scholarly journals Modified High Dose Versus High Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Camille V Edwards ◽  
Dina Brauneis ◽  
Karen Quillen ◽  
Vaishali Sanchorawala
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Older Patients ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Board ◽  
High Dose ◽  
Al Amyloidosis ◽  
Free Survival

Introduction: High dose melphalan and autologous stem cell transplantation (HDM/SCT) results in deep and durable responses and prolonged survival in highly selected patients with systemic immunoglobulin light chain (AL) amyloidosis. HDM/SCT is offered to select patients >65 years but melphalan dose is often reduced due to concerns for tolerability and toxicities in older patients. However, older adults are a diverse population and chronological age alone does not accurately predict chemotherapy tolerance. While both melphalan 140 mg/m2 (MEL-140) and 200 mg/m2 (MEL-200) are commonly used in clinical practice, there are very few studies comparing these two doses in older patients. Available studies suggest that MEL-140 may be associated with worse event-free survival and progression-free survival, but it is unclear whether this is confounding for increased co-morbidities and frailty in this group. We report transplant-related toxicities and outcomes in patients >65 years undergoing first HDM/SCT with MEL-140 versus MEL-200 within 12 months of diagnosis of AL amyloidosis. Methods: We analyzed transplant-related toxicities and outcomes of patients >65 years who received first HDM/SCT within 12 months of diagnosis between January 2011 and June 2020. We excluded patients receiving additional conditioning agents and those undergoing tandem or second transplantation. Patients were stratified based on melphalan dose. All statistical analyses were performed using GraphPad Prism version 8©. Independent (unpaired) t tests with unequal variance and a 95% confidence interval were used to calculate the two-tailed p values for continuous variables. Chi-squared tests were used to compare categorical variables. Hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (CI) and p values are reported. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and log-rank tests were used to compare the survival measurements of each group. In this cohort, PFS was defined as the time from SCT to hematologic progression, next line of therapy and/ or death, whichever came first. Transplant-related mortality was defined as death occurring within 100 days of SCT. Results: Forty patients were included in the final analysis with a median follow up of 55.0 months (range 7 - 109, n = 18) for surviving patients in both groups. Table 1 displays patient and disease characteristics, transplant-related toxicities, 2-year PFS and median OS. Patients receiving MEL-140 were older (69 versus 66 years, p <0.0001) and more likely to be male (82.6% versus 47.1%, p 0.0383). Karnofsky performance status (KPS) was similar in both groups. Median number of organs involved was 2 with 91.3% and 82.4% of patients having renal involvement in the MEL-140 and MEL-200 groups, respectively. For patients who underwent induction therapy with anti-plasma cell agents, 22.2% treated with MEL-140 and 50.0% treated with MEL-200 were in >VGPR prior to HDM/ SCT (p 0.3348). There was no transplant-related mortality observed in either group. Severe transplant-related toxicities (grade >3) were reported in 88.2% of the MEL-200 group versus 72.7% of the MEL-140 group (p 0.4260) but the frequency of various toxicities were different. Patients who underwent conditioning with MEL-200 were significantly more likely to experience febrile neutropenia, sepsis and infections (88.2%, n = 15 versus 50.0%, n = 11; OR 0.13, 95% CI 0.03 - 0.73, p 0.0173 [Table 2]). Notably, the 2-year PFS was almost twice as long in the MEL-200 group (82.5% versus 42.6%, p 0.0534 [Figure 1]). The median PFS was 12.1 months in the MEL-140 group but was not reached in the MEL-200 group. There was no difference in median OS among the two groups (not reached, p 0.1454). Conclusion: Our study results suggest that highly selected patients ≥65 years with good performance status can safely undergo melphalan at a dose of 200 mg/m2 prior to stem cell transplantation in AL amyloidosis although there may be an increased risk of febrile neutropenia, sepsis and infections. Additionally, the melphalan conditioning dose 140 mg/m2 is potentially associated with a significantly shorter progression-free survival than 200 mg/m2 in older patients undergoing HDM/SCT for AL amyloidosis. Disclosures Sanchorawala: Takeda: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Prothena: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

