Improved Post-Transplant Outcomes in Hematologic Malignancy Patients Undergoing Non-Myeloablative Hematopoietic Stem Cell Transplant (NMHSCT) Using a 400 cGy Total Body Irradiation (TBI) Dose with Fludarabine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3674-3674
Author(s):  
Ronald M. Sobecks ◽  
Karl S. Theil ◽  
Lisa Rybicki ◽  
Roger Macklis ◽  
Brad Pohlman ◽  
...  
Keyword(s):  
T Cell ◽  
Median Time ◽  
Graft Rejection ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Disease Relapse ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Preparative Regimen

Abstract Fludarabine and TBI (200 cGy) is a common NMHSCT preparative regimen. However, this regimen resulted in a 14% graft rejection rate and 42% incidence of disease relapse at our institution. We hypothesized that escalation of the TBI dose to 400 cGy may improve post-transplant outcomes. From 12/10/03 to 4/19/05, 17 patients (pts) with hematologic malignancies underwent NMHSCT using a preparative regimen of fludarabine 30 mg/m2/d IV on days −5, −4 and −3 and TBI 200 cGy on days −1 and 0 (total dose 400 cGy). Immunosuppressant therapy consisted of cyclosporine and mycophenolate for matched sibling donor pts (n = 10) or Tacrolimus and mycophenolate for matched unrelated donor pts (MUD) (n = 7), which was started day −1 and discontinued day +56 in the absence of GVHD. Diagnoses included 4 NHL, 3 AML, 2 MDS, 2 myelofibrosis (MFB), 1 Hodgkin lymphoma (HL), 1 ALL, 1 multiple myeloma (MM), 1 CLL, 1 chronic myeloproliferative disorder (CMD) and 1 bilineal acute leukemia (BAL). Only 2 (12%) pts were in complete remission at the time of transplant (both AML). The median time from diagnosis to transplant was 11 months (range, 3–246 months). All transplants were performed as an outpatient, but 16 (94%) pts required hospitalization and the most common reason was for fever (9 pts– 56%). The median CD34+ and CD3+ cell doses infused were 4.92 x 106/kg and 4.44 x 108/kg, respectively. The median time to absolute neutrophil count recovery of ≥500/μL was 10 days (range, 8–13 days) while time to platelet recovery ≥20K/μL was 12 days (range, 11–16 days). T-cell (CD3+) chimerism was monitored by short tandem repeat analysis and complete donor chimerism (CDC) was defined as ≥ 95% donor DNA in CD3+ T-cells. CDC was achieved in 14 (82%) pts at a median of 28 days (range, 21–130 days), whereas, in our prior analysis with pts receiving 200 cGy TBI, 75% of pts achieved durable CDC at a median of 77 days (range, 14–310 days). Ten (59%) pts developed acute GVHD at a median of 61 days (range, 13–85 days) with 4 grade I, 4 grade II, 1 grade III, and 1 grade IV. Chronic GVHD developed in 5 (29%) pts at a median of 10 months (range, 3–13 months) and only 1 (6%) developed extensive chronic GVHD. Responses included 4 CR (1 NHL, 1 AML, 1 CLL, 1 MFB), 4 PR (2 NHL, 1 HL, 1 MM), 2 stable disease (1 CMD, 1 NHL), and 3 not evaluable (2 MDS, 1 MFB). Graft rejection occurred in only 1 AML patient with a MUD and HLA-B and -Cw disparities. Three (18%) pts (1 ALL, 1 AML, 1 BAL) had disease relapse at a median of 6 months post-transplant (range, 2–12 months). The Kaplan-Meier method reported a median relapse-free survival of 11.6 months. Seven pts died, 3 within 100 days of NMHSCT; estimated median survival was 12.7 months. Causes of death included 2 acute GVHD, 1 chronic GVHD, 1 relapse, 1 sepsis, 1 ARDS, 1 cardiac arrest. We conclude that escalation of the TBI dose to 400 cGy in combination with fludarabine for NMHSCT is an effective approach which when compared to the 200 cGy regimen has resutled in less graft rejection (6% vs. 14%, respectively) and a lower relapse rate (18% vs. 42%, respectively). The more rapid achievement of T-cell CDC may be responsible for these differences. Further investigation and follow-up with this regimen is warranted.

