GvHD Prophylaxis with Everolimus and Mycophenolate in Allogeneic Hematopoietic Cell Transplantation - A Phase I/II Study.

Abstract Abstract 4642 Next to the control of malignant disease, tolerance induction of the grafted cells remain to be a critical issue for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are believed to be involved in the process of tolerance induction to solid organ grafts and in the regulation of alloreactivity, e.g. graft versus host disease (GvHD) and graft versus leukemia effect (GvL), after allogeneic HCT. Since GvHD causes substantial morbidity, medication with calcineurin inhibitors (CI) like cyclosporine are established prophylactic measures for the prevention of GvHD after HCT. Next to the substantial renal toxicity of CI, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. In contrast, data from in vitro and animal experiments suggest that inhibition of the mammalian target of rapamycin (mTOR) has not only an antiproliferative effect on many malignant cell lines but also results in an inhibition of proliferation of alloreactive T cells with sustained Treg function in a murine HCT model. Therefore we initiated a phase I/II, monocenter trial using everolimus and mycophenolate sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after conditioning with fludarabine, melphalan, and BCNU (FBM). No additional T cell depleting agents were used for conditioning/GvHD prophylaxis. Enrolment was started in april 2008, and up to august 2009 10 patients were included (median age: 50.7 years, range: 26-64). The diagnoses included de novo AML (n=3), sAML (n=4), RAEB II (n=1), CML (n=1), T-PLL (n=1). 6/10 patients were regarded as high risk (not in CR1) for early relapse. PBSC grafts were obtained from unrelated (n=5) and related (n=5) HLA-matched donors. With no graft failures, engraftment kinetics for myeloid cells were normal, and reconstitution of the T cell compartment reached median cell counts of 251 CD4+ cells/μl and 163 CD8+ cells/μl at day +30. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow-up of 6 month two patients have died. The causes were acute GvHD, refractory to several lines of treatment, in a patient with CML, and severe pulmonary toxicity/BOOP in a patient with sAML. Out of 9 patients reaching CR after HCT, only one high risk patient relapsed after 6 month. In total 6 patients are alive and show complete donor chimerism for time periods of 1-14 months post transplant. The observed early recovery of T cell immunity correlated in 8/10 patients with an early brief period of acute GvHD, with 4 patients experiencing grade III/IV severities. Most of the cases could be controlled with steroids alone. Chronic GvHD could be observed in 6/7 patients, with mild to moderate forms in 5 cases, mainly involving skin, mucosa and liver. Interestingly, while early tapering of MMF-Na did not cause any problems, reduction of everolimus earlier as 6 month after HCT resulted in an induction of GvHD symptoms. Although viral reactivation (CMV, HHV6) did occur in patients receiving additional immunosuppression with steroids, no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of mild to moderate chronic GvHD. Since this sustained mild alloreactivity might reduce the risk of relapse, this GvHD prophylaxis could well be suited for patients undergoing HCT with advanced or uncontrolled malignant disease. Disclosures: Marks: Novartis: Research Funding. Off Label Use: Everolimus for prophylaxis of GvHD. Finke:Novartis: Research Funding.

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Everolimus and Mycophenolate as GvHD Prophylaxis Results In Improved Control of Advanced Disease and Reduced Bacterial and Fungal Infectious Complications After Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v116.21.1264.1264 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1264-1264

Author(s):

Reinhard E Marks ◽

Hartmut Bertz ◽

Ralph M. Waesch ◽

Wolfgang Melchinger ◽

Juergen Finke

Keyword(s):

