Nonmyeloablative HLA-Haploidentical (NMA Haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Is Associated with Similar Outcomes to Matched BMT When Stratified By Disease Risk Index (DRI)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 680-680 ◽  
Author(s):  
Shannon R. McCurdy ◽  
Jennifer A. Kanakry ◽  
Margaret M. Showel ◽  
Hua-Ling Tsai ◽  
Javier Bolaños-Meade ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Gvhd ◽  
Multivariate Analyses ◽  
Disease Risk ◽  
Risk Groups ◽  
Low Risk ◽  
Competing Risk ◽  
Survival Outcomes ◽  
High Dose ◽  
Gvhd Prophylaxis

Abstract Background: Recent advances in NMA haplo BMT, including high-dose PTCy for GVHD prophylaxis, have expanded potentially curative treatment options for patients (pts) without a matched donor. The DRI (Blood 2012;120:905), based on disease type and status, was developed to stratify pt risk across histologies and conditioning regimens. The current study evaluated the newly refined DRI (Blood 2014;123:3664) in the largest series of NMA haplo BMT to date. Methods: We retrospectively analyzed the outcomes of 374 consecutive adult hematologic malignancy pts who received NMA related haplo BMT with PTCy at Johns Hopkins. Eligibility included ECOG PS ≤ 2, LVEF ≥ 35%, adequate pulmonary and renal function and absence of uncontrolled infection. All pts received fludarabine (30 mg/m2IV D -6 to -2), Cy (14.5 mg/kg IV D -6 and -5), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil and tacrolimus. Maintenance therapy (e.g., imatinib) after engraftment was permitted. The median age was 55 (range 18-75) at BMT, 132 (35%) pts were aged ≥ 60 and 71 (19%) had prior autologous BMT. Diagnoses were acute leukemia or lymphoblastic lymphoma (115 pts; 31%), MDS or MPN (36 pts; 10%), aggressive NHL (95 pts; 25%), Hodgkin lymphoma (36 pts; 10%), mantle cell lymphoma (29 pts; 8%) and indolent lymphoid cancers (63 pts; 17%). By the new DRI, disease risk was low in 72 pts (19%), intermediate (int) in 242 (65%), high in 50 (13%) and very (v) high in 10 (3%). Overall results: With a median follow-up of 3.4 (range 0.5-11.4) years (y) in surviving pts, 3-y probabilities of PFS and OS were 40 (95% CI 35-45)% and 50 (45-56)%, respectively. The probability of neutrophil recovery was 89% by D30 (median 17 d). By competing-risk analyses, the D180 probability of nonrelapse mortality (NRM) was 8 (95% CI 5-10)%, grade 2-4 acute GVHD was 32 (27-37)%, and grade 3-4 acute GVHD was 4 (2-6)%. The 2-y probability of chronic GVHD was 13 (10-17)%. Results by DRI: Among the 3 DRI risk groups (low, int, high/v high), there were no statistically significant differences in histology (lymphoid vs myeloid), HCT-CI risk category, median CD34+ graft dose or pt CMV serostatus. Median pt age was greater in the higher risk groups (P = 0.01). On unadjusted analyses of the new DRI, the probability of relapse by competing-risk differed clearly between the groups (P < 0.0001; Fig. A), with no statistically significant difference in NRM (P = 0.53). This was coupled with statistically significant differences in both PFS and OS. In low, int and high/v high risk groups, 3-y PFS estimates were 64%, 37% and 22%, respectively (P < 0.0001; Fig. B), and 3-y OS estimates were 69%, 49% and 34% (P = 0.0001). Furthermore, on multivariate analyses adjusted for age and year of BMT, the new DRI was independently associated with overall outcomes. Compared to low-risk pts, the HR for relapse was 3.0 (95% CI 1.8-5.2) for int risk pts (P = 0.0001) and 4.7 (2.6-8.5) for high/ v high risk pts (P < 0.0001). HRs for both PFS and OS were ≥ 2-fold greater for int and high/v high risk pts compared to low risk pts (each P ≤ 0.0002). On multivariate analyses, the original DRI (13% low risk, 68% int, 19% high/v high) was also independently associated with relapse, PFS and OS (each P ≤ 0.003). When stratified by DRI, survival outcomes with reduced-intensity, matched related or unrelated BMT (based on 614 pts from the original DRI study cohort; personal communication, P. Armand) and haplo BMT with PTCy appeared similar (Table). Conclusion: The DRI appears to effectively stratify and prognosticate pts undergoing NMA haplo BMT. When stratified by DRI, the efficacy and survival outcomes with NMA haplo BMT with PTCy appear comparable to those reported with matched BMT. Within this transplant platform, the results support the use of the DRI in outcome analyses and randomized clinical trials involving heterogeneous groups of pts. Figure 1 Figure 1. Table Survival Estimates by DRI 3-y PFS (%) 3-y OS (%) Original DRI Matched Haplo Matched Haplo Low 66 63 70 71 Intermediate 31 39 47 49 High / very high 15 25 25 38 Figure 2 Figure 2. Disclosures Off Label Use: High-dose posttransplantation cyclophosphamide.

