We have recently described an algorithm combining biomarkers and clinical characteristics that, at the onset of acute GVHD symptoms, predicts outcomes such as treatment response and non-relapse mortality (NRM). We have now evaluated whether a combination of pre-HCT clinical characteristics and a biomarker panel measured early post-HCT can predict future GVHD. From 2001-2011, we prospectively collected clinical data and plasma samples from 393 patients receiving related donor HCT at our institution. The cumulative incidence of grade 2-4 GVHD by day 100 was 31% (n = 121; median onset = day 40). We divided patients randomly into a training set (n=264) to develop GVHD predictive algorithms using logistic regression, and a validation set (n=129) to test the algorithms. There were no statistically significant differences in pre-HCT clinical parameters between the 2 sets. We measured 4 GVHD biomarkers (IL-2Rα, TNFR1, elafin, and REG3α) on post-HCT day 7 plasma samples by ELISA. Grade 2-4 GVHD onset within 2 months of HCT served as the predictive endpoint. We developed 3 predictive models for GVHD in the training set: 5 validated clinical risk factors alone (patient age, myeloablative conditioning [MA]), HLA-match, GVHD prophylaxis, graft source, use of TBI); the 4 biomarker panel alone; and a combination of all 9 clinical and biomarker parameters. We compared all 3 models at a specificity of 50% for their respective sensitivities. Clinical factors alone provided 51% sensitivity, 4 biomarkers alone provided 66% sensitivity, and all 9 parameters combined provided 77% sensitivity (combined vs. clinical model, P < .001; vs. biomarker model, P = .07). The combined model provided similar sensitivity in the validation set (75%) which allowed us to combine the 2 sets for further analyses. We used the algorithm to stratify patients as high (N=211) or low risk (n=182) for developing GVHD. High risk patients were twice as likely to develop grade 2-4 GVHD (Figure 1A; 38% vs. 20%, P < .001) which developed almost 1 month earlier than in the low risk group (median day = 39 vs. 65). The greater incidence of GVHD in high risk patients resulted in significantly greater NRM by day 180 post-HCT (Figure 1B; 12% vs. 3%; P = .001). The relapse rate was identical in both groups (24%), thus overall survival (OS) was significantly better in the low risk group (84% vs. 73%, P = .004). The differences between high and low risk patients remained significant at 1-yr post-HCT for NRM (17% vs. 6%, P < .001) and OS (61% vs. 72%, P = .01). In conclusion, combining a panel of 4 biomarkers at day 7 post-HCT and 5 pre-HCT clinical parameters produced the best algorithm to predict GVHD following related donor HCT. The algorithm successfully stratified patients into high and low risk groups for GVHD, NRM and OS. We hypothesize the use of such an algorithm may permit preemptive therapy for patients who are at greatest risk in the early transplant course.
