Improved Long Term Survival with Minimal GVHD after Myeloablative Unrelated Donor Stem Cell Transplantation Using In Vitro and In Vivo T Cell Depletion with CAMPATH-1H.

Abstract In allogeneic stem cell transplantation (SCT) T-cell depletion reduces transplant related mortality by diminishing GVHD. We have investigated a myeloablative regimen for matched unrelated donor SCT using both in vivo and in vitro CAMPATH-1H for effective T-cell depletion, utilising DLI at a later time point for graft versus tumor effect if necessary. Thirty patients (median age 33 years, range 18–48) were transplanted from January 1997 to June 2002. Diagnoses were: CML CP (n=9), CML AP (n=2), AML/MDS (n=9), ALL (n=8), NHL (n=1) and Fanconi anemia (n=1). Six patients had one HLA mismatch, the others were identical for HLA A, B, C, DR and DQ. Conditioning consisted of CAMPATH-1H 5mg/d on days −8 to −4, TBI 6 Gy on days −8 and −7 and cyclofosfamide 60 mg/kg on days −6 and −5. T-cell depletion was performed by in vitro incubation of the graft with 20 mg CAMPATH-1H for 30 minutes (Campath “in the bag”). Post-transplant GVHD prophylaxis consisted of cyclosporine A and methotrexate. The stem cell source was bone marrow in 19 patients (63%) and peripheral blood in 11 patients. One graft failure was observed, all other patients had sustained engraftment of donor cells. Acute GVHD was observed in 12 patients (40%), maximally grade I-II skin. No severe acute GVHD (grade III-IV) was experienced. Limited chronic GVHD developed in 2 patients, resolving after treatment. Only in one patient extensive chronic GVHD developed, which did not resolve. CMV reactivation occurred in 23% of patients, one patient developed CMV disease. No EBV disease was observed. Ten patients received donor lymphocyte infusion (DLI) at a median of 17.4 months after SCT (8 patients with relapsed CML, one patient with relapsed ALL, one patient with autoimmune hemolytic anemia). After DLI acute GVHD grade I-II developed in 4 patients, and GVHD grade III-IV in 3. Chronic GVHD developed in 5 patients, of which 2 extensive, resolving in all except one patient. With a median follow up of 37 (range 21–84) months 17 patients are alive (57%). One of the CML patients shows persistence of molecular disease not responding to increasing doses of DLI. All other patients are in CR with the CML patients in molecular remission. Five patients (17%) died because of relapsed disease (2 AML/MDS and 3 ALL). Treatment related mortality was 26% (1 rejection, 2 GVHD, 1 myocardial infarction, 4 infections). In conclusion, matched unrelated donor SCT following myeloablative conditioning using T-cell depletion with CAMPATH-1H in vivo as well as in vitro results in good engraftment, minimal grade I-II GVHD and an overall survival of 57%. Relapse rate was not increased with this strategy. This regimen appears to be successful for young adults with high-risk malignancies.

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Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽

10.1182/blood.v116.21.2305.2305 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2305-2305 ◽

Cited By ~ 1

Author(s):

Robert J Soiffer ◽

Jennifer LeRademacher ◽

Vincent T Ho ◽

Fangyu Kan ◽

Andrew Artz ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hazard Ratio ◽

Cell Depletion ◽

P Value ◽

Unrelated Donor ◽

T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

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HLA-Mismatch Is Associated With Worse Outcomes After Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: A Cibmtr Analysis

Blood ◽

10.1182/blood.v122.21.547.547 ◽

2013 ◽

Vol 122 (21) ◽

pp. 547-547 ◽

Cited By ~ 2

Author(s):

John Koreth ◽

Kwang Woo Ahn ◽

Joseph Pidala ◽

James L. Gajewski ◽

Hailin Wang ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Gvhd Prophylaxis ◽

Conditioning Intensity

Abstract In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p<0.0001) and 29.2% vs. 38.1% (p<0.0007) respectively. Adjusted 1- and 3-year OS was 54.7% vs. 48.8% (p=0.01) and 37.4% vs. 30.9% (p=0.005) respectively (Figure). There was no difference between allele and antigen mismatches. HLA-A, -B, -C, and -DRB1 locus mismatches were each associated with 1 or more impaired outcomes (acute GVHD, NRM, DFS, and/or OS). Table 1 7/8 vs. 8/8 HLA HR (95% CI) p-value Acute GVHD II-IV 1.29 (1.09-1.53) 0.003 Acute GVHD III-IV 1.69 (1.00-3.36) 0.05 Chronic GVHD 1.11 (0.96-1.28) 0.15 Relapse 1.01 (0.87-1.17) 0.92 NRM 1.52 (1.29-1.79) <0.0001 DFS 1.20 (1.07-1.34) 0.0015 OS 1.25 (1.11-1.40) 0.0001 Compared to 8/8 MUD, both 7/8 allele and antigen MMUD RIC HCT have greater treatment toxicity and worse survival, of a magnitude similar to that seen in myeloablative transplantation. An isolated mismatch at HLA-A, -B, -C, or -DRB1 was associated with 1 or more adverse outcomes. In unrelated donor RIC HCT, matching for all alleles of HLA-A, -B, -C and -DRB1 loci results in superior outcomes. Disclosures: No relevant conflicts of interest to declare.

