Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4308-4308
Author(s):  
Jean El-cheikh ◽  
Luca Castagna ◽  
Sabine Furst ◽  
Catherine Faucher ◽  
Benjamin Esterni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Allogenic Stem Cell Transplantation ◽  
Related Mortality

Abstract Abstract 4308 Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality. We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor; 41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease. With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation. The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5]. 2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC). Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies. Disclosures: No relevant conflicts of interest to declare.

Psychosocial and Behavioral Issues in Stem Cell Transplantation

2006 ◽  
Author(s):  
Sean Phipps
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Well Being ◽  
Unrelated Donor ◽  
Behavioral Issues ◽  
Leukemic Relapse

Stem cell transplantation (SCT) or bone marrow transplantation (BMT) has evolved from a heroic, experimental therapy of last resort to a standard therapy for many high-risk leukemias and the preferred first option after leukemic relapse (Sanders, 1997; Santos, 2000; Treleaven & Barrett, 1998; Wingard, 1997). The indications for SCT have widened to include a number of other malignant disorders, including lymphomas, solid tumors, and even brain tumors, as well as to a growing number of nonmalignant disorders (Meller & Pinkerton, 1998; Santos, 2000; Treleaven & Barrett, 1998). The growth of bone marrow registries that allow for wider use of unrelated donor transplants and developments in stem cell selection techniques that allow for haplotype transplants using mismatched family donors, including parents, have greatly increased the availability of SCT as a viable treatment option for seriously ill children (Mehta & Powles, 2000). At the same time, advances in supportive care have led to improved survival outcomes and thus to a rapidly growing number of long-term survivors of SCT (Santos, 2000; Treleaven & Barrett, 1998). Yet, despite the extraordinary medical and technical advances that have saved the lives of many children, SCT remains a high-risk medical procedure involving a prolonged and physically demanding treatment regimen that can challenge the coping capacities of patients and their families. Psychosocial research in pediatric SCT has progressed more slowly, but available studies indicate that SCT is a stressful experience that can have a negative impact on the social functioning, self-esteem, and general emotional well-being of survivors (Barrera, Pringle, Sumbler, & Saunders, 2000; McConville et al., 1990; Parsons, Barlow, Levy, Supran, & Kaplan, 1999; Phipps, Brenner, et al., 1995; Phipps & Barclay, 1996; Rodrigue, Graham-Pole, Kury, Kubar, & Hoffman, 1995; Stuber, Nader, Yasuda, Pynoos, & Cohen, 1991; Vannatta, Zeller, Noll, & Koontz, 1998). A number of studies have also focused on parental response to SCT (Barrera et al., 2000; Kronenberger et al., 1998; Manne et al., 2001, 2002; Phipps, Dunavant, Lensing, & Rai, 2004; Rodrigue et al., 1996; Streisand, Rodrigue, Houck, Graham-Pole, & Berlant, 2000). Much of the literature to date has focused on long-term outcomes in survivors, particularly neurocognitive and academic outcomes.

Allogeneic Stem Cell Transplantation with Reduced-Intensity, Fludarabine-Based Conditioning in Relapsed and Refractory Hodgkin’s Disease: Low Transplant-Related Mortality and Impact of Intensity of Conditioning Regimen on Survival.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2135-2135
Author(s):  
Paolo Anderlini ◽  
Rima Saliba ◽  
Michele Donato ◽  
Sergio Giralt ◽  
Borje Andersson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Hodgkin’S Disease ◽  
Conditioning Regimen ◽  
Related Mortality