Encouraging Outcomes In Older Patients (Pts) Following Nonmyeloablative (NMA) Haploidentical Blood or Marrow Transplantation (haploBMT) With High-Dose Posttransplantation Cyclophosphamide (PT/Cy)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 158-158 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Gabrielle Prince ◽  
Javier Bolaños-Meade ◽  
Hua-Ling Tsai ◽  
Leo Luznik ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Older Age ◽  
Low Risk ◽  
Aggressive Lymphoma ◽  
High Dose ◽  
Platelet Recovery ◽  
Gvhd Prophylaxis ◽  
The Impact

Abstract Background Recent advances in NMA haploBMT have expanded potentially curative treatment options for pts lacking a matched donor. However, there is a paucity of data on the safety and efficacy of haploBMT in pts aged ≥ 60 y. This study evaluated the impact of older age on outcomes of NMA haploBMT with PT/Cy. Patients and methods We retrospectively analyzed the outcomes of 273 consecutive pts with poor-risk or advanced hematologic malignancies, aged 50-75 y, who received NMA related haploBMT with PT/Cy at Johns Hopkins. Eligibility included ECOG PS ≤ 1 or 2, LVEF ≥ 35%, adequate pulmonary and renal function and no uncontrolled infection. Morphologic CR was required for acute leukemia, ≥ PR for aggressive lymphoma. All pts received Cy (14.5 mg/kg IV days -6 and -5), fludarabine (30 mg/m2 IV days -6 to -2), TBI (200 cGy day -1) and T-cell replete bone marrow (272 pts) or peripheral stem cells (1 pt). GVHD prophylaxis consisted of high-dose PT/Cy (50 mg/kg IV) either once (day 3; 10 pts) or twice (days 3 and 4; 263 pts), mycophenolate mofetil and tacrolimus. Maintenance therapy was permitted and included rituximab in 55/126 B-NHL or CLL cases (44%). Results Of the 273 pts (median age 61 y, range 50-75), 154 were aged ≥ 60, including 27 pts aged 70-75. Diagnoses were aggressive lymphoma (79 pts), mantle cell lymphoma (25), indolent lymphoma or CLL (41), acute leukemia or lymphoblastic lymphoma (76), MDS (20), MPD (17), Hodgkin lymphoma (8) or multiple myeloma (7). Forty-one pts (15%) had prior autoBMT, and 138 (51%) had a high-risk comorbidity index score (HCT-CI ≥ 3). There were no statistically significant differences in HCT-CI risk category, histology (lymphoid vs myeloid), graft dose or CMV mismatch according to age by decade. By Disease Risk Index (DRI) category (Blood 2012; 120: 905), 32 pts (12%) were low-risk, 197 (72%) intermediate-risk, 44 (16%) high-risk and none very high-risk. No pts aged ≥ 70 were in the low-risk group. a) Overall results: With a median follow-up of 2.1 (range < 1 - 7.9) y in event-free pts, 2-y probabilities of PFS and OS were 39 (95% CI, 32-44)% and 53 (47-60)%, respectively. The probability of neutrophil recovery was 89% at day 30 (median 16 days). The probability of platelet recovery ≥ 20,000/µL was 85% at day 60 (median 26 days). Graft failure occurred in 12% of evaluable pts, with autologous count recovery in most cases. By competing-risk analysis, the 180-day probability of nonrelapse mortality (NRM) was 11 (95% CI, 7-14)%, grade 2-4 acute GVHD was 32 (27-38)%, and grade 3-4 acute GVHD was 3 (1-6)%. The 1-y probabilities of NRM and chronic GVHD were 14 (95% CI, 10-19)% and 12 (8-16)%. b) Age-specific results: Notably, as compared to age 50-59, we found no statistically significant association between advanced pt age and either NRM (fig A) or PFS. On univariate analysis, older age relative to ages 50-59 was associated with a tendency toward more grade 2-4 acute GVHD, without an evident increase in severe acute GVHD. The 2-y PFS probabilities for pts in their 50's, 60's and 70's were 39%, 36% and 39%, respectively (p = 0.9; fig B), with corresponding 2-year OS probabilities of 51%, 56% and 44 % (p = 0.9). In univariate analyses, no statistically significant association was seen between PFS and older age as a continuous variable (HR 1.01, 95% CI 0.99-1.03, p = 0.44) or categorical variable (ages 60-69 and ≥ 70, relative to 50-59). In contrast, the DRI category was significantly associated with both PFS (p < 0.003; fig C) and OS (p = 0.01). Likewise, in a multivariate analysis adjusted for year of BMT, the DRI was independently associated with PFS (p = 0.047). However, in multivariate analyses of PFS and NRM, no statistically significant association was seen with older age. Conclusion These data suggest that in NMA related haploBMT with PT/Cy, advanced pt age is not associated with prohibitive toxicities. In fact, there was no apparent decrement in overall outcome in pts aged ≥ 70 when compared to those in their 50's. Additionally, the DRI is useful for risk stratification. Advanced age is thus no longer a barrier to successful outcomes with partially HLA-mismatched BMT. Disclosures: Off Label Use: Posttransplantation cyclophosphamide for GVHD prophylaxis.

