Alemtuzumab Reduces Chronic Graft Versus Host Disease (cGVHD) and Treatment Related Mortality (TRM) after Reduced Intensity Conditioning for AML and MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1076-1076 ◽  
Author(s):  
Koen van Besien ◽  
Marcos de Lima ◽  
Andrew Artz ◽  
Betul Oran ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Cancer Center ◽  
P Value ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Md Anderson

Abstract In vivo T-cell depletion with alemtuzumab has been used to reduce acute and chronic GVHD. In order to evaluate its overall effect on transplant outcomes in AML and MDS we compared 90 pts who received fludarabine/melphalan/alemtuzumab (FMA) conditioning and post-transplant tacrolimus at the University of Chicago, with 112 who received fludarabine/melphalan (FM) and post-transplant tacrolimus/methotrexate at MD Anderson Cancer Center. Pt and transplant characteristics were well balanced except for a higher proportion of MDS in the FM group. Median age, proportion unrelated donor tx and proportion high/intermediate and low risk by ASBMT criteria were balanced between the groups. With median follow up of 28 months in both groups, one year progression free survival and overall survival are identical. TRM is significantly higher after FM, but relapse is higher in FMA. 19/103 d 28 survivors after FM vs 7/84 after FMA developed gr III–IV acute GVHD (p=0.04). 46/77 d100 survivors after FM developed ext cGVHD vs 7/63 after FMA (p=0.0000). 43 patients remain alive after FM and 27 have ext cGVHD. 41 remain alive after FMA and 1 has ext cGVHD. Alemtuzumab results in a considerable reduction in acute and particularly chronic GVHD. TRM is reduced compared with standard GVHD prophylaxis. Low incidence of chronic GVHD and reduced TRM may be the major benefit of this strategy. Relapse rates are increased, because of reduced GVL effects or because of improved early survival of high risk patients. Other approaches are necessary for improving long term outcomes. Patient Characteristics and Outcome FMA FM P-value N 90 102 Age (range) 54 (22–74) 51 (17–77) 0.6 AML/MDS 13/77 29/83 0.04 MUD/related 42/48 59/63 0.5 High./Intermediate/LowRisk 48/13/28 76/10/26 0.12 Median Follow up mths (range) 28 (3–89) 28 (1–66) 0.07 TRM@ 100 days 13% + 7% 24% + 8% 0.04 TRM@ 1 year 30% + 12% 42% + 10% 0.04 Relapse @ 1 year 40% + 12% 26% + 10% 0.01 PFS @ 2 years 33% + 11% 37% + 9% 0.9 OS @ 2 year 42% + 11% 44% + 9% 0.5 AGVD gr III–IV 7/84 19/103 0.04 Ext cGVHD 7/63 46/77 0.0000 Ext cGVHD in survivors 1/41 27/43 0.0000

Campath-IH Combined with Fludarabine/Cyclophophamide/Rituximab (FCR) as Conditioning for Unrelated Non-Myeloablative Hematopoietic Transplantation (NMT) for Non-Hodgkin’s Lymphoma (NHL): Low Mortality Rate and Lower Than Expected Incidence of Cytomegalovirus (CMV) Reactivation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2902-2902
Author(s):  
Issa F. Khouri ◽  
Jeffrey J. Tarrand ◽  
Grace-Julia Okoroji ◽  
Rima M. Saliba ◽  
Chitra M. Hosing ◽  
...  
Keyword(s):  
Disease Progression ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
Unrelated Donor ◽  
Positive Serology ◽  
Hematopoietic Transplantation ◽  
Cmv Reactivation

