scholarly journals Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma Improved Overall Survival in Upfront Hematopoietic Stem Cell Transplantation — a Large Retrospective Study By the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3464-3464
Author(s):  
Charlotte Gran ◽  
Junfeng Wang ◽  
Hareth Nahi ◽  
Linda Koster ◽  
Goesta Gahrton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Relapse Rate ◽  
Research Funding ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Background Allogeneic hematopoietic stem cell transplantation (AlloSCT) for treatment of multiple myeloma (MM) is controversial mainly due to high non-relapse mortality (NRM) with myeloablative conditioning. However, AlloSCT is probably the only treatment that result in cure of a small fraction of patients. Treosulfan is a prodrug of a bifunctional alkylating agent which has both myelotoxic and immunosuppressive properties. Conditioning regimes with treosulfan have been tried in various hematologic neoplasia such as AML and MDS indicating low NRM and increased progression free survival (PFS). Previous studies on use of treosulfan condition in AlloSCT for MM indicated feasibility, stable engraftment and low NRM. In the present study we have analysed the results of low and high dose treosulfan respectively on OS, RFS, relapse incidence and NRM as well as results of Treosulfan conditioning compared to non-Treosulfan reduced intensity conditioning (RIC) and non-Treosulfan myeloablative conditioning (MAC). Patients and Methods We conducted a retrospective analysis of 4544 patients with MM undergoing AlloSCT 2008-2016 reported to the EBMT data registry. Out of 537 patients receiving Treosulfan based conditioning the impact of dose could be analysed in 441. Three hundred and twenty-seven patients received a total dose of >36g/m2 and 114 <=36g/m2.These patients were compared to 2830 patients receiving RIC, and 1177 receiving MAC. 1103 patients were transplanted upfront and 3441 patients in later lines following relapse/progression. Patient characteristics shown in table 1. Results The 5-year OS in upfront Treosulfan conditioned patients was 62%, which was significantly superior to both non-Treo RIC and MAC patients respectively, apparently due to a tendency for lower NRM (10%) albeit a higher relapse rate (Table 2). Patients in later lines of conditioning had either low NRM (3rd line) or no significant difference (2nd line) (Table 2). Heterogeneity in the material makes it difficult to interpret results in the patients transplanted late in the course of the disease. A higher total treosulfan dose, >36g/m2, showed a tendency for improved OS and RFS compared to the lower dose treosulfan as well as RIC and MAC (table 2) respectively. In multivariate analysis of upfront transplanted patients, with a model adjusted for ISS score at diagnosis, age, Karnofsky score, response at AlloSCT, interval between diagnosis and transplant, donor type and donor - patient sex match, treosulfan and RIC retained significance for OS, HR 0.57 (P=0.006) and RFS, HR 0.65 (P=<0.005). For 2nd line Treosulfan RFS was significantly worse, HR 1.46 (P=<0.005) while there was no significant difference for OS between conditioning regimes in 2nd or for OS and RFS in 3rd line (table 2). The factors associated with most inferior OS in upfront line of conditioning was Karnofsky <90 and ISS score III at diagnosis. ISS score III at diagnosis was also associated with inferior OS also in 2nd and 3rd line (Table 2) A less then partial response at AlloSCT was consistently a factor associated with inferior RFS regardless of line of treatment with HR 1.67 (P=<0.005) in upfront, HR 1,63 (P=<0.005) in 2nd line and HR 1,66 (P=<0.005) for 3rd line or later (Table 2) In multivariate analysis of treosulfan based conditioning regimes, upfront line of conditioning was superior for OS, PFS and relapse as expected (Table 3). Notably was an increased hazard ratio for donor-patient sex match other than female to male in OS, PFS as well as relapse, HR 1.64 (P=0.02), HR 1.66 (P=0.004) and HR 1.83 (P=0.003) respectively (Table 3). Conclusions Conditioning upfront with Treosulfan containing regimens for AlloSCT in multiple myeloma, is associated with a superior overall survival and a low NRM, however with a slightly higher relapse rate compared to other regimens. A higher dose > 36g/m2 tends to further improve OS, RFS and relapse rate without increasing NRM. The better results of Treo conditioning in female to male transplants as compared to other sex combinations and in contrast to MAC transplants may be due to the overall lower NRM with treosulfan, thus utilizing the GVM more effectively as indicated by the trend for lower relapse rate. In conclusion, Treosulfan containing regimens appear to be of value in upfront AlloSCT. Prospective studies on Treosulfan conditioning are warranted to further define the best dosing in MM AlloSCT. Disclosures Niederwieser: Miltenyi: Speakers Bureau; Novartis: Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Garderet:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Kroeger:Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding.

