scholarly journals Long-Term Survival after Transplantation in Patients with Chronic Myeloid Leukemia from HLA-Compatible Unrelated Donors: May the Stem Cell Source Influence the Outcome?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5775-5775
Author(s):  
Michael Koldehoff ◽  
Ahmet H. Elmaagacli ◽  
Hellmut Dietmar Ottinger ◽  
Ulrich Dührsen ◽  
Dietrich W. Beelen
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Disease Stage ◽  
Unrelated Donor ◽  
Advanced Stages

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes regarding graft sources are not well described. Results Here the outcomes of CML after alloSCT with bone marrow (BM, n=134) were compared to those of peripheral blood stem cell (PBSC, n=172) in the HLA-compatible unrelated donor setting. Patients were transplanted in 1st CP (Bone marrow transplantation (BMT), n=100, and Peripheral blood stem cell transplantation (PBSCT), n=103), in >1st CP (BMT, n=24, and PBSCT, n=52) and in blast crises (BMT, n=10, and PBSCT, n=17). Median follow-up were 54 months after BMT and 106 months after PBSCT. No significant differences were found in the incidence of acute and chronic graft-versus-host disease (GvHD) between both study-groups. The 5-year estimated probability of hematological relapse was 11% for patients in 1st CP CML and 49% for patients in advanced disease after BMT (p<0.001) and 18% for patients in 1st CP and 22% for patients in advanced disease after PBSCT (p= n.s.). The estimated probability for 10-year overall survival (OS) for patients in 1st CP and patients in advanced stages of CML were 58% and 20% after BMT and 59% and 52% after PBSCT, respectively (not significant for 1st CP and p<0.0001 for advanced stages). In the multivariate analysis patient age (age > 40 years), disease stage, acute GvHD, chronic GvHD and immunprophylaxis with use of ATG influenced OS significantly. For leukemia-free survival, the following risk factors were significantly in the multivariate analysis, graft source, patient age, gender constellation, disease stage, acute GvHD and chronic GvHD. Conclusions This large trial show significant difference between transplant recipients who received PBSC and those who received BM from unrelated donor. These finding may influence the selection of a graft source for alloSCT from unrelated donor. Disclosures Dührsen: Amgen: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support.

Post-Transplant Cyclophosphamide Following Myeloablative Peripheral Blood Stem Cell Transplantation: A Single Institutional Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3911-3911
Author(s):  
Racquel Innis-Shelton ◽  
Donna Salzman ◽  
Antonio Di Stasi ◽  
Lawrence S. Lamb ◽  
Melissa Gazi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Blood Stem Cell Transplantation