High Dose Intravenous Busulfan (BU) and Melphalan (MEL) Followed by Bortezomib (BTZ) as Conditioning with Autologous Peripheral Blood Stem Cell Transplantation (ASCT) for Patients with Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1355-1355
Author(s):  
Tulio E. Rodriguez ◽  
Patrick J. Stiff ◽  
Scott E. Smith ◽  
Jonathan L. Kaufman ◽  
Mary Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Interstitial Pneumonitis ◽  
Research Funding ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Preparative Regimen

Abstract Abstract 1355 Background: Overall survival for patients with MM has improved significantly over the past 10 years primarily as a result of novel therapeutics. High dose therapy with ASCT continues to be an effective modality but the progression-free survival following ASCT has improved minimally over the same period of time due to a continued reliance on single agent melphalan. Many chemotherapy/chemoradiotherapy regimens have been used in preparation for stem cell transplantation. However, no regimen has proven superior to high dose melphalan 200 mg/ m2 (MEL 200) which is considered the standard conditioning for patients with MM with relatively predictable results. In order to improve progression free survival (PFS) and overall survival (OS), continued efforts in developing effective preparative regimens are needed. Busulfan is an alkylating agent that affects cells in an AUC-dependent manner. Recent data suggests that the combination of BU and MEL delivers better PFS compared to MEL 200 alone (Grande and Lahuerta; PETHEMA, 36th EBMT meeting. Vienna 2010). Moreover, the addition of bortezomib following MEL 200 appears to increase the VGPR rate when compared to historical cohort receiving MEL 200 alone (Lonial, et al; Blood. ASH Annual Meeting Abstracts, Nov 2008; 112: 3332). Furthermore, the recently published IFM trial of MEL 200 plus BTZ also demonstrated superior response rates and PFS compared to historical controls (Roussel et al Blood. 2010;115:32-7). Rationale: The combination of intravenous BU and MEL followed by BTZ (BuMelVel) will be an effective preparative regimen with acceptable toxicity for patients with MM. Methods: Patients received intravenous BU 130 mg/kg over 3 hours daily × 4 days from D-6 to D-3. Based on the pharmacokinetics of the first two doses, the subsequent 2 doses were adjusted to achieve an AUC of 20,000 mMol-min (5,000 mMol-min/day). MEL was administered at 140 mg/ m2 IV over 15–30 minutes on day -2. Bortezomib was administered IV push over 3–5 seconds on day -1. Bortezomib administration followed a phase I dose escalation design starting at 1.0 mg/m2 for the first cohort; then, 1.3 mg/m2 for the second cohort; then, 1.6 mg/m2/kg for the 3rd cohort and subsequent subjects at the 3rd dose level if no limiting toxicity was observed. Autologous stem cell infusion occurred on day 0. Results: 20 patients have been enrolled to date, with 19 evaluable for toxicity and 13 for response assessment at D +100. The median age is 61 (47 - 69). The median time for engraftment for ANC ≥ 500 and plts ≥ 20, was 10 days. The median length of stay (LOS) was 18 days (16 – 21 days). 12 patients required a median of 2 units of PRBC and 16 patients required a median of 1 platelet transfusion. PRBC and PLT transfusions as well as LOS are not significantly different to what has been observed at our institution with MEL 200 (2 PRBC, 2 RD PLT transfusions, and 15 days LOS, respectively). All patients responded including: 77% ≥ VGPR and 54% nCR, CR, or sCR. The most common grade ≥ 3 toxicities were neutropenic fever (n = 11), mucositis (n = 9), and hypophosphatemia (n = 7). Three patients developed reversible transaminitis. One patient developed Clostridium difficile colitis and Klebsiella pneumonia UTI. Another patient developed E. coli UTI. No cases of VOD or interstitial pneumonitis were observed. There were no treatment related deaths and no re-admissions post discharge. Conclusion: BuMelVel proved to be an effective preparative regimen with ≥ VGPR and nCR/CR/sCR of 77% and 54%, respectively, as compared to responses reported with MEL/BTZ (70% and 32%, respectively); and to MEL 200 alone (43% and 11%, respectively) by Roussel et al. Furthermore, BuMelVel had an acceptable toxicity profile without any cases of VOD or interstitial pneumonitis, and mucositis/infections incidence and severity are comparable to our institutional experience with MEL 200. Therefore, the regimen of BuMelVel may lead to improvements in PFS and OS, critical criteria to improve the outcomes of patients with MM. These promising results will be further evaluated in a planned Phase III clinical trial with MEL 200. Disclosures: Rodriguez: Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau.