Impact of ATG Dose on the Outcome of Patients Undergoing Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

2016 ◽  
Vol 136 (4) ◽  
pp. 193-200 ◽  
Author(s):  
Jérôme Cornillon ◽  
Marie Balsat ◽  
Aurélie Cabrespine ◽  
Emmanuelle Tavernier-Tardy ◽  
Eric Hermet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.

The Use of Novel Agents In Patients with Multiple Myeloma Initially Treated with Allogeneic Stem Cell Transplantation Results In A Significant Prolongation of Post Relapse Survival.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4580-4580
Author(s):  
Christopher P. Venner ◽  
Heather Sutherland ◽  
John Shepherd ◽  
Yasser Abou Mourad ◽  
Michael J. Barnett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Research Funding ◽  
Statistical Significance ◽  
Novel Agents ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Significant Prolongation ◽  
Significant Difference ◽  
Relapsed Disease

Abstract Abstract 4580 Background: The use of allogeneic hematopoietic stem cell transplant (alloHSCT) in the treatment of Multiple Myeloma (MM) remains controversial. Although there is hope that alloHSCT may result in a cure, relapse continues to be a significant problem. The morbidity associated with late complications of allogeneic transplantation further compounds the issues faced when addressing relapsed disease. The use of Novel Agents (NA) in this patient population has been poorly characterized. Here we present our experience of NA use in patients initially treated with alloHSCT. Patients: 108 patients underwent an allografting procedure for their MM at our center between 1989 and 2009. 84 received a fully myeloablative procedure (15 received donor lymphocyte infusion). 24 received an autologous HSCT followed by a reduced intensity allogeneic procedure. 56 have relapsed with this population making up our primary cohort for analysis. 22 patients received NAs and very few patients received them prior to transplant (4/108). Endpoints examined were post relapse survival after the initial HSCT procedure (PRS), overall survival from time of initial treatment (OS) and progression free survival (PFS) measured in months (m). Results: Of the entire cohort of 108 patients median OS was 78.6m (95% CI; 24.5–132.6). Median PFS was 23.6m (95% CI; 15.4–31.8). Of the non-relapsed patients (n = 52) the median OS was 125.9m. In this cohort 67% of the deaths occurred within 1.5 years. Of the relapsed patients (n = 56) median PFS was 18.7m (95% CI; 14.6–22.8), median PRS was 31.5m (95% CI; 17.0–46.0), and median OS was 67.0m (95% CI; 31.6–102.5). The effect of NA was examined in the cohort of relapsed patients. No significant difference was noted in PFS between those exposed to NA and those who were not exposed (19.0m (95% CI; 10.1–22.8) vs 13.7m (95% CI; 5.8–21.6); p = 0.27). Exposure to NA showed improvements in PRS (42.3m (95% CI; 7.3–77.2) vs 10.4m (95% CI; 5.2–15.7); p = 0.01, Figure 1). A trend toward superior OS was noted (71.4m (95% CI; 37.9–105.5) vs 24.6m (95% CI; 3.0–46.1); p = 0.11) although this did not reach statistical significance. Conclusion: Ongoing management of relapsed patients with multiple myeloma in the post alloHSCT setting remains a significant challenge. This retrospective study demonstrates that the use of NA is both safe and effective in treating relapsed disease. The predominant impact of these drugs is seen in the relapsed setting. Exposure to NA correlates with a 22m improvement in PRS. A 46m improvement in OS is noted however, likely due to the small cohort, it failed to reach statistical significance. Disclosures: Sutherland: Celgene: Honoraria; Orthobiotech: Honoraria. Shepherd:Celgene: Honoraria; Orthobiotech: Honoraria. Nevill:Celgene: Honoraria. Toze:Hoffman La Roche: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria.