Abstract BACKGROUND Graft versus host disease (GVHD) remains a major complication after allogeneic peripheral blood stem cell transplantation (PBSCT). Post-transplant cyclophosphamide (CY) has been shown to mitigate risk of GVHD after T-cell replete HLA haploidentical (haplo) bone marrow transplantation. We sought to identify the benefit of post-transplant CY in various diseases following myeloablative PBSCT. METHODS We treated 71 patients with post-transplant CY following allogeneic PBSC (T-cell replete) HLA matched unrelated donor (MUD), HLA mismatched unrelated donor (mMUD), haplo, and HLA matched related donor (MRD) transplant. The conditioning regimens were fludarabine (160 mg/m2)/busulfan (AUC 12-20,000) (+/- TBI 4 Gy for haplo) for myeloid malignancies, fludarabine (160 mg/m2)/TBI 10 Gy (or 8 Gy for haplo) or CY/TBI 12 Gy for lymphoid malignancies (total CY dose 120 mg/m2 including post-transplant CY). GVHD prophylaxis consisted of post-transplant CY 50 mg/m2 on day +3 (and day +4 for haplo), tacrolimus, day +5 to +100 (then taper over 3 months) and mycophenolate mofetil, day +5 to day +35. All patients received G-CSF (5 mcg/kg/day) starting day +5 until neutrophil engraftment. All patients received prophylactic antifungal (until day +75), antiviral (for one year), PCP prophylaxis (day +30 to +180) and antibacterial therapy (until day +100) or longer if on high-dose steroid. RESULTS The 71 patients were treated between July 2012 and July 2014 at our institution. The donors were MUD, mMUD, haplo, or MRD (N = 46, 11, 13, 1 respectively). Patients had acute myeloid leukemia (n = 31 either in first or subsequent remission) including one patient with blastic plasmacytoid dendritic cell neoplasm, myelodysplastic syndrome (n = 13), acute lymphoblastic leukemia (n = 5, all in CR1 or 2), non-Hodgkin lymphoma (n = 5), Hodgkin lymphoma (n = 3), primary myelofibrosis (n = 6), chronic myeloid leukemia (n = 4), chronic lymphoid leukemia (n = 1), severe aplastic anemia (n = 2), and erythropoietic porphyria (n = 1). The median age of patients was 50 years (range: 17-72), 36 were males and 62 were Caucasians. Five patients had prior autologous transplant. All patients engrafted except one halpo patient who was successfully re-transplanted with repeat haplo (different donor) using non-myeloablative regimen (FLU/CY/TBI 4 Gy). Neutrophil and platelet engraftment occurred after a median of 12 days (range: 6-18) and 13 days (range: 5-40). The cumulative incidence of acute GVHD grade II-IV and III-IV was 16% and 8% respectively. The cumulative incidence of chronic GVHD was 54% (mild, moderate and severe; 22%, 24% and 8%). The overall cumulative relapse rate was 20%, however, 65% of AML patients relapsed after MUD transplant (n = 23) while none of them relapsed after mMUD or haplo transplant (n = 8). The overall non-relapse mortality (NRM) was 14% (total of 10 patients died as follows: GVHD; 2, infections; 4, hepatic failure; 1, toxic epidermal necrolysis; 1, pulmonary embolism; 1, lung injury; 1). The 1-year overall survival was 68% (95% CI: 54-79) (figure 1) and the 1-year disease-free survival (DFS) was 58% (95% CI: 43-71) (figure 2). CONCLUSION The use of post-transplant CY following myeloablative (using disease-specific preparative regimens) T-cell replete PBSCT of HLA-matched/mismatched unrelated and haploidentical donors is feasible with acceptable risk of acute and chronic GVHD, and NRM. The use of one dose of post-transplant CY after MUD transplant was associated with high risk of relapse in AML patients. Caution is to be exercised in designing clinical trials of MUD transplant for AML using post-transplant CY. DISCLOSURES: See Conflict of Interest (COI) Disclosure statements submitted by all authors Figure 1A: OS of the whole cohort (n = 71) Figure 1A:. OS of the whole cohort (n = 71) Figure 1B: OS of the Haplo transplant cohort (n = 13) Figure 1B:. OS of the Haplo transplant cohort (n = 13) Figure 2 DFS of the whole cohort (n = 71) Figure 2. DFS of the whole cohort (n = 71) Disclosures Off Label Use: Cyclophosphamide used after stem cell transplant for graft vs host disease prophylaxis in haploidentical, matched and mismatched unrelated donor T cell replete myeloablative transplants..

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2285-2285
Author(s):  
Simona Pagliuca ◽  
Antonio M Risitano ◽  
Sylvie Chevret ◽  
Flore Sicre de Fontbrune ◽  
Alienor Xhaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Treosulfan Compared to Total Body Irradiation-Based Preparative Regimens Before Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia : A Retrospective Long-Term Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2149-2149
Author(s):  
Dietrich Wilhelm Beelen ◽  
Tanja Gromke ◽  
Rudolf Trenschel ◽  
Inken Hilgendorf ◽  
Daniel Wolff ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Disease Stage ◽  
Risk Category ◽  
Clinical Endpoints ◽  
Advanced Stages ◽  
Total Body