Reduced Intensity Allogeneic Stem Cell Transplantation for Mantle Cell Lymphoma Is Associated with Substantial Late Transplant Related Mortality and a Poor Outcome in Patients with Chemoresistant Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2260-2260 ◽  
Author(s):  
Stephen P. Robinson ◽  
Norbert Schmitz ◽  
Goli Taghipour ◽  
Anna Sureda
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell ◽  
Reduced Intensity ◽  
Related Mortality

Abstract The prognosis for patients with mantle cell lymphoma (MCL) treated with conventional chemotherapy remains poor. Dose escalation and stem cell transplantation has been increasingly employed in an attempt to improve the outcome in these patients. However, due to the advanced age of many patients with MCL, high dose therapy and allogeneic stem cell transplantation is particularly hazardous. Reduced intensity allogeneic transplantation (RIT) may reduce the toxicity of allogeneic stem cell transplantation, facilitate allogeneic engraftment and graft versus lymphoma reactions. However, the results reported to date with this treatment modality have been based on small numbers of patients and provide conflicting results. We have therefore analysed the outcome of a large cohort of patients with MCL reported to the EBMT registry who have undergone RIT. A total of 144 patients (123 male) with a histological diagnosis of MCL were reported by 81 centres. The median age at transplant was 49 years (range 28–68 years) and the median time from diagnosis to transplant was 25 months (range 0.25–13.2 years). The patients had received a median of 2 (range 1–5) lines of prior chemotherapy and 60 (42%) had undergone a prior high dose procedure. At the time of RIT 100 patients had chemosensitive disease, 22 chemoresistant disease and 22 had untested relapse. Patients underwent conditioning with reduced intensity regimens prior to transplantation with allogeneic peripheral blood stem cells (122), bone marrow (20) or both (1). Fully matched sibling donors were used in 109 cases, matched unrelated donors in 21 and 9 patients received mismatched stem cells. 123 of 126 patients assessable for engraftment demonstrated sustained engraftment. With a median follow up of 9 months 84 patients remain alive and 60 have died (15 from progressive disease and 45 from non-relapse mortality). The transplant related mortality (TRM) was 12% at 100 days but by Kaplan-Mier analysis the TRM was 35% at 1 year and 50% at two years. In univariate analysis there was a non-significant trend to a higher TRM in patients with chemoresistant disease (p=0.067) and those with a prior transplant (p=0.062). Patient age and the number of lines of prior therapy had no impact on TRM. At two years following transplant 57% of patients had evidence of disease relapse or progression which was significantly worse in those with chemoresistant disease prior to transplant (p=0.02). The overall survival (OS) at 1 year and 2 years was 55% and 31% respectively and was worse for patients with chemoresistant disease. The progression free survival (PFS) at 1 and 2 year was 43% and 26% respectively. Only disease status at transplantation predicted for a worse PFS. Acute GVHD (grade II-IV) developed in 52 patients and chronic GVHD in 23 patients. Although the early transplant related toxicity is low there remains a significant TRM following RIT for MCL and consequently a low progression free survival. Patients with chemoresistant disease have a particularly poor outcome.

Pretransplant hemoglobin and serum creatinine levels correlate with progression free survival in myeloma patients undergoing autologous stem cell transplantation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19532-e19532
Author(s):  
Taner Demirer ◽  
Guldane Cengiz Seval ◽  
Selami Kocak Toprak ◽  
Sinem Civriz Bozdag ◽  
Meltem Kurt Yuksel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Serum Creatinine ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
The Impact

