In Vivo Purging Followed by AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) in PATIENTS with MULTIPLE MYELOMA (MM): Preliminary RESULTS of a Pilot STUDY

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4458-4458
Author(s):  
Imma Attolico ◽  
Domenico Vertone ◽  
Nunzio Filardi ◽  
Michele Pizzuti ◽  
Monica Poggiaspalla ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Stem Cell ◽  
Pilot Study ◽  
Conditioning Regimen ◽  
Optimal Schedule ◽  
High Dose ◽  
Phase Ii Trials ◽  
Pbsc Mobilization

Abstract In the past decade, thalidomide, bortezomib, and lenalidomide have emerged as highly active agents in the treatment of MM. However, the optimal schedule and association of these drugs is still under investigation. Thalidomide has shown to be highly thrombogenic in induction therapy, especially in patients with high tumor burden, while Bortezomib (BOR) is not; moreover BOR does not affect peripheral blood stem cell (PBSC) collection and it has also been used in combination with Melphalan (MEL) before ASCT. Both in vitro laboratory data and preliminary phase II trials suggest synergistic effects when BOR is combined with Cyclophosphamide (CY); this drug is effective in treatment of MM and is not stem cell toxic. We started a pilot study in high risk MM patients, fit for ASCT, combining BOR, CY and dexamethasone (DEX) as induction and mobilizing therapy (CY-BOR), followed by supplemented BOR-ASCT, to determine: 1-feasibility and Response Rate (RR): percentage of complete remission (CR) and near CR (nCR) at day + 90 after ASCT; 2- clearance of Minimal Residual Disease (MRD) both in PBSC harvest and in bone marrow at day +90 after SCT; the percentage of plasma cells (PC) in PBSC harvested has been assessed by flow cytometry (FC), by using CD38, CD45, CD56, CD138, CD19, kappa and lambda staining. Patients receive three 3-weeks treatment cycles with BOR 1.3 milligrams/squared-meter/dose on days 1,4,8,11, in combination with DEX 40 milligrams/day i.v. on days 1,4,8,11 and CY i.v. 300 milligrams/squared-meter/dose on days 1,8,15. After the third course, patients achieving at least PR, undergo PBSC mobilization with BOR 1.3 milligrams/squared-meter/dose on days 1,4,8,11 in combination with DEX 40 milligrams/day i.v. on days 1,4,8,11 and CY i.v. 3000 milligrams/squared-meter/dose on day 8; Granulocyte-Colony Stimulating Factor (5 micrograms/kilogram) is given starting on day 9. Patients who successfully mobilize an adequate PBSC amount are planned to receive conditioning regimen, combining high-dose MEL(on day -1) with BOR (1.3 milligrams/squared-meter/dose on days -8 and -4). At present 10 patients (6 female and 4 male; median age: 71) have been enrolled and 8 are evaluable for response before PBSC harvest; 4 patients have been mobilized: in all of them we were able to collect a sufficient PBSC amount (median 11.1; range 3–11.2 CD34+ cells/kilograms) and to perform ASCT. Conditioning was well tolerated and was followed by quick engraftment: the median time to neutrophils>500/mcl was 9 days and 12 days for unsupported platelets count>20,000/mcl, without major extrahematological toxicity. With a minimum follow-up of 90 days after ASCT, 3 evaluable patients are alive, two in VGPR and one in CR; with a median follow up of 108 days (range 95–201) all 10 patients are alive and 100% of the evaluable patients achieved at least PR after only 2–3 courses of CY-BOR (table 1). The hematological toxicity was negligible and we did not observe neither thromboembolic events nor grade 3–4 neurotoxicity. Only one patient experienced a transient increase of liver enzymes during the first two courses of therapy. The study of MRD by flow cytometry in PBSC harvest of two evaluable patients shows complete clearance of plasmacells; in the others the MRD study is still ongoing and complete data will be further presented. This preliminary experience shows that this schedule is well tolerated and very effective also in elderly patients, allowing to collect a clonal plasmacells free harvest. Whether this will translate in an “in vivo” MRD clearance after ASCT, it should be confirmed by a longer follow up and by a PCR monitoring with patients specific probes (which is still ongoing). Pts UPN Age Sex Stage ISS Previous lines of treatment Response before PBSC mobilization Harvest: CD34+ cell amount SCT Status at last Follow-up 1 59 F III A III 1 nCR 3,99×106/kg Yes A&W (CR) 2 68 M III B III 2 nCR 11×106/kg Yes A&W (nCR) 3 73 F III A III 0 VGPR 11,2×106/kg Yes A&W (VGPR) 4 72 F III A II 1 VGPR 3×106/kg Yes A&W (VGPR) 5 69 M II A I 0 PR NE NE A&W 6 77 F III A II 1 PR NE NE A&W 7 52 M III A III 0 PR NE NE A&W 8 74 F III B II 2 VGPR. NE NE A&W 9 64 F II B II 3 N.E. NE NE A&W 10 73 M III A II 0 N.E. NE NE A&W Table 1: Baseline characteristics of patients and outcome Legenda: ISS: International Staging System; NE: not evaluable; A&W: alive and well; VGPR: very good partial remission