Abstract Graft-versus-host disease (GVHD) remains a significant cause for morbidity following unrelated hematopoietic transplantation. We investigated the addition of Campath-IH in vivo, at a total dose of 45 mg, to the FCR conditioning regimen for unrelated NMT for relapsed chemosensitive NHL. 25 consecutive patients (pts) with various lymphoid histologies {Follicular = 9, Mantle cell = 7, Large cell =9}were treated. Median age was 52 yrs (range, 31–64). Median # of prior chemoregimens received was 3, and 5 pts (20%) had failed a prior autologous transplant. Ten pts (40%) were in complete remission, and 15 (60%) had evidence of active disease at study entry. Pts received rituximab at 375 mg/m2 on day −8, −1, +6 and +13. Campath-IH 15 mg/iv was given daily on days −4,−3,−2. Chemotherapy was provided on the same days as the Campath-IH and consisted of fludarabine 30 mg/m2/day x 3, and cyclophosphamide 1000 mg/m2 /day x 3. Transplantation was given on day 0. Bone marrow was the source of graft in 20 pts (80%), and 5(20%) received peripheral blood. Tacrolimus (maintained at a low trough level of 5) and methotrexate were used as additional GVHD prophylaxis. Median time to recovery of an ANC>500 was 11 days (range, 9–21). Nine pts (36%) did not require any platelet transfusions. All pts engrafted donor cells (median 81%, at 30 days); 19 pts remained mixed chimera at the time of their last follow-up. Five pts required donor lymphocyte infusion (DLI) for disease progression: 3 achieved complete, one partial and one had no response. With a median follow-up time of 16 mos (range, 3–45 mos), overall survival was 90% (95%CI, 66–99), and the current progression-free survival rate was 68% at 18 mos. Acute GVHD occurred in one pt (grade 1) pre-DLI, and in 3 pts (one grade 1, one grade 2, and one grade 3) post DLI. Chronic extensive GVHD occurred in 3 pts pre-, and 2 additional pts post DLI. Two pts died: one of chronic GVHD, and one of disease progression. Seventeen of the 25 transplants had either the recipient or the donor with CMV-positive serology. CMV prevention consisted of a once daily dose of foscarnet, and twice-weekly screening using the CMV Direct Antibody Fluorescent Stain Antigenemia test. With this strategy, only 9 pts (36%) had evidence of CMV reactivation (defined as any detection of CMV cells). No pt developed or died from CMV disease. These data suggest that unrelated NMT after Campath-FCR conditioning is associated with a low incidence of GVHD and treatment-related mortality. Foscarnet prevention with bi-weekly CMV screening is associated with a lower than expected risk for CMV reactivation. The regimen is a promising approach for unrelated donor transplantation for patients with advanced lymphoma.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2305-2305 ◽  
Author(s):  
Robert J Soiffer ◽  
Jennifer LeRademacher ◽  
Vincent T Ho ◽  
Fangyu Kan ◽  
Andrew Artz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Cell Depletion ◽  
P Value ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation for patients over age 65 with acute myelogenous leukemia and myelodysplastic syndrome.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6529-6529
Author(s):  
Henry Jacob Conter ◽  
Gabriela Rondon ◽  
Nhu-Nhu Nguyen ◽  
Julianne Chen ◽  
Elizabeth J. Shpall ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Age Groups ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Acute Myelogenous ◽  
Grade Ii ◽  
Md Anderson ◽  
Active Disease

6529 Background: ASCT represents a potentially curative approach for AML and MDS, diseases that primarily affects patients in 7th and 8th decade of life. Here, we report outcomes of patients older than 64 treated at the MD Anderson Cancer Center from 1996 until December 2011. Methods: 182 patients older than 64 received an ASCT for AML (n=143) or MDS (n=39). Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), incidence of relapse, and overall survival (OS) - which were estimated from the date of transplant. Results: The median age of patients was 67 (range 65-79). Most patients were transplanted with active disease (table). Median follow-up for alive patients was 12.6 months (n=63; range 0-118). The cumulative incidence of 100-day, 1 year, and 3 year TRM was 14%, 18%, and 21%, respectively. 26% of patients developed grade II-IV acute GVHD and 35% suffered from chronic GVHD. The actuarial incidence of relapse was 46% at 1 year and 53% at 3 and 5 years. Actuarial OS was estimated to be 45% at 1 year, 28% at 3 years, and 21% at 5 years. 3 year OS for patients transplanted in CR and with active disease was 40% versus 23% (p=0.02). OS of patients age 65-69 or >69 was 30% vs. 20% (p=0.06) at 3 years for all patients; compared to 38% versus 27% (p=0.23) for patients in those age groups transplanted in CR. Conclusions: Although a significant minority of patients older than 64 years may achieve long-term disease control, new approaches are needed to reduce TRM and relapse in this cohort of patients. [Table: see text]

FOLFOXIRI versus doublet-regimens in the first-line therapy of MSI-S right-sided (RS) metastatic colorectal cancer (mCRC): A survival analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15060-e15060
Author(s):  
Alexandre A Jacome ◽  
Bryan K. Kee ◽  
David R. Fogelman ◽  
Imad Shureiqi ◽  
Arvind Dasari ◽  
...  
Keyword(s):  
Statistical Difference ◽  
Randomized Clinical Trials ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Cancer Center ◽  
Braf Mutations ◽  
First Line Therapy ◽  
Treatment Naïve ◽  
Md Anderson

e15060 Background: Microsatellite stable (MSI-S) RS mCRC patients (pts) have a worse prognosis relative to left sided tumors for overall survival (OS). The present analysis aims to test the hypothesis that a triplet-regimen is superior compared to doublet-regimens (DR; FOLFOX or FOLFIRI) for OS. Methods: Pts with treatment-naive RS mCRC at MD Anderson Cancer Center between January/2011 to December/2018 were selected. We compared the progression-free survival (PFS) and OS of mCRC pts treated with FOLFOXIRI versus DR. Pts treated with anti-EGFR therapy were excluded. Results: A total of 37 pts were treated with FOLFOXIRI and 111 pts with DR. There were no statistical difference between groups regarding gender, KRAS and BRAF mutations, peritoneal metastasis and bevacizumab use. There were statistical difference in age (median: 46y vs 59y) and metastasectomy rates (14% vs 32%) (p < 0.001). KRAS mutation was found in 65% of the population. Median follow-up was 55.3m. Median PFS was 6.5m vs 11.2m (HR: 1.30 95% CI 0.85 – 1.99) and median OS was 17.0m vs 26.3m (HR: 1.01 95% CI 0.60 – 1.68). By univariate analysis, pts who have undergone metastasectomy had superior PFS (14.9m vs 9.2m; p<0.001) and OS (32.4m vs 22.9m; p=0.003). By multivariate analysis adjusted for age, BRAF mutation, metastasectomy, bevacizumab use and, treatment regimen, only age and metastasectomy had prognostic influence for PFS (p=0.039 and p=0.026, respectively). Conclusions: Despite RS having a poor prognosis for OS, our study does not suggest that RS mCRC pts benefit from intensive treatment. Randomized clinical trials may suggest more individualized therapies.