e19532 Background: High dose melphalan and autologous stem cell transplantation (ASCT) significantly prolong survival for patients with multiple myeloma (MM). The purpose of this study is to assess the effects of hemoglobin (Hgb) and serum creatinine (Crea) values at the time of transplantation on the overall outcome of patients with multiple myeloma treated at our transplant center. Material & Methods: This analysis included 247 consecutive patients who underwent ASCT for MM between 2010-2016. Hemoglobin was grouped as low or high relative to their sample median. Patients were also stratified according to serum Crea value at the time of transplantation ( < 2 or ³2 mg/dl). Results: The median age was 57 (29-75) years and most patients were male (n = 151, 61.1%), IgG subtype (n = 124, 50.2%), and ISS stage 3 (n = 122, 49.4%). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). The most commonly induction regimens included VAD (vincristine, doxorubicin and dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), respectively. Since maintenance was not an approved treatment in myeloma most patients did not receive any. For the entire cohort, the median Hgb and Crea were 11.5 g/dL and 0.9 mg/dL respectively. No difference in progression free survival (PFS) was observed between a lower and higher Hgb (82 vs. 81 months, p = 0.96). However, the median PFS was significantly longer in patients with a lower Crea compared to those with a higher Crea (83 vs. 48 months, p = 0.01). Patients with both a lower hemoglobin and higher Crea experienced shorter PFS compared to those with a higher hemoglobin and lower Crea (45 vs. 82 months, p < 0.001). We failed to demonstrate the impact of creatinin levels on time to neutrophil and platelet engraftment. There were no differences in OS according to lower vs. higher Hgb (58 vs. 52 months; p = 0.29, respectively) but in higher crea cohort worse OS was observed (41 months vs. 57 months; p = 0.02, respectively). Conclusions: We demonstrate that hemoglobin and creatinine represent important determinants of clinical outcomes after ASCT. A lower hemoglobin and higher creatinine, individually and when combined, were associated with shorter PFS. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant Hgb and Crea levels on ASCT outcomes.

The Survival of Multiple Myeloma Patients: A Single Institution Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5223-5223
Author(s):  
Zwi N. Berneman ◽  
An-Sofie Verstraete ◽  
Alain Gadisseur ◽  
Ann Van de Velde ◽  
Wilfried A. Schroyens
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Conventional Chemotherapy ◽  
Free Survival

Abstract Background: For a long time, multiple myeloma has been a disease with a poor outcome. High dose (melphalan) chemotherapy followed by autologous stem cell transplantation has been reported to improve the overall and progression-free survival of these patients. Objective: To determine the survival of multiple myeloma patients treated with conventional chemotherapy and compare it with that of patients treated with high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. Design/Methods: 83 myeloma patients treated at a single institution were included in this retrospective study. They were divided into two groups: one group of patients who were received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (n=42) and one group of patients who only received conventional chemotherapy and were eventually also treated with thalidomide and/or corticosteroids (n=41). The distribution of the stages of the disease according to Salmon and Durie were similar in both groups of patients. For both groups, the overall and progression-free survival was calculated. Results: In the general analysis, myeloma patients who underwent an autologous transplant had a significantly longer overall survival (58.8 vs. 52.2 months, p=0.036) and progression-free survival (39.6 vs. 11.8 months, p &lt; 0.001) in comparison with the conventional chemotherapy group. If analysis was restricted to those patients who were transplanted as a first-line treatment, there was no significant difference in overall survival in comparison with conventional chemotherapy (51.8 vs. 52.2 months, p= 0.422); progression-free survival was significantly better in the first-line transplant arm as compared to the conventional chemotherapy arm (35.4 vs. 11.8 months, p= 0.003). As the median age in the transplant arm was significantly lower than in the conventional chemotherapy arm, we also performed a sub-analysis of patients who were between 60 and 70 years of age at diagnosis; there was no significant difference in overall survival between the two groups (60.7 vs. 69.5 months, p= 0.656), while the progression-free survival was again better in the autologous transplant group as compared to the conventional chemotherapy group (41.0 vs. 8.4 months, p= 0.020). Conclusion: High-dose chemotherapy and autologous stem cell transplantation in the treatment of myeloma is associated with improved progression-free survival and in the general analysis, with improved overall survival. The overall survival of patients who were only treated with conventional chemotherapy is somewhat higher (more than 4 years) as compared to that of historical controls (2–3 years).

