scholarly journals The Role of Anti-Thymocyte Globulin (ATG) in Patients with AML Transplanted in CR1 from Sibling and Unrelated Donors with or without Measurable Residual Disease (MRD) at the Time of Allogeneic Stem Cell Transplantation: A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 248-248 ◽  
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Gerard Socie ◽  
Anne Huynh ◽  
Maija Itälä-Remes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Residual Disease ◽  
Inclusion Criteria ◽  
Free Survival ◽  
Unrelated Donors ◽  
Grade Ii ◽  
The Impact ◽  
Measurable Residual Disease ◽  
Grade Iii

Abstract Background: Measurable residual disease (MRD) status pre-allogeneic stem cell transplantation (alloSCT) has been shown to predict outcome after transplant. Nonetheless, the impact of MRD persistence pre-alloSCT (MRD+) on transplant outcome might be modulated by relevant procedure features, such as conditioning intensity (Am J Hem 2018) or the use of anti thymocyte globulin (ATG) to prevent chronic graft versus host disease (cGVHD). Thus, since cGVHD is associated with graft versus leukemia effect (GVL), there is a concern that ATG may hamper GVL and increase relapse after transplant, especial in patients (pts) with a higher risk such as MRD+. For this purpose, we investigated whether MRD status pre-alloSCT modifies the effect of ATG on AML relapse post alloSCT in a large cohort of pts undergoing alloSCT in CR1, adjusting for other important variables on outcome. Methods: Inclusion criteria were adult AML pts with intermediate or adverse risk cytogenetics according to MRC and known FLT3-ITD status undergoing alloSCT in CR1 from either a HLA matched sibling (MSD) or (10/10) matched unrelated donors (MUD) during 2006-2017 period. First, we assessed the impact of MRD status, cytogenetics, FLT3-ITD and ATG as part of the conditioning in the whole population. Then, we studied the impact of ATG in accordance to MRD status at time of transplantation. Results are given at 2 years. Results: 1509 pts (1083 MRD negative (MRD-) and 426 MRD+) met the inclusion criteria. In the MRD- group, 552 (48%) pts did not receive ATG and 561 (52%) received ATG, whereas within MRD+ cohort, 187 (44%) received no ATG and 239 (58%) received ATG. Median age was 51 (range 18-73) years, 51% were females. Median year of alloSCT was 2014; 85% and 15% of the pts harbored intermediate and adverse risk cytogenetics, respectively. FLT3-ITD was identified in 51% of the pts, and NPM1 was mutated in 689 (56%). 59% of the pts underwent alloSCT from MSD while 41% from MUD. 82% of the pts received PB grafts; 58% received myeloablative (MAC) while 42% reduced intensity conditioning (RIC). The GVHD prophylaxis was CSA/MTX followed by CSA/MMF in the majority of the pts (75 %). 24% of pts developed grade II-IV while 7% grade III-IV acute (a) GVHD. cGVHD occurred in 30% of the pts, being extensive in half of them. In the overall population, aGVHD grade III-IV, cGVHD total and extensive were significantly lower in pts who received ATG in comparison to those who did not (6% vs 9%, p=0.04; 30% vs 45%, p<10-5; 15% vs 25%, p<10-4, respectively), translating into better GVHD-relapse-free survival (GRFS; 52% vs 43%, p=0.007). Non relapse mortality (NRM), relapse (RI), leukemia-free survival (LFS) and overall survival (OS) did not differ statistically between pts who received or did not receive ATG. Focusing on the influence of MRD status, RI was higher in MRD+ (39% vs. 23%, p<10-5), and LFS, OS and GRFS were all significantly superior in the MRD- cohort (66% vs 51% p<10-5; 73% vs 60% p=<10-5 and 51% vs 37% p<10-5, respectively). In contrast, NRM and GVHD did not differ between the groups. Then, we investigated the effect of ATG separately in MRD- and MRD+pts. By multivariate analysis, in MRD- pts, ATG did not affect RI (24% vs. 21% in no ATG and ATG; HR 0.80, P=0.17), but was associated with lower incidence of grade II-IV aGVHD, grade III-IV aGVHD, cGVHD, extensive cGVHD and NRM (HR 0.71 P=0.04, HR 0.37 P<10-3; HR 0.55 p<10-4, HR 0.42 P<10-4 and HR 0.66 p=0.05, respectively). As a consequence, ATG was associated with improved LFS, OS and GRFS (HR 0.74 P=0.02, HR 0.69 P=0.01 and HR 0.62 P<10-3). In MRD+ pts, ATG was associated with lower incidence of cGVHD and extensive cGVHD (HR 0.56 p= 0.03, HR 0.40 P=0.01, respectively), without a significant impact on any other alloSCT outcome parameters, including RI (39% vs 39% in no ATG and ATG; HR 1.02 P=0.92). FLT3 was associated with a higher RI in both MRD- and MRD+ pts. Finally, in both MRD- and MRD+groups, there was no interaction between ATG and cytogenetics, FLT3 and donor type as neither of these 3 factors influenced significantly the effect of ATG. Conclusions: ATG reduces severe (grade II-IV) acute and both chronic and extensive chronic GVHD in AML pts undergoing alloSCT in CR1, resulting in improved GRFS. Most importantly, the clinical benefit of ATG in terms of GVHD prevention was not achieved at the expense of an increased relapse incidence including in MRD+ pts pre-alloSCT. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria.

