Development Of Extensive Chronic Graft-versus-host Disease Research Articles

Vascular biomarkers reveal a unique toxicity profile of posttransplant cyclophosphamide: secondary analysis of BMT CTN 0402 and 1202

AbstractPosttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis regimens are associated with very low rates of severe acute and chronic GVHD after hematopoietic cell transplant (HCT). However, concerns about cardiac and other organ toxicities persist. This study aimed to compare the vascular biomarker profile of PTCy with other GVHD regimens, including tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), to generate hypotheses for toxicity mitigation strategies. Plasma samples from day +28 after transplant were analyzed against pretransplant baseline measurements in patients receiving PTCy-based GVHD prophylaxis as part of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 (n = 112) vs Tac/MTX (n = 98) and Tac/Sir (n = 95) regimens from BMT CTN 0402. Compared with Tac/MTX, PTCy was associated with increasing angiopoietin-2 levels and decreasing epidermal growth factor levels at day +28. In contrast, Tac/Sir displayed increasing follistatin and endoglin levels and decreasing vascular endothelial growth factor receptor 2 (VEGFR2) plasma levels after HCT. Across all cohorts, increasing epidermal growth factor was protective from nonrelapse mortality, and decreasing VEGFR2 was associated with subsequent development of extensive chronic GVHD. These distinct biomarker profiles offer insights that could guide strategies to mitigate unique GVHD prophylaxis–associated toxicities.

Feasibility and safety of the discontinuation of systemic immunosuppressive treatment after single-unit cord blood transplantation in adults

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

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

AbstractAbstract 1948Previous 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. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

AbstractAllogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.

Comparable Analysis of Outcomes for Allogeneic Peripheral Blood Stem Cell Transplantation from Matched Related and Matched Unrelated Donors in Acute Myeloid Leukemia

This study compared the results of allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated and related donors in 142 consecutive patients with acute myeloid leukemia (AML). The cumulative incidence of acute graft-versus-host disease (GVHD) was 37.6% in the related PBSCT group and 53.7% in the unrelated PBSCT group. The cumulative incidence of extensive chronic GVHD was also higher in the unrelated PBSCT group (19.5%) than in the related PBSCT group (8.9%). The overall survival rate at 4 years was 62.4 ± 5.4 and 53.8 ± 1.2% (p = 0.535) in the related and unrelated PBSCT group, respectively. In a multivariate analysis, unrelated PBSCT was identified as a risk factor for the development of extensive chronic GVHD (hazard ratio = 3.019, p = 0.027). Unfavorable cytogenetics and the disease status at the time of transplantation were found to be related to overall survival. In the case of high-risk AML, the survival rate and relapse incidence were significantly better in the matched unrelated PBSCT group (p = 0.047 and 0.039, respectively). In conclusion, the allogeneic PBSCT outcomes for AML were comparable in the matched related and matched unrelated groups. Nonetheless, for high-risk AML patients, matched unrelated PBSCT was found to be preferable to matched related PBSCT.

Comparative analysis of outcomes of allogeneic peripheral blood stem cell transplantation from related and unrelated donors

This study compared the results of allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated and related donors, and involved 235 consecutive patients from ten centers between Jan 2004 and Dec 2008. Among these patients, 160 (68.1%) received a human leukocyte antigen-matched related PBSCT and 75 (31.9%), a matched unrelated PBSCT. The cumulative incidence of acute graft-versus-host disease (GVHD) was 43.9% for the related PBSCT and 59.3% for the unrelated PBSCT. Although the cumulative incidence of chronic GVHD was no different between the related (54.2%) and unrelated (64.9%) PBSCT, the cumulative incidence of extensive chronic GVHD was higher among the unrelated PBSCT (34.9%) than among the related PBSCT (17.0%). The overall survival rate at 4 years was 58.2% versus 49.1%, and the cumulative incidence of relapse was 28.4% versus 25.0% for the related and unrelated PBSCT, respectively. Among the factors examined, unrelated PBSCT, the CD34-positive cell count, and cytomegalovirus infection were all related with a higher incidence of extensive chronic GVHD. However, in a multivariate analysis, only unrelated PBSCT was identified as a risk factor for the development of extensive chronic GVHD (hazard ratio = 2.012; P value, 0.048). In conclusion, the survival and relapse incidence were not significantly different between the related and unrelated PBSCT.