Double Induction Containing Two Courses Versus One Course of High- Dose AraC/ Mitoxantrone (HAM) and Autologous Stem Cell Transplantation Versus Prolonged Maintenance for Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 272-272
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Older Patients ◽  
De Novo ◽  
High Dose ◽  
Age Group ◽  
Relapse Free Survival ◽  
Free Survival

Abstract Intensification by high-dose araC in post-remission (NEJM331:896,1994) or induction (Blood87:1710,1996; Blood88:2841,1996) therapy, and autologous stem cell transplantation (Lancet351:700,1998) are efforts to improve the cure rate in AML. Starting in 1999 the German AMLCG randomized the patients to receive double induction (Blood93:4116,1999) by TAD- HAM (TAD, standard dose thioguanine/araC/daunorubicin; HAM, high-dose araC 3 (age &lt;60y) or 1 (age 60+y) g/m2 x 6 with mitoxantrone) versus HAM-HAM. The 2nd course was initiated on day 21 in all patients of &lt;60 years and in those older patients with residual b.m. blasts. By the same up-front randomization patients &lt;60 years were assigned to post-remission BuCy myeloablative chemotherapy and autologous stem cell transplantation, or to prolonged maintenance by monthly reduced TAD courses (JCO21:4496,2003), whereas all patients of 60+ years went on to maintenance. Each of the two initial randomizations was balanced for the other, and was also balanced for age, de-novo versus secondary AML/high-risk MDS, cytogenetic groups (favorable, intermediate, unfavorable), LDH, and WBC. A total of 1770 patients entered the trial with 840 patients of &lt;60 years and 930 patients of 60+ years, 1324 patients with de-novo AML, 295 patients with AML after MDS, 97 patients with tAML, 54 patients with high-risk MDS. The outcome in the younger and older patients was 70% and 53% CR, 42% and 19% overall survival at 3 years, 40% and 19% relapse-free survival, and 47% and 23% ongoing remissions. The calculated dosage of araC delivered for remission induction differed by factor 2 within each age group. There was, however, no difference in the CR rate, overall survival, relapse-free survival, or remission duration between the two randomized induction arms in any age group. Furthermore, there was no such difference in any risk group defined by de-novo or other AML, favorable or intermediate or unfavorable karyotype, WBC, LDH, and day 16 residual b.m. blasts. Similarly, the randomization to autologous transplantation versus maintenance failed to produce different outcome in any prognostic subgroup. These findings were even true after adjustment for allogeneic stem cell transplantations which were performed with priority in patients having matched family donors. In conclusion, on the basis of age adapted TAD-HAM double induction and prolonged maintenance the cytotoxic potential may have been exhausted and may not be further escalated in any prognostic group of AML. Only novel targeted chemotherapy and optimized conditioning allogeneic stem cell transplantation is expected to contribute additional curative potential to current management for AML.