Impact of HLA Allele Mismatch on the Outcome of Patients with Reduced-Intensity Allogeneic Haematopoietic Stem Cell Transplantation from Unrelated Donors: Analysis of 103 Patients of the French Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3149-3149 ◽  
Author(s):  
Andrea Toma ◽  
Marie-Lorraine Balere-Appert ◽  
Zina Chir ◽  
Jean-Michel Boiron ◽  
Pierre Bordigoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donors ◽  
Grade Ii ◽  
The Impact ◽  
Hla Mismatches ◽  
Reduced Intensity

Abstract Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age <46y was only associated with less acute GvHD grade II to IV (p=0.008). Among HLA mismatches, we found that HLA-A and/or -B allelic mismatches had a negative impact on OS (p=0.006), DFS (p=0.006), acute GvHD grade II to IV (p=0.05). On the other hand, HLA-C or -DQB1 mismatches did not impact on OS, DFS, acute or chronic GvHD. We could not analyze DRB1 mismatch since there was only 2 patients reported. In conclusion, HSCT following RIC, with match or mismatch unrelated donors, is a feasible approach with best results observed for patients with lymphoid malignancies (NHL, CLL or HD). Among allelic HLA mismatches, HLA-A and/or -B seemed to be deleterious as compared to HLA-C or DQB1. These results help to identify most suitable donors and patients who are likely to benefit from RIC with unrelated donors when there is not a fully HLA match donor available.

Improved Immune Reconstitution Following Pre-Emptive CD8-Depleted Donor Lymphocyte Infusions (DLIs) after Haploidentical Stem Cell Transplantation (SCT) Using a Reduced-Intensity Conditioning (RIC) Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2908-2908
Author(s):  
Paolo Corradini ◽  
Anna Raganato ◽  
Matteo Carrabba ◽  
Lorenza Gandola ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Immune Recovery ◽  
Grade Ii ◽  
The Impact

