospective comparison with conventional-dose regimens in a minimally selected NHL patient population.

High-Dose Myeloablative Zevalin Radioimmunotherapy with Tandem Stem-Cell Autografting Has Promising Activity, Minimal Toxicity and Full Feasibility in an Outpatient Setting.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3047-3047 ◽  
Author(s):  
Liliana Devizzi ◽  
Ettore Seregni ◽  
Anna Guidetti ◽  
Chiara Forni ◽  
Angela Coliva ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Outpatient Setting ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Antibiotic Administration ◽  
Severe Toxicity ◽  
Hematopoietic Stem ◽  
Stem Cell Support ◽  
Cell Support

Abstract Background: Because of severe toxicity, in particular mucositis, neutropenia and thrombocytopenia, myeloablative regimens with stem cell support can be safely delivered only to clinically fit and younger pts, require prolonged hospitalization, and have a limited impact in the therapy of NHL. With the aim of rendering high-dose chemotherapy a well tolerated and widely applicable regimen, we carried out a pilot study using high-dose Zevalin with tandem stem-cell support in a prospective cohort of refractory or relapsed NHL patients. Methods: From June 2004 through June 2006, 29 overall NHL patients entered into the study (DLBCL, n=11; follicular, n=10; mantle cell, n=3; small lymphocytic, n=4; Richter syndrome, n=1). Median age was 62 yrs (29–76). The median number of prior chemotherapy regimes was 2 (1–4). Prior to Zevalin, all patients received 3 cycles of standard-dose salvage chemotherapy (DHAP or CHOP, as appropriate), followed by one cycle of high-dose cyclophosphamide plus rituximab, and one cycle of high-dose cytarabine and rituximab, at patient-adapted doses. Hematopoietic stem cells were harvested from the peripheral blood during the post-cyclophosphamide and/or the post-cytarabine recovery phase, and tested for MRD. Zevalin was administered at 0.8 mCi/kg (n=13 pts) or 1.2 mCi/kg (n=16 pts), respectively, and followed by tandem autografting of CD34+ on day +7 and an on day +14, respectively. The latter procedure was performed late, when the radiation absorbed dose to the reinfused stem cells was estimated to be less than 5cGy. In addition, all patients received on day +7 a limited amount (0.8–4.3 x 106/kg) of CD34+ cells. The aim of this early reinfusion, performed in the presence of myelotoxic levels of body radioactivity, was to foster a rapid albeit transient hematopoietic recovery, thus reducing the extend and duration of severe post-Zevalin pancytopenia. Results: Grade 4 neutropenia was observed in 13 pts (45%), and lasted a median of 4 days only (1–14). Grade 4 thrombocytopenia occurred in 19 pts (65%) for a median duration of 5 days (1–14). Fifteen patients (52%) required platelet transfusions (median 2, range 1–6), and 14 pts (48%) received 1 RBC transfusion each. No extra-hematologic toxicity was observed except for mild nausea in 17% of the patients, and all but 3 patients were cared for as outpatients. The 3 hospital admissions lasted 2, 4 and 11 days respectively, and were required for FUO that resolved upon antibiotic administration. Bone marrow analysis performed at 6 (n=5 pts) and 12 months (n=10 pts) showed in all a normal karyotype and a colony growth comparable to controls (NHL pts autografted following BEAM chemotherapy). After a median follow-up of 12 months, the 2-yr OS rate was 87% for indolent and 85% for aggressive lymphoma pts, respectively, while the EFS rate was 55% and 77%, respectively. Conclusions: High-dose Zevalin with tandem stem-cell transplantation was minimally toxic in this pretreated and elderly patient population, proved fully applicable in an outpatient setting, and showed promising activity. Its upfront inclusion as consolidation step after induction chemotherapy warrants a prospective comparison with R-CHOP, in particular in elderly pts with aggressive NHL.

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