Pharmacokinetic Dose Guidance of IV Busulfan with Fludarabine with Allogeneic Stem Cell Transplantation Improves Progression Free Survival in Patients with AML and MDS; Results of a Randomized Phase III Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 892-892 ◽  
Author(s):  
Borje S Andersson ◽  
Marcos J de Lima ◽  
Rima M Saliba ◽  
Elizabeth J Shpall ◽  
Uday Popat ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Research Funding ◽  
Progression Free Survival ◽  
Fixed Dose ◽  
Free Survival ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 892 The myeloablative, reduced toxicity regimen, IV Busulfan (Bu) and fludarabine (Flu), is effective conditioning for allogeneic stem cell transplantation for treatment of patients with AML and MDS. We performed a prospective randomized study to optimize the antileukemic cytoreduction of this regimen, testing the hypothesis that pharmacokinetically (PK-) guided IV Bu-dosing to an average daily AUC of 6,000 μMol-min yields improved leukemia-free survival compared with a fixed IV Bu dose of 130 mg/m2, which gives a median AUC of approximately 5000 μMol-min. The study was approved by the M.D. Anderson Cancer Center IRB and all patients provided informed consent. 139 patients were in a first or second complete remission (CR), 86 were not in remission, including patients with marrow remission but with incomplete hematologic recovery (CRi) or with active disease. Median age was 50 years (range 13–65). 51% received a transplant from a related donor and 49% had unrelated donors. 28% patients received bone marrow and 72% PBPC grafts. Disease characteristics are summarized in the following table. Median follow-up of surviving patients was 25 months (2–66). The patients receiving PK guided busulfan dosing had significantly better progression free survival at 3 years than the fixed dose group, 56% (45–66%) vs. 42% (32–52%) P=0.03, as well as lower cumulative incidence of progression 23% (16–34%) vs. 35% (27–46%) p=0.03. Overall survival at 3 years for the two groups was 57% (46–68%) vs 47% (36–57%) p=0.2. The greatest effect was seen in patients not in remission at the time of transplant. The cumulative incidence of disease progression for the PK Guided and Fixed dose groups was 20% and 25% in patients transplanted in remission (P=0.5), and 29% and 50% for patients transplanted not in remission (P=0.03). Major outcomes are summarized in the following table. There was no significant difference in toxicity pattern, incidence of acute GVHD or treatment related mortality between the PK-guided/adjusted and fixed- dose groups. In multivariate analysis, poor risk cytogenetics and flt3 mutation was associated with inferior PFS. In conclusion, administration of higher dose intravenous busulfan using pharmacokinetic dose guidance targeting an AUC of 6000 μMol-min combined with fludarabine improved progression free survival in patients undergoing allogeneic stem cell transplantation for treatment of AML and MDS, without increasing the risks for serious toxicity and treatment-related mortality. Disclosures: Andersson: Otsuka: Consultancy, MD Anderson Cancer holds a patent on busulfan. Off Label Use: Busulfan for conditioning for AML. Popat:Otsuka: Research Funding. Jones:Otsuka: Membership on an entity's Board of Directors or advisory committees. Nieto:Otsuka Corp: Research Funding. Kebriaei:Otsuka: Research Funding. Worth:Otsuka Corp: Research Funding. Champlin:Otsuka Corp: Research Funding; NCI CA55164: Research Funding.

Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer

2006 ◽  
Vol 24 (24) ◽  
pp. 3919-3926 ◽  
Author(s):  
Nicolaus Kröger ◽  
Markus Frick ◽  
Oleg Gluz ◽  
Svjetlana Mohrmann ◽  
Bernd Metzner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Metastatic Breast Cancer ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival

Purpose To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. Patients and Methods Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. Results One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. Conclusion Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Resistance, Outcome and the Development of Mutations with Dasatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1122-1122 ◽  
Author(s):  
Neil Shah ◽  
Erkut Bahceci ◽  
Alexandre Lambert ◽  
Lynn Ploughman ◽  
Jerald Radich
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Once Daily ◽  
Free Survival ◽  
Loss Of Response ◽  
New Mutations