Abstract Allogeneic stem cell transplantation (SCT) from an haploidentical family donor has been reported as a viable option in acute leukemias when matched donors are unavailable. However, the extensive T-cell depletion (TCD), required to prevent graft-versus-host disease (GVHD), is associated to delayed immune recovery and high transplant-related mortality. In an ongoing phase I–II trial for patients (pts) with advanced hematological malignancies, we combined a RIC regimen, including thiotepa (10 mg/kg), fludarabine (120 mg/ms), cyclophosphamide (60 mg/kg) and TBI (2 Gy), with pre-emptive administration of CD8-depleted DLIs (starting from 1x104 up to 1x105 cells/kg). Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (30 mg day −2), respectively. The aim of the study was to investigate in a dose finding study the safety and the impact on immune-reconstitution of CD8-depleted DLIs. Six-teen pts with hematological malignancies (n=14 NHL/HD, n=1 ALL, n=1 AML) were included, median age was 35 years (range, 15–65), 10 (63%) were chemorefractory, and 68% and 75% had failed a previous auto or at least 3 CT lines, respectively. Pts received a median of 10.6 x106/Kg CD34+ and 1x104/kg CD3+. All pts engrafted with full donor chimerism from day +30. At a median follow-up of 9 months, 12 pts were alive and 4 died (n=1 infection, n=3 disease). The estimated OS at 2 years was 58%; 7 of 16 (44%) relapsed at median time of 100 days after SCT. CD8-depletion of 14 donor lymphocyte aphereses was performed with a new depletion protocol (Clinimacs CD8-Microbeads) that reduces the content of CD8+ cells by at least 3 logs. The median CD3+, CD4+, CD56+/CD3+, CD20+ cell recovery were 62% (range, 35–91%), 88% (63–128%), 51% (8–78%), 76% (33–128%), respectively. Before DLIs, only 1 of 16 pts (6%) developed de novo acute GVHD (grade II). A total of 22 CD8-depleted DLIs were administered to 9 of 16 pts without any engraftment problem. The first cohort of pts (n=5) received a total dose of 3–6x104/kg CD8depleted DLIs starting at day +45 divided in 3 monthly infusions: none of them developed aGVHD. Given no toxicity, we escalated doses and the second cohort (n=4) received a total dose of 10–25x104/kg CD8-depleted DLIs divided in 3 monthly infusions: 3 pts had acute GVHD (grade II). Overall, the incidence of acute GVHD was higher (75% vs 0%, P&lt;0.04) in pts receving larger numbers of donor cells. Interestingly, the median values of CD4+/ul and CD8+/ul were 98 (range, 8–612) and 150 (range, 15–988) at 4 months; 247 (range, 55–333) and 235 (range, 3–1000) at 5 months after SCT. The median value of CD19+/ul cells were 134 (range, 0–292) and 160 (range, 0–256) at 4 and 5 months, respectively. NK cells remained between the value of 394/ul and 569/ul in the first 6 months after SCT. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment and a low acute GVHD incidence; (2) pre-emptive CD8-depleted DLIs are feasible without GVHD until the total dose of 6 x104/kg; 3) higher doses can induce acute GVHD, but no grade III–IV was observed; 4) despite the limited number of pts, we observed a faster immune recovery and a relatively low mortality rate for infections.

Donor Type Impacts the Incidence of Severe Acute but Not Chronic Graft- Versus-Host Disease (GVHD) after Reduced Toxicity Conditioning and Allogeneic Stem Cell Transplantation (ASCT) for Treatment of AML/MDS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2227-2227
Author(s):  
Ri ma M. Saliba ◽  
Krishna V. Komanduri ◽  
Ebru Koca ◽  
Amin M. Alousi ◽  
Sergio Giralt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Donor Type ◽  
Grade Ii ◽  
Reduced Toxicity ◽  
Grade Iii