Stem Cell ◽

T Cell ◽

Cell Transplantation ◽

Malignant Disease ◽

Chronic Gvhd ◽

Tolerance Induction ◽

Infectious Complications ◽

Cell Counts ◽

Treg Function ◽

Gvhd Prophylaxis

Abstract Abstract 1264 Tolerance induction together with sustained disease control remain to be critical for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are involved in the regulation of graft versus host disease (GvHD) and graft versus leukemia effect (GvL). Although calcineurin inhibitors are frequently being used for the prevention of GvHD, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. Data from animal models of HCT suggest that inhibition of the mammalian target of rapamycin (mTOR) results not only in suppressed T cell alloreactivity but also in sustained Treg function. On the other hand severe reduction of T cell alloreactivity might result in diminished control of especially advanced malignant disease. To explore the clinical efficacy of a calcineurin-free GvHD prophylaxis regimen, we initiated a phase I/II monocenter trial using everolimus and mycophenolate-sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after reduced toxicity and standard conditioning. 28 patients were included (median age: 49,2 years, range: 21–65). The diagnoses were: AML/MDS (n=16), ALL (n=3), CML/MPS (n=3), T-PLL (n=1), NHL/CLL (n=6). At the time of transplantation 22/28 (78%) patients were at high risk (not in CR1/CP, untreated) for early relapse. Conditioning included fludarabin based reduced intensity (n=24) or standard regimens containing busulfan (n=2) or clofarabine (n=2). Four CR1 patients received additional alemtuzumab (total 10mg) for GvHD prophylaxis. PBSC grafts were obtained from unrelated (n=20) and related (n=8) HLA-matched donors. No graft failure occurred. Engraftment kinetics for myeloid cells were normal, patients without alemtuzumab showed rapid reconstitution of the T cell compartment with median cell counts of >200 CD4+ cells/μl at day +30 together with complete donor chimerism in 15/18 evaluable patients. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow up of 9 months, 3 relapses of 24 patients with CR after HCT (12,5%) occurred, of those one AML patient could be salvaged with withdrawal of immunosuppression. Nine patients have died. The causes were underlying malignant disease (n=2), GvHD (n=2), viral infections (n=3 with two cases of HHV6 associated encephalitis), post-surgery thrombembolism (n=1), and one unknown. Treatment related mortality after 100 days is 14,2%, after 1 year 21,4%. Due to the early recovery of T cell immunity mild forms of acute skin GvHD were common early after reconsitution, while acute GvHD Grade III-IV could be observed in 8/26 patients. Chronic GvHD occurred in 15/22 patients (68%) with moderate and severe forms in n=10 and n=3 patients, respectively. Cytomegalovirus (CMV) reactivation could be seen in 5/20 patients at risk, while no CMV disease developed. Importantly, in the first year after HCT no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. The whole cohort experienced a median overall survival of 20 months, median progression free survival was 19 months. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of moderate chronic GvHD without major bacterial and fungal infectious complications. Since this sustained alloreactivity might reduce the risk of relapse this regimen could be suited for patients undergoing HCT with advanced or uncontrolled malignant disease. Disclosures: No relevant conflicts of interest to declare.

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CD28-Directed T Cell Costimulation Blockade with Abatacept to Prevent GvHD During High-Risk Unrelated HSCT: A First-in-Disease Feasibility Trial,

Blood ◽

10.1182/blood.v118.21.4078.4078 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4078-4078

Author(s):

Leslie S. Kean ◽

Amelia Langston ◽

Muna Qayad ◽

H. Jean Khoury ◽

Divya Tiwari ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Feasibility Trial ◽