Overall and Disease-Specific Outcomes Following T-Cell Replete Haploidentical Transplants Using Post-Transplant Cyclophosphamide: An Analysis Of 115 Patients Transplanted At a Single Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3337-3337
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Zaamin Hussain ◽  
Stacey Brown ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Rejection ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Effective Control ◽  
Post Transplant

Abstract Many patients with hematologic malignancies who may benefit from the curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) will lack a conventional matched sibling (MRD) or matched unrelated (MUD) donor. An HLA-haploidentical related donor is available for nearly all such patients. Attempts to use haploidentical donors that employ stringent ex-vivo T-cell depletion to abrogate GVHD are associated with poor immune reconstitution and high rates of graft rejection. In contrast, the recent use of T-cell replete grafts with post-transplant cyclophosphamide (haplo-ptCy) has resulted in effective control of alloreactivity with low rates of post-transplant infection, graft-rejection and non-relapse mortality using both non-ablative and ablative regimens (Luznik at al BBMT 2008, Solomon et al BBMT 2012.). We recently demonstrated similar outcomes for 53 haplo-PtCy to contemporaneous MRD and MUD transplants performed at our enter (Bashey et al JCO 2013). However there are limited data with respect to the outcome of specific hematologic malignancies using haplo-ptCy. For this study all consecutive patients who underwent haplo-ptCy as a first allogeneic transplant at our center between Oct 2005 and May 2013 (n=115) were included [median age 50 (20-74); M 57%, F 43%; diagnosis- AML(38), ALL(20), CLL(13), NHL(13) HL(10), CML+MPS (12), MDS (7) others (2); graft-BM(58%),PBSC(42%); prior autotranplant(18%); CIBMTR disease risk score high(35%), intermediate(32%) low(33%). Sorror Comorbidity Index-median =1(0-5)]. Preparative regimens used included non-myeloablative [fludarabine 30 mg/m2/d d -6 to -2; TBI 200cGy d-1, Cy 14.5 mg/kg/d on d-6,-5 and 50mg/kg/d on d+3,+4, n=73 ] and myeloablative [regimen 1- same as non-ablative except busulfan 110-130 mg/m2 /d i.v. on d-7 to-3 instead of TBI n=21; regimen 2- fludarabine 30 mg/m2/d d -7 to -5, TBI 150cGy bid x 8 doses (total dose =1200cGy) and Cy 50mg/kg/d d+3,+4 n=21]. Patient characteristics and outcome data were collected prospectively and obtained from our comprehensive database. Survival and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated using relapse as a competing risk. GVHD was assessed and documented prospectively by a dedicated GVHD nurse. Median CD34+ and CD3+cell doses infused were 4.21 x 10e6/kg (0.84-8.13) and 5.81 x 10e7/kg (1.4-59.5). median time to ANC > 500/mm3 and platelets > 20,000/mm3 were 16 and 26 d. Median % donor chimerism on d 30 were 100% and 100% for PB CD3+ and CD33+ cells respectively. With a median follow-up for living patients of 20 months, the 12 m and 24 m cumulative incidences (CI) of NRM were 10% and 18% and of relapse/progression were 25% and 25% respectively (Fig.1). CI of acute GVHD gd II-IV and gd III-IV at 6 m were 34% and 13% respectively, and of extensive and severe chronic GVHD at 12 m were 40% and 9% respectively. Estimated 12m and 24m probabilities of survival were 73% and 56% and of DFS were 65% and 57% respectively. On a Cox multivariate analysis assessing patient, disease and transplant related covariates, high risk CIBMTR disease score (HR 1.88, p=0.043) and acute GVHD gd 3-4 HR=2.54, p=0.0145) were the only factors significantly associated with survival. For the most frequently treated diagnoses - AML, ALL and mature lymphoid malignancies (CLL, NHL, HL) - the respective estimated 24 m probabilities of DFS were 61%, 58% and 50% respectively (Fig.2). These data demonstrate that haplo-ptCy transplants represent a safe and effective alternative for most patients who may benefit from allo-HCT but lack a conventional donor. They should be offered as standard of care in such patients. Disclosures: No relevant conflicts of interest to declare.

Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sézary Syndrome (SS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2544-2544 ◽  
Author(s):  
Wen-Kai Weng ◽  
Randall Armstrong ◽  
Sally Arai ◽  
Laura Johnston ◽  
Ginna G. Laport ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advanced Stage ◽  
Molecular Remission ◽  
Curative Therapy ◽  
Post Transplant ◽  
Preparative Regimen ◽  
Grade Ii

Abstract Introduction: The majority of patients with refractory, advanced stage MF or SS have a life expectancy less than 5 years. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed allogeneic transplant in 29 patients as a prospective clinical study using a novel non-myeloablative preparative regimen to provide prolonged disease control. Patient and Transplant Regimen: This cohort included 11 patients with MF and 18 patients with SS. The median age was 62 years (range 20-75). These patients were heavily treated with a median number of prior systemic therapies of 5 (range 2-13). The median time from diagnosis to transplant was 33 months (range 9-147). Five patients had stage IIB disease and 24 patients (83%) had stage IV disease (21 with IVA and 3 with IVB). All 11 patients with MF had evidence of large cell transformation. All patients had active disease at the time of preparative regimen (skin: 100%, blood: 62%, lymph node: 62%). The patients received total skin electron beam therapy (TSEBT, 24-36 Gy) as part of preparative regimen for skin disease control, immediately followed by total lymphoid irradiation (TLI, 8 Gy) and rabbit anti-thymocyte globulin (ATG). All patients received G-CSF mobilized peripheral blood hematopoietic cells from either an HLA-matched related (n=11), HLA-matched unrelated (n=13) or HLA-mismatched unrelated (n=5) donor. Cyclosporine or tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. The entire protocol required only a 5-day inpatient stay during the infusion of ATG. Results: As planned, all patients received their allograft infusion as outpatient. Patients tolerated the immediate post-transplant period extremely well. Fifteen patients required hospital admission within 100 days after transplant, with a median length of hospital stay of 4 days. The most common cause for admission was delayed ATG reaction. At day +90, full donor chimerism (donor CD3+ > 95%) was achieved in 10 patients (34%) and mixed chimerism was found in 14 patients (48%). Of these 14 patients, 9 of them subsequently achieved full donor chimerism and 1 had secondary graft rejection. Five patients (17%) had primary graft rejection (donor < 5%). Three of the 6 with graft rejection received a second transplant after experiencing disease progression. The incidence of GVHD in our study was considerably lower than reported in other studies using reduced intensity regimens. The cumulative incidence of grade II-IV acute GVHD was 21%. Five patients had grade II acute GVHD (4 skin, 1 GI) and 1 had fatal grade IV acute GVHD (GI). The cumulative incidence of extensive chronic GVHD at 1 and 2 years was 13% and 23%, respectively. One death was attributed to complications of chronic GVHD. At 3-month post transplant, 19 patients achieved a complete response and 7 had a partial response (ORR 90%). Two patients experienced disease progression immediately after transplant, and 1 patient had stable disease. The median post-transplant follow-up for the entire cohort was 22.2 months and for the surviving patients was 24.5 months. The 2-year OS and PFS were 76% (95% CI, 54–88%) and 50% (95% CI, 28–68%), respectively. Among the surviving 21 patients, 81% (n=17) were in CR at last follow-up (16 with durable CR lasting >1 year). Of the 8 deaths in this study cohort, 3 were from NRM, each due to acute GVHD, complications related to chronic GVHD, or secondary malignancy (B-cell acute lymphoblastic leukemia). The 1-year cumulative NRM was 3%. High-throughput sequencing (HTS) of TCRß CDR3 was used for minimal residual disease (MRD) monitoring (Sci. Transl. Med.5:214ra171, 2013) (ImmunoSEQ, Adaptive Biotech). Of the 24 patients assessed, 11 patients (46%) achieved molecular remission in the blood after transplant. The median time to achieve molecular remission in the blood was 60 days (range 30-540). Of these 11 patients, 10 of them also achieved molecular remission in the skin. The 2-year OS and PFS for patients who achieved molecular remission were 86% (95% CI, 34–98%) and 71% (95% CI, 26–92%), respectively. Conclusion: We have developed an effective novel preparatory regimen with low transplant related mortality for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. Using the utmost sensitive TCRß HTS method to assess MRD, we were able to demonstrate a potentially curative therapy with molecular remission in this patient population. Disclosures No relevant conflicts of interest to declare.