Abstract The use of reduced intensity conditioning has resulted in a significantly lower incidence of severe acute GVHD (aGVHD) compared with myeloablative conditioning. It is not known if reduced toxicity myeloablative conditioning has a similar impact. To answer this question, we evaluated the incidence of acute and chronic GVHD in a homogeneous group of AML/MDS patients treated with Fludarabine (Flu) and IV Busulfan (IVBu) between April 2001 and August 2005 at MD Anderson Cancer Center. METHODS: Retrospective analysis of all 195 consecutive AML/MDS patients (pts) who received conditioning with IVBu (130 mg/m2 for 4 days) and Flu (40 mg/m2 for 4 days) and allogeneic stem cell transplantation (ASCT). The cumulative incidence of GVHD was estimated considering disease progression or death in the absence of GVHD as competing risks. Cox’s proportional hazards regression analysis was used to compare the rates of GVHD. RESULTS: Median age at the time of transplantation was 46 years (12–65) with 4 pts being younger than 18 years. 45% of pts (n=93) were females and 47% (n=92) were in complete remission at the time of transplant. 55% (n=107) received a graft from a matched related donor (MRD), 38% (n=74) from a matched unrelated donor (MUD), and 7% (n=14) from a 1 Ag mismatched related or unrelated donor. Stem cell source was peripheral blood in 85% of recipients of a MRD graft and bone marrow in 88% of recipients of a MUD graft. The median number of CD34+ cells infused was 4.6 x 106/Kg (range 1.1–8.9) and 3.8 x106/Kg (range 0.2–13) in the two groups respectively. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. In addition, 29/74 recipients of a MUD graft received varying doses of pentostatin on a phase I/II clinical trial. Evaluation of GVHD was limited to pts who received a graft from a MRD or MUD and engrafted (n=179/181). With a median follow-up among survivors of 48 months (range 16–80), 100 day actuarial survival was similar in recipients of a MRD (96%) and MUD (93%) graft (p=0.3). A total of 50 pts (28%) developed grade II-IV and 15 pts (8%) grade III-IV aGVHD within 100 days after ASCT. Donor type was the most significant predictor of the incidence of grade II-IV aGVHD with a cumulative incidence of 18% (95% CI: 12–27) in recipients of a MRD graft and 38% (95% CI: 29–51) in recipients of a MUD graft (HR=0.4, p=0.001). Similarly the rate of grade III-IV aGVHD was significantly lower in recipients of a MRD graft (4% vs. 15%, HR=0.2, p=0.007). In contrast, donor type did not impact the incidence of chronic GVHD with a comparable cumulative incidence by 2 years in recipients of a MRD (53%, 95% CI: 44–63) and MUD graft (45%, 95% CI: 35–58), (HR=0.9, p=0.8). Similar results were observed when the comparison was restricted to de novo chronic GVHD (n=32). Use of peripheral blood stem cells was the only significant factor associated with a higher rate of chronic GVHD in recipients of a MRD graft (56% vs. 35%; HR=2.5, p=0.03). Female gender was associated with a significantly lower rate of chronic GVHD in recipients of a MUD graft (HR=0.4, p=0.006). There was no significant impact for age, percent donor chimerism at the time of engraftment, diagnosis (AML versus MDS), or donor/recipient CMV serostatus on the rate of grade II-IV aGVHD or chronic GVHD. CONCLUSION: The incidence of grade II-IV aGVHD is low following IVBuFlu conditioning and ASCT in AML/MDS patients. In this setting, donor type affects the incidence of acute but not chronic GVHD. Figure Figure