Antithymocyte Globulin (Rabbit) Enhanced The Efficacy Of Tacrolimus and Mycophenolate For Graft-Versus-Host Disease Prophylaxis In Recipients Of Unrelated Stem Cell Transplant Resulting In Improvement Of Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3300-3300
Author(s):  
Voravit Ratanatharathorn ◽  
Abhinav Deol ◽  
Lois Ayash ◽  
Divaya Bhutani ◽  
Lawrence G Lum ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Chronic Gvhd ◽  
Low Risk ◽  
Cell Transplant ◽  
Intermediate Risk ◽  
Gvhd Prophylaxis ◽  
High Risk Disease

Abstract Introduction Antithymocyte globulin (ATG, Thymoglobulin, Genzyme) derived from New Zealand rabbit immunized with fresh thymocytes has diverse biologic activities against immune response antigens, adhesion and cell-trafficking molecules. These properties are conceptually critical for effective immunosuppression to prevent organ rejection or GVHD. In this study we tested the efficacy of the combination of ATG, tacrolimus (T) and mycophenolate mofetil (M) in the prevention of GVHD in the recipients of allogeneic stem cell transplant from unrelated donor (UHCT). Methods From June 2008 to December 2012, we performed UHCT in 197 consecutive patients with hematologic malignancies: ALL (N=24), AML (N=85), CLL (N=16), CML (N=8), Hodgkin lymphoma (N=2), MDS/MPN (N=35), non-Hodgkin lymphoma (N=25), myeloma (N=1) and prolymphocytic leukemia (N=1). Patients received either TM (N=121) or ATG-TM (N=76) for GVHD prophylaxis. The distribution of diagnosis between TM and ATG-TM was not different (P=0.72). TM was started on day -3. T dose was 0.03 mg/kg continuous IV daily, M was administered IV at the dose of 10 mg per kg every 8 hours and converted to oral route when patients tolerated oral intake. M was discontinued on day 30 if patients did not develop acute GVHD. ATG total dose of 4.5 mg/kg IV was given daily over 3 days. Stem cell graft was infused within 24 hours of the last dose of ATG. The intensity of the regimen was categorized according to CIBMTR criteria. Disease-risk category was classified as low-risk if CR1, intermediate-risk if CR2 and high-risk if presence of active disease. Demographics ATG-TM cohorts were older, median age 56 vs 52 (P=0.04). Patients with high-risk disease were more likely to receive RIC (P=0.004). There were higher proportion of patients with mismatched graft (P=0.004), and RIC (P=0.005) who received ATG-TM. The remaining other characteristics - HCT-CI score and sex were evenly distributed between TM and ATG-TM. Median follow up for survivors was 20 months. Results Cumulative incidence of grade II-IV acute GVHD for the TM and ATG-TM cohorts were 49% (95% CI, 39%-59%) and 61% (95%CI, 49%-73%)(P=0.11). Incidence of grade III-IV acute GVHD for the TM and ATG-TM cohorts were 27% (95% CI, 19%-35%) and 14% (95%CI, 4%-24%)(P=0.02) (Fig A). There was no difference in the incidence of relapse or disease progression between TM and ATG-TM cohorts, 16% (95%CI, 8%-24%) vs 23% (95%CI, 0%-47%) (P=0.64). Non-relapse mortality was significantly lower in ATG-TM cohort, 20% (95%CI, 10%-30%) vs 37% (95%CI, 29%-45%) (P=0.01) (Fig B). Cumulative incidence of chronic GVHD was 43% (95%CI, 40% - 72%) in patients who received ATG-TM and 56% (95%CI, 46% - 66%) in TM cohort (P<0.001). Patients receiving ATG-TM had a significantly lower severity of chronic GVHD than patients receiving TM (P=0.004). In univariate analysis, disease-risk status correlated with PFS. PFS at 4 years for low-risk disease was 72% (95%CI, 60%-84%, N=66), 44% (95%CI, 24%-64%, N=24) for intermediate-risk and 36% (95%CI, 24%-48%, N=107) for high-risk disease (P<0.001). PFS at 2 years was better in ATG-TM cohort compared to TM cohort: 54% (95%CI, 32%-76%, N=76) vs 43% (95%CI, 33%-53%, N=121) (P=0.02) (Fig C). Multivariate analysis showed high-risk disease status was independently predictive of poor PFS (P<0.001) and intermediate-risk disease was marginally significant (P=0.05). ATG-TM cohort showed a trend of improved PFS (P=0.07). Disease-risk status at the time of transplant correlated with overall survival (OS) at 4 years: 72% (95%CI, 60%-84%, N=66)) for low risk, 51% (95%CI, 26%-76%, N=24) for intermediate risk and 34% (95%CI, 20%-48%, N=107) for high-risk group (P<0.001), respectively. OS at 2 years was significantly better in ATG-TM cohort: 64% (95%CI, 48%-80%, N=76) vs 49% (95%CI, 39%-59%) (P=0.01) in TM cohort. There were no significant difference among patients who received 9/10 vs 10/10 matched donor, intensity of preparative regimen, and HCT-CI. Multivariate analysis revealed unfavorable impact of high-risk disease and favorable OS in patients who received ATG-TM for GVHD prophylaxis. Conclusion ATG dose of 4.5 mg/kg given in conjunction with TM improved the efficacy of GVHD prophylaxis without increased risk of relapse. Lower non-relapse mortality, lower incidence of severe acute and chronic GVHD resulting in improvement of OS and PFS in the ATG-TM cohort. Disclosures: Off Label Use: Thymoglobulin is approved only for renal transplant rejection. Al-Kadhimi:Genzyme: Research Funding.

