Use of Pre-Emptive Donor Lymphocyte Infusions To Achieve Durable Remission Following Alemtuzumab Based Reduced Intensity Conditioning (RIC) Transplantation for AML or MDS.

Abstract Use of alemtuzumab in RIC HSCT reduces the incidence of graft rejection and graft vs host disease(GvHD). However, there can be a delay in full T-cell donor engraftment. As a dominant donor T-cell chimerism may be important to achieve a strong graft vs leukaemia effect(GvL), we examined the impact of pre-emptive DLI (pDLI) on patients with falling donor chimerism. 76 patients with AML or MDS were treated with RIC HSCT (fludarabine 150mg/m2, busulphan 8mg/kg, alemtuzumab 100mg). Complete sublineage chimerism data up to day +100 was available on all patients. The underlying diagnoses were AML n=27, MDS n=49. 33 patients had early disease vs 44 advanced disease (advanced disease as defined by AML >CR1, MDS RAEB or AML with multilineage dysplasia). The median recipient age was 51.6 years (range:19–72), with median follow-up of 526 days (range:137–1256). There were 30 sibling and 50 VUD allografts. Stem cell source was 61 PBSC vs 15 BM. 62 patients were fully HLA matched and 14 patients were HLA mismatched. CD15 engraftment occurred rapidly with 95% of patients achieving full donor chimerism(FDC) at day 30 and 96% at day 100. In contrast, CD3 engraftment was significantly delayed, with only 50% of patients FDC at day 30, 47% at day 100. Incremental doses of pDLI were considered for patients with falling donor chimerism (<50% donor) after day 100. Patients had immunosuppresion withdrawn, and had to have no GvHD. 20 patients received a total of 55 doses of pDLI. 10/20 had advanced disease, and 6/20 had unfavourable cytogenetics. Median donor CD3 chimerism at time of pDLI was 31.5%(range:7–59). The median CD3 dose of pDLI was 8.4x106/kg, with the first dose given at a median of day +176 (range:104–494). The median interval between pDLI was 8 weeks(range:4–22). 15 patients had FDC restored at median of 130 days following first doses of pDLI (range:36–523). 8/20 developed acute Gd II-IV GvHD following pDLI, with 2 patients dying of GvHD related complications. 2 patients relapsed with AML following treatment: with 1 death, and 1 patient currently undergoing treatment. 2 patients had not reached FDC at follow-up. A further 9 patients received DLI for cytogenetic or morphological relapse. Time to first dose of DLI was 257 days (range:76–837). The median CD3 dose was 1.67 x 107/kg. 3 patients were FDC and 6 patients MDC at time of relapse. All 3 patients with FDC failed to respond to DLI. Complete remission was seen in 3/6 patients with MDC. 4/9 patients developed acute Gd II-IV GvHD. 5/9 patients have died(all of underlying AML). The outcome of patients receiving pDLI was compared with patients with FDC(n=28), and stable mixed chimerism(defined as donor CD3 chimerism >70%) who did not receive DLI(n=18). There was no significant difference in recipient age, disease, disease stage, HLA type, cell source or cell dose between groups. However, there were more sibling donors in the group receiving pDLI(p=0.02). The 2 year DFS, OS and relapse rate was comparable between patients with FDC, stable chimerism and those receiving pDLI (59% vs 83% vs 67% p=0.22), (62% vs 88% vs 75% p=0.13), (12% vs 17% vs 15% p=0.74) respectively. In summary, pre-emptive DLI is effective in reversing falling donor chimerism, and can induce prolonged remission, even in a sub-group of patients with high risk disease. A dominant donor CD3 chimerism(>70%) may be sufficient to acheive an allo-immune effect in majority of patients.

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Low Pre-DLI Lymphocytes Counts Are Predictive of Good Disease Responses in Patients with Mixed Chimerism Following Campath-Containing Reduced Intensity Transplants.

Blood ◽

10.1182/blood.v108.11.261.261 ◽

2006 ◽

Vol 108 (11) ◽

pp. 261-261

Author(s):

Bronwen E. Shaw ◽

Jenny L. Byrne ◽

Emma Das-Gupta ◽

Ian Carter ◽

Nigel H. Russell

Keyword(s):