Comparative Analysis of Outcomes of Allogeneic Peripheral Blood Stem Cell Transplantation From Related and Unrelated Donors.

Abstract 3381Poster Board III-269This study compared the results of allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated and related donors, and involved 235 consecutive patients from 10 centers who received an allogeneic PBSCT for hematological malignancies between Jan 2004 and Dec 2008. Among these patients, 160 (68.1%) received an HLA-matched related PBSCT and 75 (31.9%) a matched unrelated PBSCT. Sixty-five patients (27.7%) had a high-risk disease status at transplantation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 43.9% for the related PBSCT group and 59.3% for the unrelated PBSCT group (P-value:0.011). Although the cumulative incidence of chronic GVHD was no different between the related (54.2%) and unrelated (64.9%; P-value:0.199) PBSCT groups, the cumulative incidence of extensive chronic GVHD was higher among the unrelated PBSCT group (34.9%) than among the related PBSCT group (17.0%; P-value:0.015). Plus, the unrelated PBSCT group showed a higher cumulative incidence of CMV infection (44.6%) than the related PBSCT group (26.8%; P-value:0.002). The overall survival rate at four-year was 58.2% versus 49.1% (p=0.698) and the cumulative incidence of relapse 28.4% versus 25.0% (P-value:0.289) for the related and unrelated PBSCT groups, respectively. Among the factors examined, unrelated PBSCT (P-value:0.024), the CD34-positive cell count (>6 × 106/kg; P-value:0.041), and CMV infection (P-value:0.066) were all related with a higher incidence of extensive chronic GVHD. However, in a multivariate analysis, only unrelated PBSCT was identified as a risk factor for the development of extensive chronic GVHD (hazard ratio=2.012, 95% confidence interval=1.006-4.023; P-value:0.048). In conclusion, the overall survival and relapse incidence were not significantly different between the related and unrelated PBSCT groups. However, a higher incidence of CMV infection and extensive chronic GVHD was observed in the unrelated PBSCT group. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults.

The prognosis for Philadelphia chromosome-positive ALL (Ph+ALL) is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently considered the only established procedure with curative potential. It is therefore quite important to clarify what are essential elements of the success of allogeneic HSCT. Thus, we performed a retrospective study covering 197 Ph+ALL cases aged 16 years or older who underwent allogeneic myeloablative HSCT to identify factors affecting the transplant outcome. The subjects comprised 120 males and 77 females, and their median age was 37 years (range, 16 to 59 years). Transplantation during complete remission (CR) accounted for 57% (112 cases), and only 19 patients received transplantation during their second or subsequent CR. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (p<0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation (TBI), and human leukocyte antigen (HLA)-identical sibling donor (p<0.0001, p<0.0001, p=0.0301, p=0.0412, respectively). Next, we investigated whether development of graft-versus-host disease (GVHD) had a significant influence on survival. The presence or absence of each type of GVHD (grade II-IV acute GVHD, grade III-IV acute GVHD, any form of chronic GVHD, and extensive chronic GVHD) was included separately in the Cox model containing the four significant pre-transplant risk factors. Although the survival rate was almost identical for patients with and without grade II-IV acute GVHD, grade III-IV acute GVHD had a significant impact on survival (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.34 to 0.98; p=0.0430). For patients developing any form of chronic GVHD, there was a non-significant increase in survival rate compared with those who did not (HR, 1.40; 95% CI, 0.85 to 2.32; p=0.1877). As for extensive chronic GVHD, the survival advantage was statistically significant (HR, 2.10; 95% CI, 1.13 to 3.88; p=0.0179). The 5-year survival rate was estimated to be 51% for those with extensive chronic GVHD, and 29% for those without. Chronic GVHD was associated with a lower risk of relapse without increasing the risk of treatment-related mortality (TRM), whereas acute GVHD was associated with a higher risk of TRM without diminishing the risk of relapse. From the analysis of the data for 197 Ph+ALL patients who had undergone allogeneic myeloablative HSCT, we identified four prognostic pre-transplant factors. Younger age, CR at the time of transplantation, TBI conditioning, and HLA-identical sibling donor were found to be associated with significantly better survival. Chronic GVHD reduces the risk of relapse without increasing the risk of TRM, and development of extensive chronic GVHD even prolongs survival. These findings should be helpful for achieving the success of allogeneic HSCT for Ph+ALL.