scholarly journals Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 374
Author(s):  
Simon Bailey ◽  
Nicolas André ◽  
Lorenza Gandola ◽  
Maura Massimino ◽  
Stefan Rutkowski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Disease Risk ◽  
Risk Groups ◽  
Randomised Clinical Trial ◽  
Paediatric Oncology ◽  
High Dose ◽  
The Status ◽  
Risk Patients

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

Applying the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) in Myeloablative MUD Transplants Predicts NRM and OS Using a Modified 2-Tier Scoring System.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1988-1988
Author(s):  
Tibor Kovacsovics ◽  
Byung Park ◽  
Brandon Hayes-Lattin ◽  
Jose F. Leis ◽  
Peter T. Curtin ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Scoring System ◽  
Clinical Decision Making ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Risk Groups ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background: The HCT-CI is a recently developed comorbidity score which has been adapted to hematopoietic stem cell transplantation, and identified 3 risk groups with increased non-relapse mortality (NRM) and lower overall survival (OS) (Blood2005;106:2912). We determined the HCT-CI score in a cohort of patients who underwent myeloablative MUD transplantation in a single arm, institutional trial assessing the efficacy of a combination of cyclosporine, methotrexate and prednisone for GVHD prophylaxis. Methods: The analysis included all patients undergoing MUD transplant from 1996–2006 who received GVHD prophylaxis with cyclosporine 2 mg/kg iv BID from day −2, methotrexate 15 mg/m2 iv on day +1 and 10 mg/m2 iv on days +3 and +6, and methylprednisolone 0.25 mg/kg iv BID beginning on day +7 and tapering from day +28. Patients were stratified by disease risk per CIBMTR classification. The comorbidities were obtained by retrospective chart review and scored according to the HCT-CI score. Results: 150 patients (median age 40) received the 3 drug-regimen, including 38% with low-, 34% with intermediate- and 28% with high-risk disease. Diagnoses included acute leukemia in 50%, MDS in 12%, CML in 15%, lymphoma in 18%, and multiple myeloma in 3.0%. Conditioning regimens included Cy-TBI in 64% and Bu-Cy in 21%. Source of stem cells was PBSC in 47.3% and marrow in 50.7%. HCT-CI scores of 0, 1–2 or ≥3 were found in 17%, 30% and 53% of patients evaluated. The majority of comorbidities were pulmonary (72%). With a median follow-up of 46 weeks, day 100 and 5-year OS were 82.7 and 33%, with a 23% and 50.4% cumulative incidence of NRM. Five year relapse-related mortality was 15.8%. Although higher HCT-CI scores were associated with increased NRM and decreased OS, no statistically significant differences were detected when using the published HCT-CI grouping of 0, 1–2 and ≥3. Unadjusted hazard ratio (HR) for inferior survival were 0.9 (CI 0.47–1.85, P=.79) and 1.65 (CI 0.885–3.090, P=.11) for scores 1–2 and ≥3, respectively. We then determined an alternate prognostic model based on 2 groups. Statistical modeling separated patients with a score of 0–3 (n=97, 64%) and ≥4 (n=53, 35.6%), with a 3 month and 5 year OS of 84% and 45% versus 52% and 10%, respectively (P&lt;.0001). Cumulative incidence of day 100 and 5-year NRM was 16% and 38% versus 43% and 73%, respectively. Unadjusted HR for inferior survival was 2.77 (CI 1.816–4.225, P&lt;.0001) for a score of ≥4. By multivariate analysis, only the HCT-CI score (P&lt;.0001) and the disease risk per CIBMTR (P=.0058) were predictive of OS and NRM, but not age, CMV positivity, sex- or HLA-mismatch, or regimen. Conclusions: While our data confirm that the HCT-CI score is predictive of NRM and OS in a high-risk MUD transplant cohort, we were unable to detect statistically significant differences between the 3 risk groups defined in the original score. A modified 2-group scoring system readily stratified the patient population into low-risk and high-risk risk groups with scores of 0–3 and ≥4, respectively, that was predictive of OS and NRM. This simplified, 2-tiered scoring system will have utility in clinical decision-making and in defining patient populations eligible for clinical trials. Additional single and multi-institutional analyses will ultimately determine the optimal applications of the HCT-CI score.