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Comparable Outcomes after Allogeneic Stem-Cell Transplantation with Intravenous Busulfan or Treosulfan-Based Reduced-Intensity and Reduced Toxicity Regimens in Acute Myeloid Leukemia. a Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽

10.1182/blood.v128.22.2280.2280 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2280-2280

Author(s):

Avichai Shimoni ◽

Myriam Labopin ◽

Bipin N. Savani ◽

Rose-Marie Hamladji ◽

Dietrich W. Beelen ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Advanced Disease ◽

Chronic Gvhd ◽

Working Party ◽

Cell Depletion ◽

T Cell Depletion ◽

Reduced Toxicity

Abstract Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). Myeloablative conditioning (MAC) is associated with prohibitive rates of non-relapse mortality (NRM) in older and less medically fit patients. Several reduced intensity conditioning regimens (RIC) and more recently the more dose-intensive reduced toxicity myeloablative (RTC) regimens were designed to replace MAC in this setting. The backbone of these regimens is usually fludarabine with busulfan and more recently also with treosulfan, but there is no clear data on the comparative outcomes with these different regimens in the different SCT settings. The current study included 3561 patients with AML given a first allogeneic SCT from an HLA-matched sibling (n=1683) or a 10/10 matched unrelated donor (n=1878) between the years 2000-2014 and reported to the acute leukemia working party (ALWP) of EBMT. Only patients given fludarabine with either intravenous busulfan (ivBu), (FB, n=2990) or treosulfan (FT, n=571) alone were analyzed. Fludarabine and ivBu at 6.4 mg/kg (n=1457) or treosulfan at 30-36 gr/m2 (n=168) were considered RIC regimens while fludarabine with ivBu at a total dose of 9.6-12.8 mg/kg (n=1533) or treosulfan at 42 gr/m2(n=403) were considered RTC regimens according to EBMT criteria. The median age of FB and FT recipients was 55.5 and 58.3 years, respectively (P< 0.0001). The status at SCT was 72.5% CR1, 15.0% CR2 and 12.5% advanced disease in the FB group compared to 55.0%, 20.3% and 24.7% in the FT group, respectively (P<0.0001). More FT recipients had SCT from unrelated donors (64.8% Vs. 50.4%, P<0.0001) but less had in-vivo T-cell depletion (58.4%Vs 70.5%, P<0.0001). Cytogenetic subgroup distribution was similar between the groups. Ninety percent had peripheral blood stem cell grafts in both groups. The median follow-up was 19 and 43 months after FB and FT, respectively. Using univariant analysis, the 2-year relapse incidence (RI) was 32.7% and 35.5%, respectively (P=0.49). NRM was 17.6% and 19.4%, respectively (P=0.09). Leukemia-free survival (LFS) and overall survival (OS) were 49.5% and 54.8% after FB and 45.1% and 52.6% after FT, respectively (P=0.04, P=0.17). Acute GVHD grade II-IV and chronic GVHD were 23.1% and 35.7% after FB and 18.8% and 39.8% after FT, respectively (P=0.03, P=0.04). In all, the GVHD/ relapse-free survival (GRFS) was 36.5% and 31.5%, respectively (P=0.08). After adjusting for the differences in patient characteristics, there was no difference between the FB and FT groups in RI, NRM, LFS, OS and GRFS. However, acute GVHD grade (II-IV) was higher after FB (HR, 1.49, P=0.0004). The same observations were seen when the analysis was limited to RIC or RTC regimens only, or when only patients in remission were analyzed. However, when analyzing only the 516 patients with advanced disease at SCT, 2-year OS was 29.7% and 43.0% after FB and FT (P=0.002) and this difference remained significant in the multivariant analysis (HR, 1.50, p=0.003). Among the entire group, the factors associated with reduced survival were advanced age (HR 1.01, P<0.0001), secondary AML (HR 1.19, P=0.005), CR2 (HR 1.21, P=0.007) and advanced disease (HR 2.02, P<0.0001) compared to CR1, and female donor to male recipient (HR 1.15, P=0.03). Conditioning type and intensity, donor type, CMV status and in vivo T-cell depletion were not significant. Relapse was lower and NRM was higher with RTC compared with RIC, but OS was similar. The same factors predicted for GRFS, a surrogate for quality of life, with the only difference been the positive role of in vivo T-cell depletion (HR 0.8, P=0.0002). In conclusion, RIC and RTC regimens with ivBu or treosulfan-based regimens are associated with similar transplantation outcomes. OS is primarily affected by disease factors such as status of disease at SCT and secondary leukemia. Treosulfan- based conditioning is associated with a lower rate of acute GVHD, but with similar rates of chronic GVHD, NRM and GRFS. Treosulfan conditioning may have some advantage in patients with advanced disease at SCT. Disclosures No relevant conflicts of interest to declare.