Abstract Forty patients with relapsed or refractory Hodgkin’s disease (HD) underwent allogeneic stem cell transplantation (allo-SCT) following a fludarabine-based conditioning regimen from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18-58). The median number of chemotherapy regimens received prior to allo-SCT was five (range 2-9). Thirty (75%) and thirty (75%) patients had received prior radiotherapy or a prior autologous SCT, respectively. The median time to progression after autologous SCT was nine months (3–52). Disease status at SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens employed were fludarabine (25 mg/m sq IV x 5 days)-cyclophosphamide (1 g/m sq IV x 3 days) ± antithymocyte globulin (30 mg/kg IV x 3 days) (FC±ATG) (n=14), a less intensive regimen, and fludarabine (25 mg/m sq IV x 5 days) -melphalan (70 mg/m sq IV x 2 days) (FM) (n=26), a more intensive one. The two groups had similar demographics and prognostic factors. Chimerism studies indicated 100% donor-derived engraftment in 26/26 (100%) FM patients and in 9/13 (69%) evaluable FC±ATG patients. Day 100 and cumulative (18-month) transplant-related mortality (TRM) were 5 % and 22%, respectively for the whole group. There was a nonsignificant trend towards a lower cumulative TRM in the FM group (18% vs. 30% at 18 months, p=0.2). The cumulative incidence of acute (grade II-IV) GVHD was 38%. The cumulative incidence of chronic GVHD at 18 months was 69%. There was a trend for a lower relapse rate after the occurrence of GVHD, however, this was not statistically significant (hazard ratio 0.8; p= 0.6). Progression rates were similar in the FM and FC patients (53% vs. 57% respectively at 18 months, p=0.4). However, disease progression occurred later in FM patients (range 2–34 months) than in FC patients (range 0.7–13 months). In addition, with comparable follow-up time after progression, the FM group experienced a lower death rate after progression. Twenty-four patients (60%) are alive (fourteen in complete remission) with a median follow-up of 13 months (4–78). Sixteen patients expired (TRM n=8, disease progression n=8). FM patients had significantly better overall survival (73% vs. 39% at 18 months; p=0.03), and a trend towards better progression-free survival (37% vs. 21% at 18 months; p=0.2). We conclude that allo-SCT with fludarabine-based, less intensive conditioning from matched related and unrelated donors are feasible in high-risk HD patients with a low TRM. The intensity of the preparative regimen affects survival.

Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy In Adults with Hematopoietic Disorders Undergoing Matched Unrelated Donor Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1317-1317
Author(s):  
Adam Giermasz ◽  
Lloyd E. Damon ◽  
Lawrence D Kaplan ◽  
Willis H. Navarro ◽  
Kristen Hege ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 1317 Introduction: Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility. Patients and Method: Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The engraftment was documented as follows: ANC >1.0 median: day 12 (SD3.5), Plt >50×10e9/L median: day 16 (SD 7.2), Plt >100×10e9/L median: day 20 (SD 40.7). The frequent (>20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death. Disclosures: No relevant conflicts of interest to declare.

Ruxolitinib As Pretreatment Before Allogeneic Stem Cell Transplantation For Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 392-392 ◽  
Author(s):  
Nicolaus Kröger ◽  
Haefaa Alchalby ◽  
Markus Ditschkowski ◽  
Dominik Wolf ◽  
Gerald Wulf ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Allogeneic Stem Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Spleen Size ◽  
Rebound Phenomenon

