Improved Acute Graft-versus Host Disease (aGVHD) and Progression Free Survival with Post-Transplant Cyclophosphamide in AML/MDS Patients (pts) with Prior CTLA-4 or PD-1 Blockade

Abstract Because pretransplant antithymocyte globulin (ATG) seems to reduce graft-versus-host disease (GVHD) and transplant-related mortality (TRM) after unrelated donor bone marrow transplant (BMT) we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Of 82 adults receiving myeloablative conditioning and first MRD BCT between 01/99 and 05/02, 54 were matched for disease and stage with 54 patients (pts) not given ATG between 12/94 and 11/98. Median age was 42 (range 18 – 63) for ATG pts and 41 (range 22 – 54) for controls. Included in each group were 22 standard-risk pts (16 AML CR1, 6 ALL CR1), and 14 with high-risk acute leukemia of whom 12 had active AML (7 arising from MDS, 3 induction failures, 1 refractory, 1 relapse), and 2 ALL (1 refractory, 1 relapse). An additional 18 pts included 2 AML CR2, 1 ALL CR2, 2 CML AP/CP2, 2 MM, 8 relapsed/refractory NHL (2 mantle cell, 4 low, 1 intermediate, 1 high-grade) and 3 relapsed/refractory CLL. More control pts had conditioning incorporating TBI (32 vs 11, p<0.0001). All pts were given cyclosporine A and “short course” methotrexate with folinic acid. The study group received Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. ATG recipients were followed for 22 to 62 months (median 46) and control patients for 65–112 months (median 84). The actuarial incidence of acute GVHD grades II – IV was 25±6% in ATG recipients compared with 37±7% in the controls (p = ns). The figures for grade III – IV disease were 13±5% and 20±7% respectively (p = ns). Incidence of cGVHD at two years was 40±7% with ATG vs 97±3% without ATG (p < 0.0001), figures for extensive disease were 32±7% and 94±3% respectively (p < 0.0001). Sites of involvement by cGVHD were similar apart from gastrointestinal disease which was relatively more frequent in those ATG recipients who developed cGVHD (26% vs 5%, p = 0.03). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 32±7% at 2 years (p = 0.004). Deaths were GVHD related in 3 ATG treated patients vs 13 controls (p=0.01). In the control group 2 year TRM was 26±8% in 32 TBI recipients compared with 42±11% in 22 patients not given TBI (p = ns). Relapse rate at 2 years was 36±7% for ATG recipients and 23±7% in controls (p = 0.06). Six of 21 relapsing patients in the ATG group survive having achieved another remission (4) or disease stabilization (2) after more treatment. One of 12 control patients who relapsed is currently alive in remission after a second BCT. Survival at 2 years was 70±6% in the patients given ATG vs. 54±7% in the controls (p=0.08) and progression-free survival was 57±7% vs 52±7% respectively. This study indicates that MRD BCT recipients given pretransplant ATG experience less cGVHD, less overall TRM and lower mortality related to both acute and chronic GVHD. These findings are not due to more control pts receiving TBI. Despite a trend to more relapse progression-free survival is unaffected, there is a trend to improved survival and presumably quality of life is generally better in ATG recipients because fewer of them have cGVHD.

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High Levels of Donor Chimerism Early after Non-Myeloablative Transplantation Predictive of Overall and Progression Free Survival but Not Risk of Acute Graft Versus Host Disease for Patients with AML or MDS.

Blood ◽

10.1182/blood.v104.11.185.185 ◽

2004 ◽

Vol 104 (11) ◽

pp. 185-185

Author(s):

Edwin P. Alyea ◽

Shuli Li ◽

Haesook Kim ◽

Vincent T. Ho ◽

Corey Cutler ◽

...