High Overall Response Rate in Calcineurin Inhibitor-Free Treatment with the mTOR Inhibitor Everolimus in Advanced Extensive Chronic GvHD after Allogeneic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2210-2210 ◽  
Author(s):  
Anne Klink ◽  
Kristina Schilling ◽  
Katrin Rapp ◽  
Klaus Höffken ◽  
Herbert G. Sayer
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Free Treatment ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Background: The mammalian target of rapamycin (mTOR) inhibitor Everolimus (RAD001, Certican®) is a new immunosuppressive drug and beside of sirolimus used and approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with calcineurin inhibitors (CNI) showed clinical responses in chronic graft-versus-host disease (cGvHD). In this single centre retrospective analysis, we report on 29 patients (pts) with severe cGvHD treated with Everolimus without CNI. Patients and Methods: Twenty-nine pts (17 AML, 3 CML, 4 ALL, 3 CLL, 2 NHL) with a median age of 44 years [range: 25–61] underwent allogeneic stem cell transplantation between September 1999 and August 2007. Myeloablative conditioning was used in 21 pts, reduced-intensity conditioning in 8 pts. Except for one patient receiving bone marrow, all pts received peripheral blood stem cells for transplantation. Family donors (2 non-fully HLA matched) were used in 7 pts (24%) and unrelated donors (7 non-fully HLA-matched) in 22 pts (76%). GvHD-prophylaxis consisted of CNI (cyclosporine or tacrolimus) in 4 pts, CNI+Methotrexate (MTX) in 8 pts, CNI+Mycophenolate (MPA) in 8 pts and CNI+MPA+MTX in 9 pts. Antithymocyte globulin (ATG) as in vivo T-cell depletion was used in 9 pts. Cytomegalovirus (CMV)-serostatus was positive in 14 pts, with seronegative donors in 5 pts. Acute GvHD occurred in 27/29 (93.3%), grade II-IV in 25 (86.2%). At the same time, CMV reactivation/infection was observed in 11 pts and thrombotic microangiopathy (TMA) in 3 pts. All pts developed severe cGVHD with extensive disease. Organ involvement included skin with scleroderma in 21 pts, mucous membranes in 22 pts, eyes in 22 pts, lungs in 8 pts, liver in 11 pts, gut in 9 pts and arthralgia in 6 pts. At the time of treatment start with everolimus (0.75 mg Certican ® twice a day orally), CNI medication was stopped. The intended plasma therapeutic levels of everolimus were 3–8 mg/l. In addition all pts received prednisone and in 18 pts (62%) MPA as third immunosuppressive agent was continued. Results: Median treatment duration was 8.4 months [range: 2.5–21.7]. None of the pts developed CMV disease or TMA. Adverse events were: arterial hypertension in 1 patient, atrial fibrillation in 1 patient, pneumonia in 1 patient, sinusitis in 1 patient, herpes labials infection in 1 patient, renal insufficiency grade II in 2 pts and myalgia in 2 pts. 96.6% are still alive, 1 patient (3.4%) died due to relapse of ALL. Two pts (6.9%) achieved a complete response of their cGvHD and 18 pts (62.1%) a partial response resulting in an overall response rate of 69.0% (n=20) according to the recent consensus NIH report (Biol. Blood Marrow Transplant. 2006 May; 12(5): 491–505). No change was observed in 3 pts (10.3%) and progression occurred in 6 pts (20.7%). Complete response in HLA-identical related donors was 20% (1/5) and with HLA-matched unrelated donors was 6.7% (1/15). 100% (n=2) of pts with a HLA-mismatched related donor achieved a partial remission and 85.7% (n=6) of pts with a HLA-mismatched unrelated donor. The gender of recipient or donor did not impair the observed responses with everolimus. Prednisone could be tapered in 62.1% of all pts (18/29). In the triple combination with MPA, MPA could be tapered in 22.2% (4/18) and could be stopped in 38.9% (7/18). Conclusions: A CNI-free treatment of advanced extensive cGvHD with everolimus seems to be feasible and effective with a high overall response rate of nearly 70 %. It should be emphasized that a low toxicity profile without TMA was observed. Our data supports further clinical and immunological investigations with m-TOR inhibitor everolimus in treating GvHD.

Impact of the New Anti-Myeloma Drugs on Outcome of Allogeneic Stem-Cell Transplantation with Reduced-Intensity Conditioning in Patients with High-Risk Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4456-4456
Author(s):  
Jean El-Cheikh ◽  
Roberto Crocchiolo ◽  
Jean Marie Boher ◽  
Sabine Furst ◽  
Anne Marie Stoppa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Graft Versus Host ◽  
Significant Difference ◽  
The Impact ◽  
Reduced Intensity