Lymphocyte Count ◽

Residual Disease ◽

Suppressor Cells ◽

Mixed Chimerism ◽

Post Transplant ◽

Donor Chimerism ◽

Significant Difference ◽

Group B ◽

The Impact ◽

Reduced Intensity

Abstract Following reduced intensity conditioned (RIC) transplants, donor leukocyte infusions (DLI) are frequently used either to convert mixed chimerism (MC) to full donor chimerism (FDC) or for residual or relapsed disease. Unfortunately, DLI are not universally successful and few factors are known (e. g disease type and level of pre-DLI chimerism) which predict for good responses. We analysed the impact of the chimerism pattern in 125 recipients of (CAMPATH containing) RIC transplants for malignant diseases. Of these, 68 (55%) had FDC (group A), 49 (39%) developed MC and 8 (6%) lost DC and had autologous reconstitution (group D). The patients who developed MC could be further subdivided into those with persisting MC post transplant (27, 55%; group B: non-responders) and MC post transplant with subsequently development of FDC (22, 45%; group C: responders). These two groups were analysed further. The median patient age was 55 (range: 19–71). The donors were siblings (22) or unrelated (27). The diseases were as follows: AML/MDS 14, CML 4, Myeloma, 4, lymphoma/CLL 26, MF 1. Stem cell source was PBSC (38) and bone marrow (11). Conditioning consisted of fludarabine, melphalan and campath (fmc) in 24 patients; fludarabine, busulphan and campath (fbc) in 5; BEAM, campath +/− fludarabine in 18 and FLAG in 2. There were no significant differences in any of these features between groups B and C. 25/49 patients received DLI. This was for disease relapse in10 patients, residual disease in 6 and MC alone in 8 (Unknown in 1). A complete disease response (CDR) was seen in 9/14 (64%) evaluable cases. There was a highly significant difference in CDR between the two groups (group B: 0/4, group C: 9/10, p=0.005). The reason for the difference in response rate was investigated. Median time to DLI was 196 days (range: 57–2123), not significantly different between the groups (p=0.561). The indication for and total number of DLI, the underlying disease and the degree of pre-DLI donor chimerism were not significantly different. In addition there was no significant difference in the incidence of post DLI GvHD (p=0.137), although this was 10/13, 77% in those who responded and 2/5, 40% in those who did not. Conversely, there was a significant difference in the pre-DLI lymphocyte counts (p=0.036). The median count was 2.24 × 109/l. In group B 3/11 (27%) were below this while 10/14 (71%) in group C were below this. The pre-DLI lymphocyte count was not significantly correlated with the time post transplant at which DLI was given, the type of donor, the indication for DLI or the disease, conditioning or post transplant immunosuppression regimen. The predicted overall survival at 2 years was significantly better in group C than in group B (95% versus 57%, p=0.002). This was largely due to the higher relapse risk in group B (77%) compared to group C (32%) (p=0.043). In conclusion, in patients with MC, the development of FDC was significantly associated with a superior OS. In those receiving DLI, the factor most significantly predictive for a ‘responsive’ (C) versus ‘non-responsive’ (B) pattern was the presence of a low pre-DLI lymphocyte count, suggesting that a lack of ‘space’ for expansion or increased suppressor cells in the lymphoid compartment mediate DLI resistance. We postulate that DLI ‘non-responders’ (those with higher lymphocyte counts) may be converted to ‘responders’ by the addition of pre-DLI lymphoreduction, thus reducing relapse and improving outcome.

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Matched Pair Analysis of Intravenous vs Oral Busulphan as Part of Fludarabine-Busulphan-Campath (Alemtuzumab) Reduced Intensity Conditioning (RIC) Haematopoietic Stem Cell Transplantation (HSCT).

Blood ◽

10.1182/blood.v106.11.1762.1762 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1762-1762

Author(s):

ZiYi Lim ◽

Dragana Milojkovic ◽

Laurence Pearce ◽

Michelle Kenyon ◽

Aloysius Ho ◽

...

Keyword(s):