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Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplant with in Vivo T-Cell Depletion By Alemtuzumab: Incidence, Outcome and Pattern of Organ Involvement

Blood ◽

10.1182/blood.v124.21.3912.3912 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3912-3912 ◽

Cited By ~ 1

Author(s):

Maria Chiara Finazzi ◽

Cristina Boschini ◽

Janice Ward ◽

Charles Craddock ◽

Alessandro Rambaldi ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Stem Cell Transplant ◽

Chronic Gvhd ◽

Cell Depletion ◽

Organ Involvement ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

T Cell Depletion

Abstract Introduction Graft-versus-Host Disease (GvHD) is one of the leading causes of mortality and morbidity following allogeneic stem cell transplant. In vivo T cell depletion by alemtuzumab as part of the transplant conditioning is an effective strategy to reduce the risk of GvHD. While it is recognised that the overall incidence of GvHD is reduced by alemtuzumab, the incidence of chronic GvHD as defined by the National Institute of Health (NIH) consensus criteria, the impact on outcome, and the pattern of organ involvement have not been defined yet in this transplant setting. Methods Consecutive patients (n = 323) undergoing allogeneic stem cell transplantation at the Queen Elizabeth Hospital, Birmingham, between January 1 2008 and June 30 2012 were reviewed in this retrospective, single centre study. Medical records were examined and data regarding the development of GvHD were collected; NIH consensus criteria for diagnosis and staging of chronic GvHD were stringently applied. Clinical characteristics of GvHD occurring in patients transplanted following T cell depletion by alemtuzumab administration (n=248) were compared with those of patients transplanted with a T cell replete graft (n=75). Patients receiving alemtuzumab were mainly treated with reduced-intensity conditioning protocols, while patients in the no-T-cell depletion group were mainly treated with a myeloablative, sibling transplant. Results After a median follow up of 38.4 months, the cumulative incidence (CI) of grade II-IV classic acute GvHD was 35% and 48% for patients transplanted respectively with or without T cell depletion by alemtuzumab (p= 0.041, Figure 1); with a CI of grade III-IV classic acute GvHD of 13% and 27% (p=0.007). The 2-years CI of grade II-IV late acute GvHD was not significantly different in the two groups (20% and 23% for patients respectively treated with or without alemtuzumab, p=0.589, Figure 2). T cell depletion by alemtuzumab significantly reduces the 3 years cumulative incidence of classic chronic GvHD (5% versus 31%, p<0.0001, Figure 3.A), but without a significant difference in the incidence of overlap syndrome between patients with and without T cell depletion (3 years CI respectively 6% and 7%, p=0.839, Figure 3.B). The pattern of organ involvement by classic acute GvHD was similar in patients with and without T cell depletion. The pattern of organ involvement by late acute GvHD in the alemtuzumab group was, however, significantly different compared to the T cell replete group (skin-gut-liver involvement reported respectively in 83%-28%-4% of patients and 56%-48%-20% of patients, p=0.003). Distribution of organ involvement by classic chronic and overlap syndrome was similar in the two groups; however, it seems that alemtuzumab prevents the development of lung GvHD (lung GvHD developed in 4 patients over the 75 patients of the no-T-cell depletion group, while none of the 248 patients transplanted with alemtuzumab experienced lung GvHD). In a multivariate analysis, the development of chronic GvHD was an independent predictor of higher mortality risk (HR 1.66, p = 0.04) and severe NIH global score at peak was confirmed as a poor prognostic factor for survival (HR 2.27, p=0.02). The negative impact of chronic GvHD and of the severe forms of chronic GvHD was independent of age and alemtuzumab administration. Conclusion This retrospective analysis provides for the first time data on the incidence rates of NIH-defined GvHD categories in patients transplanted after T cell depletion by alemtuzumab. Patients transplanted with alemtuzumab experienced a lower incidence of classic acute and classic chronic GvHD compared to patients not receiving T cell depletion. In contrast, alemtuzumab conditioning appeared to have no effect on the incidence of late acute GvHD or overlap syndrome, suggesting that these two entities of GvHD are driven by different immunological mechanisms as compared to classic acute and classic chronic GvHD. We also confirmed the utility of the NIH classification of GvHD and of the NIH global severity score to predict survival in alemtuzumab-conditioned allogeneic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