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

The Utility of Consolidative Upfront High Dose Chemoradiotherapy and ASCT in Patients with Mantle Cell Lymphoma (MCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2072-2072
Author(s):  
Daniel Persky ◽  
Carol S. Portlock ◽  
Simone Lessac-Chenen ◽  
Alexia Iasonos ◽  
Andrew D. Zelenetz ◽  
...  
Keyword(s):  
Bone Marrow Involvement ◽  
Conditioning Regimen ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Significant Difference ◽  
Dose Dense

Abstract Introduction: Two approaches to improve progression-free survival (PFS) in MCL are intensifying induction, as with hyperCVAD/M-A regimen, or intensifying consolidation with high dose chemoradiotherapy (HDT) and ASCT as in the prospective European MCL Network Trial. At MSKCC the strategy is to incorporate both approaches by administering an anthracycline-containing regimen in a dose dense fashion (CHOP- or R-CHOP-14) followed by consolidation with ICE (ifosfamide, carboplatin, etoposide) and HDT/ASCT. Patients: Forty six patients with newly diagnosed MCL underwent HDT/ASCT between 11/96 and 2/05. The median age was 55 years; 74% were male; 72% had bone marrow involvement, 39% had GI involvement, 7% were in leukemic phase, and 91% presented with stage IV disease. Splenomegaly was seen in 35%, B symptoms in 9%, KPS>70 in 93%, elevated LDH in 23%, and blastoid histology in 9%. Results: Induction was 4 to 6 cycles of CHOP-14 (43%), R-CHOP-14 (37%), or other doxorubicin-containing regimen (20%). Consolidation was performed with 2–3 cycles of ICE in 53% or R-ICE in 39%. Upfront treatment was well tolerated and permitted adequate stem cell collection and prompt transition to HDT/ASCT. Conditioning regimens were TBI/CY/VP-16 (59%) and BEAM (41%). Involved field radiation therapy was administered to 65%. Post-ASCT rituximab maintenance was given to 39%, with 57% of patients receiving rituximab as part of their treatment. Anthracycline-based induction led to CRu of 44% and ORR of 98%. Seventy two percent of patients were transplanted in CR, while the remaining 28% were in PR. At a median follow-up of 2.5 years (range 0.4–8.0 years) 17% of the patients have died and 24% have had progressive disease. The median OS and PFS have not been reached (lower 95% CI, 5.7 years and 4.4 years, respectively). The 5-year PFS and OS are 58% and 83%, respectively. The use of rituximab at any point during treatment prolonged PFS - only 1 of 26 patients receiving rituximab relapsed, as compared to 10 of 20 patients who were rituximab naive (p=0.03); thus far there is no significant difference in OS. There was no day 100 treatment related mortality. One patient developed bronchiolitis obliterans after ASCT and died of pulmonary fibrosis 6.5 years later; 3 patients have died of secondary cancers - one case each of MDS (1.6 years after ASCT), melanoma and lung cancer. Conclusion: These data provide evidence that dose-dense induction with CHOP-14 or R-CHOP-14 and consolidation with ICE/HDT/ASCT appears to be safe and effective, with minimal acute toxicity. Although the median follow-up is short, the use of rituximab appears to improve PFS. This contrasts with the findings of German LGLSG and may be a consequence of in vivo rituximab purging. Future therapy could incorporate all the successful elements of prior treatment programs, including R-CHOP-14, R-ICE, and radioimmunotherapy with high dose chemotherapy conditioning regimen, followed by ASCT and rituximab-based maintenance. PFS stratified by Rituximab PFS stratified by Rituximab