Abstract Introduction We investigate early outcome after allogeneic SCT in 22 patients – male (n = 13) and female (n = 9) – with myelofibrosis who received ruxolitinib prior to transplantation in order to reduce spleen size and constitutional symptoms. Patients and methods The median age of the patients was 59 years (r: 42 – 74 y) and ruxolitinib was given at doses between 2 x 5 mg (n = 5), 2 x 15 mg (n = 5), and 2 x 20 mg (n = 12) before first (n = 19) or second (n = 3) fludarabine-based reduced intensity conditioning from related (n = 2), and matched (n = 14), or mismatched (n = 6) unrelated donor. Thirteen patients had primary myelofibrosis and 9 post ET/PV myelofibrosis. Before ruxolitinib the patients were classified according to DIPSS as intermediate-1 (n = 3), intermediate-2 (n = 14), or high risk (n = 5). Stem cell source was PBSC (n = 21) or bone marrow (n = 1) with a median CD34+ cell count of 7.1 x 106/kg. Before ruxolitinib 21 patients (96%) had constitutional symptoms and all patients had splenomegaly. The median time from start of ruxolitinib to allogeneic SCT was 133 days (r: 27 – 324) and the median treatment duration was 97 days (r: 20 – 316). Most patients (n = 82%) received ruxolitinib until start of conditioning therapy. Four patients (18%) discontinued ruxolitinib between 28 and 167 days before transplantation due to progressive disease or no response (n = 3) or cytopenia (n = 1). Results At time of transplantation 86% had improvement of constitutional symptoms and 45% had major response (>50% palpable) of spleen size, 28% had response of spleen size which was less than 50%, and 27% had no response or progressive spleen size after ruxolitinib treatment. After discontinuation of ruxolitinib at first day of conditioning regimen no “rebound” phenomenon was seen. One patient transformed to sAML before transplantation despite response of spleen size and constitutional symptoms. After busulfan (n = 16), treosulfan (n = 3), or melphalan (n = 3) dose reduced conditioning no graft failure was observed and the median time for leukocyte and platelet engraftment was 15 days (r: 10 – 66) and 17 days (r: 8 – 122) respectively. Acute GvHD I-IV was seen in 50% of the patients which was severe (III/IV) in 18%. During follow-up 4 patients died, 1 patient with sAML at time of transplant due to relapse on day 102 and 3 patients due to therapy-related mortality. One female patient who received a second unrelated HLA-matched transplantation after treosulfan-based regimen died of CMV pneumonitis on day 75. She did not response to ruxolitinib regarding spleen size and constitutional symptoms. A second patient with iron overload and liver fibrosis died of liver toxicity on day 47. This patient initially responded to ruxolitinib but progressed regarding spleen size prior to transplantation. One patient who responded to ruxolitinib regarding constitutional symptoms and spleen size (< 50%) died of GvHD on day 77. The estimated 1-year OS and PFS was 76% (95% CI: 54 – 98%). Conclusion Ruxolitinib reduces spleen size and constitutional symptoms in the majority of patients before allogeneic stem cell transplantation. Discontinuation of ruxolitinib at start of conditioning did not induce rebound phenomenon and did not negatively impact engraftment after transplantation. Longer follow-up is needed to determine late outcome. Disclosures: Wolf: Novartis: Research Funding.

Long-Term Follow-Up of Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3032-3032
Author(s):  
John Kuruvilla ◽  
Qikun Bao ◽  
Mira Goldberg ◽  
Vikas Gupta ◽  
Thomas L. Kiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Conditioning Regimen ◽  
Small Sample ◽  
Unrelated Donor

Abstract Introduction Allogeneic stem cell transplantation (Allo-SCT) remains an option for patients with chronic lymphocytic lymphoma (CLL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics and prior therapy. We performed a retrospective analysis to examine long-term disease control and treatment toxicity. Methods A total of 52 patients (pts) are included who underwent allo-SCT at our institution between Aug 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. Reduced intensity conditioning (RIC) SCT were typically performed with Fludarabine 50 mg/m2 for 4 days and 2 Gy TBI. GVHD prophylaxis was with cyclosporine A and methotrexate. Results There were 34 males and 18 females. The median age at the time of transplant was 51 years (range 26 to 65). Histologic subtype was: CLL and/or small lymphocytic lymphoma (SLL); 48 and T-prolymphocytic leukemia (PLL): 4. The median number of prior chemotherapy regimens was 3 (range 1 – 10) and was unavailable in 16. Prior chemotherapies included: anthracycline-based: 24, prior purine analog: 32, prior platinum-based: 8, prior auto-SCT: 1, prior rituximab: 5. The median time from diagnosis to allo-SCT was 58 months (range 5 – 260). 10 pts underwent RIC SCT. Graft source was: matched sibling (MSD) bone marrow (BM): 18, MSD peripheral blood stem cells (PBSC): 20, Mismatch related (MMRD) bone marrow (BM): 1, MRD PBSC: 4, matched unrelated donor (MUD) BM: 8, MUD PBSC: 1. At 5 years, the overall survival of the entire cohort is 51% (95% confidence intervals: 34 – 68%) with two long-term survivors of 14 and 17 years. Treatment-related mortality (TRM) was 20 of 52 pts (38%). 4 pts have relapsed ((8% of total cohort) and non-relapse mortality was 1 pt (2%). Overall survival by intensity of SCT conditioning regimen was not significant (p=0.3). TRM was similar in pts who received fully myeloablative SCT (40% vs. 20% in RICSCT group, p=0.29). Conclusions Acceptable survival post-SCT is possible using an allo-SCT strategy in CLL. However, TRM remains high in this group of heavily pre-treated patients with a median age of over 50 that predominantly received fully myeloablative allo-SCT. Due to small sample size, the potential benefit of reduced TRM with RICSCT cannot be demonstrated. Ideally, allo-SCT should be considered earlier in the course of the disease based on risk stratification utilizing traditional risk factors and modern prognostic factors such as FISH studies and novel markers.