Abstract Abstract 1122 Poster Board I-144 Dasatinib is an FDA approved tyrosine kinase inhibitor (TKI) targeted at BCR-ABL for the treatment of CML after imatinib resistance or intolerance. A phase III dose-optimization study of dasatinib in CML-CP, where patients received either 100 mg or 140 mg of dasatinib on a once- or twice-daily schedule, indicated that 100 mg once daily dasatinib provided durable disease control with an estimated progression-free survival (PFS) of 73% at 36 months. We conducted a retrospective analysis to expand on these results to determine if earlier cytogenetic response (CyR) predicts superior outcomes within this dosing arm and also to quantify progression to advanced-phase CML and characterize the quality of BCR-ABL mutations associated with loss of response to dasatinib. Our landmark analysis demonstrated that 90% of patients receiving dasatinib 100 mg once daily who achieved complete cytogenetic response (CCyR) at 12 months were progression-free at 36 months, a considerable improvement over those without CCyR at 12 months (Table 1). Of the 164 patients receiving dasatinib 100 mg once daily, 59 had attained CCyR at 6 months of therapy. The rate of PFS after 36 months within this cohort was 93%, whereas those with partial CyR or those without major cytogenetic response (MCyR) at 6 months had 36-month PFS rates of 76% and 54%, respectively. A total of 36 subjects experienced progression events while receiving dasatinib 100 mg once daily: 8 due to death, 5 due to development of advanced phases of CML, 3 due to increases ≥30% in Ph+ metaphases, 9 due to increasing white blood-cell count, 4 due to loss of complete hematologic response, 4 due to loss of MCyR, and 3 for unknown reason. The majority (86%) of patients who do progress while receiving dasatinib remain in CP at 36 months. The development of mutations in BCR-ABL is a known mechanism of loss of response to dasatinib. In participants with loss of response to dasatinib who have available mutation data (n=61), the incidence of developing mutations during dasatinib therapy (at any dose) is 19% (5/27) in patients without baseline mutations, and 47% (16/34) in those with mutations at initiation of dasatinib. Of the patients who lost response to dasatinib and developed new mutations during therapy, 13 patients harbored T315I, 6 possessed F317L, 3 had V299L, and 1 acquired E255K. Three other patients developed mutations not associated with resistance to dasatinib (Table 2). New mutations that emerged in the 100 mg once daily arm and 70 mg twice daily arm were of similar frequency. In conclusion, patients who achieve early and complete CyRs to second-line dasatinib exhibit reduced rates of long-term progression versus those without CCyR at 6 months. Of the patients who do progress while receiving dasatinib, the majority remain in CP at 36 months. Of patients treated with 100 mg once daily, only 3% progressed to accelerated or blast phase with 36 months of follow-up. This transformation-free survival rate favors the use of dasatinib following imatinib failure in patients who have the option of pursuing allogeneic stem cell transplantation. Finally, the development of new mutations leading to resistance during dasatinib therapy is uncommon, and the lower total daily dose employed by the 100 mg once daily regimen does not appear to select for a greater variety of mutations than have been previously identified in patients treated with 70 mg twice daily. In patients who lose response to dasatinib and develop new mutations, a switch to an alternate TKI or stem-cell transplantation may be appropriate. Table 1. Progression-free survival of subjects with or without cytogenetic responses receiving dasatinib 100 mg once daily Cytogenetic Response PFS (95% CI) 12 months CCyR (n=55) 90% (81–100) partial CyR (n=23) 77% (60–95) minimal/minor/none (n=33) 63% (43–83) 6 months CCyR (n=59) 93% (85–100) partial CyR (n=26) 76% (59–93) minimal/minor/none (n=53) 54% (36–73) Abbreviation: CI, confidence interval. Table 2. Subjects developing new mutations during dasatinib by select dosing arms All subjects* (n=61) 100 mg once daily* (n=13) 70 mg twice daily* (n=14) M244V 1 0 0 E255K 1 0 1 V299L 3 2 1 F311L 1 0 1 T315I 13 3 3 F317L 6 3 1 M351T 1 0 0 * Subjects with loss of response to dasatinib and available baseline and progression/end-of-treatment mutation data. Disclosures Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Ploughman:Bristol-Myers Squibb: Employment. Radich:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Rituximab, ifosfamide, carboplatin, and etoposide (RICE) compared with ICE in relapsed diffuse large cell lymphoma (DLCL) before autologous stem cell transplantation

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18532-18532
Author(s):  
D. C. Case ◽  
F. R. Aronson ◽  
K. S. Ebrahim ◽  
J. A. Hedlund ◽  
M. A. Boyd ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Cohort Analysis ◽  
Progression Free Survival ◽  
Adult Patients ◽  
High Dose ◽  
Free Survival ◽  
Small Series