High Dose Therapy / ASCT with Rituximab for In-Vivo Purging and Post-ASCT Consolidation in Relapsed Follicular Lymphoma Achieves Prolonged Clinical and Molecular Remissions.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 914-914 ◽  
Author(s):  
Anthony C. Woods ◽  
Rena Buckstein ◽  
Joy Mangel ◽  
Kevin Imrie ◽  
David Spaner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Follicular Lymphoma ◽  
Patient Specific ◽  
High Dose ◽  
Molecular Remission ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Grade 3

Abstract High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is associated with prolonged remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT predicts durable remissions and is a desirable endpoint. Rituximab (R) as an in vivo purge prior to HDT/ASCT and as consolidation after ASCT may help achieve this. To study this question, patients with relapsed FL were enrolled in a prospective, non-comparative phase II study between January 1998 and April 2000. Methods: 23 consecutive patients age <65 yrs with <3 relapses underwent HDT/ASCT with CBV (Cyclophosphamide, BCNU and VP-16) following salvage with CHOP or DHAP. Patients achieving ≥75% reduction in bulk and <15% marrow involvement underwent stem cell mobilization with chemotherapy plus G-CSF 10 μg/kg daily x 5. R 375 mg/m2 was given as a single-dose purge prior to collection, and repeated as 4 weekly courses at 2 and 6 months post-ASCT. Samples for PCR detection of minimal residual disease (MRD) were taken from stem cell grafts, as well as blood and marrow for all patients with detectable disease at baseline. Response assessments were clinical, laboratory and radiologic, and analysis was intention-to-treat. Results: Median cohort age at assessment was 50 yrs (32–57). Median number of prior regimens was 3 (1–7) and total treatment cycles was 9 (3–28). Median response duration to the preceding regimen was 10 months (1–86). Transplants were a median 2.4 years after diagnosis. At median follow-up of 4.5 yrs (1.3–6.3), there have been 10 relapses at a median of 2.8 yrs. 3 patients have died, 2 with relapse and one of presumptive sudden cardiac death. Significant toxicities were seen: 11 episodes of pneumonia (1 fungal), 4 episodes of herpes zoster (1 grade 3), 4 early episodes of grade 3/4 interstitial pneumonitis, and 1 episode each of grade 4 TTP and grade 3 optic neuritis. One patient developed AML at 4.7 years post-ASCT. Immune recovery has been delayed; at 600 days post ASCT, 16/18 (89%) of evaluable patients had not recovered IgG levels to normal. At baseline, 12/23 patients had detectable markers by PCR analysis (sensitivity 0.01%) for t(14;18) or patient-specific VDJ rearrangements in marrow or blood. Of these, all achieved at least a brief molecular remission in blood and marrow, 11/12 doing so pre-R consolidation. 5/12 patients have since relapsed at a median 3 yrs (2–4.5) post ASCT. Molecular relapse preceded clinical in 3/5 cases. 6/12 have had prolonged (median 4.8 yrs, range 3–5) molecular and clinical remissions. Median event-free survival for all patients is 63 months, with median overall survival not reached. Conclusions: HDT/ASCT with R for in vivo purging and post-ASCT consolidation for relapsed FL is feasible and associated with prolonged clinical and molecular remission. Delay in recovery of humoral immunity may play a role in the high incidence of infectious complications. A single infusion of Rituximab for in-vivo purging did not eradicate PCR detectable disease in the graft, although sustained molecular remissions of at least 24 months were achieved in 75% of evaluable patients post transplant, possibly due to post ASCT Rituximab consolidation. Whether this translates into survival benefit will require longer follow-up and further comparative studies.