Outcome and Immune Reconstitution Following T Cell Depleted Nonmyeloablative Allogeneic Transplantation Using Matched Donors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2036-2036 ◽  
Author(s):  
David A. Rizzieri ◽  
Liang Piu Koh ◽  
Gwynn D. Long ◽  
Cristina Gasparetto ◽  
Jerald Z. Gong ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Allogeneic Transplantation ◽  
Stable Phase ◽  
Immune Recovery ◽  
Post Transplant ◽  
Donor Cells

Abstract To minimize toxicity and monitor immune recovery without interference of long term use of immunosuppressive agents, we have investigated T-cell depleted, nonmyeloablative allogeneic therapy using matched family member donors. Methods: Seventy five patients who were not candidates for ablative therapy due to age or comorbid diseases received fludarabine 30mg/sq m and cyclophosphamide 500mg/sq m IV qd x 4 with alemtuzumab 20mg IV qd x 5 followed by stem cell infusion. No other post transplant immunomodulation was provided. Results: Patient diagnoses included lymphoma/myeloma (20), leukemias/MDS (30), myelofibrosis/aplasia (7) and metastatic solid tumours (18). The median age was 50 (range 18–17) with a median follow up of 18 months. The median CD34+ cell dose collected was 13.4 x 106/kg. Engraftment occurred in 100% of patients with a median of 97% donor cells responsible for patient hematopoiesis by 3 months. Forty six also had a DLI (range 106–108 CD3+ cells/kg). Overall, Grade III–IV acute GVHD occurred in only 5/75 (7%) and 18 (29%) had grade II–IV. Four patients developed chronic GVHD. The transplant regimen was well tolerated with 4% 100 day treatment related mortality. In those with hematologic malignancies, only 7% started in remission, though 45 (60%) attained a CR. The most common cause of death in this group was progressive disease (28%), followed by infections (5%), and GVHD (5%). A subgroup of 21 of these older, more infirm patients who had high risk AML in 1–2nd CR or PR or ≥2 chronic stable phase CML, partially responding lymphoma, or severe myelofibrosis have been followed for at least 1 year. At 1 year, 13/21 (62%) remain alive and in continuing remission. Phenotypic analysis of lymphocyte subsets (measured by flow) revealed recovery at 6 months. Figure Figure T cell VBeta family recovery (spectratype analysis using PCR) revealed robust recovery by 6 months as well (first figure pre and second is 6 months post transplant), despite T depletion. Figure Figure TRECs analysis reveals little, if any, recovery in these patients for at least 12–18 months. Conclusions: Nonablative allogeneic transplantation using alemtuzumab for T cell depletion results in reliable engraftment with little acute GVHD or TRM. Immune recovery assays reveal that despite T cell purging, T cell subset and VBeta families have significant recovery by 6 months and TRECS results show the recovery is primarily from peripheral expansion of transplanted donor cells, not education of new T cells. These data possibly reflect the advantage of low dose donor lymphocyte boosts without planned long term use of immunosuppressive agents. The future challenge will to be to develop strategies to further improve immune recovery in this setting.

Addition of Clofarabine to TLI/ATG Conditioning: Impact on Immune Reconstitution and Clinical Outcomes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4066-4066
Author(s):  
Brett Glotzbecker ◽  
Heidi Mills ◽  
Jacalyn Rosenblatt ◽  
Robin Joyce ◽  
James Levine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Median Time ◽  
Cd8 T Cells ◽  
Fold Increase ◽  
Disease Relapse ◽  
Platelet Recovery ◽  
Post Transplant ◽  
T Cell Reconstitution