Early and Favourable Immune Reconstitution After Unmanipulated Haploidentical Stem Cell Transplantation With High Dose Post-Transplant Cyclophosphamide Regardless Intensity Of Conditioning Regimen

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4620-4620
Author(s):  
Isabel Gonzalez-Gascon y Marin ◽  
Ana María Pérez-Corral ◽  
Jorge Gayoso ◽  
Javier Anguita ◽  
Ana Carolina Franco ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
High Dose ◽  
Post Transplant ◽  
Haploidentical Stem Cell Transplantation

Introduction Favourable immune reconstitution (IR) has been reported after reduced intensity conditioning (RIC) Unmanipulated Haploidentical Stem cell transplantation (Haplo SCT) with high dose post-transplant cyclophosphamide, and it has been suggested as a relevant factor for the good clinical outcomes observed. Due to the encouraging results in our centre the intensity of conditioning regimen has been increased in some patients with high risk of relapse. The aim of this study is to analyze whether the increase in intensity of conditioning influences immune reconstitution after Haplo-SCT. Methods and patients 22 patients (pts) with high risk hematologic malignancies treated in our centre with Haplo-SCT from 2007 to 2013 were included in the analysis. 8 pts received myeloablative(MA) conditioning regimen(fludarabine 30 mg/m2 IV (day -6 to -3) and busulfan 3.2 mg/kg IV (day -6 to -3) or fludarabine 30 mg/m2 IV (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 to -5), and busulfan 3.2 mg/kg IV (day -4 to -2)). 14 pts received RIC conditioning regimen (fludarabine 30 mg/m2 (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 and -5), and busulfan 3.2mg/kg IV (day -3 or day -4 to -3)). GVHD prophylaxis was high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for all patients. Median age was 43 years (26-65) and underlying diseases included: AML (8); ALL (1); MDS (2); MM (2); Hodgkin´s disease (7); mantle cell lymphoma (1); accelerated myelofibrosis (1). Median follow-up was 16 m (5-53). 13 pts were alive and disease-free at last follow-up and 4 pts died (3 relapse, 1 progressive multifocal leukoencephalopaty). We evaluated lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, NK, NKbright, and CD19) by flow cytometry (FC500 Beckman Coulter® cytometer) at 1, 3, 6, 9 and 12 months (m) post Haplo-SCT in the two groups (MA and RIC conditioning regimen). Immunoglobin serum levels were recorded at the same time points. For comparison Mann–Whitney U-test was used. Results In the 22 pts, NK cells were the first lymphocyte subset to recover with a median of 84/μl (5-480) and 145/μl (12-562) by m1 and m3 respectively. A high proportion of NKbright cells was observed at m1 post-transplant. This NKbright population decreased from a median of 83% (15-95) at m1 to 32% (9-95%) at m3, and 30% (9-57%) at m6. CD3+ T-lymphocytes (TL) reached normal levels at m3 after haplo-SCT (median 1109/μl (40-3187), and remained at normal range throughout the study period. CD4+ reached levels > 200/μl at m3 with a median of 247/μl (1-570), and also remained above this threshold during the follow up. Reconstitution of CD19+ B lymphocytes was adequate, with a median of 2/μl (0-76); 91/μl (0-556); 139/μl (3-600); 238 (105-575) and 236/μl (12-1098) on m1, 3, 6, 9 and 12 respectively. No difference was observed between RIC and MA conditioning for NK, NKbright; CD3+, CD4+, CD8+ T-lymphocyte and CD19+ B-lymphocyte count recovery. IgM was the first immunoglobulin to recover, reaching normal levels by m3 (61 mg/dL (10-264)), followed by IgG (normal levels at m12 (692 mg/dL (242-1530)). IgA reconstitution was delayed and did not reach normal levels by m12, as described before. No difference was found between RIC and MA conditioning for immunoglobulin recovery. Table 1 shows IR after haplo-SCT. Conclusions Rapid and favourable immunologic recovery was observed after haplo-SCT as reported before. Intensity of conditioning did not have any significant impact on the kinetics of immune recovery. Acknowledgments This work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures: No relevant conflicts of interest to declare.