Radioimmunotherapy (90Y-Zevalin®) Combined with BEAM Conditioning Regimen and Autologous Stem Cell Transplantation for the Treatment of Non Hodgkin Lymphomas: Results of An Italian Multicenter Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1144-1144 ◽  
Author(s):  
Vincenzo Pavone ◽  
Anna Mele ◽  
Antonio Rana ◽  
Cosimo Del Casale ◽  
Anna Rita Messa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Treatment Plan ◽  
Conditioning Regimen ◽  
Haematological Toxicity ◽  
Significant Risk ◽  
High Dose

Abstract Radioimmunotherapy (RIT) with 90Y-Zevalin® combined with high dose therapy and autologous stem cell transplantation (ASCT) is gaing increasing importance for the treatment of relapsed or refractory non Hodgkin Lymphoma (nHL). We evaluated the feasibility and the clinical results of the addition of 90Y-Zevalin® at standard dose to BEAM regimen (Z-BEAM) in nHL pts who failed to achieve complete remission (CR) after previous chemoimmunotherapy. Methods. Between October 2005 and June 2008, 53 patients were enrolled in 11 italian centers. The treatment strategy is shown in figure 1. Salvage treatment consisted of 2 courses of R-DHAP. PBSCs were collected after mobilization with DHAP and G-CSF plus in vivo purging with Rituximab. Patients’ characteristics are shown in table 1. Results. The median CD34+ cells infused was 5.5 x10^6/Kilograms (range 2.55–34). All patients engrafted. The median number of red blood cell and platelet transfusion were 4 (1–7) and 6 (1–8), respectively. The median time to platelet and neutrophil counts higher than 20x10^9/L and 0.5x10^9/L were 14 (range, 9–60 days) and 10 days (range, 8–20), respectively. Mucosites occurred in all pts (grade III in 20 and grade IV in 5 patients). Febrile neutropenia occurred in 39 pts (74%). Eight pneumonitis and 12 blood stream infections, mainly by Gram+, were documented. One patient developed an atrial fibrillation. Five pts were not evaluable for response because too early. The 90-day overall response rate was 86% with 74% of CR. Three relapses (relapse rate 9%) and four progression were documented at a median follow-up of 247 days post Z-BEAM (range, 125–818). The potential factor to predict CR was: at last PR before Z-BEAM (p=0.06). Fourthy patients are alive at a median follow-up of 175 days post HST (range, 6–590): thirty pts in CR (57%), three pts in PR (5.5%), three pts in progressive disease (PD, 6%)(fig. 2). Fourtheen pts died (26%): 5 deaths due to TRM before day 90, 1 for ARDS (+230), 1 TRM post a subsequent RIC allotransplant (+95) and 6 due to PD (median follow-up 110 days, range 97–150). The Kaplan-Meyer estimated 3y-EFS is 64%. Five early deaths before day-90 occurred: 2 due to septic shock (day +6 and +39), 1 to pneumonitis (+22), 1 for BK viral encephalites (+61) and 1 to MOF (+14). The Kaplan-Meyer estimated Treatment Related Mortality (TRM) is 9.3%. Two statistically risk factors for 90-day TRM (p&lt;0.03) were documented: age elderly then 65 and non follicular lymphomas histology. Cox multivariate regression analysis demonstrated that age more than 65 is a significant risk factor for TRM (3.4% in pts aged less then 65 years and 21,05% in older pts; p&lt;0.01). Conclusion. In pts with different histology nHL, who failed to achieve CR after previous immuno-chemotherapy, RIT integrated with high-dose chemotherapy (Z-BEAM) is capable to induce 86% of ORR, 74% of CR and 3 ys EFS of 64%, with sustained engraftment and an acceptable extra-haematological toxicity, mainly restricted to pts older then 65 ys. The power of this program needs to be assessed in a larger series of patients and in a randomized fashion. Table 1: Patient Characteristics and 90-day response post HST Figure. 1 Treatment Plan Figure. 1. Treatment Plan

Combination Therapy with BCNU/Etoposide/Melphalan (BEM) as Conditioning Regimen for Autologous Stem Cell Transplant In Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4587-4587
Author(s):  
Shanshan Liu ◽  
Ann Mohrbacher ◽  
Dan Douer ◽  
Vishesh R Kothary ◽  
Lisa Hanna ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Conditioning Regimen ◽  
Autologous Stem Cell Transplant ◽  
Bone Lesions ◽  
High Dose ◽  
Cell Transplant ◽  
Lytic Bone Lesions