Keyword(s):

Overall Survival ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Early Stage ◽

Progression Free Survival ◽

Free Survival ◽

Host Disease ◽

Graft Versus Host ◽

Donor Chimerism ◽

The Impact

Abstract Non-myeloablative (NST) transplantation is increasingly used in the treatment of patients with AML and MDS who are not candidates for myeloblative transplant. Relapse of disease remains a major cause of treatment failure after NST. Predictive factors to identify patients at high risk of relapse are needed to identify patients who would benefit from additional interventions. Attainment of a high degree of donor engraftment achieved early after transplantation may indicate the presence of a more significant allo-immune effect. We have performed a retrospective analysis of 64 patients with AML and MDS receiving NST, assessing the impact of donor chimerism when measured early after transplantation on outcome. Overall survival (OS), progression free survival (PFS) and risk of graft versus host disease (GVHD) were compared for patients achieving ≥90 % or <90% donor derived hematopoiesis when measured 1 month after transplant. All patients received fludarabine 30 mg/m2/day x 4 days and intravenous busulfan (Busulfex)0.8 mg/kg/day x 4 days for conditioning. All patients received calcineurin-inhibitor based GVHD prophylaxis. All patients received PBSC with G-CSF at 5 mcg/kg beginning day 1 after transplantation. Chimerism was measured using FISH for sex mismatched patient donor pairs or by STR analysis. 37 patients had ≥90% donor derived hematopoiesis, 27 patients had <90% donor derived hematopoiesis after transplantation. The two groups had similar characteristics with a median age of 57 yrs (range 21–70) for patients ≥90% and 58 yrs (range 32–69) for patients <90%. Of patients achieving ≥90%, 23 patients had AML and 14 MDS. Of patients <90%, 13 had AML and 14 with MDS. 7 of 16 (44%) patients with early stage disease(AML in CR1 or early stage MDS) achieved ≥90% donor hematopoiesis, while 30 of 48 (63%) patients with advanced disease achieved ≥90%. 17 of 29 (59%) patients with unrelated donors achieved ≥90% donor derived hematopoiesis, while 20 of 33 (61%) patients with matched related donors achieved ≥90% donor derived hematopoiesis. 21 of 32 (66%) patients with donor-recipeint sex mismatch achieved ≥90% while 16 of 32 (50%) patients with same sex donors were ≥90%. The median follow-up for surviving patients achieving ≥90% donor chimerism was 12 months and 15 months for those <90%. Patients achieving ≥90% donor chimerism had a significantly improved 1-year (71% versus 41%) and 2-year (39% versus 19%) OS (p=0.05). Similarly, for patients achieving ≥90% donor chimerism, there was a trend toward an improved PFS at 1-year (49% versus 30%) and 2-years (32% versus 19%) (p=0.08). There was no difference in the risk of developing stage 2–4 acute GVHD, 19% for both patients above and below 90%. Achieving high levels of donor chimerism when measured early after NST predicts for an improved overall survival and there is a trend toward an improved progression free survival. This may represent the presence of an enhanced graft versus leukemia effect in these patients. The degree of donor chimerism does not predict the development of acute GVHD. These results suggest that patients with <90% donor derived hematopoiesis may be candidates for strategies to enhance donor chimerism.

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Elevated Serum Interleukin-7 Levels Precede the Development of Acute Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v110.11.1064.1064 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1064-1064

Author(s):

Robert M. Dean ◽

Terry Fry ◽

Crystal Mackall ◽

Seth M. Steinberg ◽

Frances T. Hakim ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Multiple Time ◽