Abstract Background: The tolerability and efficacy of high-dose dihydroxy-busulfane (Treosulfan [Treo]), a water-soluble bifunctional alkylating agent with profound stem cell toxicity, as the major myelotoxic component of the preparative regimen preceding allogeneic stem cell transplantation (alloSCT) in patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) has been recently demonstrated in phase II clinical trials. Since no prospective trials directly comparing Treo-based conditioning to a myeloablative total body irradiation (TBI) regimen will be available in the near future, the major clinical endpoints after Treo-based conditioning in comparison to a myeloablative TBI regimen were evaluated in adult pts with AML. Methods: A total of 203 pts who underwent alloSCT between 1999 and 2005 were included in this bi-centre retrospective study, of whom 46 pts (23%) had received a Treo-based regimen (3 x 14 g/ m2), while 157 pts had been conditioned with TBI (4 x 2.5 Gy to 6 x 2 Gy), each combined with either fludarabine (5 x 30 mg/m2) or cyclophosphamide (2 x 60 mg/kg). Both cohorts were well comparable in terms of patient age, donor type, disease stage, cytogenetic risk category, and the hematopoietic cell transplantation comorbidity index (HCT-CI). The median follow-up time of all pts is 58 months (mo) (range 4 – 110 mo). Results: For 125 pts transplanted in complete remission (CR)(CR1: 61 pts, CR2: 64 pts), non-relapse mortality (NRM) at 100 days, 1, and 3 years (yrs) after transplant was 6% (95% confidence limits [CL]: 0%–15%), 13% (95%-CL: 9%–24%), and 30% (95%-CL: 13%–30%) after Treo-compared to 10% (95%-CL: 4%–16%), 16% (95%-CL: 9%–24%), and 22% (95%-CL: 13%–30%) after the TBI-based regimen (ns). Similarly, no significant difference of NRM between the two regimens was detectable for the 78 pts in more advanced disease stages. Further, the post transplant risk of hematologic relapse (RR) was not influenced by the conditioning regimen: The RR for CR pts at 1 and 3 yrs was 13% (95%-CL: 1%–25%) and 16% (95%-CL: 3%–30%) after Treo-compared to 25% (95%-CL: 16%–34%) and 33% (95%-CL: 23%–43%) after TBI-based conditioning (ns). The corresponding figures for more advanced stages were 43% (95%-CL: 16%–70%) and 57% (95%-CL: 27%–87%) compared to 29% (95%-CL: 17%–40%) and 33% (95%-CL: 21%–46%), respectively (ns). Overall survival (OS) for all CR pts at 1 and 3 yrs was 77% (95%-CL: 63%–92%) and 54% (95%-CL: 36%–73%) after Treo-compared to 68% (95%-CL: 58%–67%) and 49% (95%-CL: 38%–60%) after TBI-based conditioning (ns). For pts transplanted in CR1, OS at 1 and 3 yrs reached 79% (95%-CL: 61%–97%) and 63% (95%-CL: 41%–85%) after Treo- and 70% (95%-CL: 58%–82%) and 53% (95%-CL: 39%–66%) after TBI-based conditioning (ns). In more advanced stages, OS at 1 and 3 years declined to 29% (95%-CL: 0%–7%) and 21% (95%-CL: 0%–50%) after Treo- and to 29% (95%-CL: 15%–44%) and 16% (95%-CL: 1%–32%) after TBI-based conditioning, respectively (ns). Major determinants of OS and RR were the disease stage (CR vs more advanced stages) and the cytogenetic risk category (low-intermediate vs high risk). The HCT-CI (stratified to &lt;=2 or &gt;2) had no apparent influence on NRM, RR, or OS in this analysis. Conclusion: This retrospective long-term analysis supports that Treo-based conditioning leads to at least equivalent results regarding the major clinical endpoints of alloSCT when compared to a standard myeloablative TBI-based conditioning regimen in adult AML pts. An international prospective multicenter randomized trial has now been launched (EudraCT-No. 2008-002356-18) to compare Treosulfan-based conditioning with a reference reduced intensity conditioning regimen in AML and MDS pts.