Abstract Abstract 4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic modality for MM patients. Traditionally high-dose single agent melphalan (200 mg/m2; Mel-200) has been used as the conditioning regimen prior to ASCT for MM. We investigated the combination regimen of BCNU, etoposide and melphalan (BEM) in this setting at our center. Methods: All patients who had undergone ASCT for MM utilizing BEM conditioning regimen at Norris Cancer Center, University of Southern California, Los Angeles were eligible. BEM consisted of BCNU 12 mg/kg (actual body weight or ideal body weight whichever was lower) iv on day -5, etoposide 60 mg/Kg iv on day -3, and melphalan 140 mg/m2 iv on day -1, prior to stem cell reinfusion on day 0. Overall survival (OS) was defined as time from MM diagnosis to death, or in patients still alive, the date of last follow-up. Progression-free survival (PFS) was defined as time from ASCT to date of relapse, or in patients without documented relapse, date of death or last follow up, whichever was sooner. Survival for patients with different clinical and disease-specific characteristics was explored using logrank test. Response was assessed according to International Uniform Response Criteria for MM. Results: A total of 44 MM patients underwent ASCT utilizing the BEM conditioning regimen. Of these, evaluable data was available for 42 patients (25 males; 60%, 17 females; 40%) with a median follow up of 27.6 mths. Median age at diagnosis was 54.5 yr (range 34–68) while median time from MM diagnosis to ASCT was 10.5 mths (range 2.8–47.8). MM subtypes included IgA (n=5, 12%), IgG (n=30, 71%) and light chain-only (n=7, 17%). Median bone marrow (BM) plasmacytosis at diagnosis was 42.5% (range 0%-100%). Durie-Salmon (DS) stages included stage I (12%), II (36%) and III (52%), while 4 patients (10%) had renal dysfunction at the time of initial MM diagnosis. Majority of the patients (71%) had lytic bone lesions at the time of diagnosis and 86% (n=36) hade secretory disease. Patients had received a median of 1 prior treatment (range 1–5), while 23 (55%) patients had received novel agents (proteasome inhibitors or IMiDs) prior to the BEM regimen. Response rates prior to and after the regimen are summarized in Table 1. After BEM-ASCT an additional 16 (38%) patients achieved a CR. Median duration of hospitalization and time to engraftment were 19 days (range 15–41) and 10.5 days (range 7–19), respectively. One patient died prior to discharge from the hospital post ASCT (Day 36 post ASCT) for a treatment related mortality of 2%. CR rate post BEM-ASCT was 64% with an ORR of 97%. Relapses have been noted in 25 patients to date. Median OS for all patients was 4.9 yrs (5.6 yrs for patients in CR and 6.6 yrs for patients in PR after BEM-ASCT). Median PFS was 23.9 mths for all patients (25 mths for patients in CR and 21.8 mths for those in PR after BEM-ASCT). No statistically significant differences were noted in OS based on patient gender (p=0.47), age at diagnosis (< or ≥60 yr), MM subtype (p=0.52), DS stage at diagnosis (0.09), patients without lytic bone lesions at diagnosis (p=0.054), secretor status (p=0.2), response status at the time of BEM-ASCT (p=0.9) or prior exposure to novel agents (p=0.62). Conclusions: BEM is a well-tolerated conditioning regimen prior to ASCT in MM and has efficacy comparable to Mel-200. BEM can be effectively employed in patients where Mel-200 is not feasible. We are particularly intrigued by its ability to deliver high CR rates (64%) compared to <30% (historical control). Very encouraging median OS (4.9 yr) and PFS (23.9 mth) rates were noted which were even better in patients who had a measurable response after this regimen. Further investigations will be needed to optimally define its potential as standard conditioning regimen in MM patients undergoing ASCT. Disclosures: No relevant conflicts of interest to declare.

PK-Directed Intravenous Busulfan In Combination With High-Dose Melphalan and Bortezomib As Conditioning Regimen For Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5513-5513
Author(s):  
Stefan K Barta ◽  
Amitabha Mazumder ◽  
Jason Carter ◽  
Lawrence Almanzar ◽  
Richard Elkind ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Conditioning Regimen ◽  
High Dose ◽  
Cell Transplant ◽  
Treatment Dose ◽  
Gi Symptoms ◽  
High Dose Melphalan

Abstract Introduction High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2; Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. Methods Patients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov (NCT01605032). Results To date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. Conclusion PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures: Barta: Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma.

Engraftment and molecular monitoring of CD34+ peripheral-blood stem-cell transplants for follicular lymphoma: a pilot study.