Effector Memory ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

The Mean

Abstract Abstract 4078 Background: Acute GvHD remains the major cause of complications and death following unrelated-donor HSCT. In a non-human primate model, we have previously shown that in vivo costimulatory blockade of donor T-cells could provide effective protection against GVHD. To begin to explore its clinical utility, we are conducting a trial (Clinical Trials.Org # NCT01012492) to determine the feasibility of combining abatacept (CTLA4-Ig) with cyclosporine and methotrexate as acute GVHD prophylaxis for patients undergoing unrelated marrow and peripheral blood stem cell transplants for hematologic malignancies. Methods: Patients older than 12 with advanced hematologic malignancies, conditioned with either TBI/Cytoxan, Busulfan/Cytoxan or Fludarabine/Melphalan are eligible. Abatacept is administered IV on days −1, +5, +14, and +28 at 10 mg/kg in addition to standard GvHD prophylaxis consisting of cyclosporine (day −2 to day 100), and methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, 6 and 11). Patients are then followed for clinical outcomes and immunologic reconstitution through day +365. Results: 9 patients (planned enrollment = 11 patients) have thus far been enrolled on the study of which 5 are evaluable for engraftment, toxicity and acute GvHD. The other four patients consist of 2 who are currently receiving abatacept, 1 who was discovered to have an ongoing viral infection at the start of the first abatacept infusion so was removed from the treatment regimen, and 1 who is awaiting transplant. The median age for the 5 evaluable patients is 47 years (17–74 years). 3 patients had AML and 2 had ALL. Patients were conditioned with Bu/Cy (n=1), TBI/Cy (n=2) and Flu/Melphalan (n=2). 4 donor-recipient pairs were allele matched at 9 of 10 loci (A, B, C, DRB1 and DQB1), while 1 was fully matched. Four of the 5 patients are currently alive and in remission and 1 relapsed at day +98 (and died on day +121 with refractory AML). The four other patients are surviving without relapse with a follow-up of 155–313 days. All 5 patients received the 4 scheduled abatacept doses. No infusional side effects were noted. All patients achieved neutrophil engraftment (median day +20 (11–47). 4 of 5 patients have achieved platelet engraftment (median day +27 (14–35). Donor engraftment (100% CD33 and 99–100% CD3 at Day +30) occurred in all cases. All patients have demonstrated rapid lymphocyte engraftment, with the mean ALC reconstituting to >500 cells/μL by day +21 post-transplant. At day +100, the mean CD3+ count was 673 +/− 251 cells/μL. Both CD8+ and CD4+ T cells reconstituted by day 100, with the mean CD8+ count = 384 +/− 148 cells/μL and the mean CD4+ count = 229 +/− 119 cells/μL. T cell reconstitution was accompanied by a shift away from naïve (Tn, CCR7+/CD45RA+) toward a CCR7-/CD45RA- effector memory (Tem)-predominant phenotype. Thus, the average proportion of CD4+ Tem cells in the recipient increased from 22 +/− 6% pre-transplant to 46 +/− 7% at day +100 with a concomitant loss of CD4+ Tn cells. Likewise, the proportion of CD8+ Tem also significantly increased, from an average of 15 +/− 4% pre-transplant to 32 +/− 7% at day +100, also with a reciprocal decrease in CD8+ Tn cells. One patient developed steroid responsive grade 3 acute GVHD involving the skin and the liver, followed by steroid responsive liver chronic GvHD. This patient is currently weaning corticosteroids. Another patient developed steroid responsive late-onset (day +217) acute GVHD (liver and GI) during cyclosporine weaning, which was also steroid responsive, and is also currently weaning corticosteroids. No other systemic acute or chronic GvHD has occurred. No unexpected complications or life-threatening infections were observed. 3 patients have experienced 5 episodes of CMV reactivation, all responsive to antiviral therapy. One patient developed polyclonal EBV-related PTLD (plasmacytic hyperplasia) in the absence of EBV viremia, which regressed without intervention. No other EBV-related disease has occurred. Conclusions: These preliminary data suggest that abatacept can be safely added to cyclosporine and methotrexate for GVHD prophylaxis in recipients of hematopoietic grafts from unrelated donors, with encouraging rates of acute GVHD. As such, they support the conduct of a larger, randomized phase 2 study. Disclosures: Off Label Use: Abatacept: It is an immunosuppressive agent that targets the CD28/B7 T cell costimulation pathway. It is approved for use in Rheumatoid arthritis.

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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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Low Incidence of Chronic Graft-Versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Using Matched Related or Unrelated Donors: Phase II Study Interim Analysis

Blood ◽

10.1182/blood-2021-147569 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1811-1811

Author(s):

Najla H El Jurdi ◽

Daniel O'Leary ◽

Fiona He ◽

Todd E. DeFor ◽

Armin Rashidi ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Preparative Regimen