Hematopoietic Stem ◽

Host Disease ◽

Allogeneic Hsct ◽

Graft Versus Host ◽

Post Transplant ◽

Interleukin 7 ◽

Gvhd Prophylaxis ◽

Acute Graft

Abstract BACKGROUND: Despite advances in transplantation immunology, there is no clinically practical tool to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Murine models indicate that aGVHD is promoted by interleukin-7 (IL-7), a homeostatic cytokine for naïve CD4+ and CD8+ T-cells. We hypothesized that serum IL-7 levels might be associated with the development of aGVHD in patients (pts) undergoing allogeneic HSCT, and evaluated this using serum samples obtained for this purpose in a prospective clinical trial. METHODS: Thirty-one pts underwent allogeneic HSCT from HLA-identical siblings. Pts received 1 to 3 pre-transplant chemotherapy cycles to induce profound, uniform host lymphopenia (CD4<100), followed by fludarabine-based reduced-intensity conditioning. GVHD prophylaxis was cyclosporine & methotrexate. Serum IL-7 was measured by ELISA at baseline and multiple time points from the day of transplant through 1 year after allogeneic HSCT. IL-7 levels were evaluated for associations with blood lymphocyte counts, aGVHD, and survival. Other variables examined for association with aGVHD were pt and donor age; CD3+ and CD34+ cell doses; donor gender; donor-recipient gender mismatch; donor or recipient CMV status, prior rituximab therapy; donor lymphoid or myeloid chimerism >95% at day +14; serum IL-15 levels; and levels of soluble tumor necrosis factor-α receptors 1 and 2 (sTNFR1 and sTNFR2). RESULTS: Grades I, II, and III aGVHD occurred in 3%, 23%, and 19%, respectively; none had grade IV. Median (range) IL-7 levels rose from baseline 12.1 (0–46.9) pg/ml to 37 (13.3–79.2) pg/ml on day 0 before allografting, then fell to 12.0 (1.3–74.7) pg/ml by day +14; these changes were inversely correlated with absolute lymphocyte counts, CD3, CD4, and CD8 counts at baseline and day +7. The development of aGVHD was associated with IL-7 levels at day +7 (p=0.01) and day +14 (p=0.000033) post-transplant (Figure), along with the allograft CD34+ cell dose (p=0.012). Higher IL-7 levels at day +14 corresponded to more severe grades of aGVHD (p<0.0001). Figure Figure In logistic regression models, these factors jointly classified pts according to development or avoidance of aGVHD with a maximum sensitivity of 86% and a specificity of 100%. IL-7 levels were more strongly associated with aGVHD than were sTNFR levels or other parameters. CONCLUSIONS: Determination of serum IL-7 levels in the early post-transplant period accurately predicted the risk of developing aGVHD after allogeneic HSCT and holds promise as a simple, reproducible test to select pts for pre-emptive therapy. These data support preclinical observations that demonstrate a critical role for IL-7 in inducing aGVHD and provide a rational basis for novel approaches to GVHD prophylaxis through modulation of the IL-7 homeostatic pathway.

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Association of Skin and Blood Dendritic Cells with Acute Graft Versus Host Disease after Human Haematopoetic Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.1238.1238 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1238-1238

Author(s):

Susanne Auffermann-Gretzinger ◽

Lars Eger ◽

Martin Bornhaeuser ◽

Christian Thiede ◽

Knuth Schaekel ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host ◽

Time Points ◽

Post Transplant ◽

Kinetics Of ◽

Acute Graft

Abstract Both number and origin of dendritic cells (DC) in the blood have been associated with acute graft-versus-host disease (aGvHD), graft-verus-leukemia effect, relapse and graft failure after human allogeneic haematopoietic cell transplantation (aHCT). Aim of this study was the systematic simultaneous investigation of skin and blood DC subtypes, the analysis of their host/recipient origin after HCT and the correlation of DC kinetics with treatment, outcome and incidence of aGVD and its treatment in 31 recipients of allogeneic HCT. Epidermal shave biopsies and peripheral blood samples were collected from patients pre and at defined time points following aHCT, DC from skin and blood isolated and examined by FACS and quantitative PCR for Short Tandem Repeat markers. A significant reduction in number of skin and blood DC subtypes was observed already before start of conditioning chemotherapy in patients compared to healthy volunteers. A majority of donor derived epidermal Langerhans Cells (median 95%, range 53–100%) and also dermal DC (median 94%, range 39–100%) was found in all examined patients even early after transplant independent from chemotherapy regimen, graft, occurrence of skin GvHD or time point after transplantation. Numbers of both skin DC subsets remained low for months post HCT. Reconstitution kinetics of CD 11c+ preDC1 and CD 123+ preDC2 blood DC were similar to each other and pre transplant numbers were reached again around day +112 post transplant. Recipients of grafts containing higher T cell numbers had lower preDC1 counts on day +28. PreDC2 reconstitution was negatively affected by steroid treatment. Patients with aGvHD tended to have more preDC1 on day +28 and lower numbers of both preDC subsets on day 56 post transplant. Residual host blood DC were rare at all time points (median <3% at all investigated timepoints range 2–97%). The kinetics of DC reconstitution at different sites might become an important diagnostic tool to predict the occurrence of acute and chronic GvHD and to monitor the efficacy of prophylactic and therapeutic interventions.

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