1997 ◽  
Vol 15 (6) ◽  
pp. 2288-2295 ◽  
Author(s):  
I G McQuaker ◽  
A P Haynes ◽  
S Anderson ◽  
C Stainer ◽  
R G Owen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pilot Study ◽  
Follicular Lymphoma ◽  
Peripheral Blood ◽  
Blood Stem Cell ◽  
High Dose ◽  
Nested Polymerase Chain Reaction ◽  
Cd34 Selection

PURPOSE A pilot study to validate the use of CD34+ selection (Ceprate SC) of blood stem-cell collection in patients with advanced follicular lymphoma receiving myeloablative chemoradiotherapy. PATIENTS AND METHODS Seventeen patients were entered onto the protocol. Thirteen of 17 patients have undergone transplantation; the median age is 42.5 years (range, 33 to 51), seven of 13 are stage IVB, two stage IVA, three stage IIIB, and one stage IIB. All except two patients were treated after first or subsequent relapses after receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to achieve a good partial (six of 13) or complete (seven of 13) response before stem-cell mobilization with cyclophosphamide 3 g/m2 and filgrastim 300 microg once daily. RESULTS Eleven of 13 patients had a detectable t(14;18) by nested polymerase chain reaction (PCR). Median CD34+ count before selection was 2.9 x 10(6)/kg (range, 1.17 to 11.3) and after CD34+ selection was 1.54 x 10(6)/kg (range, 0.88 to 7.6) with a median CD34+ yield of 62.4% (range, 17% to 95%) and purity of 60% (range, 39.3% to 73%). Of the 11 patients known to have t(14;18), 10 had PCR-detectable contamination of stem-cell harvests that became PCR negative in six of the 10 after CD34+ selection. Engraftment was rapid with a median day to absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L of 13 days (range, 11 to 21) and platelet count greater than 20 x 10(9)/L of 14 days (range, 10 to 44). With a median follow-up duration of 15 months, three patients have remained persistently PCR-positive, two of whom received PCR-positive stem cells. Two have relapsed. Of the seven patients who received PCR-negative stem cells, five have had no PCR-detectable disease in posttransplant bone marrow samples. CONCLUSION Longer follow-up duration is required to determine the significance of these findings, but we have confirmed the feasibility of CD34+ selected cells to deplete peripheral-blood stem cells of tumor cells from patients undergoing high-dose therapy for follicular lymphoma.

Palifermin Treatment in Patients Receiving High Dose Melphalan or BEAM Prior to Autologous Peripheral Blood Stem-Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5241-5241
Author(s):  
Anne Sonet ◽  
G. Bries ◽  
N. Meulemans ◽  
A. Van Hoof ◽  
E. Steel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Peripheral Blood Stem Cell ◽  
Conditioning Regimen ◽  
Opioid Analgesics ◽  
High Dose ◽  
Conditioning Regimens ◽  
Autologous Pbsct ◽  
Blood Stem Cell Transplantation