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning is currently the standard of care for young and fit patients; however, graft-versus-host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one combining strategies that reduce incidence and severity of GVHD, without compromising graft-versus-tumor effect. We hypothesized that GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) will reduce the incidence of chronic GVHD in patients receiving a standard hematopoietic myeloablative HCT without an increase in risk of malignant relapse. Methods This is an interim analysis of a phase II study using a myeloablative preparative regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Patient and disease characteristics are detailed in Table 1. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. Results Through October 2020 we treated 63 patients with a median follow up of 502 days post-transplant. Of those, 48% were female and n=11 (17%) younger than 18 with median age at HCT of 36 years (range, 2-55; Interquartile range [IQR], 20-48). Donor source was 8/8 MRD in 44 patients (70%), 8/8 MUD in 18 (29%), and one with 7/8 MUD. Graft source was BM in n=28 (44%) and PB in n=35 (56%). Preparative regimen was TBI in 94% of patients. All patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-27). Overall, 94% achieved platelet engraftment by 6 months, median 25 days (range, 16-98). At day 100, 48 patients (86%) achieved full donor bone marrow chimerism (>95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as >95% donor). 42 patients (66%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by 100 days post-transplant was 14% overall (95% confidence interval CI: 6-23%), 7% for MRD and 32% for the MUD group; Grade III-IV acute GVHD was 5% overall (CI: 0-10%), similar for both MRD and MUD group. At 1 year, only two patients receiving a PBSC graft developed chronic GVHD requiring immune suppression, for a cumulative incidence of 3% overall, one in the MRD group and one in the MUD group. Two-year cumulative incidence of relapse was estimated at 21% overall, 22% and 16% for the MRD and MUD groups, respectively. Two year cumulative incidence of non-relapse mortality was 13% overall, 15% and 5% for MRD and MUD, respectively. Estimated 2-year overall survival was 79% overall (CI: 65-88%), 75% for the MRD group and 95% for MUD. Estimated 2-year GVHD-free relapse free survival (GRFS) was 57% overall (CI: 42-69%), 56% and 63% in the MRD and MUD groups, respectively. Discussion Myeloablative transplantation with a TBI preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in very low incidence of chronic GVHD. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes can be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

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Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T Cells (Treg) After Allogeneic Hematopoietic Cell Transplantation (HCT), and Is More Effective Than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft Vs. Host Disease (GVHD) and Moderate to Severe Chronic Gvhd

Blood ◽

10.1182/blood.v118.21.323.323 ◽

2011 ◽

Vol 118 (21) ◽

pp. 323-323 ◽

Cited By ~ 1

Author(s):

Joseph Pidala ◽

Jongphil Kim ◽

Heather Jim ◽

Hugo F. Fernandez ◽

Marcie Tomblyn ◽

...

Keyword(s):