Abstract Abstract 4066 The fundamental challenge in designing an effective conditioning regimen for allogeneic transplantation involves the prevention of disease relapse while minimizing the risk for Graft versus Host Disease (GVHD). Treatment with total lymphocyte irradiation (TLI) and anti-thymocyte globulin (ATG) has been shown to minimize the risk of GVHD through the biasing of the T cell reconstitution towards an inhibitory phenotype. However, disease relapse remains a significant concern. Clofarabine is a second generation nucleoside analog with potent cytoreductive capacity and demonstrates efficacy in hematological malignancies. In this study, we examined the combination of clofarabine, TLI and ATG with respect to T cell reconstitution, risk for GVHD and transplant outcome. Sequential cohorts of 5 patients were treated with TLI and ATG alone or in conjunction with 20 mg/m2, 30 mg/m2 or 40 mg/m2 of clofarabine for 5 days. Cyclosporine and mycophenolate mofetil were administered as GVHD prophylaxis. Twenty patients have been enrolled (5 AML/MDS, 2 ALL, 6 lymphoma, 2 CLL, 5 myeloma) and received HLA matched peripheral blood stem cells collected from related (N=11) and unrelated donors (N=9). Of 19 evaluable patients, 15 are alive with a median follow up of 665 days. Day 30 and 100 mortality was 0% for TLI and ATG and 0% and 10% for those receiving clofarabine. The maximum tolerated dose (MTD) of clofarabine was 30 mg/m2 as 2 patients experienced treatment related mortality at the 40 mg/m2 dose level. Grade 5 infections and multiorgan failure occurred in both patients. All patients demonstrated engraftment with mean bone marrow donor chimerism of 92.5% at Day 30. The first cohort's ANC did not drop below 500 cells/uL, while median time to neutrophil engraftment in the patients who received clofarabine was 9 days. The median time to platelet recovery was 11 and 12 days for patients receiving TLI and ATG alone or with clofarabine, respectively (p=0.39). T cell reconstitution studies demonstrated a significant decrease in CD4+ cells to (<200 cells/uL) persisting for more than 6 months and a more than a two fold increase in circulating CD56+ NK cells. No significant decrease in CD8 T cells in the early post-transplant period was seen in either group. The mean percentage of regulatory T cells (CD4+/25+/FoxP3+) rose in the early post-transplant period following TLI and ATG (5.5 to 14.2% from baseline to day 30; p=0.015), but not in those receiving clofarabine (8.1 to 6%; p=0.15). Assessment of T cell polarization at these time points demonstrated a two fold increase in CD8+ T cells expressing IL-4 at Day 30 in patients receiving TLI and ATG alone (p=0.04); but not following clofarabine containing conditioning. Consistent with these findings, the incidence of grade II-IV GVHD was 0% and 42% in those receiving TLI and ATG alone or in conjunction with clofarabine, respectively. cGVHD was seen in 20% and 42% of patients, respectively. In contrast, disease progression was seen in 60% of patients receiving TLI and ATG alone as compared to 27% receiving clofarabine, TLI, and ATG. In summary, the addition of clofarabine to TLI and ATG conditioning resulted in a decrease in circulating regulatory T cells, decreased CD8+ T cell expression of IL-4, and was associated with an increased risk of GVHD and a potential for a decrease in the risk of relapse. Disclosures: Chen: Genzyme: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Research Funding.

A Novel Chemotherapy-Based Allogeneic Hematopoietic Stem Cell Transplant Regimen for Very Young Children with Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3149-3149
Author(s):  
Susan E. Prockop ◽  
Nancy A. Kernan ◽  
Elizabeth G Klein ◽  
Rachel Kobos ◽  
Andromachi Scaradavou ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Young Children ◽  
Cord Blood ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant

Abstract Abstract 3149 Young children in need of allogeneic hematopoietic stem cell transplant (HSCT) are at increased risk of unacceptable side effects from total body irradiation (TBI) and have historically been considered candidates for non-TBI containing regimens. However, disease free survival (DFS) has been poorer in cohorts of very young patients transplanted without TBI and novel chemotherapy based regimens are needed. We report results in a cohort of 14 children all under three years of age at the time of transplant (6 – 32 months; median 19.8 months) using a clofarabine-based ablative regimen. Fourteen patients in this age group have undergone transplant with a regimen consisting of clofarabine 20 mg/m2/day × 5, thiotepa 10 mg/Kg/day × 1 and melphalan 70 mg/m2/day × 2. All patients had high risk disease. Seven (7) pts were transplanted for ALL, 6 for AML and 1 for JMML. Patients with ALL or AML in first remission (CR1) or CR2, were categorized as patients with good risk disease while all other pts were considered as poor risk irrespective of all other factors. Transplant risk was good for 6/7 with ALL, and 3/6 with AML. The patient with JMML had stable disease. Stem cell grafts consisted of unmodified bone marrow (BMT) (N=6), double cord blood (dCBT) (N=7) and T cell depleted PBSCT (N=1). Donors were matched unrelated (N=5) or mismatched unrelated (N=9) including 7 double umbilical cord blood grafts, and one T cell depleted graft. Graft versus host disease (GvHD) prophylaxis was with tacrolimus and methotrexate for unmodified BMT, tacrolimus and mycophenolate for dCBT or T cell depleted HSCT. Two patients died early post transplant of infection (1) and acute GvHD (1). Neutrophil engraftment for the 13 evaluable patients was at a median of 13 days (10 –29 days) for PBSC and BM grafts and 17.5 days (12 –23 days) for recipients of CB grafts. Platelet engraftment for the 12 evaluable patients was at a median of 23 days (16 – 36 days) for recipients of PBSC and BM grafts and 43.5 days (36 –66 days) for recipients of CB grafts. In all five patients developed grade II-IV GvHD, and two patients chronic GvHD. Seven patients developed transaminitis which resolved in all cases. No patients developed Grade IV mucositis. One patient (AML) died after relapsing 5.5 months post transplant. Two patients are alive after relapsing at 1.3 months (AML) and 10.8 months (JMML) post-transplant. Nine of the 14 patients are alive in continuous complete remission seven of whom are greater than 36 months from transplant (40.2 – 71 months). The seven patients without chronic GvHD have had robust immune reconstitution, have responded to vaccination, and continue to meet growth and developmental milestones. Only one patient (transplanted at 14 months of age) has mild neurocognitive deficits. This novel chemotherapy based regimen is associated with durable engraftment of unmodified and cord blood HSCT grafts and promising disease free survival in very young children with leukemia. Based on the low toxicity profile in this cohort of patients higher dosing of clofarabine will be explored as a possible way to improve leukemia remission in the highest risk patients. Disclosures: Off Label Use: Clofarabine.

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 ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3912-3912 ◽  
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.

Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4389-4389
Author(s):  
Oscar Gonzalez-Llano ◽  
Elias Eugenio Gonzalez-Lopez ◽  
Ana Carolina Ramirez-Cazares ◽  
Edson Rene Marcos-Ramirez ◽  
Guillermo J. Ruiz-Arguelles ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Children And Adolescents ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Post Transplant

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

Busulfan/Fludarabine/Thymoglobulin as a Reduced Intensity Conditioning Regimen for Lymphoid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3335-3335
Author(s):  
Jeevan Sekhar ◽  
Keith Stockerl-Goldstein ◽  
Qin Zhang ◽  
Amanda F Cashen ◽  
Camille N. Abboud ◽  
...  
Keyword(s):  
Median Time ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Median Number ◽  
Cell Transplant ◽  
Single Institution ◽  
Reduced Intensity Conditioning ◽  
Prior Therapy ◽  
Lymphoid Malignancies ◽  
Reduced Intensity