Previous History ◽

Disease Free Survival ◽

Disease Stage ◽

Haematopoietic Stem Cell ◽

Matched Pair ◽

Donor Chimerism ◽

Matched Pair Analysis ◽

Significant Difference ◽

Oral Group ◽

The Impact

Abstract The use of IV busulphan (Bu) has reported improved bioavailability with lower variability of plasma levels, and may reduce the incidence of hepatic veno-occlusive disease (HVOD) and lower the transplant related toxicity. We performed a retrospective matched 2:1 case analysis to evaluate the impact of the use of oral vs IV busulphan as part of RIC HSCT on toxicity as well as engraftment. 75 patients received fludarabine (30mg/m2 x 5 days), alemtuzumab (20mg x 5 days) and either oral Bu (4mg/kg x 2 days) (25 patients) or IV Bu (3.2mg/kg x 2 days) (50 patients). 25 patients received IV Bu between Jan 2004 and Jan 2005. Each of these patients was matched for sex, diagnosis, disease stage, donor status and cell source with 2 comparable historical patients receiving oral Bu. There were 42 male and 33 female patients. Median age was 55 years (range:22–72). Median follow-up was 850 days (range: 39–1820) for the oral Bu group and 228 days (range: 38–453) for the IV Bu group. All patients were being treated for myeloid malignancies: AML n=21, MDS/MPD n=45, CML n= 9. There were 33 sibling matched HSCT, 27 matched VUD HSCT and 15 HLA-mismatched VUD HSCT. 63 patients received PBSC and 12 received BM, the median CD34 cell dose was 5.17 x 106/kg (range:1.2–18.5) and 2.49 x 106/kg (range:0.7–4.9) respectively. 28 patients had early disease vs 48 advanced disease (advance disease defined as AML > CR1, CML > CP1, MDS with RAEB or AML with multilineage dysplasia). 5 patients in the oral group and 3 patients in the IV group had a previous allogenic HSCT. No patients had a previous history of hepatic impairment. Median time to neutrophil (>0.5x10^9/kg) and platelet (>20x10^9/kg) regeneration was 12 days and 14 days respectively, with no significant difference between both arms. There was 1 case of primary graft failure and 1 case of HVOD in both arms. Both patients with HVOD had a previous allogeneic HSCT. Myeloid (CD15) engraftment occurred rapidly in both groups with full donor chimerism (>95% donor chimerism) achieved at day+28/day+100/day+180 in 92%/90%/86% IV and 90%/85%/89% oral Bu patients. Lymphoid (CD3) engraftment was delayed in both groups, with full donor chimerism in 28%/26%/37% of IV Bu and 56%/57%/49% of oral Bu patients at day+28/day+100/day+180. 14 patients in the oral Bu group had grade I–III acute graft versus host disease (aGvHD), of which 3 had Gd III aGvHD. In contrast, 4 patients in the IV Bu group developed Gd I–III aGvHD, with 1 patient having Gd III aGvHD. The day +100 treatment related mortality (TRM100) was 8% in both groups. The overall survival (OS), disease free survival (DFS) and relapse incidence at day +200 for the IV vs oral groups was (86% vs 70%, p=0.30), (75% vs 60%, p=0.21), and (18% vs 24%, p=0.36) respectively. In summary, RIC HSCT with both oral and IV busulphan appears to be safe and well tolerated regimen with a low incidence of HVOD and low TRM100. Persisting CD3 mixed donor chimerism is seen in both arms, with a trend to lower incidence of aGvHD with IV Bu (p=0.09) with no significant difference in early relapse, DFS, OS.

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Use of Intravenous Busulphan for Reduced Intensity Conditioning (RIC) Haematopoietic Stem Cell Transplantation (HSCT) Is Associated with Delayed T-Cell Full Donor Chimerism and Lower Incidence of Acute Graft Versus Host Disease.

Blood ◽

10.1182/blood.v110.11.1994.1994 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1994-1994 ◽

Cited By ~ 1

Author(s):

ZiYi Lim ◽

Murugaiyan Thanigaikumar ◽

Shreyans Gandhi ◽

Laurence Pearce ◽

Michelle Kenyon ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Lower Incidence ◽

Acute Gvhd ◽

Advanced Disease ◽

Disease Stage ◽

Transplant Outcomes ◽

Donor Chimerism ◽

Significant Difference ◽

Advanced Disease Stage

Abstract The use of IV busulphan (Bu) has reported improved bioavailability with lower variability of busulphan plasma levels, and may reduce the effects of transplant related toxicity particularly in the context of myeloablative regimens. In contrast, there is limited data avaliable on the use of IV Bu in the setting of reduced conditioning (RIC) regimens. We retrospectively analysed data from 163 consecutive patients treated at our centre for myeloid malignancies (AML n=78, MDS/MPD n=73, CML n= 12) using RIC HSCT, and evaluated the engraftment and chimerism kinetics as well as the early transplant outcomes between patients receiving either IV or oral Bu. Patients received fludarabine (30mg/m2 × 5 days), alemtuzumab (20mg × 5 days) and either oral Bu (4mg/kg × 2 days) or IV Bu (3.2mg/kg × 2 days). 84 consecutive patients received oral Bu up to Jan 2004. Thereafter, 79 consecutive patients received IV Bu. The median age of the cohort was 53 years(range: 19–72). 50 patients received stem cells from HLA-matched sibling donor, and 113 from a volunteer unrelated donor. 128 patients received PBSC and 35 received BM stem cells. 64 patients had early disease vs 99 advanced disease (advance disease defined as AML > CR1, CML > CP1, MDS with RAEB or AML with multilineage dysplasia). Median follow-up was 1531 days (range: 853–1987) for the oral Bu group and 551 days (range: 228–1072) for the IV Bu group. There was no difference between groups in terms of recipient age, stem cell dose/source, donor type, prior therapies or disease type. However, patients receiving IV Bu had more advanced disease compared with oral Bu (70% vs 52%, p=0.03). There was no significant difference in the median time to neutrophil and platelet regeneration between groups. In contrast lymphoid(CD3) engraftment was significantly delayed in the IV Bu group, with 35% vs 53%(p=0.04) recipients achieving full donor chimerism(FDC) at day 30, and 32% vs 51%(p=0.03) at day 100. The cumulative incidence of acute GvHD was lower in the IV Bu group 18% vs 29%(p=0.04), with no difference in the cummulative incidence of chronic GvHD between groups. Early(1-year) transplant-related mortality (TRM) was higher in the oral Bu group(TRM:: 25%vs13%, p=0.07) with a significantly lower overall survival(60%vs79%, p=0.02) primarily as a result of death from GvHD and related infection complications. There was no significant difference in relapse incidence at 1 year between cohorts(IV Bu 27% vs oral Bu 23%, p=0.84). On multivariate analysis, the type of conditioning regimen had no effect on the overall transplant outcomes. Attainment of CD3 FDC at day 30(HR: 2.14, 95%CI: 1.26–3.63, p<0.01) and advanced disease stage(HR:2.62, 95%CI: 1.41–4.89, p<0.01) were the only significant variables associated with a poorer OS. In contrast, the presence of CD3 mixed donor chimerism at day 30(HR:2.70, 95%CI: 1.24–5.90, p=0.01) was the only independent variable associated with improved TRM. Advanced disease stage was the only independent predictor of disease relapse(HR:2.34, 95%CI: 1.17–4.66, p=0.02). In summary, RIC HSCT with IV busulphan is a safe and well tolerated regimen. When compared with oral Bu, use of IV Bu as part of an FBC regimen is associated with delayed attainment of CD3 FDC, and is associated with a corresponding lower incidence of acute GvHD and early complications.