scholarly journals Academic Centers Are Associated with Improved Survival Outcomes in High Risk Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4747-4747
Author(s):  
Daniel A. Ermann ◽  
Victoria Vardell Noble ◽  
Avyakta Kallam ◽  
James O. Armitage
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Median Survival ◽  
Risk Score ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Low Risk ◽  
Survival Outcomes ◽  
Intermediate Risk ◽  
Hazard Ratios

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and is characterized as a heterogenous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for baseline prognostic assessment in these patients. In this study we aimed to determine the impact of treatment facility (academic versus non-academic centers) on overall survival outcomes in DLBCL patients stratified by IPI score risk groups, with a focus on high risk disease as this is associated with poorer outcomes. Methods: The 2018 National Cancer Database (NCDB) was utilized for patients diagnosed with DLBCL between 2004-2015. Patients were then stratified based on IPI risk score from low to high risk. Four risk groups were formed: low (0-1), low-intermediate (2), high-intermediate (3), and high (4-5). Overall survival was calculated using Kaplan-Meyer analysis with bivariate cox proportional hazard ratios to compare survival by facility type (academic or community centers) within these risk groups. Results: A total of 160,137 patients were identified. Of these cases 31.8% were classified as low risk, 21.9% were low-intermediate risk, 22.2% were high-intermediate risk, and 24% were high risk. 59.3% of patients were treated at a community center and 40.7% were treated at academic centers. Treatment at academic centers was associated with a significantly improved overall survival (OS) for each risk category. Median survival (in months) for high risk IPI score DLBCL was 47.9 months in community and 61.1 months in academic centers (p<.0001). Median survival for high-intermediate risk score was 48.3 months in community and 87.3 months in academic centers (p<.0001). Median survival for low-intermediate score was 90.3 months in community and 122.8 months in academic centers (p<.0001). Median survival for low risk score was 132 months in community and 148 months in academic centers (p<.0001). Hazard ratios for academic center versus community center for high risk, high-intermediate, low-intermediate and low risk are 0.768, 0.71, 0.848 and 0.818 respectively (p<.0001). Conclusions: Facility type is significantly associated with improved survival outcomes across all IPI based risk groups for DLBCL. This benefit is especially significant in higher risk disease where positive outcomes are less common, suggesting treatment at academic centers may be particularly beneficial in these patients. Some of the possible reasons for this difference may include provider experience, increased access to resources, and opportunity for clinical trials. Further investigations into the factors contributing to such disparities should be done to help standardize care and improve outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Serum Biomarker Panel Composed of C-Reactive Protein and Albumin Could Predict the Transplant-Related Complications and the Outcomes of Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3147-3147
Author(s):  
Kazutaka Ozeki ◽  
Yukiyasu Ozawa ◽  
Naomi Kawashima ◽  
Yusuke Yamaga ◽  
Yoshitaka Adachi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Low Risk ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Grade Iii