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Decreased Incidence of GvHD after Reduced Intensity Conditioning and a Fixed T-CELL Dose in Hematological Malingnancy Patients

Blood ◽

10.1182/blood.v124.21.5889.5889 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5889-5889 ◽

Cited By ~ 1

Author(s):

Audrey Simon ◽

Eddy Roosnek ◽

Yordanka Tirefort ◽

Yan Beauverd ◽

Carole Dantin ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Two Factors

Abstract Introduction: To decrease graft versus host disease (GvHD), the Geneva transplantation team has performed allogeneic hematopoietic stem cell (alloHSCT) with reduced intensity conditioning (RIC) and T cell depletion (TCD) to treat hematological malignancies for older or non fit for myeloablative conditioning patients. This is a new approach of engineering stem cell products that lowers the risk of GvHD while preserving graft versus leukemia (GvL) as much as possible. Patient and methods: We report a retrospective study of 73 patients who received alloHSCT with RIC and TCD between 2001-2013. The median age was 59 years (21-70), 60% were male. Disease at transplant time was acute leukaemia for 45%, Hodgkin lymphoma and non-Hodgkin lymphoma for 24%, myelodysplastic disorders for 13%, myeloproliferative disorders for 9,3 % and multiple myeloma for 8%. Source of stem cell was peripheral in 96% of the cases. 41% of the donors were matched related donor, 37% matched unrelated donor, 19% mismatched unrelated donor and 3% mistmatched related donor. The conditioning regimen consisted on fludarabine with busulfan or melphalan and ATG. Extensive T-cell depletion was done using Campath in the bag followed by washing procedures to remove free antibody. Fixed number of CD3+ T-cell addback was given on d+1 to preserve GvL with minimal residual disease (MRD) assessment and early donor lymphocyte infusions (DLI) given if MRD positive. Doses of DLI were preserved and frozen at the time of stem cell harvest. GvHD prophylaxis was with ciclosporine and mycophenolate mofetil. Results: With a median follow up of 5 (0.5-11) years, the 5-year overall survival (OS), disease free survival (DFS), current disease free survival, relapse rate and non relapse mortality (NRM) were 41.7% (95%CI 30.7-53.7%), 38.8% (95%CI 28.8-50.8%), 39,5% (95%CI 27.7-51.7%), 45.3% (95%CI 32.7-57.2%) and 15.8% (95%CI 8.3-25.4%) respectively. The main cause of death was relapse 38.7 % followed by GvHD 17% and infection 1.3%. In this cohort, the cumulative incidence (CI) of acute GvHD was 15.1% (95% CI: 8.0-24.3%) as well as for acute GvHD grade II-IV. CI of chronic GvHD was 14.7% (95%CI:7.2-23.6%) with extensive chronic GvHD CI being 5.9% (95% CI: 1.9-13.4%). Five patients received DLI for relapses, 27 for mixed chimerism and 8 for both causes. The average number of DLI was 2. Twenty-eight patients entered CR, 4 PR and 13 did not respond to DLI. In univariate analysis, two factors GvHD before DLI and GvHD after first DLI have a tendency for favorable impact on OS respectively p=0.093 and 0.071. For DFS, two factors are significant: disease risk index and GvHD after first DLI respectively p=0.013 and 0.044. For NRM disease risk index is the only factor which is statistically significant p=0.005. For relapse no factors were significant. Discussion: Our study showed a lower rate of acute and chronic GvHD as compared to other studies with unmanipulated stem cells. However, we describe a high rate of relapse incidence and relapse mortality. We have found in univariate analysis two factors statistically significant for DFS GvHD before and after first DLI. Our cohort is a heterogeneous group with different diseases at different stages, which can explain those results. It’s a monocentric study and small number of patient can be a limit for this work. Of note, since 2009 we have changed our strategy introducing a day +100 preemptive DLI infusion in the absence of GvHD, with escalading doses of lymphocytes every 8 weeks up to 5x 107 CD3/kg in the absence of GvHD to improve response. We don’t have enough patients and follow up to draw any conclusion regarding this new strategy. To improve the outcomes, the selection of patients who may receive partial T-cell depletion should be refined, avoiding transplanting patients with high risk of relapse with this strategy. To help decision making, the revised disease risk index as presented by Armand et al. (Blood 2014;123:3664) may be useful. Disclosures No relevant conflicts of interest to declare.