Abstract Abstract 3335 Poster Board III-223 Introduction Over the last decade there has been an increase in the use of reduced intensity conditioning (RIC) regimens to mitigate transplant related toxicity while maintaining graft viability and maximizing the graft versus disease effect. There is an abundance of data on busulfan (Bu) based RIC for myeloid malignancies; however, there is a paucity of data on Bu based RIC regimen for allografting in lymphoid malignancies. We conducted a retrospective analysis of a large cohort of patients treated at a single institution who were transplanted using a uniform RIC regimen of Bu/Fludarabine (Flu)/Thymoglobulin (Thymo) for a variety of lymphoid neoplasms. Methods We identified 40 patients (pts) who were transplanted for lymphoid malignancies between 2004 and 2008 using the RIC regimen of Bu 0.8 mg/kg q6 hrs x 8 doses on d-4 and d-3, Flu 30 mg/m2 IV daily on days -7 to -3, and Thymo 2 mg/kg x 4 doses on d-4 to d-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.03 mg/kg starting d-2)/methotrexate (5mg/m2 on d+1, 3, 6, 11)/mycophenolate (15mg/kg bid starting d-2) in 34 pts (85%), tacrolimus/methotrexate in 5 patients (12.5%), cyclosporine/mycophenolate/methotrexate in 1 pt (2.5%). Chimerism analysis was done on days +30, 90, 180, and 365. Demographics Median age was 54 (range 35-65) years; males 26 (65%) and females 14 (35%); CLL/SLL 22 (55%), non-Hodgkins lymphoma 15 (37.5%) and transformed lymphomas 3 (7.5%). Median number of lines of therapy prior to transplant was 4 (range 0-12). 12 pts (30%) were refractory to initial therapy (less than a PR). 15 pts (37.5%) had received prior radiation therapy (XRT). 12 pts (30%) had undergone a prior autologous stem cell transplant (ASCT). 22 pts (55%) had chemo-sensitive disease at the time of transplant, and 18 (45%) had disease refractory to their pre-transplant regimen. The donor was related (RD) in 10 pts (25%) and unrelated (URD) in 30 pts (75%). The graft source was peripheral blood for 36 pts (90%) and bone marrow in 4 pts (10%). Median number of CD34+ cells infused was 7.9×10 6 (range, 1.1-17.9) /kg recipient body wt. Results Median time to absolute neutrophil count recovery was 12 (0-21) days. Median time to platelet recovery was 18 days (9-57 days). Median time to 100% donor chimerism was 39 (24-321) days. After a median follow-up of 25.8 (0.87-48.9) months, Kaplan-Meier estimates of median overall survival (OS) and progression-free survival (PFS) were 11.3 months and 9.9 months, respectively. The 2-yr OS and PFS were both 44%. We performed an analysis of the effects of histology, number of lines of prior therapy, prior XRT, prior ASCT, disease status at time of transplant, and graft source (URD vs RD) on OS and PFS (Table 1). Non-relapse mortality (NRM) at 100 days, 1 year, and 2 years was 8% (95% CI, 3-22%), 33% (95% CI, 20-52%), and 41% (95% CI, 26-60%), respectively. Acute GVHD was seen in 19 pts (48%) with Grade III/ IV acute GVHD in 9 pts (23%). Chronic GVHD was seen in 17 pts (43%), limited in 5 pts (13%), extensive in 12 pts (30%). Acute GVHD was more common among pts receiving URD vs RD transplants (35% vs. 13%, p=0.016), but incidence of chronic GVHD did not differ between these two cohorts. Conclusion This analysis represents the largest single institution experience using the RIC regimen of Bu/Flu/Thymo in lymphoid malignancies. Our results demonstrate that this Bu based RIC regimen can successfully be used to allograft heavily pre-treated patients with lymphoid malignancies, with prompt and durable engraftment and relatively low early NRM. In this patient population, OS and PFS were not significantly associated with lymphoma histology, prior therapy, or chemosensitivity. Disclosures DiPersio: Genzyme Corp.: Honoraria. Vij:Otsuka Pharmaceuticals: Research Funding.

scholarly journals 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 ◽  
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 (&gt;95% donor DNA); 29 (52%) and 52 (95%) achieved full donor peripheral blood CD3 and CD33 chimerism (defined as &gt;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.

scholarly journals A Critical Role for Donor-Derived IL-22 in Cutaneous Chronic Gvhd

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 69-69
Author(s):  
Kate H Gartlan ◽  
Hemamalini Bommiasamy ◽  
Katelyn Paz ◽  
Andrew Wilkinson ◽  
Mary Owen ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Protein Detection ◽  
Cytokine Gene Expression ◽  
Cell Transplant ◽  
Cutaneous Manifestations ◽  
Post Transplant