T Cells ◽

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Advisory Committees ◽

Graft Vs Host Disease ◽

Grade Ii

Abstract Abstract 323 Sirolimus/Tacrolimus Facilitates Preferential Recovery of Regulatory T cells (Treg) after Allogeneic Hematopoietic Cell Transplantation (HCT), and is More Effective than Methotrexate/Tacrolimus in Preventing Grade II-IV Acute Graft vs. Host Disease (GVHD) and Moderate to Severe Chronic GVHD Background: Clinical translation of the Treg suppressive potential will require definition of a pharmacologic immune suppressive platform conducive to preferential Treg reconstitution post-HCT. Sirolimus has differential impact on Treg and conventional T cells. Patients and Methods: We performed a prospective, randomized phase II trial of sirolimus (SIR) and tacrolimus (TAC) vs. methotrexate (MTX) and TAC. From 9/2008 to 5/2011, a total of 74 patients were randomized 1:1 to SIR/TAC vs. MTX/TAC, stratified by age (> or ≤ 50) and donor relation (related vs. unrelated). SIR was administered as a 9 mg oral loading dose on day -1, followed by maintenance with 4 mg daily adjusted to target 8–12 ng/ml; SIR was continued for at least 1 year. MTX was 15 mg/m2 on day +1, then 10 mg/m2on days +3, 6, and 11. TAC was administered at 0.02 mg/kg/day IV or equivalent oral dosing starting on day -3. Target TAC levels were 3–7 ng/ml for the SIR arm versus 10–15 ng/ml for the MTX arm and were maintained through day 60. TAC was tapered thereafter in the absence of acute GVHD. Patient age for the whole study was 23 to 69 (median 49) years, and disease diagnoses included AML (23), ALL (15), MDS (9), MM (8), NHL (8), CLL (7), CML (2), and MPD (2). Patients received peripheral blood mobilized stem cells from HLA-A, B, C, and DRB1 matched sibling (n=35) or unrelated donors (n=39). Age, diagnosis, disease risk and donor relation were balanced across the two study arms. Serial peripheral blood samples were obtained at baseline pre-HCT, day 0, and days 30, 90, 180, and 360 post-HCT. Treg were defined by the surface CD4+CD25brightCD127negative phenotype. The reciprocal relationship between negative surface CD127 and high intracellular FoxP3 expression was confirmed in a subset (n=15) of day 30 patient samples (r=0.94). Results: Median percent Tregs among blood CD4 T cells at day 30 was 16.3 (range 12.5–17.9) for SIR versus 9.9 (8.6–13.5) for MTX, p < 0.0001, and 14.6 (10.8–18.1) for SIR and 9.7 (7.5–11.6) for MTX at day 90 post-HCT, p = 0.0009. SIR-treated patients had increased absolute numbers of Treg, and decreased absolute numbers of non-Treg CD4+ cells on days 30 and 90. The 100-day cumulative incidence of grade 2–4 acute GVHD for SIR was 43% (95% CI 30–63%), and 89% (95% CI 80–100%) for MTX, p<0.0001. Grade 3–4 acute GVHD for SIR was 16% (95% CI 7–36%) and 13% (95% CI 5–33%) for MTX, p=0.16. The incidence of any grade chronic GVHD for SIR was 51% (95% CI 34–78%) and 67% (95% CI 52–85%) for MTX, p=0.56. The cumulative incidence of NIH consensus-defined moderate to severe chronic GVHD was 20% (95% CI 9–43%) following SIR, and 63% (95% CI 47–83%) for MTX, p=0.013. Median time to neutrophil engraftment was comparable (SIR 16, range 11–22 days; MTX 16, range 12–28, p=0.57), and platelet engraftment was improved with SIR (SIR 12, range 6–20; MTX 16, range 10–33, p=0.012). No significant differences in peak mucositis, hepatic veno-occlusive disease (VOD), or thrombotic microangiopathy were observed between SIR and MTX. Overall survival did not significantly differ, log-rank p=0.55. Causes of death in SIR included relapse (n=2), and non-relapse death (septicemia 2, acute GVHD 1, chronic GVHD 1, influenza pneumonia 1, RSV pneumonia 1, VOD 1, multi-organ failure 1). Causes of death in the MTX arm were relapse (n=7), and non-relapse death (diffuse alveolar hemorrhage 1, GVHD 1). We performed serial assessment of patient-reported quality of life (QOL) with the FACT-BMT. While those patients in the MTX group had significantly better mean FWB and FACT-G scores at baseline pre-HCT, we did not detect significant differences in any FACT-BMT domain or summary score at day 30 or 90 post-HCT. Further follow up is needed to study longer term recovery of QOL in SIR and MTX treated patients. Conclusions: These results of a randomized, controlled study provide evidence that the combination of SIR/TAC favors Treg recovery and more effectively prevents acute GVHD and moderate to severe chronic GVHD after allogeneic HCT. Disclosures: Alsina: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

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A Phase I/II Trial of Intravenous Azacitidine for Acute Gvhd Prophylaxis in Patients Undergoing Matched Unrelated Stem Cell Transplantation: Phase I Results

Blood ◽

10.1182/blood.v126.23.1935.1935 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1935-1935 ◽

Cited By ~ 1

Author(s):