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In Vivo T Cell Depletion with Thymoglobulin or Alemtuzumab Is Associated with Worse Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients Transplanted in Remission

Blood ◽

10.1182/blood.v126.23.3115.3115 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3115-3115

Author(s):

Scott R. Solomon ◽

Melissa Sanacore ◽

Xu Zhang ◽

Katelin Connor ◽

Melhem Solh ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Cell Depletion ◽

T Cell Depletion ◽

Hematopoietic Stem

Abstract In vivo T Cell Depletion with Thymoglobulin or Alemtuzumab Is Associated With Worse Outcome Following Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients Transplanted in Remission. Allogeneic hematopoietic stem cell transplantation (HSCT) reduces relapse risk in adults with acute myeloid leukemia (AML) due in large part to the potent graft-versus-leukemia effect of donor lymphocytes. However, this benefit must be balanced by the increased morbidity and mortality associated with graft-versus-host disease (GVHD). Serotherapy, in the form of thymoglobulin or alemtuzumab, has been used for in vivo T cell depletion as a strategy to reduce GVHD. We analyzed 144 consecutive AML patients transplanted in remission (CR1 - 111, CR≥2 - 33) from either a matched related (MRD, n=44), unrelated (MUD, n=62), or haploidentical (haplo, n=38) marrow of PBSC donor, in order to analyze the effect of serotherapy, in relation to other disease-, patient- and transplant-related risk factors, on post-transplant outcomes. Patients were transplanted at a single institution between 3/15/06 to 12/19/14. Baseline characteristics of the patient cohort included age >50 in 88 (61%), KPS<90 in 93 (65%), CMI ≥3 in 61 (42%) of patients. Disease risk index (DRI) was defined as low, intermediate, and high in 5 (4%), 110 (76%), and 29 (20%) patients respectively per the revised Dana Farber/CIBMTR criteria. Myeloablative chemotherapy was given in 96 (67%) patients, and PBSC was the source of stem cells in 120 (83%) patients. Serotherapy was utilized in 21 (15%) patients [thymoglobulin - 8, alemtuzumab - 13]. Serotherapy patients were more likely to be older (median age 59 vs. 52 years, p=0.013) and have a MUD (81% vs. 37%, p<0.001), but otherwise had similar baseline characteristics in regards to disease status, DRI, regimen intensity. Acute GVHD grade II-IV occurred in 38% of patients, whereas chronic GVHD was seen in 44%. Chronic GVHD occurred less often in patients receiving serotherapy (19% vs. 49%, p=0.016). Estimated one year non-relapse mortality (NRM) at 1 and 3 years was 4% and 13% respectively and was statistically similar in serotherapy and non-serotherapy patients. The estimated 3 year OS, DFS, and relapse was 58%, 51%, and 37% respectively for the whole cohort; 64%, 55%, and 33% in non-serotherapy patients vs. 29%, 27%, and 57% in serotherapy patients (figure 1). Cox analysis was performed utilizing the following variables: age, disease status, DRI, KPS, CMI, transplant type (MRD, MUD, haplo), conditioning intensity, stem cell source, use of serotherapy, year of transplant, acute and chronic GVHD. Variables were selected by a 10% threshold. Acute and chronic GVHD were modeled as time-dependent variables. In multivariate analysis, unfavorable risk factors for survival included only two variables: the use of serotherapy (HR 3.11, p<0.001) and high risk DRI (HR 1.89, p=0.038). Use of serotherapy also had a negative effect on relapse (HR 2.69, p=0.003) and DFS (HR 2.73, p<0.001), with no effect on NRM. Following allogeneic HSCT for AML patients in remission, the use of serotherapy for in vivo T cell depletion had a major negative impact on survival due to increased relapse risk. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Reduced-Intensity Conditioning (RIC) with Busulfan, Fludarabine and Campath-1H Is Complicated by a High Rate of Graft Failure and Severe Viral Complications in Patients with CLL.

Blood ◽

10.1182/blood.v104.11.5080.5080 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5080-5080 ◽

Cited By ~ 1

Author(s):

Johannes Schetelig ◽

Martin Bornhaeuser ◽

Christian Thiede ◽

Brigitte Mohr ◽

Uta Oelschlaegel ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unknown Etiology ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