Abstract Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after allogeneic stem cell transplant (allo-SCT). Chronic cutaneous manifestations of GVHD are common late after allo-SCT with limited treatment options beyond protracted steroid therapy. Cytokines are critical mediators of inflammatory processes during GVHD and both IL-17A and IL-22 have been found to have dual pathogenic and protective roles, which are largely dependent upon their cellular source. We have demonstrated in mice that whilst recipient-derived IL-17A and IL-17R signaling suppresses inflammatory responses and prevents gut dysbiosis, donor T cell-derived IL-17A is pathogenic and drives GVHD in both lung and skin. Similarly, contrasting roles have also been described for IL-22 in mice, such that recipient-derived IL-22 helps maintain gut epithelial integrity after allo-SCT, but donor IL-22 can exacerbate acute GVHD pathology. To date, investigation of the effects of donor-derived IL-22 in allo-SCT has focused on acute GVHD, with no data regarding the role of IL-22 in chronic GVHD. Given the complexities and the potential competing risks of targeting IL-22 early post-transplant, we examined IL-22 deficiency in murine models of chronic GVHD following allo-SCT. In the absence of donor-derived IL-22, we observed a significant decrease in skin GVHD clinical scores and chronic GVHD skin pathology (histopathology scores in WT donors: 10.2±2.1, vs. IL-22-/- donors: 2.6±0.9, p &lt;0.01), which is in line with the pathogenic role of IL-22 in autoimmune skin diseases. Intriguingly, lung manifestations of chronic GVHD (i.e. bronchiolitis obliterans) were not IL-22-dependent (histopathology scores in WT donors: 1.6±0.5, vs. IL-22-/- donors: 1.5±0.3, p &gt;0.05), despite the fact we have recently defined their IL-17-dependency. These data demonstrate a relationship between IL-22 and IL-17 and the distribution of chronic GVHD. We identified CD4+ T cells as the major source of donor IL-22 by both direct protein detection and cytokine reporter systems, where we observed co-expression of IL-22 with a range of pro-inflammatory cytokines including IL-17A, IFNγ, GM-CSF and TNF. We identified IL-22+IL-17A+ and IL-22+IL-17A- CD4+ T cells as two distinct sources of donor-derived IL-22 post-transplant (2.2±0.1% and 6.5±0.3 % of LN CD4+ T respectively), both of which were highly dependent upon IL-6 for their development (IL-22+IL-17A+: IgG 1.3±0.2% vs. anti-IL-6Rα 0.08±0.01% of splenic CD4+ T, p &lt; 0.001; IL-22+IL-17A-:IgG 3.4±0.2 vs. anti-IL-6Rα: 0.6±0. 1% of splenic CD4+ T, p &lt; 0.001). Since we have previously identified significant cytokine plasticity within IL-17A+ T cells after allo-SCT, we performed lineage assessment to determine if these two populations arose independently. Using IL-17creRosa26YFP fate-mapping mice that permanent label any cell that has expressed IL-17A, we found that IL-22+IL-17A- CD4+ T cells did not have a history of IL-17A production and were therefore identified as a definitive Th22 population after allo-SCT. Since IL-22 and IL-17A have been reported to induce synergistic responses in the skin, we also explored the possibility of interdependence between Th17 and Th22 development. Using both IL-17RC-/- mice and an IL-17creRosa26YFP/iDTR reporter-deleter system we demonstrate that IL-17 signaling to donor Th22 directly promotes their development in allo-SCT (WT donors: 6.5±0.4 %, Th/Tc17 deleter donors: 3.6±0.2, IL-17RC-/- donors: 3.7±0.3 % Th22 in LN CD4+ T, p &lt;0.001). Finally, we observed a similar pro-inflammatory cytokine gene expression signature (Il22, Il17, Ifng) in the skin of patients who developed cutaneous GVHD &gt; 100 days following allo-SCT but not in those after autologous SCT. These data demonstrate a key role for donor-derived IL-22 in chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation. Together these findings suggest that IL-22 intervention late post-transplant may reduce cutaneous chronic GVHD, whilst maintaining the protective effects of IL-22 in the gut early after transplant. Disclosures Serody: Merck: Research Funding.

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