Mark A. Schroeder ◽

Jaebok Choi ◽

Matthew L Cooper ◽

David Schwab ◽

Sarah Willey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Phase I ◽

Phase Ii ◽

Research Funding ◽

Acute Gvhd ◽

Gvhd Prophylaxis ◽

Primary Graft Failure ◽

Final Cohort

Abstract Background The negative impact of acute graft-versus-host disease (GvHD) on morbidity and mortality after allogeneic transplant is significant; thus, finding a means to harness the beneficial Graft versus tumor effect (GVT) while reducing or eliminating GvHD is a major goal of transplant trials. Alterations in immune subsets present after transplant can work to suppress allo-reactive T-cell responses by increasing regulatory T-cells and suppressing allo-reactive T-cell proliferation. Azacitidine (AZA) treatment in pre-clincal models resulted in an increase in regulatory T-cells, a decrease in allo-reactive T-cell proliferation and prevention of acute GvHD while preserving GVT effects. (Choi et al. Blood 2010). Based on these results a phase I/II study was designed to test the safety and efficacy of AZA administered shortly after transplant for the prevention/prophylaxis of acute GvHD and relapse in subjects receiving transplants from matched unrelated stem cell donors. We report the results for the Phase I portion of this trial. Methods Patients with hematologic malignancies in remission age 18 - 70 were eligible. Myeloablative or reduced intensity conditioning without antithymocyte globulin was used. All recipients were required to receive at least 2 x 106 CD34/kg and have at least 1 x 106 CD34/kg cryopreserved as back up in case of primary graft failure. AZA was administered intravenously on day +7 for five consecutive days and repeated every 28 days for a total of 4 cycles after allogeneic transplant from a 10/10 HLA matched unrelated donor. Standard GvHD prophylaxis with mini-methotrexate and tacrolimus was given. A Phase I, 3+3 dose escalation design of 4 cohorts (AZA dose levels 15, 30, 37.5, and 45 mg/m2) was used to determine toxicity and recommended phase II dose. The primary outcome for phase II is the rate of grade II - IV acute GvHD at day 180 after transplant. Results We have transplanted 16 subjects on trial, 15 have received study drug. Recipient characteristics include: median age 57, 67% male, and diagnoses of AML in CR (9), ALL in CR (2), or MDS (4). One DLT was observed in the final cohort of 6 subjects. The DLT experienced in the final cohort was primary graft failure. The subject had developed Clostridium difficile colitis during conditioning and fungemia shortly after transplant. A total CD34 dose of 2 x 106/kg was infused after myeloablative conditioning of Busulfan and Cytoxan. The subject received the cryopreserved back up donor leukocyte infusion at day +28 but died at day 29 of sepsis without evidence of neutrophil engraftment. Contributing causes to the DLT were thought to be the CD34 dose infused, sepsis, severe colitis and possibly AZA administration. For the remainder of subjects treated in phase I the median CD34 dose infused was 5 x 106/kg (range 2 - 5), median ANC engraftment was 14 days (range 10 - 22 days). Median platelet engraftment was 22 days (range 14 - 70). No grade III/IV acute GvHD has been observed. Grades 1 and 2 skin and gut GvHD have been observed, and all cases have responded to steroids except one case of steroid refractory GvHD in cohort 1 (15mg/m2 AZA). At the recommended phase 2 dose of 45mg/m2 AZA, 3 cases of skin GvHD were observed occurring just prior to or at the time of cycle 2 of treatment. All responded to steroids. With a median follow up of 233 days (range 29 - 784), only 2 subjects have relapsed and 11 (73%) remain alive. The most common non-hematologic grade 3 or 4 AEs were gastrointestinal toxicity (mucositis, nausea and diarrhea), electrolyte abnormalities, and infections. In conclusion, AZA can be given safely starting at day +7 after MUD transplant up to a dose of 45mg/m2 tested. Phase II is currently enrolling subjects. Because of the DLT experienced in phase I, the infused CD34 dose will be increased to a minimum of 4 x 106 CD34/kg with 1 x 106 CD34/kg cryopreserved in backup. Correlative studies from banked Phase I biospecimens evaluating dynamics of regulatory T-cells, T-cell subsets and methylation before and after treatment are being analyzed and will be reported. Disclosures Schroeder: Incyte: Consultancy; Celgene: Other: Azacitidine provided for this trial by Celgene. Off Label Use: Azacitidine for GVHD prophylaxis. Abboud:Gerson Lehman Group: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy.

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Reconstitution of Regulatory T Cell Subpopulations After Allogeneic Hematopoietic Stem Cell Transplantation and Graft-Versus-Host-Disease

Blood ◽

10.1182/blood.v120.21.1948.1948 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1948-1948

Author(s):