Abstract Background. Oral mucositis (OM) is a common complication of high-dose (HD) chemotherapy conditioning regimens used with peripheral blood stem-cell transplantation (PBSCT). Severe grades of OM are associated with higher morbidity such as infections, need for total parenteral nutrition (TPN), opioid analgesics and prolonged hospitalization and has been historically underreported. Recent epidemiology reveals an incidence of severe OM of 50–60%. Moreover, OM is reported by patients as the worst and most debilitating complication of PBSCT. The keratinocyte growth factor, palifermin, stimulates the growth, differentiation, migration, and survival of epithelial cells. Palifermin is now approved in the US and the EU to decrease the incidence, duration, and severity of OM in patients (pts) with hematological malignancies requiring autologous PBSCT. Objective. This report describes the treatment of 60 pts who received palifermin through an early access program in Belgium. We evaluated the effect of palifermin on OM in pts with multiple myeloma or non-Hodgkin’s lymphoma receiving HD melphalan (HD Mel) or BEAM conditioning regimen, respectively, prior to autologous PBSCT. Methods. The pts received palifermin (IV bolus: 60 μg/kg/day) for 3 days before and 3 days after HD Mel or BEAM. The common OM prevention strategy included basic oral hygiene, mouth washes and oral cryotherapy during HDM administration (n=9). For each patient, follow-up data were collected on mucositis grading, duration of hospitalization, neutropenic fever, treatment with G-CSF, IV antibiotics, opioids, and TPN. The grade of OM during treatment was assessed according to the WHO oral-toxicity scale (grade 0 to 4). Drug-related adverse events were also recorded. Results. Thirty pts received HD Mel and 30 pts received BEAM before PBSCT. All 60 pts received at least 3 palifermin bolus injections; the scheduled doses (6 bolus) were administered to 55 (91%) of 60 pts. Analysis of the follow-up data revealed that 10 (16%) pts experienced no OM. Furthermore, a low incidence (31%) of severe (grade 3 and 4) OM was observed with each conditioning regimen. The median duration of severe OM with the HD Mel regimen was 7 days (range 3–27) contrasting with a median OM duration of 3 days (range 2–12) with the BEAM regimen. Two pts in each regimen required prolonged hospitalization due to OM. With either regimen, neutropenic fever and use of IV antibiotics were common (70% of pts), while bacteremia was infrequent (20% of pts). Myeloid growth factors were administered post PBSCT to the majority of pts. Forty percent (40%) of HD Mel-treated pts and 26% of BEAM-treated pts required opioid analgesics. The percentages of pts receiving TPN were similar in the 2 conditioning regimens (66% of all pts). TPN was used in 16 (84%) pts with severe OM and in 24 (58%) pts with no or grade 1–2 OM. Adverse events clearly related to palifermin were reported in 25 (41%) of 60 pts. The most common adverse events included rash (18 events, 8 severe), disorders of tongue and oral mucosa (13 events, 2 severe), edema (10, no severe) and pruritus (7, no severe). Conclusions. These results indicate that palifermin use prior to HD Mel or BEAM and immediately following the transplantion may provide effective support in the prophylaxis of severe OM in pts undergoing autologous PBSCT, without major toxicity.

Activated B-Cell (ABC) Profile Does Not Have An Inferior Outcome Compared to Germinal Center B-Cell (GCB) Profile Determined by Immunohistochemistry Tissue Microarray in Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Rituximab and Dose- Dense and High-Dose Chemotherapy (HDC) Plus Autologous Stem Cell Transplantation (ASCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1139-1139
Author(s):  
Annalisa Chiappella ◽  
Domenico Novero ◽  
Alessandra Tucci ◽  
Maria Giuseppina Cabras ◽  
Anna Marina Liberati ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
B Cell ◽  
Tissue Microarray ◽  
Conditioning Regimen ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Dose Dense

Abstract Introduction: A specific molecular signature divides DLBCL into GCB and ABC profiles; in pre-Rituximab era, GCB group had a better prognosis. The addition of Rituximab (R) to chemotherapy improves the outcome in DLBCL. It remains uncertain the prognostic significance of GCB and ABC subgroups in Rituximab era. Patients and methods: from August 2000 to September 2006, 120 previously untreated patients &lt;61 years affected by DLBCL, at aa-IPI intermediate/high or high risk, were enrolled into a phase II GIMURELL trial: 4 courses of bi-weekly R-MegaCEOP14 (375 mg/m2 R on day 1, 1200 mg/m2 CTX + 110 mg/m2 EPI + 1.4 mg/m2 VCR on day 3 and 40 mg/m2 PDN days 3 to 7), 2 R-MAD (8 mg/m2 Mitoxantrone + 2 g/m2/12h Cytarabine + 4 mg/ m2/12h Dexamethasone days 1 to 3 and 375 mg/m2 R on day 4 and before peripheral blood stem cell harvest as in vivo purging) followed by ASCT with BEAM as conditioning regimen. Thus far, tissue microarray (TMA) blocks were created from 92 cases and they were studied in immunohistochemistry; sections were stained with antibodies to CD20, CD3, CD10, CD138, Ki67, Bcl6, Bcl2, MUM1 and cyclinD1. Patients were classified as GCB or non-GCB (ABC) according to the Hans’ algorithm. The samples were scored positive for CD10, Bcl-6 and MUM-1 if 30% or more of tumor cells were stained. Cases with the coexpression of CD10 and MUM-1 were classified as GC-activated according to Chang and grouped with GCB for analysis purpose. Crude Kaplan-Meier overall (OS) and event-free (EFS) survival curves were estimated both overall and stratified by TMA features. Differences between curves were tested using the 2-tailed log-rank test.. Results: 92 samples were centrally reviewed and studied in immunoistochemistry. Overall 69 were evaluable; 23 were excluded due to inadequate pathological materials in 16 and incorrect inclusion criteria in 7. Thirty-seven patients were classified as GCB, 24 as ABC and 8 as GC-activated. Patient characteristics were well balanced between GCB and ABC subtypes. With a median follow-up of 53 months, OS in all 92 patients was 81% (95% CI: 71% - 88%); at the same timeframe, OS in GCB was 77% vs 86% for ABC (p=.5). With a median follow-up of 46 months, EFS in all 92 patients was 74% (95% CI: 64% - 82%); at that time, EFS in GCB was 65% vs 87% for ABC (p=.2). Conclusions: Rituximab as adjuvant to dose-dense and HDC with ASCT support is effective in high risk DLBCL in both GCB and ABC subgroups. In this R-HDC+ASCT study ABC profile as determined by TMA does not represent a poor prognostic feature. However 25% of patients still experienced progression. Further and more detailed biological analysis are needed to better identify these patients.