Abstract Background: Non-infectious transplant-related complications (TRCs) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with an unfavorable prognosis. Despite several proposed biomarkers, it remains difficult to predict survival outcomes before transplantation. Here we tested clinically available serum markers to identify patients at high risk of poor survival. Patients and methods: Patients (median age, 45 years; range, 16-68 years) who received allo-HCT at 2 institutions between May 2000 and August 2014 were included in the analysis. A total of 383 patients [203 patients from Konan Kosei Hospital (KKH) and 180 patients from Japanese Red Cross Nagoya First Hospital (RCH)] were evaluated. TRCs within 100 days were categorized as complications with endothelial damage (TRC-ED), acute graft-versus-host disease (GVHD), and other complications. TRC-ED was defined as sinusoidal obstruction syndrome, transplant-associated microangiopathy, capillary leak syndrome, and idiopathic pulmonary syndrome. C-reactive protein (CRP), albumin (Alb), ferritin, cholinesterase (ChE), and uric acid (UA) were selected as candidate biomarkers based on the literature. The above biomarkers were evaluated for their associations with the TRC incidence and probabilities of overall survival (OS) and non-relapse mortality (NRM). Results: Patient characteristics were comparable between the 2 hospital cohorts, except for a lower unrelated donor bone marrow transplant rate (38% vs. 58%) and a longer follow-up duration (5.6 years vs. 2.6 years) in the KKH cohort. Overall, 68% patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome, and 37% patients had a high disease risk (non-remission). The graft source was cord blood in 24% patients, and 73% patients received a myeloablative conditioning regimen. The cumulative TRC-ED incidence was 21.7% at day 100. Acute GVHD occurred in 38.1% patients (n = 147) with grade III/IV seen in 41 patients. Low serum Alb (<3.5 g/dL) and ChE (<200 IU/L) with high CRP (>0.5 mg/dL) and ferritin (>2000 ng/mL) levels before pre-conditioning were significantly associated with inferior OS in a univariate analysis (log-rank test). All markers except ferritin and UA were statistically significant prognostic factors for NRM (Gray test). Low Alb and high CRP, which had the lowest p-values, were chosen as risk markers for a combined panel. The 5-year OS was 60% for patients with neither risk marker, 48% for those with either marker, and 20% for those with both markers. When patients were divided into low-risk (high Alb and low CRP) and high-risk combinations (low Alb and/or high CRP), the high-risk combination was identified as a strong prognostic factor for NRM [hazard ratio (HR): 2.27; 95% confidence interval (CI), 1.48-3.47; p = 0.00016; Fine-Gray test] and OS (HR: 1.60; 95% CI, 1.16-2.22; p = 0.0045; Cox regression hazard model) in a multivariate analysis with clinical confounders. Disease risk was another risk factor for OS, but not NRM. The high-risk combination also predicted TRC-ED occurrence. The cumulative TRC-ED incidence at day 100 was 31% and 17% in patients with high-risk and low-risk combinations, respectively (p = 0.00165). Substituting low ChE for low Alb as a marker yielded a combination of high CRP and low ChE, which was a better predictor for TRC-ED. Both combined markers were independently associated with a higher TRC-ED incidence in a multivariate analysis. No significant differences were observed in the cumulative incidence of grade III/IV acute GVHD at day 100 between the high-risk and low-risk groups for any biomarker. Conclusions: A combined panel comprising Alb and CRP provided significant power for pre-transplant TRC-ED occurrence and survival predictions. Independent cohort confirmations and further investigations of underlying mechanisms are warranted in future studies. Disclosures No relevant conflicts of interest to declare.

A Gene Expression-Based Risk Stratification Model Developed in Newly Diagnosed Multiple Myeloma Treated with High Dose Therapy Is Predictive of Outcome in Relapsed Disease Treated with Single Agent Bortezomib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 656-656 ◽  
Author(s):  
Fenghaung Zhan ◽  
Barb Bryant ◽  
Bart Barlogie ◽  
George Mulligan ◽  
John D. Shaughnessy
Keyword(s):  
High Risk ◽  
Risk Model ◽  
Single Agent ◽  
Risk Groups ◽  
Low Risk ◽  
High Dose ◽  
Newly Diagnosed ◽  
Gene Model ◽  
High Dose Therapy ◽  
Relapsed Disease

Abstract Using data derived from the U133Plus2.0 microarray (U2), we recently constructed a 17-gene model predictive of high-risk multiple myeloma (MM). In the model, 13% of newly diagnosed cases were considered to have high-risk MM with 24 month overall survival estimates of 50% and 90% in the high- and low-risk groups, respectively (p<0.0001). Although validated in a separate cohort of newly diagnosed cases also receiving high dose therapy, it is not known whether this model has broader utility. To address this issue we applied the model to a dataset from a pharmacogenomic effort as part of a multi-center phase III trial testing the efficacy of the proteasome inhibitor bortezomib compared to dexamethasone. For purposes of evaluating the robustness of our model, this dataset is particularly useful in that it differs from the UAMS dataset in several important areas, such as relapsed vs. newly diagnosed disease, single agent bortezomib or dexamethasone vs. multi-agent induction therapy and high-dose melphalan-based tandem transplants, multiple centers vs. single center, delayed processing of bone marrow aspirates vs. immediate processing, negative vs. positive selection of plasma cells, and microarray platform U133A/B (UA) vs. U2 in the Millennium and UAMS datasets, respectively. A total of 144 of the first 351 UAMS cases applied to the U2 had also been applied to UA and were analyzed together with the 188 Millennium samples. Of the 17 genes on U2 we were able to find exact matches for 16 genes on UA. We applied the UA signal intensities of the 16 genes and the exact multivariate stepwise discriminant analysis (MSDA) model used to derive the 17-gene model using U2 data to the 144 UAMS cases. Risk scores for the 144 UAMS cases using the 17-gene U2- and 16-gene UA-derived models were calculated and a strong correlation observed (r=0.89; P<0.001). Using a score of greater than 1.6 as the high-risk cut-point with both models, a confusion matrix revealed a 96.5% agreement between high- and low-risk annotations among the 144 cases. Kaplan-Meier survival analysis of high- and low-risk groups defined by the 17- and 16-gene models revealed similar survival differences between high- and low-risk MM (U2: P=0.0046, HR=2.49; UA: P=0.0026; HR=2.58). These data suggests that the risk model is highly stable across these platforms. We then applied the 16-gene model to 188 cases of relapsed disease treated with bortezomib. Using the same discriminant score cut-off of 1.6 on the Millennium data, the 16-gene model defined 17.6% of cases as high-risk and this subset had significantly shorter overall survival times (P<0.0001; HR=2.93). The estimated 24-month survival was 9% in the high-risk vs. 40% in the low-risk cohort. The model also identified high-risk disease in a dexamethasone treated cohort (P<0.0001; HR=3.01). These data suggest that the 17-gene high-risk model is robust and not confounded by variables distinguishing these two datasets. These data also reveal a common molecular signature of high-risk MM in patients with newly diagnosed and relapsed disease pointing to a potential common molecular mechanism of drug resistance in MM that is revealed in this signature. We are currently developing and validating the 17-gene model using technology that quantifies tumor RNA directly in purified cells.