Alienor Xhaard ◽

Helene Moins ◽

Marc Busson ◽

Maryvonnick Carmagnat ◽

Marie Robin ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

T Cell ◽

Malignant Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cd4 T Cell ◽

Effector Memory ◽

Hematopoietic Stem ◽

Graft Versus Host

Abstract Abstract 1948 Previous studies on the reconstitution of regulatory T cells (Treg) after allogeneic hematopoietic stem cell transplantation (HSCT) have shown a delayed reconstitution in patients (pts) with acute graft-versus-host-disease (GvHD) (Magenau, 2010) and an association between impaired Treg reconstitution and the development of extensive chronic GvHD (Matsuoka, 2010). However, no studies have analyzed naive (nTreg) versus memory (mTreg) Treg reconstitution in a longitudinal cohort with large numbers of pts. From 2006 to 2009, 165 consecutive pts were prospectively analyzed in our center post-HSCT. Fresh whole blood samples were obtained 3 (n=155), 6 (n=162), 12 (n=165) and 24 (n=94) months after HSCT and analyzed by flow cytometry to quantify CD4 T cells, including naive, activated, central memory and effector memory subsets (Sallusto, 1999), as well as Treg (CD4+ CD25+ CD127neg/lo), including nTreg (CD45RA+) and mTreg (CD45RAneg). The results are presented as median values of circulating cells. Median age was 41 years (range: 6–68). The indication for HSCT was malignant disease in 92%. The conditioning regimen was reduced-intensity (RIC) in 51%. The donor was an HLA-identical sibling in 56%. The source of stem cells was peripheral blood (PBSC), bone marrow (BM) and cord blood (CB) in 65%, 28% and 7%, respectively. All pts received cyclosporine as GvHD prophylaxis. GvHD was defined as acute if occurring before day 100 and chronic thereafter. Total Treg (tTreg) increased from 13/μL at 3 months to 44/μL at 24 months, but always remained inferior to healthy controls (HC) (66/μL). nTreg increased from 1.8/μL at 3 months to 4.8/μL at 24 months (HC: 24/μL). mTreg increased from 10.7/μL at 3 months to 33.3/μL at 24 months (HC: 42/μL). The CD4/Treg ratio remained stable at 12.6 at 3 months and 11.6 at 24 months while the nCD4/nTreg ratio increased from 17.4 at 3 months to 42.7 at 24 months, showing a larger expansion of naive cells in the CD4 T cell compartment than in the Treg compartment (Figure 1) and a larger expansion of memory cells in the Treg than within the CD4 cells. At 3 months post-HSCT, tTreg, nTreg and mTreg were significantly higher in PBSC recipients (18.4, 2.7 and 14.5/μL) than in BM (8.1, 0.9 and 6.5/μL) and CB recipients (6.5, 0.6 and 5.3/μL) (p=0.0001), respectively. Pts transplanted after a RIC regimen had significantly more tTreg and mTreg than pts transplanted after a standard regimen (17 and 14/μL, compared with 9.8 and 8/μL, p=0.004 and 0.008 respectively). Pts transplanted for an aplastic anemia had significantly fewer nTreg than pts transplanted for a malignant disease (0.4 and 1.9/μL, p=0.001). At 6 months post-HSCT, tTreg, nTreg and mTreg were significantly higher (p=≤0.01) in pts transplanted from an HLA-identical sibling (19.5, 1.9 and 17.2/μL) compared with pts transplanted from an unrelated donor (13.2, 1.2 and 11/μL). At 12 and 24 months post-HSCT, younger pts (≤15 years) had significantly more nTreg than older pts (9.8 and 28.7/μL compared with 2.1 and 4.2, p=0.001). In pts with previous acute GvHD, tTreg and mTreg were significantly lower at 3 (8.5 and 7.7/μL) and 6 months (14.6 and 12.5/μL) compared with pts without (15.6 and 13.8/μL at 3 months, p=0.005 and 21.3 and 18.2/μL at 6 months, p≤0.007), respectively. Absolute numbers of tTreg, nTreg and mTreg, and the frequencies of Treg relative to activated, effector memory and central memory CD4 T cells at 3, 6 and 12 months post-HSCT did not predict the occurrence of a later episode of chronic GvHD up to 2 years post-HSCT. In our population, total, naive and memory Treg reconstitution was delayed post-HSCT and remained below the normal range up to 2 years after HSCT. tTreg reconstitution post-HSCT was mostly due to mTreg expansion. RIC regimen and PBSC as source of stem cells were associated with a better short-term reconstitution. At 6 months, pts transplanted from siblings had a better reconstitution while nTreg long-term reconstitution was mainly influenced by recipient age (better if ≤15 years). While previous acute GvHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4 T cell subsets) at 3, 6 and 12 months post-HSCT were unable to predict chronic GvHD in this large cohort of patients. We believe these data are of particular interest regarding the recently increasing number of Treg interventional studies in humans in the context of HSCT. Disclosures: No relevant conflicts of interest to declare.