One Year

Abstract Recently we demonstrated that RIC with busulfan, fludarabine and ATG followed by allogeneic hematopoietic stem cell transplantation (HSCT) induced molecular remissions in patients (pts) with advanced CLL. However, this approach was hampered by severe GVHD. In an attempt to lower the rate of severe GVHD we replaced ATG by campath in a new study protocol. Patients and Methods: 20 pts with a median age of 54 years (range, 43 to 64) and advanced CLL were included. A median of 3 prior chemotherapy regimens had been given before HSCT, including fludarabine-containing regimens in all but two pts with autoimmune hemolysis. High risk cytogenetic features (17p−, 11q−, +12) were present in 9 pts. After conditioning with busulfan (8 mg/kg), fludarabine (150 mg/m2) and campath (75 mg) on days −9 to −5 peripheral blood stem cells from matched related (n=4) or unrelated donors (n=16) were transplanted. GVHD prophylaxis consisted of CSA monotherapy. Campath levels were analysed in frozen serum samples by BioAnaLab, Oxford, UK. Results: Two pts had no detectable campath level at the day of HSCT, while four pts had levels between 0.5 to 1.8 microgram/mL. Regeneration of neutrophils (>0.5/nl) and platelets (>20/nl) required a median of 17 (range, 14–25) and 10 (range, 0–27) days, respectively. Incomplete T-cell chimerism (<50%) was observed in 7 pts and subsequently 3 pts experienced secondary graft failure on days 134, 152 and 324. Six pts received donor lymphocyte infusions (DLI) for the conversion of incomplete T-cell chimerism (N=4) or progressive disease (N=2). Sponaneous acute GVHD II° to IV° occurred in 9/20 pts. After DLI four additional pts developed acute GVHD II° to IV°. Limited chronic GVHD occurred in 9 and extensive disease in 2 pts. In CMV seropositive pts the day 100 probability of CMV infection was 74% (95% CI, 44% to 100%). Severe encephalitis (HHV6, EBV and JC virus as suspected agents) was observed in 5 pts. Two pts recovered without sequelae, 2 pts are cognitively handicaped and one pt died. Hemorrhagic cystitis (CTC 2/3) occurred in 2 pts. After a median follow-up of 13 months (range, 6 – 26 months), 15 pts are alive. Four pts died from treatment related complications. Causes of death were pneumonia of unknown etiology (N=2), encephalitis (N=1) and GVHD grade IV (N=1). One pt died from severe acute GVHD subsequent to the treatment of relapse with DLI. One-year overall and progression-free survival was 75% (95% CI, 55% to 95%) and 50% (95% CI, 25% to 75%), respectively. The one-year probability of non-relapse mortality was 20% (95% CI, 2% to 38%). The number of binding sites for campath is highly variable in pts with progressive CLL resulting in interindividually highly variable pharmacokinetics. Differences in the extent of in vivo T-cell depletion might therefore explain the individually varying T-cell engraftment pattern. In addition, the high incidence of severe viral infections reflects impaired immunoreconstitution. Including pts after DLI we observed a substantial rate of severe GVHD. Based on these data we decided to skip the strategy of in vivo T-cell depletion with campath in patients with CLL.

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Post-Transplant Immune Suppressive Therapy Is Not Necessary In Related and Unrelated Reduced Intensity Conditioning Stem Cell Transplantation Using Low Dose Alemtuzumab In Vivo T Cell Depletion Combined with Alemtuzumab-Mediated In Vitro T Cell Depletion of the Graft

Blood ◽

10.1182/blood.v116.21.2328.2328 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2328-2328

Author(s):

P.A. Von Dem Borne ◽

C.J.M. Halkes ◽

C.W.J. Starrenburg ◽

W.A.F. Marijt ◽

J.H.F. Falkenburg

Keyword(s):