A novel High dose chemotherapy strategy with Bendamustine in Adjunct to Etoposide, Aracytin and Melphalan (BeEAM) Followed by Autologous Stem cell rescue in Resistant/Relapsed Hodgkin and Non-Hodgkin Lymphoma Patients: a Phase I Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4351-4351
Author(s):  
Giuseppe Visani ◽  
Lara Malerba ◽  
Piero Galieni ◽  
Claudio Giardini ◽  
Sadia Falcioni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
High Dose Therapy ◽  
Stem Cell Rescue ◽  
Relapsed Lymphoma ◽  
Autologous Stem Cell Rescue ◽  
Grade Iii

Abstract Abstract 4351 We designed a phase I study to evaluate the safety and the efficacy of increasing doses of Bendamustine, coupled with fixed doses of Etoposide, Cytarabine and Melphalan in the conditioning regimen to autologous stem cell transplant for resistant/relapsed lymphoma patients. Nine patients (median age 54 years, range 18-70) with resistant/relapsed non-Hodgkin's (6) or Hodgkin's (3) lymphoma were consecutive enrolled in the study, starting from August, 1st 2008. The new conditioning regimen (BeEAM) consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of three patients each were treated starting with Bendamustine 160 mg/m2 given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected maximum tolerated dose, but not higher than 200 mg/m2. Patients were carefully monitored for any adverse event, particularly for cardiotoxicity. Electrocardiography and troponin monitoring was performed at baseline and thereafter at 24, 72 and 96 hours after the two-days Bendamustine administration. The administration of Bendamustine was safe in all the three cohorts of patients. No grade III or IV non hematological toxicities were observed at any dose of the drug. In particular, we did not observe any grade III-IV cardiotoxicity. All patients engrafted, with a median time to ANC>0.5×109/l of 11 days (range: 11-27). Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 15 days respectively. Six out of 9 patients experienced an episode of FUO (66%), whereas 1/9 (11%) presented a bacteriemia. However, the median number of days with fever was 2 (range: 0-5), with a median number of 9 days of intravenous antibiotics (range: 3-22). All patients received G-CSF after transplant for a median time of 8 days (range: 8-24). At the time of writing all patients are alive and in complete remission, after a median follow-up of 5 months from transplant. It is of note that 2/9 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue. However, the small number of the patients and the short duration of follow-up might be taken in account when analyzing these preliminary data. In conclusion, the new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Further studies are warranted to compare the efficacy of this new regimen with the conventional BEAM regimen for resistant/relapsed lymphoma patients submitted to ASCT. All the future studies who want to incorporate Bendamustine on such conditioning regimens for ASCT in lymphoma patients should use Bendamustine at a dose of 200 mg/m2 daily given overt 2 days. The study was conducted in accordance with the principles of the Helsinki Declaration, Good Clinical Practices and the current National Rules for conducting clinical studies. The study was registered at European Medicines Agency (EMEA) with the EUDRACT no 2008-002736-15. Acknowledgments We kindly acknowledge Mundipharma Italy and Mundipharma Europe for providing us the drug for the study free of charge. The study was supported in part by AIL Pesaro Onlus, Disclosures: Off Label Use: Bendamustine is used in adjunct to etoposide, cytarabine and melphalan in a novel strategy of high-dose therapy followed by autologous stem cell rescue.

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