Final Report of Safety and Efficacy From a Novel Conditioning Regimen, Individualized Once-Daily Intravenous Busulfan with Bortezomib, in Relapsed Multiple Myeloma Patients Undergoing a Second Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3080-3080
Author(s):  
Edward A. Stadtmauer ◽  
Voravit Ratanatharathorn ◽  
Rosa F. Yeh ◽  
Cesar O. Freytes ◽  
Juan J. Toro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Test Dose ◽  
Hematopoietic Stem ◽  
Once Daily ◽  
Disease Response ◽  
Pharmaceutical Development

Abstract Abstract 3080 Background: Salvage therapeutic options are limited for multiple myeloma (MM) patients who relapse after autologous hematopoietic stem cell transplantation (ASCT). A second ASCT using a different conditioning regimen may provide long-term disease control. We report efficacy and safety of daily intravenous busulfan (IV Bu) conditioning given with bortezomib for second ASCT. Materials and Methods: In this prospective, multicenter, Phase IIa study, thirty MM patients who relapsed ≥ 1 year after initial ASCT and were candidates for second ASCT were enrolled at eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between Days -12 and -9 prior to ASCT. Pharmacokinetic (PK) analysis from test dose determined Bu exposure as area under the concentration-time curve (AUC). This analysis was used to determine individualized Bu PK-directed dosing for the conditioning regimen in order to achieve a total regimen AUC of 20,000 mM*min. IV Bu was administered over 3 hours once daily from Day -5 to Day -2. Confirmatory PK analysis was conducted in all patients on Day -5. Bu doses were adjusted on Days -3 and -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. Disease response was evaluated prior to the ASCT and at 3 and 6 months post-transplant, based on the International Myeloma Working Group uniform response criteria in 2006. Results: Patient Demographics: Median age at second ASCT was 59 years (range: 48–73). All patients had previously been treated with bortezomib (86.7%), thalidomide (46.7%), and/or lenalidomide (66.7%). All subjects underwent first ASCT with high-dose melphalan. Median time from first ASCT to second ASCT was 28.0 months (range: 12–119). The disease status at second ASCT was seven very good partial response (VGPR; 23.3%), twelve partial response (PR; 40.0%), two stable disease (SD; 6.7%); and nine progressive disease (PD; 30.0%). Safety: The most common grade 3 or 4 adverse event (CTCAE v3.0) was febrile neutropenia in 15 patients (50.0%), followed by stomatitis in 13 patients (43.3%), nausea in four (13.3%) and hypokalemia in three (10.0%). One transplant-related death due to pulmonary complications was reported for a patient with Parkinsonism on post-transplant Day 20. There was no instance of seizure, worsening neuropathy, or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy: 28 patients had evaluable disease response at least at one time point after second ASCT. Disease response at 3 months were two complete responses (CR; 6.7%), five VGPR (16.7%), four PR (13.3%), eight SD (26.7%), nine PD (30.0%), and two cases without evaluable assessment (6.7%). Two patients who achieved CR at 3 months had PD and VGPR prior to ASCT, respectively. Disease response at 6 months were one stringent CR (sCR; 3.3%), one CR (3.3%), four VGPR (13.3%), seven SD (23.3%), fourteen PD (46.7%), and three cases without evaluable assessment (10.0%). Median progression-free survival was 191 days, while median overall survival has not been reached yet. PK: 40.0% (n=12/30) of patients had AUC outside the expected range from pre-transplant test dose, 0.8 mg/kg of IV Bu: eleven cases with AUC <1,000 μM*min and one case with AUC >1,500 μM*min. If only weight was used (e.g. 3.2 mg/kg daily) to determine the dose without considering difference in individual busulfan metabolism, this 40% would have been dosed outside the total target AUC range. Based on test PK, IV Bu dosing for conditioning was individualized ranging between 1.99 and 4.73 mg/kg, which resulted in 93.3% of patients (n=28/30) falling between 16,000 and 24,000 μM*min as a total target AUC without any further dose alteration during conditioning. Only 2 patients (6.7%) needed dose reduction on Days -3 and -2. Mean Bu clearance for test dose and on Day -5 were comparable, 3.00 and 2.92 ml/min/kg, respectively. Conclusions: Disclosures: Stadtmauer: Millenium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: IV busulfan and bortezomib-based conditioning regimen prior to transplant for myeloma. Freytes:Otsuka Pharmaceuticals: Research Funding. Shaughnessy:Otsuka: Honoraria, Speakers Bureau. White:Otsuka: Honoraria, Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmaceutical Development & Commercialization, Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialisation., Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding.