Pharmacokinetics/Pharmacodynamic Relationship in Busulfan Conditioning Regimen: Results from a Large Pediatric Cohort Undergoing Hematopoietic Stem-Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 425-425
Author(s):  
Angelo Paci ◽  
Benedicte Neven ◽  
Vianney Poinsignon ◽  
Laura Faivre ◽  
Philippe Bourget ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Alkylating Agent ◽  
Conditioning Regimen ◽  
Therapeutic Window ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT). Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age <1 year at transplantation. Incidence of aGVH was 33%. However, these incidences were very different according to the CR. BuFlu showed the lowest incidence compared to other combinations of drugs (p < 0.001 and =0.022 for VOD and niPD, respectively). When using a second alkylating agent, incidence of VOD reached 41% (vs 19% in BuFlu, p<0.001) and niPD 17% (vs 8% in BuFlu, p<0.040). Toxicities were also related to BW, with 48% vs 30% (p<0.013) for VOD below or above 9 kg, and respectively, 28% vs 9% (p<0.0002) for niPD. This tendency was also found with a 15 kg cut-off for aGVH. No correlation was found with Bu AUC. However, there was a trend for lower OS (HR 1.60 [1.00-2.58], p=0.051) in patients with AUC D1 <900 µM.min compared to patients with AUC D1 > 900 µM.min. OS was 69.1% at last follow up and was not significantly associated with CR and age at transplantation. Conclusion: In this large series of pediatric BMT recipients, we found that toxicities as VOD and niPD correlated with type of CR and age at transplantation in univariate analysis. Combination of 2 alkylating agents with Bu or BuFlu and transplantation < 1 year of age were associated with the highest incidence of toxicites. The TW targeting performance was improved in this cohort compared to previous reported data (Paci et al. TDM 2012). Specific TW for each group of pathologies will be proposed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of the Francophone Society for Stem Cell Transplantation and Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3447-3447
Author(s):  
Regis Peffault De Latour ◽  
Matthieu Resche-Rigon ◽  
Didier Blaise ◽  
Johan Maertens ◽  
Patrice Ceballos ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Sibling Donor