scholarly journals The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2091-2097 ◽  
Author(s):  
J Cortes ◽  
SM O'Brien ◽  
S Pierce ◽  
MJ Keating ◽  
EJ Freireich ◽  
...  
Keyword(s):  
High Risk ◽  
Systemic Chemotherapy ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
High Dose ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Relapse Rates

Although central nervous system (CNS) leukemic relapse is frequent in adult acute lymphocytic leukemia (ALL), the need for prophylaxis in different risk groups for CNS relapse, the value of high-dose systemic and intrathecal (IT) chemotherapy, and the timing of prophylaxis are not well defined. This analysis was conducted to investigate these questions and to assess the value of a risk-oriented CNS prophylaxis approach. We analyzed the incidence of CNS leukemia after initiation of therapy in patients treated on 4 consecutive trials for adult ALL including different CNS prophylactic modalities. The treatment groups included (1) the program preceeding the vincristine-Adriamycin- dexamethasone (VAD) regimen, with no CNS prophylaxis; (2) the VAD regimen with prophylaxis using high-dose systemic chemotherapy; (3) the modified VAD program with high-dose systemic chemotherapy to all patients and IT chemotherapy for high-risk patients after achieving complete remission; and (4) the hyperCVAD program with early high-dose systemic and IT chemotherapy starting during induction to all patients, with more IT injections (16IT) administered to the high-risk group for CNS relapse compared with the low-risk group (4IT). A total of 391 patients were included, 73 of whom were treated with preVAD, 112 with VAD, 114 with modified VAD, and 92 with hyperCVAD. The overall CNS relapse rates were 31%, 18%, 17%, and 3%, respectively for the 4 groups (P < .001). For the high-risk group for CNS relapse, they were 42%, 26%, 20%, and 2%, respectively (P < .001). The differences in CNS relapse rates in the low-risk group were not statistically significant. At 3 years, the overall CNS leukemia event-free rates were 48%, 76%, and 98%, respectively (P < .001). In the high-risk group, the CNS event- free rates were 38%, 66%, 75%, and 98%, respectively (P < .001); however, there was no difference in the low-risk group. We conclude that (1) high-dose systemic chemotherapy is a useful prophylactic measure; (2) early IT chemotherapy is necessary to reduce the incidence of CNS leukemia overall and in the high-risk group; and (3) a risk- oriented approach is appropriate to tailor the intensity of CNS prophylaxis.

Outcomes Of Nonmyeloablative (NMA) Haploidentical Blood Or Marrow Transplantation (haploBMT) With High-Dose Posttransplantation Cyclophosphamide (PT/Cy) For Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2091-2091
Author(s):  
Yvette L. Kasamon ◽  
Javier Bolaños-Meade ◽  
Douglas Gladstone ◽  
Lode J. Swinnen ◽  
Jennifer A. Kanakry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Risk Analysis ◽  
Acute Gvhd ◽  
Competing Risk ◽  
High Dose ◽  
Competing Risk Analysis ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Disease Specific