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A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v110.11.46.46 ◽

2007 ◽

Vol 110 (11) ◽

pp. 46-46

Author(s):

B.E. Shaw ◽

Nigel H. Russell ◽

A. Pagliuca ◽

J. Apperley ◽

G. Cook ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Increased Risk ◽

Significant Difference ◽

Cell Source ◽

The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

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Results of Haematopoietic Stem Cell Transplantation (HSCT) for Hurler’s Syndrome: European Experience 1994–2004.

Blood ◽

10.1182/blood.v106.11.402.402 ◽

2005 ◽

Vol 106 (11) ◽

pp. 402-402 ◽

Cited By ~ 1

Author(s):

Jaap Jan Boelens ◽

R. Wynn ◽

A. O’Mearra ◽

P. Veys ◽

M. Cavazzana-Calvo ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Donor Chimerism ◽

Stem Cell Source ◽

Cell Source ◽

Conditioning Regimens ◽

Hurler’S Syndrome

Abstract Worldwide more than 400 patients with Hurler’s syndrome (HS), characterized by severe neurodegeneration, cardiac disease, skeletal abnormalities and death in early childhood, have undergone allogeneic-HSCT since 1980. Although, long term follow up of successfully transplanted children is very encouraging, the engraftment and survival results are very variable between the various studies, ranging from less than 25% up to more than 85%. We retrospectively analyzed the results of 146 patients transplanted in Europe from 1994–2004, to assess: 1) the effect of conditioning regimen and grafts (-manipulation) used on the “alive and engrafted” rate and 2) the transplantation-related morbidity/mortality. HSCT with a family donor was performed in 52 patients. An unrelated donor was used in 94 patients. The majority of patients received marrow (n=103). The rest received cordblood (n=23) or peripheral blood (n=20). Twenty-eight patients received a T-cell depleted (TCD) graft. Conditioning regimens used were grouped as follows: busulfan-cyclofosfamide 200mg/kg (n=68), busulfan- with high dose cyclofosfamide (either 240mg/kg or 260mg/kg; n=41), fludarabine-based myelo-ablative (n=19) and reduced intensity conditioning regimens (RIC: n=18). Fourteen patients received dose-adjusted busulfan. Engrafted was defined as a donor chimerism of more than 10%, and an alpha-L-iduronidase level of more than the lower limit of normal for the heterozygote individuals (>4.5 nmol/hr/mg). The “alive and engrafted” rate after first transplantation and overall “alive and engrafted” rate after one to three transplantations was 83/146 (57%) and 111/146 (76%), respectively. The median follow up was 39 mth (5–120mths). Multivariate analysis (confounders: age, sex, heterozygote donor, unrelated donor, stem cell source, HLA-disparity, conditioning regimen, TCD and busulfan targeting) on the primary endpoint “alive and engrafted” showed that RIC (RR 13,4: 2,6–67,1) and TCD (RR 5,7: 1,14–28,4) are individual risk factor for graft failure. Busulfan targeting suggests to be an individual protective factor (RR 0,27; 0,04–1,8); 12/14 (86%) were “alive and engrafted” after 1st HSCT. Thirthy three patients received a 2nd graft, of whom 26/33 (82%) are alive and engrafted: 16/21 using the same, 10/12 using a different donor, and 16/19 after myeloabaltive, 10/14 after RIC. Two of the 3rd HSCTs were successful. After 1st HSCT moderate to severe aGvHD (grade ≥2) occurred in 23/146 (16%) patients. Extensive cGvHD was seen in 2/114 (1.4%) patients, only. IPS/DAH was seen in 4/134 (2.3%) patients and VOD in 12/134 (9%) patients. Main cause of death (n=28) was infectious (n=15: mainly viral). Other causes of death: GvHD (n=3), Cardiac ECI (n=2), VOD (n=2), DAH (n=1), unknown (n=1), Hurler (n=4). The majority of the “alive and engrafted” patients have a donor chimerism of >95% (91/111; 82%), 11/111 (9,9%) between 75–95%, 6/111 (5,4%) between 50–75% and 3/111 (2.7%) between 10–50%. In summary, no stem cell source (BM, cordblood and PBSC) is superior and no conditioning regimen used is superior. RIC and TCD results in inferior engraftment rates. Second HSCTs are successful in more than 80%. Relatively low morbidity rates are seen. The engraftment of HSCT for HS can be optimized by avoiding T-cell depletion, RIC and probably by busulfan-targeting.