Abstract Background: Nowadays acute myeloid leukemia (AML) patients above the age of 60 years are often candidates for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, little is known about the outcomes of HSCT in this particular population, due to the low number of HSCT with robust follow-up, the heterogeneity between centers, as well as reports usually mixing AML and other diseases such as myelodysplastic syndrome. We used the database of the Francophone society for stem cell transplantation and cellular therapy to address this question in a large cohort of patients in a recent time period. Patients and methods: 1167 consecutive patients aged ≥60 years with AML in complete remission (CR), transplanted between January 1st 2006 and January 1st 2016, reported to ProMISe (Project Manager Internet Server), an internet-based system shared by 36 Francophone transplantation centers, were reviewed. Classical post-HSCT endpoints were studied such as engraftment, acute and chronic graft-versus-host disease (GvHD), non-relapse mortality (NRM), relapse rate, leukemia free survival (LFS) as well as overall survival (OS). Cytogenetic risk was assessed according to the European Leukemia Network 2017 for patients in first complete remission. Data were analyzed using proportional hazards models and proportional sub-distribution hazards models in presence of competing risks. Results: Patients' Characteristics are detailed in Table 1. The median age at HSCT was 62.9 years (Interquartile range -IQR 61.9-66.1). Patients aged ≥60 years but less of 65 represented 63.8% of the population with 68.2% of patients transplanted in the recent period (2011-2016). Most patient had de novo AML (91.6%), in first CR (76.9%) with intermediate risk (83.8%) according to ELN-2017 classification. A matched unrelated donor (MUD) was used in 45 % of transplants and the majority of patients received peripheral blood stem cells (83.7%). Half of the patients received fludarabine and 2 days busulfan as conditioning regimen. The majority of patients (70.9%) received anti-thymocyte globuline (ATG). Engraftment occurred in 1089 patients (93.3%; 95%CI, 91.9-94.8). Day 100 cumulative incidence of grade II-IV acute GVHD was 24.6% (15.7% grade II; 5.8% grade III; 3% grade IV). At last follow up, 378 patients had developed chronic GVHD (severe in 37.2% of them; 95%CI, 34.0-40.3). With a median follow-up of 3.5 years (95%CI, 3.1-3.7 years), overall survival (OS) and LFS probabilities at 3 years were 50.7% (95%CI, 47.7-54.0) and 44.8% (95%CI, 41.8-48.1), respectively. In multivariable analysis, the only factor associated with worse OS was the use of a mismatched unrelated donor compare to MUD [Hazard Ratio (HR): 1.35 (95% CI, 1.01 to 1.80), p=0.04]. At 3 years, relapse incidence was 34.4% (95% CI, 31.5-37.4). The use of a sibling donor compared to MUD [Sub-distribution Hazard Ratio (SHR): : 1.49 (95% CI, 1.19 to 1.87), p<0.001], poor risk AML in CR1 according to ELN classification [SHR: 1.49 (95% CI, 1.10 to 2.02), p=0.01], as well as the use of ATG in the conditioning regimen [SHR: 1.57 (95% CI, 1.21 to 2.05), p<0.001] were associated with a higher risk of relapse. During the study, 534 patients died (main causes of death was relapse, 53%); leading to a CI of NRM of 20.7% at 3 years (95%CI, 18.2-23.2). A karnofsky score above 90% [SHR: 0.74 (95% CI, 0.56 to 0.98), p=0.04] and the use of a sibling donor compare to MUD [SHR : 0.43(95% CI, 0.30 to 0.63), p<0.001] were associated with reduced NRM. Conclusion: With more than 3 years follow-up, which is long enough for our results to be considered to be robust, the use of a mismatched unrelated donor was the only factor associated with worse overall survival in this population of AML patients aged of 60 years or more. Relapse appeared as the first cause of death, independently related to AML ELN poor risk classification, but also to the use of a sibling donor and of ATG in the conditioning regimen. This study highlights the major role of alloreactivity in this particular population, where modulation of T-cell alloreactivity as well as donor choice should be urgently addressed in well-designed prospective trials. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

scholarly journals Allogeneic Stem Cell Transplantation for Primary or Secondary Myelofibrosis: A Retrospective Intent-to-Treat Analysis and Impact of Mutational Status and JAK1/2 Inhibitor Ruxolitinib Prescription in Patients Who Cannot Proceed to Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3218-3218
Author(s):  
Elsa Lestang ◽  
Pierre Peterlin ◽  
Yannick Le Bris ◽  
Jacques Delaunay ◽  
Viviane Dubruille ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Triple Negative ◽  
Univariate Analysis ◽  
Allogenic Stem Cell Transplantation ◽  
Mutational Status ◽  
The Impact