NON-Cryopreserved Hematopoietic STEM CELL Transplantation in Multiple Myeloma. a Single Center Experience in Oran (ALGERIA)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1990-1990
Author(s):  
Amine MA Bekadja ◽  
Souad ST Talhi ◽  
Hafida OH Ouldjeriouat ◽  
Osmani OS Soufi ◽  
Mohamed BM Brahimi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Introduction: For younger patients under 65 years of age, induction followed by high-dose chemotherapy with autologous stem cell transplantation (ASCT) is the standard treatment in multiple myeloma (MM). There is limited experience with non-cryopreserved autologous hematopoietic stem cell transplantation. We evaluated the efficacy and safety of non-cryopreserved storage of ASCT in patients undergoing ASCT for MM. Patients and methods: Autologous stem cell was mobilized using G-CSF alone (10 µg/kg/day for 5 days). Leukapheresis to harvest stem cells were performed on day -2 and -1. The grafts were kept in a conventional blood bank refrigerator at +4°C until reinfusion on day 0. The conditioning regimen consisted of melphalan 200 mg/m2 in all patients. Results: From May 2009 to December 2013, 134 patients with MM were treated in our center in Oran. The median age at ASCT was 55 years (range; 27-67). There were 80 males and 54 females. The median harvested CD34+ cell count was 3,5x106/kg (range; 1, 22 to 13, 24). All patients had engraftment on the median of day 10 (range; 7 to 17) and platelet transfusion independence on the median of day 13 (range; 9 to 24). There was no graft failure. Mucositis grade 3/4 was seen in 68% patients. Transplant related mortality at 100 days was 2.9%. The overall response to transplant was 92%. In the 130 evaluable patients, the median post-transplant overall survival had not been reached. The estimated overall survival at 75 months was 63% with 95% confidence interval and the median post-transplant disease free Survival was 35 months (0.05%). 93 (72%) patients are alive and 75 (81%) without disease activity after a median follow-up of 35 months (range; 3 to 75). Discussion: We conclude that high dose chemotherapy and autologous transplant with non cryopreserved ASCT is a simple, effective and safe method for MM with equivalent results, and that cryopreservation is not necessary in the treatment of MM under our work conditions in developing countries Disclosures No relevant conflicts of interest to declare.

VP111 Referral Center For Multiple Myeloma Patient Care

2017 ◽  
Vol 33 (S1) ◽  
pp. 201-201
Author(s):  
Indara Saccilotto ◽  
Rosane Bittencourt ◽  
Camila Fischer ◽  
Amanda Quevedo ◽  
Vania Hirakata ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Outcome Measure ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Care Facilities