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Itolizumab As a Potential Therapeutic for the Prevention and Treatment of Graft Vs Host Disease

Blood ◽

10.1182/blood-2019-122787 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5603-5603 ◽

Cited By ~ 1

Author(s):

Cherie Tracy Ng ◽

Jeanette Ampudia ◽

Robert J. Soiffer ◽

Jerome Ritz ◽

Stephen Connelly

Keyword(s):

Weight Loss ◽

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Research Funding ◽

Chronic Gvhd ◽

Vehicle Control ◽

Control Group ◽

Employment Equity ◽

Equity Ownership

Background: CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking and is central to inflammation. While effector T cell (Teff) are CD6hi and upregulate expression upon activation, regulatory T cells (Treg) remain CD6lo/-, making this an attractive target to modulate Teff activity while preserving Treg activity. Early studies by Soiffer and colleagues demonstrated using T12, an anti-CD6 monoclonal antibody (mAb) that ex-vivo depletion of CD6+ donor cells prior to transplantation decreased the incidence of both acute and chronic GVHD, highlighting the importance of CD6+ cells in GVHD pathogenesis and validating it as a therapeutic target. However, it remains to be shown whether modulating the CD6-ALCAM pathway in vivo can attenuate GVHD. We investigated the use of itolizumab, a humanized anti-CD6 mAb that has demonstrated clinical efficacy in other autoimmune diseases, as both a preventive and therapeutic treatment for GVHD, using a humanized xenograft mouse model. Methods: Humanized xenograft mice were generated by intravenous transfer of 2x10^7 human PBMCs into 6-8 weeks old NOD/SCID IL2rγ-null (NSG). To investigate the ability of itolizumab to prevent GVHD, mice were dosed with either 60μg or 300μg of itolizumab, 150μg of abatacept (CTLA4-Ig), or vehicle, starting one day prior to PBMC transplantation. To investigate the therapeutic effect of itolizumab, mice were dosed with either 150μg of itolizumab or vehicle, starting at Day 5 post-PBMC transfer, when transplanted T cells are already activated. All treatments were administered IP every other day. Weight and disease scores were monitored throughout the study. At Days 18 and 35, peripheral blood was evaluated by flow cytometry to examine T cell prevalence, and tissues were collected for histological examination of pathology and T cell infiltration. Results: When administered as prevention (Day -1), treatment with either 60μg or 300μg of itolizumab significantly decreased mortality compared to the vehicle control (100% vs. 10%); this decrease was similar to the positive control group treated with abatacept (Figure 1). At 60μg, itolizumab-treated mice demonstrated significant reductions in the prevalence of human T cells in peripheral blood vs. vehicle-treated mice at Day 18 (<0.2% vs. 74.5%; p < 0.001). The reduction in peripheral T cells was accompanied by reductions in tissue-infiltrating T cells in lung (85-fold) and gut (9.5-fold), as well as reductions in disease scores and weight loss. When administered therapeutically, treatment with itolizumab was associated with a survival rate of 50% compared to 10% in the control group (Figure 2). Similarly, peripheral T cell prevalence (34.3% vs. 65.1%; p < 0.001), weight loss, and disease scores were inhibited by itolizumab compared to vehicle control mice. Conclusions: These data suggest that systemic treatment with itolizumab can modulate pathogenic Teff cell activity, establishing this antibody as a potential therapeutic for patents with GvHD. A phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGVHD is currently ongoing (NCT03763318). Disclosures Ng: Equillium: Employment, Equity Ownership. Ampudia:Equillium: Employment. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cugene: Consultancy; Jazz: Consultancy. Ritz:Equillium: Research Funding; Merck: Research Funding; Avrobio: Consultancy; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Draper Labs: Consultancy; LifeVault Bio: Consultancy; Celgene: Consultancy; Aleta Biotherapeutics: Consultancy; Kite Pharma: Research Funding. Connelly:Equillium: Employment, Equity Ownership.

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Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

Journal of Experimental Medicine ◽

10.1084/jem.20101709 ◽

2011 ◽

Vol 208 (5) ◽

pp. 1069-1082 ◽

Cited By ~ 103

Author(s):

Daigo Hashimoto ◽

Andrew Chow ◽

Melanie Greter ◽

Yvonne Saenger ◽

Wing-Hong Kwan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Transplantation ◽

Cell Expansion ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

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The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽

10.1182/blood.v114.22.3375.3375 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3375-3375

Author(s):

Julio Delgado ◽

Carme Canals ◽

Michel Attal ◽

Kirsty Thomson ◽

Antonio Campos ◽

...

Keyword(s):

T Cell ◽

Follicular Lymphoma ◽

Research Funding ◽

Alkylating Agent ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Off Label ◽

Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

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