Background: The purpose of this study was to compare the performance of the Spectra Optia® continuous mononuclear cell (CMNC) and mononuclear cell (MNC) apheresis protocols when collecting autologous and allogeneic PBSCs. Method: Apheresis collections from 53 CMNC and 50 MNC autologous donations and 12 CMNC and 13 MNC allogeneic donations were compared in a retrospective analysis to determine collection efficiencies (CE2%), collection predictabilities based on CD34+ pre-apheresis cell counts, platelet loss, the impact of hematocrit (Hct), run times, and product volumes. Data was analyzed using Microsoft 365 Excel and Peltier Tech software's. Results: CD34+ CE2% were similar with CMNC and MNC apheresis protocols for allogeneic (P-value = .10) and autologous (P-value = .39) collections. Correlation between pre-apheresis CD34+ cell counts and the normalized yields of CD34+ cells per liter of blood processed indicated that predictability was higher for CMNC (R2 = .9441) than for MNC (R2 = .8448) collections. This should allow for the creation of a reliable prediction algorithm, particularly for the CMNC protocol, allowing the calculation of the required blood volume to process to achieve a desired CD34+ yield. Platelet loss (normalized per total blood volume processed) was similar for both protocols, and a high correlation was found between pre- and post-platelet counts, making it possible to accurately predict the corresponding post-platelet count. Product HCT% was slightly higher for CMNC collections than for MNC collections, which is consistent with previously published results, but in all cases the RBC content in the product was well below 20 mL, making these products safe for ABO-incompatible allogeneic transplants. We were unable to find a significant correlation between product HCT% and CD34+ CE%, suggesting that collecting lighter or darker products has little impact on the corresponding CD34+ CE%. Run times were significantly shorter (P-value < .05) and product volumes were significantly smaller with CMNC collections in both autologous and allogeneic collections. Of note, CMNC product volumes were less variable than MNC product volumes. Conclusion: The CMNC protocol is a viable alternative to the MNC procedure for collecting autologous and allogeneic donations. Comparable CD34+ CE2% are obtained with MNC and CMNC collections and pre-apheresis cell counts provide a better prediction of CD34+ cell yields with the CMNC than with the MNC method. The shorter run times with the CMNC method allow for larger blood volumes processed and less days of collection for well mobilized patients. The good predictability of platelet post-counts helps make the collections with the CMNC protocol safer. The CMNC protocol allows for more efficient planning of stem cell collections to accommodate more patients.
Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening disease in immunocompromised patients. The at-risk population includes patients with HIV infection and low CD4 counts, hematological malignancies, hematopoietic stem cell (HSC) and solid organ transplant recipients, and patients receiving glucocorticoids or other immunomodulatory agents. The highest-risk group of immunocompromised patients tends to be those with HIV (human immunodeficiency virus) infection, where PJ follows an indolent course. However, in non-HIV immunocompromised patients, such as HSC transplant recipients, the infection tends to present with respiratory failure. The incidence of PJP in autologous BMT (bone marrow transplant) has not been clearly determined, and the indication for prophylaxis in this setting remains unclear. In this study we evaluate the incidence of PJP over a 10-year period in recipients of autologous transplants. A retrospective analysis of 1191 consecutive autologous HSC transplants (1-75 years) performed between 1/1/2000 and 6/30/2011 at the University of Michigan BMT Program. The data was obtained from BMT Program Database at The University of Michigan Comprehensive Cancer Center. The diagnosis of PJP was established by bronchoscopy with brochoaveolar lavage (BAL) with polymerase chain reaction (PCR). We analyzed the following risk factors for the development of PJP: diabetes, glucocorticoids, infections, cutaneous T-cell lymphoma, hypertension, and seizure disorder. A total number of 5 PJ infections were diagnosed during study period, resulting in a cumulative incidence of 0.42% (95%CI [0.136449%--0.976969%]) over 10 year period. All cases occurred between 2001 and 2006, and 3 months or later following transplantation. Most patients (n=4) were older than 50 years old, and all of them were on steroids. Diagnoses included non-Hodgkin's lymphoma (n=3), Hodgkin's lymphoma (n=1) and multiple myeloma (n=1). Conditioning regimen was BEAM (BCNU, etoposide, cytarabine, melphalan, n=4) and high dose melphalan (n=1). Only 2/5 patients were neutropenic at the time of the pneumonia, and this did not correlate with the CD34+ cell infused, which was ≥2.2x10E6/kg for all patients. Four patients were on corticosteroids for relapsed lymphoma (n=2), ITP (n=1), BCNU pneumonitis (n=1). The remainder patient was on florinef and was coinfected with candida and herpes virus. There were no particular comorbidities associated with the diagnosis of PJ pneumonia. One patient died of PJ, the remainder were treated successfully. Our retrospective analysis of a large cohort of autologous transplant recipients reveals an extremely low incidence of PJP, suggesting that PJP prophylaxis is not routinely warranted in this patient population. Patients who require systemic corticosteroids post–HSC may be considered for PJ prophylaxis.