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A Comparison of Stem Cell Source in Adult and Paediatric Recipients of T-Cell Depleted Myeloablative Transplants for Standard Risk Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v114.22.1205.1205 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1205-1205

Author(s):

Bronwen E Shaw ◽

Jane Apperley ◽

Nigel H. Russell ◽

Charles F. Craddock ◽

Effie Liakopoulou ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source ◽

Standard Risk

Abstract Abstract 1205 Poster Board I-227 The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in non relapse mortality (NRM) and decrease in survival (OS) in T-cell replete transplants. We have previously reported outcome data in 145 patients who received an unrelated donor transplant for leukaemia. In that study we reported an increase in mild acute GvHD using PBSC, but no other significant differences in outcome. We have now doubled the cohort and report our findings on 320 patients here. In this group all of the patients received pre-transplant serotherapy (Alemtuzumab = 306, ATG = 14) as part of myeloablative conditioning prior to an HLA-matched UD allograft. Patients were transplanted between January 2000 and August 2007: CML in 1CP (n=102) and acute leukaemia in CR1/2 (AML in 105, ALL in 144). 190 patients received BM and 130 PBSC. The median age of the recipients was 28.9 years (10months - 58years). There was no significant difference in age between those receiving BM or PBSC.98% and 96% of patients receiving PBSC and BM achieved neutrophil engraftment (NS), with a significantly faster time to engraftment in recipients of PBSC compared to BM (14 vs 20 days; p<0.001). The incidence of acute GvHD was significantly higher in recipients of PBSC (64%) compared to BM (51%; p=0.022), however there was no increase in grade III/IV (p=0.420) disease in PBSC recipients. The incidence of chronic GvHD at 6 years was 61% in the BM recipients and 55% in the PBSC recipients (NS), with no difference in the incidence of extensive disease. The 5-years OS was 55% in BM recipients, with a median follow-up of 59 months, compared to 54% in PBSC recipients at a median follow-up of 38 months (NS). The incidence of neither disease relapse nor NRM was significantly different between groups (relapse at 5 years: BM 44%, PBSC 36%; p=0.112, and NRM at 5 years: BM 22%, PBSC 24%; p=0.751). In view of the fact that there were more CML patients in the BM group and more AML patients who received PBSC (the distribution of ALL patients was similar) (p=0.051), we performed a subgroup analysis. The pattern of results for each outcome, dependant on the use of BM or PBSC, in patients with CML and those with acute leukaemia were similar to those reported in the group overall. In conclusion, we have confirmed the results of our previous smaller study, showing the only significant difference in clinical outcome between PBSC and BM to be a higher incidence in the occurrence (but not grade) of acute GvHD. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM. We suggest that either stem cell source can be used with a similar outcome in adult and paediatric recipients of T-cell depleted allografts for standard risk leukaemia. Disclosures: Apperley: Novartis: Consultancy, Honoraria.

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The Association of Fludarabin, Oral Busulfan and Thymoglobulin Prior to Matched-Related Allo-SCT Allows for High Long Term Outcome for Both Patients with Myeloid or Lymphoid Malignancies and Reveals the Impact of CD34+ Graft Cell Dose On Cgvhd and Outcome: Long Term Analysis of a Homogenous Cohort of 100 Consecutive Patients.

Blood ◽

10.1182/blood.v114.22.3374.3374 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3374-3374

Author(s):

Didier Blaise ◽

Laure Farnaut ◽

Benjamin Esterni ◽

Catherine Faucher ◽

Sabine Furst ◽

...

Keyword(s):