Abstract Abstract 4456 The increasing use of the novel agents, lenalinomide and bortezomib, in the treatment of multiple myeloma (MM) has contributed to higher complete remission (CR) rates and longer overall (OS) and event free survival (EFS). We assessed the impact of these drugs on the outcome of high-risk MM patients treated with allogeneic stem-cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) over the last 10 years in our program. This retrospective study compared 45 patients (group1) transplanted in our centre between January 1999 and January 2006 and who had not received either novel agent prior to transplant (as induction or relapse therapy) with 34 patients (group 2) transplanted between January 2006 and June 2010 who received either one or both drugs before allo-SCT. The median time between diagnosis and Allo-SCT was 37 months (6–161) and 41 months (9–145) in the two groups respectively (p=NS). The median time between auto-SCT and allo-SCT was 9 months (2–89) and 27 months (2–49) respectively (p<0.0001). 36 patients (80%) in the first group vs. 8 patients (24%) in the second group received a tandem auto allo-SCT (p<0.0001). The disease status at transplantation was in CR in 2 patients (4%) vs. 10 patients (29%) and PR or stable disease in 35 patients (78%) vs. 21 patients (62%) in the first and the second group respectively (p<0.0033). in the table 1 we resumed some important data. Table 1Table 1:Patients Characteristic:Characteristics n=791999-2006 n=45 (57%)2006-2010 n=34 (43%)Fisher, p valueMedian age years (range)51 (27-65)55 (39-67)Number of prior therapies 1 2318 (40) 17 (38) 10 (22)8 (24) 18 (52) 8 (24)0.1509Cytogenetics at diagnosis Normal Del(13) Del (17) t (4;14) NA5 (11) 4 (9) 36 (80)3 (9) 12 (35) 19 (56)0.00504Disease status CR ou VGPR PR ou SD PD or refractory2 (4) 35 (78) 8 (18)10 (29) 21 (62) 3 (9)0.003359Donor type Matched Sibling Unrelated Donor45 (100) 021 (62) 13 (38)0.0004517Conditioning treatment With TBI With ATG19 (42) 26 (58)9 (26) 25 (74)0.1632Legend: Allo-SCT, allogeneic stem cell transplantation; Auto-SCT, autologous stem cell transplantation; CR, complete response; VGPR, very good partial response; PR, partial response; SD, stable disease; PD, progressive disease. GVHD indicates graft-versus-host disease; CSP, cyclosporine; MMF, mycofenolate mofetyl; TBI, total-body irradiation; ATG, anti-thymoglobulin; TRM, Transplant related mortality. Groups differ in several aspects: In recent years allogeneic transplant was considered rather as salvage therapy in patients relapsing after auto-SCT than in a tandem auto-allo strategy, patients with cytogenetic aberrations (p<0.005), and stem cell source from unrelated donor (13 patients (38%) vs. none) (p<0.0004), and two days of anti-thymoglobuline (ATG 2,5mg/kg/day). (P<0.001), in the second group. Table 1 The median follow-up after transplant was 45 (2–127) and 16 (3–39) months in the first and second group respectively (p<0.001). The cumulative incidence of acute graft versus-host disease (GVHD) tended to be higher before 2006 (47% vs. 24%; p=0.0584). The cumulative incidence of chronic GVHD was statistically different (56% vs. 30%; p=0.0241). The estimated probability of TRM at day 100 was 12% in the first group vs. 0 % in the second group (p=0.077) and did not differ between groups at 2 years. (18% vs. 23% (p =0.537)). The overall survival (OS) at two years was 60% vs 70% in the first and second group respectively (p=0.1784). The progression-free survival (PFS) tended to be different at 2 years (45% vs. 65% (p=0.056)). The median of PFS is 22 months for patients transplanted prior 2006 and is not reached in the second group (p=0.1811). In our study there was no significant difference in OS or TRM between the 2 groups in multivariate analysis; only the number of previous auto-SCT with more than two high dose chemotherapies has a negative impact on the OS. There was a significant difference in the incidence of relapse between the 2 groups in the multivariate analysis. Although we cannot carry out the impact of other changes related to our practice in the same period, these data suggests an impact in transplant outcomes of novel drugs introduced in the therapy of MM (lower TRM, GVHD and higher disease control). This piece of information, if confirmed, should be taken into considerations for present and future approaches. Disclosures: No relevant conflicts of interest to declare.

Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5923-5923
Author(s):  
Amandine Le Bourgeois ◽  
Thierry Guillaume ◽  
Jacques Delaunay ◽  
Pierre Peterlin ◽  
Viviane Dubruille ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Older Age ◽  
Reduced Intensity Conditioning ◽  
The Impact ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adults Patients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100. Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%). In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series. In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD. Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT. Disclosures No relevant conflicts of interest to declare.