INTRODUCTION:Within the Brazilian Health System, Referral Centers (RCs) are care facilities that provide specialized services. The objective of this study was to evaluate the efficacy of care provided to patients with multiple myeloma (MM) at a specialized Referral Centers (Hospital de Clínicas de Porto Alegre Referral Center for Multiple Myeloma, CRMM-HCPA) and to compare quality of life between patients with MM treated at CRMM-HCPA and those treated at non-RC facilities.METHODS:A 6-month cohort study was conducted in patients with MM receiving thalidomide from the State Health Department and treated at CRMM-HCPA, and patients receiving treatment at other non-RC facilities. Thirty-two patients were included in the study, nineteen from CRMM-HCPA and thirteen from other institutions. To analyze the efficacy of care provided at CRMM-HCPA, the main outcome measure was the time from diagnosis to referral for autologous hematopoietic stem cell transplantation.This outcome measure was assessed using questionnaires specifically designed for this study. Quality of life was also assessed, using the Short-Form 36 Item Health Survey (SF-36) questionnaire.RESULTS:Time from MM diagnosis to referral for autologous hematopoietic stem cell transplantation in each group was measured only in patients aged 65 years (n = 25); of these, 15 were recruited from CRMM-HCPA and 10 from other institutions. In this analysis, there was a significant difference (p = .036) in time elapsed between diagnosis and referral for autologous hematopoietic stem cell transplantation, which was significantly shorter for patients treated at CRMM-HCPA (median, 9 months; Interquartile Range, IQR, 8.5–14.5) than for those treated elsewhere (median, 24 months; IQR, 16–24). On quality of life analysis, there was a significant difference in the Social Functioning, which relates to performance of social activities (p = .02).CONCLUSIONS:The Referral Centers model provided seems to be a more efficient treatment strategy as compared with other health care facilities, as it enabled a reduction in time to transplantation. Patients treated at CRMM-HCPA demonstrated greater ease in performing social activities, with less interference from physical or emotional problems.

Bortezomib-Based Regimens As Consolidation Therapy after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Single Center Experience from Oran (Algeria)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5121-5121 ◽  
Author(s):  
Souad Talhi ◽  
Soufi Osmani ◽  
Mohamed Brahimi ◽  
Kamila Amani ◽  
Hafida Ouldjeriouat ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Progression Free Survival ◽  
Consolidation Therapy ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Significant Difference

Abstract INTRODUCTION: Autologous stem cell transplant (ASCT) is the standard of care in transplant-eligible multiple myeloma (MM) patients and is associated witha significant improvement in progression-free survival (PFS), complete remission rates (CR), and overall survival (OS). However, the majority ofpatientsrelapse. This study compares the efficacy of autologous hematopoietic stem cells followed by consolidation bybortezomibbased regimens to the no consolidation therapy in adult patients. PATIENTS AND METHODS: This is a retrospective study over a period of 7 years (2009-2015). All patients less than 65 years with a newly MM diagnosis were included. The protocol used in induction was VD (n=47) treatment whichconsisted of four 3-week cycles of 1.3 mg/m2 bortezomib administered subcutaneously (SC) on days 1, 4, 8, and 11 and 40 mg dexamethasone on days 1Ð4 and 9Ð12. Therapy with VTD was composed of four 3-week cycles of SC bortezomib and dexamethasone at the same doses and schedules as for the VD regimen plus 100 mg/day thalidomide administered orally. Therapy with VCD was composed of four 3-week cycles of SC bortezomib and dexamethasone at the same doses and schedules as for the VD regimen plus 500 mg/m2 cyclophosphamide administered orally on days 1, 8, and 15. Recommended concomitant medications included bisphosphonates, antibiotics, and antiviral prophylaxis. Acetyl salicylic acid was systematically used in the VTD arm. Stem cells were mobilized with 15 or 10 microg/kg G-CSF alone. Leukapheresis to harvest stem cells was performed on day -2 and -1. The grafts were kept in a conventional blood bank refrigerator at 4¡C until reinfusion on day 0. The target yield was 2 x106 CD34+ cells/kg. Following induction therapy, all patients had to proceed to ASCT. The conditioning regimen consisted of melphalan 200 mg/m2 in all patients.The consolidation regimen consisted of two cycles of VD or VCD or VTD after autologous stem- cell transplantation. In our study patients were divided into two groups: Group1 (ASCT plus consolidation) and Group 2 (ASCT alone). The therapeutic evaluation focused on the overall response (CR + VGPR) and progression free survival (PFS) and overall survival (OS) calculated by the Kaplan-Meier method. RESULTS: Over a period of 7 years, 153 patients were collected divided in two group: G1 (n=71) and G2 (n=82). Baseline characteristics are summarized in Table 1. No significant difference was observed between the 2 groups. In terms of CR, 58% of the patients in the G1 achieved a CR after consolidation vs 33% in the G2 after ASCT alone (p=0.007). In terms of VGPR, 31% of the patients in the G1 achieved a least a VGPR vs 17% in the G2 (p=0.04). The relapse rate was significantly lower in the G1 (10%) than the G2 (39%), (p=0.0001). The median follow-up period was 23,4 months. PFS was significantly higher in the G1, median no reached vs 37 months in the G2 (p=0.02) but no significant difference was observed in terms of OS rate between the 2 groups, 91% (G1) versus 82% (G2) at 27 months (p=0.7). CONCLUSION: We conclude thatbortezomib-based regimens as consolidation therapy after ASCT in patients with MM was effective in the improvement of PFS and response rate. Table Patients characteristics. Table. Patients characteristics. Disclosures No relevant conflicts of interest to declare.