18532 Background: Retrospective cohort analysis suggests that the addition of rituximab to the ICE regimen (RICE) improved the complete response (CR) rate in relapsed DLCL and progression-free survival after transplantation (Blood 103:3684, 2004). We reviewed the results of two consecutive cohorts of patients treated with ICE and RICE prior to stem cell transplantation for CR rate, percent patients able to go to transplantation, and progression-free survival after transplantation. Methods: Adult patients (1996–2000) with relapsed DLCL received ICE chemotherapy [ifosfamide 1800 mg/m2 IV q.d. x3, carboplatin 250 mg/m2 IV day 1, and etoposide 75 mg/m2 IV q.d. x3 along with mesna] every 28 days to maximum response. Responding patients who were clinically stable and able received high-dose chemotherapy with autologous stem cell support. Adult patients (2001–2004) with relapsed DLCL received ICE along with rituximab 375 mg/m2 IV on day 1 of each cycle of chemotherapy. Patients in CR received autologous stem cell transplantation. Results: In the ICE series, 49 patients were treated with a 20% CR rate, and 10% went to transplant. Progression-free survival in those transplanted was 9, 12, 24, 36, and 81+ months (median 24 months). In the RICE series, 24 patients were treated with a 33% CR rate, and 25% were transplanted. Progression-free survival was 12, 18, 24+, 36, and 46+ months (median 24+ months). Myelosuppression was similar in each series. All patients were able to tolerate rituximab. The CR rate, percent of patients transplanted, and progression-free survival after transplantation appeared better with RICE but these differences were not statistically significant (P>.05). Conclusions: In our small series, Rituximab added to ICE did not have a statistically significant impact. No significant financial relationships to disclose.

High Dose Therapy and Autologous Stem Cell Transplantation Still Improves Progression Free Survival in First Relapse for DLBCL in the Rituximab Era: A Study Using Patients as Their Own Controls.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2191-2191
Author(s):  
Anna Sureda ◽  
Carme Canals ◽  
Nicolas Mounier ◽  
Roberto Foa ◽  
Eulogio Conde ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Impact

Abstract Autologous stem cell transplantation (ASCT) remains the treatment of choice for patients (pts) with diffuse large B-cell lymphoma (DLBCL) that relapse after first line chemotherapy (CT). Nevertheless, the impact of the use of the anti-CD20 monoclonal antibody (Rituximab®) (RTX) with combination CT on the ulterior results of the transplantation procedure has to be determined. One of the main factors affecting survival after ASCT is a short first remission duration. This study was designed to evaluate the benefit of this strategy, in pts with DLBCL achieving after salvage CT a 2nd complete remission (CR2), by retrospectively comparing for each pt the progression free survival (PFS) after ASCT with the duration of the previous CR. Adult DLBCL pts with MEDB information available autografted in CR2 between 1990 and 2005 in EBMT centres were included in the analysis. A total of 386 pts (224 males, median age 47 (18–71) years] were evaluated. 294 pts (74%) did not receive RTX prior to ASCT, 67 pts (17%) did receive it at all and in 34 pts (9%) this information is missing. Duration of CR1 was 12 (3 – 142) months [median (range)]; it lasted less than 6 months in 25% of the cases and was longer than 24 months in 25% of the pts. Median time from diagnosis to ASCT was 25 (6–181) months. Peripheral blood was used as the source of hematopoietic stem cells in 311 pts (81%). The BEAM protocol was the conditioning regimen most frequently used (n = 244, 63%) and only 5.5% pts were conditioned with TBI-containing regimens. After a median follow up after ASCT for surviving pts of 42 months, overall survival (OS) was 63% and PFS 48%. 158 pts did relapse after ASCT [median (range), 10 (3–200) months] and 32 pts died from non-relapse mortality. When each patient was taken as her/his own control, PFS after ASCT was longer than CR1 (p &lt; 0.001). During the initial phase of the disease, 74% pts experienced 1st relapse in less than 2 years, compared with only 32% of the patients who experienced 2nd relapse 2 years after ASCT. The use of RTX prior to ASCT did not impair the beneficial effects of the autologous procedure in the whole population of pts (RTX no: 66% vs 33%, p &lt; 0.001; RTX yes: 73% vs 26%, p = 0.001). 2-years PFS after ASCT was significantly lower in patients with a CR1 &lt; 12 months (p &lt; 0.001). However, in this subgroup of patients PFS after ASCT was significantly longer than CR1 duration when studying each pt as his/her own control (p = 0.001). ASCT can significantly increase PFS in comparison with the duration of CR2 in DLBCL and can change disease course. The use of RTX prior to ASCT does not decrease the beneficial effect of pts autografted in CR2 when compared to their prior CR1 duration. The duration of CR1 remains one of the most important prognostic factors for ASCT outcome.

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