Influence of Prophylactic Antibiotics Aiming at Gut Decontamination on Gastrointestinal Graft-Versus-Host Disease and Overall Survival Following Allogeneic Haematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4319-4319 ◽  
Author(s):  
Bertrand Routy ◽  
Caroline Letendre ◽  
Maxime Chenard-Poirier ◽  
Vikram Mehraj ◽  
David Enot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Prophylactic Antibiotics ◽  
Graft Versus Host ◽  
Grade Ii ◽  
The Impact

Abstract Introduction: The impact of commensal bacteria harbored in the gastrointestinal tract known as the microbiota has long been recognized as a pivotal factor in allogeneic hematopoietic stem cell transplantation (aHSCT). The microbiota is at the origin of acute graft-versus-host disease (aGVHD) and infections, two important lethal complications in aHSCT. High-dose conditioning chemotherapy prior aHSCT disrupts the gut epithelial barrier allowing bacterial by-products to translocate into the peripheral blood and modulates T cell response and pro-inflammatory cytokines. Such observation led to an effort by certain transplant centers to eliminate bacterial colonization prior to aHSCT to decrease the risk of gram-negative bacterial translocation. In this study, we assessed whether patients' gut decontamination prior to allogeneic stem cell infusion influenced the frequency of aGVHD, pneumomatosis coli (PC) a significant complication of gastrointestinal (GI) GVHD and overall survival. Methods: We retrospectively reviewed the charts of 543 patients who had undergone a single myeloablative or nonmyeloabaltive aHSCT for hematological malignancies from two academic hospitals in the province of Quebec, Canada between January 2005 and December 2012. Exclusion criteria included prior aHSCT, syngeneic and haploidentical aHSCT. Each university hospital has implemented a different pre-transplant antibioprophylaxis guideline. At HMR hospital, ciprofloxacin or moxifloxacine were started at initiation of the conditioning regimen for gut decontamination, but were omitted in patients with fluoroquinolone or penicillin allergy and during nosocomial infections outbreak. On the other hand, in the CHU de Quebec patients were not prescribed prophylactic antibiotics (ATB). In addition, ATB used to treat infections before the stem cells infusion were considered. To determine the impact of ATB, we performed multivariable analyses adjusting for the following confounding factors: age, gender, stem cell origin (source), donor type/match, and conditioning regimens to compare the frequency of aGVHD, PC, leucocytes recovery at day+14 and overall survival (OS) in patients receiving or not ATB. Results: 500 patients were included and a total of 240 (48%) patients received ATB at the time of conditioning regimen. Demographics were similar in both groups with mean age of 48 years. Frequency of grade II-IV aGVHD was more elevated in patients receiving ATB compared to the no ATB group (42% vs 28% respectively with adjusted OR (aOR)=1.53 (p<0.05). The severity of the aGVHD in the ATB group was driven by the GI-GVHD with a higher level of grade II-IV (20.7%) compared to no ATB group (10.8%) with aOR=2.00 (p<0.01). Severity of skin and liver GVHD were similar in both groups. Among the 12 patients that developed PC diagnosed on CT-scan, all received ciprofloxacin during conditioning and PC was associated with 80% mortality. The difference of aGVH frequency may have translated into survival as the ATB group was associated to lower 1 year survival compared to no ATB group (74% vs 88%, OR=0.36 and aOR=0.38 (p<0.05). This significant survival difference at 1 year persisted over time and median OS was 4 and 5 years respectively (p<0.05). Taking into consideration the entire follow-up period of 10 years, the hazard rates associated with ATB were estimated at 1.61(p<0.06) and 1.43 (p<0.05) after adjusting for clinical parameters. Interestingly, post-hoc analysis revealed independent impact of the ATB on D+14 neutrophils. This was reflected by a lower neutrophil count in patients on ATB that received stem cells from a match-related donor compared to no ATB counterpart with a ratio of 0.38 (p<0.05). Discussion: This retrospective study indicated that ATB were associated to a more severe aGVHD driven by digestive manifestations of the GVHD and higher incidence of PC even after multivariable analysis. These life-threatening complications may impact on the 1-year and OS that were lower in the ATB group. Without undermining the role of ATB prophylaxis to prevent infection in aHSCT setting, treatment with ATB impact on the commensal microbiota and diminishes its diversity. This imbalance created by the ATB may have contributed to the pathophysiology of GI-GVHD. This ultimately highlights the importance to reconsider antibioprophylaxis to preserve an intact flora and its benefits in aHSCT. Disclosures No relevant conflicts of interest to declare.

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