T Cell ◽

Low Dose ◽

Chronic Gvhd ◽

Cell Depletion ◽

Suppressive Therapy ◽

T Cell Depletion ◽

Post Transplant ◽

Immune Suppressive Therapy

Abstract Abstract 2328 Introduction T cell depletion with alemtuzumab administered in vivo to the patient reduces the risk of graft-versus-host disease (GVHD) and graft rejection following reduced intensity conditioning allogeneic stem cell transplantation (RIC SCT). However, high doses of alemtuzumab can result in delayed immune reconstitution, increased non relapse mortality (NRM) due to infections, and potential loss of graft versus tumor responses. Recently, the feasibility of T cell depletion with low dose in vivo alemtuzumab was demonstrated in HLA-identical related RIC SCT. Dose reduction of alemtuzumab to 30 mg combined with post-transplant immune suppressive therapy with cyclosporine tapered from 3 months after transplantation resulted in a low risk of GVHD, no increase in NRM and improved lymphocyte recovery (Chakraverty et al, Blood pre-published online June 29, 2010). Early immunotherapeutic intervention after SCT with donor lymphocytes may be hampered by the administration of post-transplant immune suppressive therapy. We investigated whether in RIC SCT using low dose in vivo alemtuzumab, post-transplant immune suppressive therapy can be replaced by alemtuzumab-mediated in vitro T cell depletion of the graft just prior to infusion (“Campath in the bag”). Patient and donor characteristics Between 2007 and 2009, 29 patients were transplanted with an unrelated donor, and 28 patients with a related donor using a RIC regimen consisting of fludarabine (50 mg/m2 p.o. day -10 to -5), busulphan (3.2 mg/kg i.v. day -6 and -5) and alemtuzumab (15 mg i.v. day -4 and -3), followed by infusion of the graft after in vitro incubation with 20 mg alemtuzumab. No additional immune suppressive therapy was used after SCT. Unrelated donors were matched for HLA-A, B, C, DR and DQ, three patient donor combinations had one HLA-DQ mismatch. Median patient age was 59 years (range 21–72). Remission status at the time of transplant was: 47% CR, 37% PR, 9% SD, 7% PD. Indications were diverse (19 AML, 16 myeloma, 6 CLL, 5 low grade NHL, 3 aggressive T-NHL, 2 aggressive B-NHL, 2 SAA, 1 CML, 1 myelofibrosis, 1 CMML, 1 ALL). The unrelated and related transplanted group were comparable regarding age, disease and remission status. The median Gratwohl transplantation risk score was 3 in the related group (range 1–5), and 5 in the unrelated group (range 3–6). Results All patients engrafted; platelet numbers of 50 × 109/L were reached after a median of 11 days (range 0–38 days), neutrophil numbers of 0.5 × 109/L were reached after a median of 18 days (range 0–161 days) post transplant. Two patients had secondary graft failure. In patients transplanted with a related donor, grade 1–2 and 3–4 acute GVHD was observed in 36% and 4% of evaluable patients, respectively, resolving in all patients without development of chronic GVHD. NRM was 0% at 3 months and 4% at 1 year. Overall survival was 100% at 3 months and 89% at 1 year. In patients transplanted with an unrelated donor more acute GVHD was observed (59% grade 1–2, 15% grade 3–4 of evaluable patients). 24% of evaluable patients developed chronic GVHD, which was limited in 75% and extensive in 25% of these patients. Chronic GVHD resolved in most patients, one patient has ongoing extensive chronic GVHD. NRM was 7% at 3 months and 24% at 1 year. Overall survival was 93% at 3 months and 55% at 1 year. Conclusions RIC SCT using low dose alemtuzumab in vivo T cell depletion combined with alemtuzumab-mediated in vitro T cell depletion of the graft without additional post-transplant immune suppressive therapy is feasible in patients transplanted with related and unrelated donors. Results are excellent in patients transplanted with related donors with low NRM and high overall survival. Although results are good in patients transplanted with unrelated donors considering the high Gratwohl score in this group, further improvement is being sought by increasing the efficiency of T cell depletion. This RIC SCT regimen without post-transplant immune suppressive therapy is an appropriate platform for early cellular immunotherapeutic interventions including donor lymphocyte infusion after SCT. Disclosures: No relevant conflicts of interest to declare.

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Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-147809 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 424-424

Author(s):

Mesire Aydin ◽

Elisabeth Dovern ◽

Mariska M.G. Leeflang ◽

Josu de la Fuente ◽

Adetola A. Kassim ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Research Funding ◽

Graft Failure ◽

Meta Analysis ◽

Cell Depletion ◽

T Cell Depletion ◽

Related Mortality

Abstract Background Allogeneic hematopoietic stem cell transplantation (SCT) is the only established curative treatment option for patients with sickle cell disease (SCD). Transplantations with an HLA-identical matched sibling donor (MSD) have resulted in excellent disease-free survival of >90% and overall survival (OS) of >95%. However, lack of HLA-identical siblings is a limiting factor. The chance of finding a potential matched unrelated donor is low for patients with a non-Western ethnic background (< 20%). Haploidentical related donors are a promising pool of donors potentially extending SCT as a curative treatment to a larger group of SCD patients with no other meaningful treatment options. Myeloablative conditioning regimens (MAC) are not recommended for adult SCD patients, as cumulative SCD-related organ damage renders these patients susceptible to increased toxicity and higher risk of transplant-related mortality. Using reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMC) in both adult and pediatric patients has resulted in decreased transplant-related toxicity and mortality. However, while successful in hematologic malignancies, NMC has been associated with significant risk of graft failure in hemoglobinopathies. In the present study, we aimed to systematically review (1) the outcomes of haploidentical SCT (Haplo-SCT), (2) the effects of conditioning intensity and modes of T-cell depletion on Haplo-SCT outcomes and (3) comparative outcomes between matched sibling donor SCT (MSD-SCT) and Haplo-SCT in selected studies. Methods A comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data was extracted by two reviewers independently and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Only studies reporting at least one of the outcomes: graft failure, OS, transplant-related mortality, and acute/chronic graft-versus-host disease (GvHD) were included. Fourteen studies met the inclusion criteria. To have an overview of the results of Haplo-SCT, we divided the included studies in four groups according to the conditioning intensity (MAC versus NMC/RIC) and the T-cell depletion method (in vivo (post-transplant cyclophosphamide (PTCy)) vs. in vitro). Results All included studies were observational cohort studies. A subgroup meta-analysis of the results of Haplo-SCT showed relatively low overall pooled proportions of graft failure (7%, 95% CI: 2 - 20), acute (4%, 95% CI: 2 - 12) and chronic (11%, 95% CI: 7 - 16) GvHD. Overall survival was high (91%, 95% CI: 85 - 94). Graft failure in MAC-in vitro, MAC-in vivo, NMC/RIC-in vitro and NMC/RIC-in vivo groups was 4% (95% CI: 1 - 14), 0% (95% CI: 0 - 100), 25% (95% CI: 10 - 51) and 11% (95% CI: 3 - 36) respectively (Figure 1). OS was 100% and 93% for MAC and NMC/RIC groups with PTCy (in vivo T-cell depletion) respectively. In patients with in vitro T-cell depletion, OS was 87% and 81% in MAC and NMC/RIC groups respectively (Figure 2). Based on a comparative meta-analysis of the three studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio 5.3, 95% CI: 1.0 - 27.6). Overall survival, transplant-related mortality and acute/chronic GvHD were not significantly different between the groups. Conclusions This systematic review shows that modifications in the intensity of the conditioning regimen and improved T-cell depletion approaches in Haplo-SCT in SCD have led to reduced transplantation-related toxicity while keeping graft failure rates low. Both in vitro and in vivo (PTCy) T-cell depletions result in very low transplantation-related mortality, though in vitro T-cell depletion is associated with a higher incidence of viral reactivations and other infectious complications. Haploidentical stem cell transplantation is becoming a viable alternative curative option for SCD, extending the availability of allogeneic SCT as a treatment option to many more transplant eligible SCD patients. Novel immunosuppression (immunoablation) and improvement in supportive care have allowed the use of RIC or NMC regimens, resulting in low risk of transplantation-related complications and improvement in engraftment rates. Figure 1 Figure 1. Disclosures Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria; Sanquin: Research Funding; Novo Nordisk: Honoraria; Celgene: Honoraria. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