scholarly journals Durable Remission and Survival in Relapsed/Refractory Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5884-5884 ◽  
Author(s):  
A. Megan Cornelison ◽  
Rima M Saliba ◽  
Sairah Ahmed ◽  
Yago Nieto ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Durable Remission

Abstract Background: The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the setting of refractory multiple myeloma (MM) is still controversial. Although potentially curative in a subset of pts, concerns regarding treatment related mortality (TRM) and graft vs. host disease (GVHD) preclude its universal use. In this study, we evaluated the role of allo-HSCT for pts with relapsed MM. Methods: 110 consecutive pts with relapsed MM underwent allo-HSCT at our institution between 2000 and 2014. The primary objective was to assess progression-free (PFS) and overall survival (OS). Results: Median age at allo-HSCT was 54 (range, 32-71) years and median time from diagnosis to allo-HSCT was 35.7 (range, 8.6 to 228.8) months. Fifty-two (47%) and 49 (45%) pts had standard-risk (SR) and high-risk (HR) cytogenetics at the time of allo-HSCT, respectively. Pts received a median of 5 (range, 1-9) prior chemotherapy regimens and 99 (90%) pts had at least 1 (range, 0-3) prior auto-HSCTs. One hundred one (92%) pts received either a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD) prior to allo-HSCT, with 65 (59%) receiving both. Sixty eight (62%) received allo-HSCT from matched related, 34 (31%) from matched unrelated, 5 (4%) from cord blood, and 3 (3%) from mismatched donors. Preparative regimen was fludarabine/melphalan-based in 88 (80%) and fludarabine/busulfan-based in 16 (15%) pts. Median time to neutrophil and platelet engraftment was 12 (range, 8-30) and 13 (range, 0-81) days, respectively. Ten pts died of non-relapse causes within 100 days (100-day TRM: 9%) and 21 (19%) within 1 year. Grade 1-4 acute GVHD was seen in 50 (45%) and cGVHD in 35 (32%) pts, respectively. Eighteen (16%) achieved a CR, 26 (23%) a VGPR and 38 (34%) achieved a PR, with an overall response rate of 73%. With a median follow up of 41.9 months (range, 6.4 to 172.9) in surviving pts, 1- and 2-year PFS were 23% and 15%, respectively (Fig 1). One and 2-year OS were 50% and 32%, respectively (Fig 2). HR cytogenetics at allo-HSCT were associated with a significantly shorter 2-year PFS (6% for HR vs. 23% for SR; p=0.007) and OS (p=0.01). A response <PR after allo-HSCT was also associated with significantly shorter 2-year PFS (p<0.001) and OS (p<0.001). Conclusions: Allo-HSCT is associated with durable remission and survival in approximately 15% of heavily pretreated pts with relapsed/refractory MM. Novel, more effective approaches are needed for patients with HR cytogenetic abnormalities. Figure 1 Progression-Free Survival Figure 1. Progression-Free Survival Figure 2 Overall Survival Figure 2. Overall Survival Disclosures No relevant conflicts of interest to declare.