Abstract Introduction: Allogenic stem cell transplantation (Allo-SCT) remains currently the only curative treatment for primary myelofibrosis (PMF) or myelofibrosis secondary (SMF) to essential thrombocythemia (ET)/polycythemia vera (PV). Indication of allo-SCT refers to high-risk patients defined by various scores such as Lille score, IPSS, DIPSS or more recently DIPSS+. However, JAK2, CALR, MPL or triple negative mutation profiles have recently been shown to impact on the outcome of PMF patients and thus may challenge the indication of allo-SCT in the future. CALRmut patients seem to have the best survival conversely to triple-negative patients, while JAK2mut and MPLmut status can be considered as an intermediate molecular signature (Tefferi, Leukemia 2014). The outcome of MF patients with a validated allo-SCT indication who do not proceed to transplant is generally unknown although relatively long survival can be documented, especially since the availability of JAK inhibitors such as ruxolitinib. Also, data regarding impact of mutational status on outcome after allo-SCT remain scarce. Patients and Methods: This single-center retrospective study considered MF patients with a validated indication of allo-SCT between 2000 and 2013. The main objective was to compare the overall survival (OS) between patients who ultimately received allo-SCT or not. Secondary objectives were to analyze the impact of mutational molecular status on OS and the use of ruxolitinib in patients not allografted. Results: An indication of allo-SCT was validated in 67 patients (males: 64%; PMF: 59%; SMF post-ET 25%, SMF post-PV 16%). At the time of indication of ASCT, the median age was 59 years (range: 41-69); DIPSS+ score was: int-2 in 40%, high risk in 60%. Mutational status, available for 86% of patients, was as follows: JAK2V617F (n=37), CALRmut (n=12); MPLmut (n=3), triple-negative (n=6). Thirty-three patients proceeded to allo-SCT (reduced intensity conditioning: 82%) while 34 did not for lack of donor (31%), comorbidity (28%), progressive disease (14%), stable disease on conventional therapy (18%), refusal (9%). The two groups (allo/non-allo SCT) were comparable for gender, year of indication of allo-SCT, type of MF, number of prior lines of treatment before allo-SCT, DIPSS+ categorization, mutational status and median follow-up. Patients who did not proceed to allo-SCT were significantly older (61 vs 57 years, p<0.005). Two allografted patients received ruxolitinib after transplant while 9 patients received it after invalidation of the transplant procedure. With a median follow-up of 44 months, median OS was 57 months for the whole cohort. A significantly lower OS was associated to unfavorable karyotype (median: 17 vs 100 months, HR: 2.6, 95%CI: 1.1-6.5, p=0.02), higher percentage of circulating blasts at time of indication of SCT (HR: 1.15, 95%CI: 1.01-1.32, p=0.01) and higher DIPSS+ score (HR: 1.3, 95%CI: 1.01-1.6 p=0.01). There was a trend for a better OS in CALRmut patients compared to other patients (median not reached (NR) vs 35 months, HR: 0.63, 95%CI: 0.25-1.51, p=0,3), especially vs triple-negative patients (NR vs 15 months, HR:0.29, 95%CI: 0.09-0.9 p=0.025). Five-year OS was similar between both groups (allo: 51% vs non-allo 44%, p=ns). However, progression to myelodysplastic syndrome or acute myeloid leukemia was significantly lower for allografted patients (19.2% vs 44.5%, p=0.01). In univariate analysis, allo-SCT benefited to patients with SMF post TE/PV (median OS: allo 115 vs non-allo 18.4 months, HR: 0.18, 95%CI: 0.05-0.5, p=0.004), unfavorable karyotype (median OS: allo: NR vs non-allo 7.9 months, HR: 0.13, 95%CI: 0.04-0.4, p=0.002) or high DIPSS+ score (median OS: allo 120 vs non-allo 18 months, HR:0.41, 95%CI: 0.16-0.9, p=0.04). Also there was a trend for better OS in allografted patients with high JAK2V617F burden (>65%) (median OS: NR vs 18 months, HR: 0.18, 95%CI:0.03 -1.11, p=0.065). Interestingly, the survival of patients who did not proceed to allo-SCT was increased by the use of ruxolitinib (median OS: NR vs 20 months, HR: 2.3, 95%CI: 0.08-0.6, p=0.003). Conclusion: Allo-SCT remains a valid strategy for high-risk MF patients with unfavorable karyotype, high DIPSS+ score and secondary MF while impact of mutational status and JAK2V617F burden have to be confirmed in larger studies. MF patients who cannot proceed to transplant likely benefit from JAK2 inhibitor prescription. Disclosures Milpied: Celgene: Honoraria, Research Funding. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

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