Stem Cell ◽

Disease Progression ◽

Disease Stage ◽

Mixed Chimerism ◽

Platelet Recovery ◽

Lymphoid Malignancies ◽

Cell Dose ◽

The Impact

Abstract Abstract 3374 Poster Board III-262 Long term follow-up of RIC-based allogeneic stem cell transplants are still scarce. While RIC are presently commonly used, most reports analyzed together patients (pts) with different intensities of conditioning, donor types and graft sources. In addition, most published reports are associated with short-term follow-up. As a consequence, results are unlikely to be helpful in assessing the real impact of RIC allograft in given pts population. In this perspective, we analysed a single-centre cohort of 100 consecutive pts treated between 2000 and 2006 with a minimal and median follow-up of respectively 28 and 56 months. All pts presented a haematological malignancy; all pts were treated with PBSC allo-SCT from a matched-related sibling donor. All pts were to receive the same RIC without TBI: oral busulfan (8mg/m2), thymoglobuline (2.5mg/kg) and fludarabine (150mg/m2 over 5 days) and the same CSA-based post graft immunosuppression. Median age was 50 (18-64). Diagnoses included acute leukemia (AL) (39%), myeloid malignancies (HMY) (16%) (Studied together: AL+HMY=55%) and lymphoid malignancies (HLY) (45%). Respectively 53, 14 and 33 pts were in CR, progression or stable disease (AL+HMY: 85%, 13%, 2%; HLY: 13%, 16%, 71%, p<.0001). EBMT disease stage evaluation was early (0-1), intermediate (2-3), and high stage (4-6) for respectively 5, 52, 41 pts (AL+HMY: 7%, 73%, 20%; HLY: 2%, 27%, 71%, p<.0001). Hematopoietic cell transplantation comorbidity index (HCT-CI) was 0, 1-2 and >2 in 31, 39 and 23 of the 92 assessable pts (AL+HMY: 36%, 35%, 29%; HLY: 25%, 56%, 19%, p=NS). Grafts were monitored for CD34, CD3, CD4, CD8, CD19, CD56 and CFU-GM cells (notably CD34: 5.6 (1.5-22.2) x10e6/kg, CD3: 316 (112-887) x 10e6/kg). All but one engrafted. Median time to neutrophil and platelet recovery was 18 (8-27) and 9 (50-99) days. aGVHD and cGVHD cumulative incidences (CI) were 43% (33-54) and 81% (73-89) respectively. cGVHD was associated with low CD34 dose (.0001) and previous Grade ≥ 2 aGVHD (.036). DLI was administered in 16 pts for purpose of mixed chimerism or disease progression in respectively 3 and 13 cases. TRM CI at 12 months and 5 years were 15% (8-22) and 25% (16-34) respectively. TRM was strongly associated with aGVHD (p=.00004) but not with EBMT score nor HCT-CI index. Overall, on the 56 assessable pts with measurable disease at transplantation, 36 (64%) achieved objective response (no difference between 2 groups). Relapse or progression occurred at a median of 11 months (1-52) in respectively 21 pts for a CI of 22.4% (11-33.7) and 22.5% (8.7-36.2) respectively in AL+HMY and HLY groups. In a landmark analysis, disease progression was associated with the absence of grade ≥2 aGVHD (p=.0045) and the absence of cGVHD (p=.0035). Five years OS and PFS probability estimate was 63% (51-78) and 61% (49-75) for HMY+LA group and 55%(42-72) and 45%(31-64) for HLY group. In multivariate analysis, improved PFS was related to CR at transplantation (p=.009) and low CD34 dose (under median) (p=.028). To conclude: results suggested a high efficiency of a RIC combining Fludarabin and limited myeloablation (busulfan) and limited thymoglobuline dose in a wide population in term of age, HSCT-CI, EBMT disease stage evaluation for both lymphoid and not lymphoid malignancies. An interest of the analysis of such an homogeneous cohort of patient is to re-evaluate the impact of scores developed in more heterogeneous populations (HSCT-CI, EBMT score) and to study the impact of other parameters generally concealed by population disparity. In this perspective, lower stem cell dose (but not other graft cells) was associated with more cGVHD and improved PFS. This observation deserves further investigation, notably inviting to revisit the impact of GCSF mobilization in RIC context. Disclosures: Bouabdallah: Roche: Research Funding.

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The Pattern of T-Cell Donor Chimerism Is a Key Predictor of Outcome Following Alemtuzumab Based Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation for MDS and AML.

Blood ◽

10.1182/blood.v108.11.42.42 ◽

2006 ◽

Vol 108 (11) ◽

pp. 42-42

Author(s):

ZiYi Lim ◽

Laurence Pearce ◽

Aloysius Y.L. Ho ◽

Linda Barber ◽

Wendy Ingram ◽

...

Keyword(s):

T Cell ◽

Disease Status ◽

Disease Stage ◽

Rapid Decline ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Cell Engraftment ◽