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Fludarabine-Busulfan Conditioning and In Vivo T-Cell Depletion with Reduced Dose of ATG Followed by Allografting Induces Durable Responses in Patients with Advanced Multiple Myeloma with No Grade III-IV aGvHD.

Blood ◽

10.1182/blood.v108.11.3029.3029 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3029-3029

Author(s):

Nizar J. Bahlis ◽

Douglas A. Stewart ◽

Mary Lynn Savoie ◽

Christopher Brown ◽

Andrew Daly ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Depletion ◽

Cell Transplant ◽

T Cell Depletion ◽

Grade Iii

Abstract Background: We have investigated a conditioning regimen with Fludarabine and intravenous Busulfan with reduced ATG dose in patients with advanced and poor prognosis myeloma exploring the possibility that a low dose ATG may be sufficient enough to prevent severe GvHD without completely suppressing the graft vs myeloma effect. Methods: 15 patients received a conditioning regimen consisting of fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. All pts received Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pre-transplant finishing D0, cyclosporine A and methotrexate with folinic acid. Results: The median age was 49 years (range 40–61). 14 (93.3%) patients had stage III (DS) disease with a median β2-microglobulin 3.12 mg/dl (1.82–5.75) and 7/11 (63.6%) in whom FISH studies were available had deletion 13, 5/15 (33.3%) patients had relapsed or progressed within 2 years of prior autologous stem cell transplant and 4 (26.6%) had progressed while on thalidomide /Dex salvage treatment. The disease status prior to allogeneic transplant was partial response (PR) in 6/15 (40%) and progressive disease (PD) in 9/15 (60%). 2/15 had plasma cell leukemia. The median number of bone marrow plasma cells prior to allo-transplant was 16% (range 3%-85%). Donors were matched siblings (MRD) for 13 (86.7%) and alternate donors in 2 (13.3%, unrelated with 2 C antigen mismatch). Cell source was blood in 14/15 (93.3%). Acute GVHD grade II-IV occurred in only 1 patient (6.6%) with no grade III-IV acute GVHD. Chronic GVHD occurred in 9/15 (60%). The TRM was 6.6%. Among 14/15 patients evaluable for response, the overall response rate (CR+PR) was 53.3% (2 CR, 6 PR, 1 MR and 5 PD); 37.5% (1CR, 2PR, 1MR and 4PD) for pts with PD at the time of the transplant and 71.4% (4PR, 1MR and 1PD) for pts with del13. After a median follow-up of 40.9 months (range 36–65.2), the estimated OS and PFS at 4 years for all patients is 38.9% (CI 95%: 13.1–64.7%) and 20.0% (CI 95%: 0–40.3%) respectively. For patients with del13 the estimated OS and PFS at 4 years is 38.1% (CI 95%: 0–77.9%) and 0% respectively. Conclusion: In vivo T-cell depletion with ATG results in a low rate of severe aGvHD with low treatment-related mortality and a substantial number of long-term survivors among patients with advanced multiple myeloma. The detection of deletion 13 by FISH however remains a predictor of short progression free survival. Figure Figure

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