α4β7± Regulatory T Cells (Tregs) at Engraftment Predict Long-Term Graft-Versus-Host Disease (GVHD) Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2237-2237
Author(s):  
Brian G Engelhardt ◽  
Madan Jagasia ◽  
Michael T Rock ◽  
Adetola A. Kassim ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Clinical Severity ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Treg Population ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract Abstract 2237 Poster Board II-214 Background: GVHD occurs unpredictably after allogeneic stem cell transplant (ASCT). GVHD is characterized by profound immune dysregulation, which suggests that abnormalities in suppressor lymphocytes known as Tregs may account for the clinical features of this disease. We have shown that the frequency of Tregs or α4β7± Tregs at neutrophil engraftment predict for recurrent grade II-IV GVHD or recurrent gut GVHD during the first 100 days of transplant, respectively. These data indicate that early lymphocyte populations may determine long-term immune-tolerance following ASCT. We hypothesized that Treg subsets present at engraftment would be associated with the occurrence, National Institutes of Health (NIH) phenotype, and severity of GVHD after day±100. Methods: Patients (pts) undergoing T cell replete ASCT were enrolled. GVHD after day±100 was classified prospectively as either: acute GVHD, overlap GVHD, or classic chronic GVHD using consensus criteria derived from the NIH. Clinical severity was determined by the modified Glucksberg criteria for acute GVHD and the NIH global assessment of severity for overlap/classic chronic GVHD. The frequency of CD45RO±CD25±Foxp3±CD127lo Tregs was quantified within the CD4± T-lymphocyte population at the time of neutrophil engraftment using polychromatic flow cytometry. Gut-homing Tregs were identified by the presence of α4β7±, and their frequency was expressed as a percentage of the total Treg population. Results: Treg analysis was performed at a median of 19 days post-transplant (range, 10-31) on 41 pts undergoing ASCT and surviving until day±100. Twenty-four (59%) pts received ablative conditioning and 17 (41%) pts received a reduced intensity regimen followed by matched related [N= 24 (59%)] or unrelated donor [N= 17 (41%)] ASCT. The stem cell source was peripheral blood, bone marrow, or cord blood for 30 (73%), 9 (22%), and 2 (5%) pts, respectively. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate [N=23 (56%)] or mycophenolate mofetil [N=18 (44%)]. The majority of patients had grade II-IV acute GVHD prior to day±100 [N=34 (83%)]. After a median follow-up of 15 months (range, 5-24) GVHD after day±100 occurred in 32 (78%) pts at a median of 152 days post ASCT (range, 103-533). GVHD phenotype was classified as: acute (N=19), overlap (N=9), or classic chronic (N=4). Grade III-IV acute and moderate to severe overlap/classic chronic GVHD occurred in 3 (7%) and 11 (27%) pts, respectively. Pts with GVHD after day±100 had lower frequencies of Tregs and α4β7± Tregs at engraftment (4.4% vs. 14.3%; P=0.145) and (9.9% vs. 20.7%; P=0.009), respectively. After excluding pts with gut GVHD, the association between α4β7± Tregs and GVHD after day±100 persisted (P=0.034). Median Treg percentages did not differ among GVHD phenotypes [acute (4.4%) vs. overlap (4.2%) vs. classic chronic (5%) vs. none (14.3%); P=0.464]. However, significant differences between α4β7± Treg frequencies and GVHD subtypes were noted [acute (11%) vs. overlap (9.6%) vs. classic chronic (11.6%) vs. none (20.7%); P=0.002]. α4β7± Treg differences were most apparent when pts with any acute GVHD (acute±overlap) were compared to pts without features of acute GVHD (none±classic chronic) (9.9% vs. 19.4%; P=0.009). Increased frequencies of Tregs and α4β7± Tregs at engraftment tended to be associated with lower grades of acute GVHD after day±100 [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.87-1.04; P=0.255 (Tregs) and OR, 0.81; 95% CI, 0.70-0.92; P=0.002 (α4β7± Tregs)] and less severe overlap/classic chronic GVHD [OR, 0.91; 95% CI, 0.79-1.04; P=0.158 (Tregs) and OR, 0.93; 95% CI, 0.86-1.01; P=0.071 (α4β7± Tregs)]. Using Cox Proportional Hazard regression (adjusting for donor type and acute GVHD prior to day ±100), increased frequencies of α4β7± Tregs at engraftment continued to be associated with decreased risk of GVHD after day ±100 (hazard ratio, 0.93; 95%CI, 0.88-0.99; P=0.013). Conclusion: Frequency of α4β7± Tregs at engraftment is associated with the incidence and severity of GVHD after day ±100. These data suggest that early lymphocyte subsets and gut associated mucosal immunity are important in determining long-term graft tolerance. Treg subsets at engraftment could be used to risk stratify pts prior to development of GVHD or as an endpoint in future clinical trials examining interventions aimed at increasing Tregs and preventing GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Rate of Long Term Complete Remission for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapse after Allogeneic Stem Cell Transplantation and Receive Salvage with Donor Lymphocyte Infusions (DLI)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5860-5860
Author(s):  
Alan P Skarbnik ◽  
Mary E DiLorenzo ◽  
Tracy Andrews ◽  
Phyllis McKiernan ◽  
Scott D. Rowley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Advisory Committees

Abstract Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center. Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes. Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival. Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos). Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD. Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months. Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates. Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Skarbnik: Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.