Prognostic significance of platelet recovery pattern after allogeneic HLA-identical sibling transplantation and its association with severe acute GVHD

Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor when assessed beyond day 100. However, little is known about the clinical significance of the platelet recovery pattern before chronic graft-versus-host disease (GVHD) develops. Eighty-five patients undergoing HLA-identical sibling SCT were stratified according to their platelet recovery pattern between day +30 and +90 and the transplant outcomes analyzed, along with the association of each component of the acute GVHD grading system. Fifteen patients (18%) were classified with persistent TP, 33 patients (39%) with unstable TP, and 37 patients (43%) as non-TP. Persistent TP, which was strongly associated with severe acute GVHD (P<0.001), exhibited the worst 2-year OS (P<0.0001) and highest NRM (P<0.0001) and opportunistic infection rates (P<0.0001). In multivariate analyses, the platelet recovery pattern was identified as an independent prognostic factor (P=0.02) together with the disease risk (P=0.02) in terms of OS, and the only independent prognostic factor in terms of NRM (P=0.005) and the incidence of infectious events (P<0.001). Persistent TP was strongly associated with the development of extensive chronic GVHD (P=0.03). The platelet recovery pattern between day +30 and +90 can be used to predict the prognosis of SCT recipients.

Reduced risk for extensive chronic graft-versus-host disease in patients receiving transplants with human leukocyte antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy against cytomegalovirus.

The aim of this study was to investigate the relationship between cytomegalovirus (CMV) and extensive chronic graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (SCT). Two hundred sixty-two consecutive patients undergoing conventional SCT with human leukocyte antigen-identical sibling donors, given cyclosporine A and methotrexate as GvHD prophylaxis and surviving more than 3 months after SCT, were retrospectively analyzed. Most patients received transplants because of a hematologic malignancy (n=226), but 36 patients with nonmalignant disorders were included in the analysis. Ninety-nine patients were monitored for CMV infection with rapid virus isolation and 163 patients by either a pp65 antigenemia test (n=5) or a qualitative polymerase chain reaction (PCR) assay for CMV-DNA (n=158). One hundred thirty (50%) of the patients developed chronic GvHD, of whom 17 (6.5%) developed extensive chronic GvHD. Risk factors for development of extensive chronic GvHD were determined by multivariate logistic regression. The strategy of PCR-based monitoring for CMV-DNA, giving preemptive antiviral therapy on demand, significantly decreased the risk for developing extensive chronic GvHD (odds ratio=0.32, P =0.03). No other factors tested, including recipient and donor age and sex, source of graft, cell dose, and acute GvHD, had any significant effect on the development of extensive chronic GvHD. We conclude that the risk for extensive chronic GvHD in this homogenous group of patients was reduced by the use of PCR-based preemptive therapy.

Sustained molecular remission in a patient with CML in blastic crisis receiving dose‐reduced hematopoietic stem‐cell transplantation followed by early withdrawal of cyclosporine and prophylactic use of interferon‐α

A 54-year-old man with chronic myelocytic leukemia in blastic phase received reduced-intensity transplantation (RIST) from an HLA-identical unrelated donor. The preparative regimen consisted of busulfan, fludarabine, and anti-thymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine alone. Because he had a high risk of relapse, we discontinued cyclosporine on day 37, but he did not develop any signs of acute GVHD. To induce GVHD and augment a graft-versus-leukemia effect, we initiated interferon-alpha therapy on day 80 to a maximum dosage of three million units five times a week. He achieved molecular remission on day 94 followed by the development of extensive chronic GVHD the severity of which paralleled to the dose of interferon-alpha GVHD gradually subsided after discontinuation of interferon-alpha and the patient remains in molecular remission 18 months after transplantation. This case suggests that early withdrawal of cyclosporine and the prophylactic use of interferon-alpha are promising in RIST for high-risk leukemia.