Low Incidence ◽

A Prospective Study ◽

The Impact

Abstract In animal models, a mixed lymphohematopoietic chimerism can be achieved after both myeloablative and non-myeloablative conditioning, establishing bidirectional tolerance for recipient and host antigens, with reduced graft rejection and GvHD. However to date, there has only been limited success in inducing stable MDC in human studies. Furthermore, conflicting reports exist regarding the association between mixed donor chimerism(MDC,5–95% donor chimerism), graft failure and relapse. We report a prospective study on the kinetics of T-cell engraftment in 110 patients with AML(n=50) and MDS(n=60) who received a RIC allogeneic HSCT regimen of fludarabine, busulphan and alemtuzumab with cyclosporine for post-HSCT immunosuppression. Median age was 53 years(range:19–72), and median follow-up:690 days(range:168–1470). Serial analysis of myeloid(CD15) and lymphoid(CD3) chimerism was performed and declining donor CD3 chimerism beyond day 100 was treated with pre-emptive DLI(pDLI). The achievement of full donor chimerism(FDC,>95% donor chimerism) in either lineage at day 30,60,90 was correlated with overall outcomes, and the attainment of CD3 FDC at day 90 was most predictive of outcomes. Based on this we identified 3 distinct chimerism patterns: 1)Patients achieving CD3 FDC by day 90(n=46). 2)Patients with stable CD3 MDC(n=22) and not requiring pDLI; median CD3 donor chimerism at day 90 was 79%. 17/22 had persisting stable MDC at a median of 675 days post-HSCT. 3)Patients with declining CD3 donor chimerism(n=42). 28/42 patients received pDLI. 14/42 had regressive CD3 donor chimerism(RDC) or loss of donor chimerism by Day 90, and did not receive pDLI due to rapid decline in chimerism and relapse. All groups were matched for age, cell dose/source, prior chemotherapy, disease type/stage; patients with stable MDC and declining MDC had a higher proportion of sibling donors(p=0.03). Patients with stable MDC had a lower incidence of GvHD compared with patients achieving FDC[grade II-IV GvHD:4(18%) vs 22(48%),extensive cGvHD:2(9%) vs 15(33%)]. 10/28 patients(36%) developed GvHD following pDLI. None of the 14 patients with RDC developed GvHD. A day 90 landmark analysis was performed to assess the impact of CD3 chimerism on 2-year outcomes. Patients achieving FDC by day 90 had an inferior DFS and OS compared with stable MDC(43% vs 76%,p=0.02 and 44% vs 87%,p=0.01) or pDLI(43% vs 77%, p=0.01 and 44% vs 80,p=0.01). Patients with FDC had a higher TRM compared to stable MDC(37% vs 0%,p=0.02), but there was no difference in TRM between the FDC and pDLI groups(37% vs 16%,p=0.07). There was no difference in relapse between groups(p=0.21). On multivariate analysis, CD3 chimerism pattern was the only independent predictor of TRM(p=0.03). Disease stage at time of transplantation (p<0.01) was the only independent variable for relapse. Both CD3 chimerism pattern(p<0.01 and p<0.001) and disease status at transplantation(p=0.01 and p<0.01) had a significant effect on DFS and OS. Following alemtuzumab-based RIC, the pattern of T-cell engraftment allows identification of patient groups with distinct outcomes. Patients with high levels of stable CD3 MDC can achieve durable DFS with low incidence of GvHD, while attainment of FDC within 100 days was associated with poorer OS due to increased TRM. Further studies need to be directed towards establishing underlying factors which dictate T-cell engraftment, expansion and homing post-HSCT.

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Bone Marrow Mixed Chimerism Is a Risk Factor for Relapse After T-Cell Depleted Allogeneic Stem Cell Transplant

Blood ◽

10.1182/blood.v120.21.4145.4145 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4145-4145

Author(s):