A Bortezomib-Based Regimen Offers Excellent Outcomes In Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: Phase II Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3335-3335
Author(s):  
John Koreth ◽  
Haesook T. Kim ◽  
Paulina B. Lange ◽  
Bhavjot Bindra ◽  
Philippe Armand ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Upper Gi ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract In a phase I/II trial of a novel bortezomib-based regimen for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) recipients of HLA-mismatched peripheral blood stem cell (PBSC) grafts, we documented low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM), with promising survival. In registry analyses, myeloablative conditioning (MAC) HSCT recipients of both HLA-matched (MUD) and 1-locus mismatched donor (MMUD) grafts also have impaired outcomes, with day +100 grade III-IV acute GVHD rates of 28% and 37% respectively, 1-year NRM of 36% and 45% respectively, 1-year progression-free (PFS) of 47% and 38% respectively, and 1-year overall survival (OS) of 52% and 43% respectively. We therefore evaluated a similar bortezomib-based regimen in MAC HSCT recipients lacking 8/8 HLA-matched (-A, -B, -C, -DRB1) related donors. In a prospective single-arm phase II trial, we enrolled patients with hematologic malignancies, aged 18-60 years, receiving MUD, MMUD, or mismatched related donor (MMRD) grafts. Myeloablative conditioning was IV busulfan (130 mg/m2, without PK dose adjustment) and fludarabine (40 mg/m2) once daily for 4 doses (days -7 to -4). T-replete PBSC grafts with ≥ 2x106 CD34+ cells/kg were infused on day 0. GVHD prophylaxis comprised bortezomib (1.3 mg/m2 IV on days +1, +4, +7), methotrexate (15 mg/m2 IV on day +1, 10 mg/m2 on days +3, +6, +11) and tacrolimus from day -3, with a planned taper starting day +100 and complete by day +180. The primary endpoint was day +100 acute GVHD incidence. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. The 34 patients (19 male, 15 female), accrued between March 2011 and November 2012, had a median age of 49 years (range, 21-60) and variable diagnoses (17 AML, 6 MDS, 4 NHL, 3 MPD, 2 ALL, 1 CML, 1 MM) and disease risk indices (Low 1, Intermediate 24, High 9). They received 8/8 MUD (n=14), 7/8 MMUD (n=18) or 7/8 MMRD (n=2) PBSC grafts. Mismatches (16 antigen-, 4 allele-level) involved HLA-A (9), -B (1), -C (6) and -DRB1 (4). The median follow up in survivors is 20 months (range, 7.2-25.5). The regimen was feasible and well tolerated. Mucositis was noted in the MAC recipients, but no doses were missed due to toxicity. Excluding 1 patient who died of sepsis prior to engraftment, neutrophil and platelet engraftment was prompt, at a median of 14 (range, 3-33) and 17 (range, 7-54) days respectively. Median day +30 donor chimerism was 99% (range, 90-100). Grade II-IV acute GVHD incidence by day +100 and +180 was 32% and 36% respectively, but only 18% and 21% respectively if upper GI GVHD (which had excellent long term outcomes) was excluded. Grade III-IV acute GVHD incidence by day +100 and +180 was 12%. 2-year cumulative incidence of NRM and relapse was 8.8% and 5.9% respectively. 2-year PFS and OS was 85% and 84% respectively (Figure). 2-year cumulative incidence of extensive chronic GVHD was 57%. For 8/8 MUD vs. 7/8 MMRD/MMUD, grade II-IV acute GVHD by day +180 was 30% vs. 40% (p=0.47) (excluding upper GI GVHD, 16% vs. 25%, p=0.42), and grade III-IV acute GVHD was 7% vs. 15% (p=0.48) respectively.FigureStudy SurvivalFigure. Study Survival In conclusion, bortezomib-based prophylaxis for MAC HSCT recipients of HLA-mismatched and unrelated donor grafts was safe and well-tolerated, with low rates of severe acute GVHD, NRM and relapse, and excellent long-term survival. On preliminary landmark analysis, upper GI GVHD did not appear to impair transplantation outcomes. Bortezomib-based prophylaxis is suitable for prospective randomized evaluation in myeloablative transplantation recipients lacking HLA-matched related donors. Disclosures: Koreth: Millennium pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy. Off Label Use: Bortezomib for GVHD prophylaxis.

scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

A Randomized, Double Blind Trial, of Hydroxychloroquine for the Prevention of Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1800-1800
Author(s):  
Tom Fong ◽  
Kim Trinkaus ◽  
Douglas R. Adkins ◽  
Ravi Vij ◽  
Steven Devine ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Double Blind ◽  
Graft Versus Host ◽  
Blood Stem Cell Transplantation

Abstract Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). We previously reported low incidences of acute GVHD in unrelated donor transplant recipients who received prophylactic HCQ in addition to standard GVHD prophylaxis (BBMT2003; 9: 714–721). We herein report results of a single-institution phase III trial, in which 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ or placebo starting 21 days pre-transplant and continued until d+365. HCQ was very well tolerated and not associated with side effects. The addition of HCQ had no effects on lymphocyte subsets both pre- and post-transplant. Overall, the incidence of acute GVHD was 59% in both arms, and severe acute GVHD occurred in 11% (HCQ) and 14% (placebo) (p=0.76). Sixty-one and 46% of patients developed chronic GVHD in the placebo and the HCQ arms, respectively (p = 0.15). With a median follow-up of 18 months, relapse-free and overall survivals were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single agent CSA was not associated with a reduction of either acute or chronic GVHD; additionally, no significant effects on relapses or survival were observed.

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