Age-Adjusted Telomere Length May Predict Treatment-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5445-5445
Author(s):  
Pasquale M Barbaro ◽  
Peter J. Shaw ◽  
Melissa Gabriel ◽  
Steven Keogh ◽  
Li Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Telomere Length ◽  
Refractory Disease ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Related Mortality

Abstract Introduction Telomeres are specialized DNA structures found at the end of linear chromosomes. In humans, they contain the repetitive sequence (TTAGGG)nalong with its complementary strand and associated proteins. With each cell division, the telomere shortens due to incomplete replication of the lagging strand, a phenomenon known as the end replication problem. Oxidative damage, as well as the action of nucleases also leads to telomere attrition. Once the telomere reaches a critically short length, cells enter senescence or apoptosis. In the general population, telomere length (TL) varies greatly, and is seen to decline with age. Patients with Dyskeratosis Congenita (DC) have inherently short telomeres, which leads to multiple organ dysfunction. These patients suffer increased organ toxicity when given standard myeloablative conditioning regimens during hematopoietic stem cell transplantation (HSCT). This is most likely due to the reduced ability of their cells to replicate and recover following cytotoxic treatment. It is not known whether patients without DC, who have telomere lengths at the lower end of the normal spectrum also suffer increased rates of toxicity. Thus we undertook a retrospective analysis to determine if there was an association between short TL and increased transplant-related mortality (TRM) following HSCT in children. Method Medical records of patients who underwent allogeneic HSCT at the Children's Hospital at Westmead (Sydney, Australia) between 2002 to 2013 were examined and demographic, prior treatment, transplant, toxicity and transplant information was extracted. The primary outcome measured was TRM, while overall survival, relapse and graft versus host disease (GVHD) being secondary outcomes of interest. Stored DNA, extracted from bone marrow, taken within 3 months prior to HSCT was used for telomere length testing, as a surrogate marker for TL in other tissues in the body. Quantitative PCR was carried out to determine relative telomere length, which was converted to an age adjusted TL (AATL) by subtracting the expected relative TL (i.e. 50th percentile for age of the patient) from the measured relative TL, so that patients of all ages could be analyzed together. Results Between 2002 and 2013, there were 121 patients who underwent allogeneic HSCT at our institution. Of these, 78 had DNA stored, with appropriate consent and ethics approval to be used in our study. Most children were undergoing HSCT for hematological malignancies (acute lymphoblastic leukemia 52%, acute myeloid leukemia 39%), with 55% having relapse or refractory disease. Matched sibling donors made up 46% of cases. At a median follow up of 3.2 years, 64% of patients remained alive. The single leading cause of death was relapse (48%) with 52% of deaths attributable to transplant-related causes. The median AATL for the entire cohort was -0.21 (range -0.61-0.28). Telomere length was not associated with relapse or refractory disease. There was no correlation between AATL and specific organ toxicity, relapse or overall survival. When the cohort was divided into 2 groups based on AATL, there was a trend (p=0.055) towards increased TRM in patients who had AATL below the median for the cohort (Figure 1). Multivariate analysis adjusting for age at transplant, CMV status, disease status and HLA matching showed a reduced risk (HR 0.33; p value 0.072) of TRM in patients with AATL above the median for the cohort. Conclusion AATL was shorter in patients pre-HSCT compared with age matched controls. There was a trend towards increased TRM in patients with shorter telomere length, however most likely due to small sample size, this did not achieve significance. If extended to a larger cohort of patients, TL may prove to be a significant marker for children at increased risk of TRM prior to HSCT. This could influence the choice to use less myeloablative conditioning in these patients. Support: NHMRC GNT1056667 Disclosures No relevant conflicts of interest to declare.

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