Abstract Background With recent advances in GVHD prophylaxis, NMA haploBMT has become a viable option for pts who lack a fully matched donor. However, relatively few data are available on disease-specific outcomes following NMA haploBMT. This study evaluated the outcomes of NMA related haploBMT with PT/Cy in pts with lymphoma. Patients and methods We retrospectively analyzed 151 consecutive pts with poor-risk or advanced lymphoma who received NMA related haploBMT with PT/Cy at Johns Hopkins, without protocol-specified posttransplantation rituximab. Pts had a first-degree related haplo donor (allele or allele-group level typing at HLA-A, -B, -Cw, -DRB1, -DQB1), ECOG PS ≤ 1 or 2, LVEF ≥ 35%, adequate pulmonary and renal function, and in general ≥ PR for aggressive NHL, ≥ SD for Hodgkin lymphoma (HL). Conditioning consisted of Cy (14.5 mg/kg IV, days -6 and -5), fludarabine (30 mg/m2 IV, days -6 to -2), and TBI (200 cGy, day -1) in 98% of cases. Grafts were T-cell replete (bone marrow in 99%). GVHD prophylaxis consisted of high-dose PT/Cy (50 mg/kg IV) either once (day 3; 1 pt) or twice (days 3 and 4; 150 pts), mycophenolate mofetil, and tacrolimus. Results Of the 151 pts (median age 55, range 14-73 y), 52 (34%) had prior autologous BMT. By Disease Risk Index (DRI) categorization (Blood 2012;120(4):905), 38 pts (25%) were high-risk, 89 (59%) intermediate-risk, and 24 (16%) low-risk. There were 38 cases (25%) of HL; 53 cases (35%) of aggressive NHL including 28 B-cell, 24 T-cell, and 1 anaplastic nos; 20 cases (13%) of mantle cell lymphoma (MCL); 39 indolent histologies (17 CLL, 19 FL, 3 other); and 1 case of HL evolved from CLL. With a median follow-up of 3.8 (range 0.5 - 8) y in event-free pts, the 3-y probabilities of both progression-free survival (PFS) and disease-free survival were 40 (95% CI, 32-48)%, with a 3-y overall survival (OS) probability of 46 (39-55)% (figure A). The probability of neutrophil recovery was 88% at day 30 (median 17 days), and the probability of platelet recovery ≥ 20,000/µL was 86% at day 60 (median 26 days). Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 17/147 evaluable pts (12%), 8 with CLL. By competing-risk analysis, 1-y probabilities of nonrelapse mortality (NRM) and relapse were 16 (95% CI, 10-22)% and 31 (23-38)%, respectively. The probability of grade 2-4 acute GVHD was 32 (95% CI, 24-39)%, grade 3-4 acute GVHD was 5 (1-8)%, and chronic GVHD was 13 (7-18)%. Disease-specific cumulative incidences of relapse, estimated by competing-risk analysis, are shown in figure B. The 3-y probabilities of PFS and OS were 53 (95% CI, 39-72) and 67 (53-84)%, respectively, in HL; 35 (25-51)% and 38 (26-54)% in aggressive NHL; 23 (9-54) and 28 (13-62)% in MCL; and 42 (29-61)% and 48 (34-67)% in indolent NHL and CLL combined. On unadjusted landmark analyses, we found no statistically significant association between PFS and the development of grade 2-4 acute GVHD treated as a time-independent variable. On unadjusted analysis, the DRI category (low, intermediate, or high) was among the variables statistically significantly associated with PFS (p = 0.02; figure C), and remained independently associated with PFS on multivariate analysis adjusted for pt age (p = 0.002). Conclusions NMA related haploBMT with PT/Cy carries acceptable toxicities that parallel those of NMA matched transplants, while producing durable disease control in a clear subset of lymphoma pts. This approach facilitates the integration of new posttransplantation strategies that could reduce the risk of relapse. Disclosures: Off Label Use: posttransplant cyclophosphamide for GVHD prevention.

scholarly journals Different Doses of Calcium Supplementation to Prevent Gestational Hypertension and Pre-Eclampsia: A Systematic Review and Network Meta-Analysis

2022 ◽  
Vol 8 ◽  
Author(s):  
Dexin Chen ◽  
Hong Wang ◽  
Xing Xin ◽  
Long Zhang ◽  
Aihong Yu ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Gestational Hypertension ◽  
Calcium Supplementation ◽  
Risk Groups ◽  
Low Risk ◽  
Cochrane Library ◽  
High Dose ◽  
Risk Population ◽  
Medium Dose

ObjectiveCalcium supplementation can prevent gestational hypertension and pre-eclampsia. However, besides the non-consensus of existing studies, there is a lack of evidence regarding the optimal dosing of calcium.MethodEight electronic databases, namely, the Cochrane Library, PUBMED, Web of Science, EMBASE, WANGFANG, VIP, CBM, and CNKI, were searched. The studies were retrieved from inception to July 13, 2021. Two researchers independently screened the literature, extracted data, and evaluated the methodological quality based on the inclusion criteria. In particular, the calcium supplementation doses were divided into three groups, namely, the high-dose (≥1.5 g), medium-dose (1.0–1.49 g), and the low-dose group (&lt;1.0 g). The participants were also divided into high-risk and low-risk groups, according to the risk of developing gestational hypertension and pre-eclampsia.Results and DiscussionA total of 48 studies were incorporated into the final analyses. All doses of calcium supplementation reduced the incidence of gestational hypertension in the low-risk population (low dose - three studies; medium dose- 11 studies; high dose- 28 studies), whereas the medium-dose (three studies) reduced the incidence of gestational hypertension in high-risk groups. Moreover, a medium dose of calcium supplementation had the maximum effect in reducing gestational hypertension in low-risk and high-risk populations. The medium (three studies) and high doses (13 studies) of calcium supplementation reduced the incidence of pre-eclampsia in the low-risk groups. However, a medium-dose calcium supplementation maximally prevented pre-eclampsia in the low-risk population. The authenticity and reliability of the results were reduced due to the limitations of contemporary studies in terms of experimental design, result measurement, statistics, and evidence quality. Therefore, high-quality studies with larger sample size are required to evaluate further the effect of calcium supplementation in preventing gestational hypertension and pre-eclampsia.

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