Cumulative Incidence Of Extensive cGVHD Research Articles

Risk Factors and Outcome of Chronic GVHD: Analysis of 5,660 Patients Undergoing Unrelated Bone Marrow Transplantation through the Japan Marrow Donor Program.

Background: Chronic GVHD (cGVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. However, there are limited data available on cGVHD after unrelated BMT (UR-BMT). We retrospectively analyzed the data of 5,660 patients who underwent UR-BMT through the Japan Marrow Donor Program (JMDP) between January 1993 and June 2004.Methods: Data were collected by the JMDP using a standard report form. Follow-up reports were submitted at 100 days, 1 year, and then annually after transplantation. Overall survival (OS) was estimated by the Kaplan-Meier method and patients surviving beyond day 100 after transplant were analyzed for the development of cGVHD. The log-rank test was used for univariate analysis and time-dependent Cox proportional hazards modeling was used for multivariate analysis. The cumulative incidence of cGVHD and of relapse was calculated using the Gray method considering death without cGVHD and death without relapse as respective competing risks.Results: The median age of all patients was 28 years and the median follow-up was 433.5 days after transplant. Estimated 5-year OS of all patients and those with hematological malignancies was 47.4% and 45.5%, respectively. A total of 3,974 patients survived beyond day 100 after transplant and their cumulative incidence of cGVHD was 43.2% at day 500 and 44.9% at day 2,000 post-transplant. The cumulative incidence of extensive cGVHD was 28.8% at day 2,000 post-transplant. In multivariate analysis, variables predicting cGVHD were recipient age (p=0.000), donor age (p=0.002), diagnosis of hematological malignancy (HR=1.99, p=0.000), HLA class I mismatch by either serology or DNA typing (HR=1.24, p=0.020), acute GVHD (I: HR=1.50, p=0.000; II: HR=2.07, p=0.000; III and IV: HR=2.25, p=0.000) and no platelet recovery over 50,000/mm3 before day 100 (HR=1.36, P=0.002). There was a significant difference between patients <20 and ≥20 years old (HR=1.27, p=0.000). However, there were no significant differences between any adults grouped by age decade (p=0.894). OS at 5 years in patients surviving >100 days post-transplant was 62.4% without cGVHD, 68.0% with limited cGVHD, and 55.4% with extensive cGVHD (p=0.000). In the patients with hematological malignancies, OS at 5 years was 58.8%, 67.3% and 55.8%, respectively (p=0.000). Cumulative incidence of relapse of hematological malignancies at day 2,000 in patients surviving >100 days post-transplant was 17.6% with limited cGVHD, 18.4% with extensive cGVHD and 27.1% without cGVHD (P=0.000).Conclusions: This study provides strong evidence of risk factors for developing cGVHD after UR-BMT and suggests that limited cGVHD provides a survival benefit to patients with hematological malignancies by reducing the risk of relapse without increasing the risk of death from cGVHD. There was a significant difference in occurrence of cGVHD between patients <20 and ≥20 years old but no differences comparing any age ≥20 years.

Reduced Intensity Conditioning Unrelated Transplant Plus Cyclosporine and MMF as GVHD Prophylaxis: Results of a Prospective Study.

Some studies have suggested that mycophenolate mofetil (MMF) offers a similar efficacy in terms of GVHD prophylaxis as compared to methotrexate (MTX) but a faster engraftment and a lower incidence of mucositis.We have analyzed the results of fludarabine (150 mg/m2) and melphalan (140 mg/m2) or busulphan (10 mg/m2) plus Cyclosporine (CsA) and MMF instead of MTX as GVHD prophylaxis in a series of 30 patients undergoing unrelated allogeneic transplantation. Median age was 44 years (18–60). Patients younger than 40 were required to have a previous comorbid condition (8 had a previous autologous transplant; 2 had proven fungal infection; 1 had severe altered lung capacity). Twelve patients were diagnosed with AML, 4 had ALL, 4 MDS, 2 CML, 3 CLL, 3 NHL, 2 MM/WM. Disease status at transplant was 1st or 2nd CR in 12 patients, >2nd CR or PR in 11 patients while the remaining patients had active disease at the time of transplant (relapse, refractory, untreated diasease). Median day to reach > 0,5 x 109 granulocytes / L was +17 and to reach > 20 x 109 platelets / L was +13. At a median follow up of 445 days among patients alive, projected overall survival (OS) and event free survival at 3 years are 47% and 30%, respectively. Overall TRM was 32%. Cumulative incidence of grades 2–4 and 3–4 aGVHD was 67% and 33%, respectively while cumulative incidence of extensive cGVHD was 70%. Gut was the organ most severely involved in aGVHD in 10 out of 16 patients while liver was involved in only 3 cases. Interestingly, among patients who developed aGVHD, incidence of skin (80%) and liver (22%) involvement were similar to that observed in a similar series of patients receiving related donor transplant using the same RIC plus CsA and MTX instead of MMF while the incidence of gut involvement was significantly higher (64% vs 42%).In conclusion, the RIC used in the current study plus CsA and MMF offers promising results in high risk patients. In terms of GVHD prophylaxis, MMF shows a good efficacy at skin and liver but poor at the gastrointestinal tract.

Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation

AbstractWe analyzed the impact of CD34+ cell dose on the outcome of 86 patients undergoing reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation. The RIC was based on fludarabine 150 mg/m2 and melphalan 140 mg/m2 or busulphan 10 mg/kg. A median of 5.68 × 106 CD34+ cells/kg and 2.86 × 108 CD3+ cells/kg were infused. All patients receiving more than percentile 75 (p75) of CD34+ cells reached complete chimerism in T lymphocytes by days 21 to 28, compared with 44β among those receiving p75 or fewer cells (P = .046). Overall, 30.3β patients developed grade 2 to 4 acute graft-versus-host disease (aGVHD). Among 83 evaluable patients, 55.8β developed chronic GVHD (cGVHD). The dose of CD34+ cells infused did influence the development of cGVHD, with a cumulative incidence of extensive cGVHD of 74β vs 47β (P = .02) among patients receiving more than p75 CD34+ cells vs those receiving p75 or fewer. Projected overall survival (OS) and event-free survival (EFS) at 43 months were 60β and 46β, respectively. Neither the dose of CD34+ cells nor the dose of CD3+ cells infused significantly influenced OS and EFS, although among patients categorized as high-risk, 36β of those receiving p75 or fewer CD34+ cells relapsed or progressed, compared with only 9β among those receiving more than p75 CD34+ cells (P = .07). Among patients receiving p75 or fewer CD34+ cells, 36β of high-risk patients relapsed, compared with 10β of low- and intermediate-risk patients (P = .004), while relapse rates were not significantly different between both subgroups when we infused more than p75 CD34+ cells, thus indicating that infusing high doses of CD34+ cells ameliorates the negative effect of advanced disease status at transplantation. cGVHD was associated with better EFS (63β vs 16β at 43 months for patients with and without cGVHD; P < .0001) and better OS (78β vs 28β for patients with and without cGHVD; P < .001). The number of CD34+ cells infused should be tailored to prevent extensive cGVHD among patients categorized as low-risk, while high-risk patients, in whom the graft-versus-leukemia effect may determine disease outcome, should receive high doses of CD34+ cells.