Amanda L Olson ◽

Juliet N Barker ◽

Hugo Castro-Malaspina ◽

Sean Devlin ◽

Sergio A Giralt ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

Research Funding ◽

Conditioning Regimen ◽

Mixed Chimerism ◽

Female Patients ◽

Donor Chimerism ◽

Significant Difference ◽

Disease Free

Abstract Abstract 4145 Background: Full donor chimerism following non myeloablative unmodified stem cell transplants (SCTs) is important for disease control and SCT outcome. The impact of mixed chimerism (MC) after myeloablative unmodified SCT remains controversial, and there are limited reports about its prognostic significance after T-cell depleted (TCD) SCT. Treatment of MC, including reduction of immunosuppression or infusion of donor leucocytes (DLI), can lead to the development of graft versus host disease (GVHD). In order to optimize the graft vs leukemia (GVL) effect of a TCD allograft while minimizing GVHD risk, we sought to determine the significance of MC on TCD SCT outcomes and to identify a subgroup that would benefit from intervention. Methods: From 2000–2010, 447 adult patients with acute myeloid and lymphocytic leukemia (AML, ALL) and myelodysplastic syndrome (MDS) underwent bone marrow (BM) or peripheral blood stem cell (PBSC) TCD SCT. Conditioning regimens were total body irradiation (TBI)/Thiotepa with Cyclophosphamide or Fludarabine, Clofarabine/Melphalan/Thiotepa or Busulfan/Melphalan/Fludarabine. Like-gender donor-recipient chimerism was analyzed using semi-quantitative PCR for polymorphisms; PCR and/or cytogenetics were used for unlike gender pairings. Relapse was cytogenetic or hematologic evidence of disease. BM chimerism and disease status were evaluated at approimately 6, 12, 18 and 24 months. BM chimerism and outcome data were reviewed to determine whether 6 month BM MC (defined as < 95% donor chimerism) was associated with 2 year post-SCT relapse, transplant-related mortality (TRM) and disease-free survival (DFS). The 6 month landmark was chosen as a reasonable time point for intervention, such as DLI, if needed. Patients who received DLI prior to landmark were excluded. Patient and SCT characteristics were compared using Wilcoxon's rank-sum test or Fisher's exact test. DFS was estimated using Kaplan-Meier methods, and time-to-relapse and TRM were estimated using cumulative incidence functions. Results: 300 of the 447 patients survived, were disease free, and had BM chimerism data at 6 months. Median age was 50.6 years. Most patients received PBSC grafts (89%). 131 (44%) and 9 (3%) related, and 86 (29%) and 74 (24%) unrelated donors, were matched and mismatched, respectively. Only patients in remission or with low level disease (BM blasts < 10%) were transplanted with TCD grafts. The majority of patients were conditioned with Busulfan/Melfalan/Fludarabine and TBI/Thiotepa/Fludarabine, 45% and 32%, respectively. 251 pts (84%) received antithymocyte globulin. 25% demonstrated MC in the BM at 6 mos. The majority (60%) with MC had a donor component of 75–95%. Diagnosis was not associated with MC at 6 months. Stem cell source and degree of HLA-match had no impact on BM chimerism. There was a significant difference in chimerism based on donor-recipient gender pairing (P = 0.04): male grafts into female patients having the greatest risk of MC and female grafts into female patients having the least. There was also a significant difference in the degree of chimerism based on conditioning regimen: Busulfan/Melphalan/Fludarabine was most likely to result in MC (P = <0.001). TRM was not significantly different between the mixed and full donor chimerism groups. However, relapse was significantly higher in the MC group (P = 0.03): 10% (95% CI: 6–14%) with full chimerism and 18% (95% CI: 7–28%) with MC at 2 years (Figure 1). Diagnosis had no impact on relapse among patients with MC. Conclusions: 25% of TCD SCT recipients had MC in the BM. Although the incidence of relapse was low for patients who survived to 6 months in the full and MC groups (10% and 18%, respectively), the difference was statistically significant. There was also a significant difference in incidence of MC based on conditioning regimen and donor-recipient gender pairings. The low percentage of relapse in the MC group precluded subset analyses to identify a group who would benefit from the GVL effect of DLI. Lineage-specific PB chimerism analysis is ongoing and may provide information about subgroups that would benefit from intervention for MC. Analyses of outcomes, i.e., GVHD, in recipients of DLI or TCD stem cell boost for MC may help to determine the risk-benefit ratio of such interventions. Disclosures: Goldberg: SOBI Biovitrum: Research Funding. Perales:SOBI Biovitrum: Research Funding.

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288. Follow-Up Blood Cultures in Gram-Negative Bacteremia: How Do They Impact Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.331 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S144-S144

Author(s):

Azza Elamin ◽

Faisal Khan ◽

Ali Abunayla ◽

Rajasekhar Jagarlamudi ◽

aditee Dash

Keyword(s):

Clinical Outcomes ◽

Antibiotic Treatment ◽

Readmission Rate ◽

Blood Cultures ◽

Categorical Variables ◽

Gram Negative ◽

Number Of Patients ◽

Significant Difference ◽

The Impact

Abstract Background As opposed to Staphylococcus. aureus bacteremia, there are no guidelines to recommend repeating blood cultures in Gram-negative bacilli bacteremia (GNB). Several studies have questioned the utility of follow-up blood cultures (FUBCs) in GNB, but the impact of this practice on clinical outcomes is not fully understood. Our aim was to study the practice of obtaining FUBCs in GNB at our institution and to assess it’s impact on clinical outcomes. Methods We conducted a retrospective, single-center study of adult patients, ≥ 18 years of age admitted with GNB between January 2017 and December 2018. We aimed to compare clinical outcomes in those with and without FUBCs. Data collected included demographics, comorbidities, presumed source of bacteremia and need for intensive care unit (ICU) admission. Presence of fever, hypotension /shock and white blood cell (WBC) count on the day of FUBC was recorded. The primary objective was to compare 30-day mortality between the two groups. Secondary objectives were to compare differences in 30-day readmission rate, hospital length of stay (LOS) and duration of antibiotic treatment. Mean and standard deviation were used for continuous variables, frequency and proportion were used for categorical variables. P-value < 0.05 was defined as statistically significant. Results 482 patients were included, and of these, 321 (67%) had FUBCs. 96% of FUBCs were negative and 2.8% had persistent bacteremia. There was no significant difference in 30-day mortality between those with and without FUBCs (2.9% and 2.7% respectively), or in 30-day readmission rate (21.4% and 23.4% respectively). In patients with FUBCs compared to those without FUBCs, hospital LOS was longer (7 days vs 5 days, P < 0.001), and mean duration of antibiotic treatment was longer (14 days vs 11 days, P < 0.001). A higher number of patients with FUBCs needed ICU care compared to those without FUBCs (41.4% and 25.5% respectively, P < 0.001) Microbiology of index blood culture in those with and without FUBCs Outcomes in those with and without FUBCs FUBCs characteristics Conclusion Obtaining FUBCs in GNB had no impact on 30-day mortality or 30-day readmission rate. It was associated with longer LOS and antibiotic duration. Our findings suggest that FUBCs in GNB are low yield and may not be recommended in all patients. Prospective studies are needed to further examine the utility of this practice in GNB. Disclosures All Authors: No reported disclosures

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