Rituximab Purging and Maintenance Improves Progression Free Survival but Not Overall Survival In Patients with Relapsed or Resistant Follicular Lymphoma Prior Receiving An Autologous Transplant

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3567-3567 ◽  
Author(s):  
Ruth Pettengell ◽  
Norbert Schmitz ◽  
Christian Gisselbrecht ◽  
Graeme Smith ◽  
William N Patton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peripheral Blood ◽  
Research Funding ◽  
Progression Free Survival ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Post Transplant ◽  
Autologous Transplant

Abstract Abstract 3567 Autologous transplantation significantly improves the progression free survival (PFS) and overall survival (OS) of patients with relapsed or resistant follicular (rFL) lymphoma compared with chemotherapy alone (Schouten H, et al. J Clin Oncol 2003;21:3918–27). Small phase II trials suggest, that rituximab (R) given peritransplant further improves survival outcome. Whilst the role of maintenance R post chemotherapy in FL is established, the benefit and safety of maintenance R following autologous transplant is unknown. In this randomised prospective study the efficacy and safety of R as in vivo purging pretransplant and as maintenance treatment immediately post transplant was assessed. From Oct 1999 to Apr 2006, 280 of a planned 420 R naïve patients with rFL in first (n=16), second (n= 222) or third remission (n=41) who achieved either a complete remission (n=83) or a very good partial remission (n=196) to induction chemotherapy, with limited bone marrow infiltration (<25% B-lymphocytes) underwent a single randomisation in a 2 × 2 design to R purging 375 mg/m2 weekly × 4 (RP) before high-dose therapy with BEAM conditioning (HDC) and maintenance R 375 mg/m2 every 3 months for 2 years (RM). The primary endpoint of the study was PFS. All analysis is by intention to treat. The median age was 51 years (range: 26–70), and baseline characteristics were well balanced between groups. On average patients were 44.1 (range 3.4–463.8) months from diagnosis with 79.3% having 2 lines of therapy and 15% three lines of prior therapy. Patients were equally distributed between low, intermediate and high FLIPI scores. Pretransplant 70% of patients were in PR and 30% in CR. Fifty seven patients failed to mobilise peripheral blood stem cells. Nineteen patients withdrew, 5 due to toxicity, 9 were ineligible. In the 196 (70%) patients transplanted, neutrophil engraftment > 0.5 × 109 /L was prompt, median 14.3 days (range 10–115) and platelets > 50 × 109/L,median 25.1 days (range 9–190). Time to engraftment and early or late toxicities did not differ significantly between the groups apart from a lower neutrophil count at 3 months in patients on maintenance. No graft failures or late neutropenia was reported. Transplant related mortality was 0.5%. Only 3 infection related deaths have been reported post 100 days. Two hundred and seventeen patients are alive on continued follow-up. Median follow-up is 6.4 years. PFS at 5 years was 62.9% for patients receiving RP + RM versus 37.6 % for patients receiving no R (logrank PFS; p=0.004; HR 0.76, 95%CI: 0.66 – 0.93). OS at 5 years was 79.5% % versus 78.4 % for patient receiving RP + RM versus no R (logrank PFS; p>0.1). Multivariate analysis was not able to define a high or low risk patient group. R in vivo purging and maintenance results in superior PFS compared to no R. R does not adversely affect peripheral blood stem cell harvesting or engraftment and maintenance R post transplant is safe. The impressive OS suggests that relapsed FL patients can be effectively salvaged post R purging and maintenance. R Purging + R Maintenance R Maintenance R Purging No R Pt number 69 69 72 70 Median PFS NR@ 6.4 y 7.23 y 4.03 y 3.34 y 5y PFS 62.9 % 56 % 46 % 37.6 % 5y OS 79.5 % 80.5 % 84.8 % 78.4 % Disclosures: Pettengell: Roche: Honoraria. Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding. Walewski:Roche: Honoraria, Research Funding. Geisler:Roche: Research Funding. Kimby:Roche: Honoraria, Research Funding. Goldstone:Roche: Honoraria, Speakers Bureau.

The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3029-3029
Author(s):  
Roberto Crocchiolo ◽  
Sabine Fuerst ◽  
Jean El-Cheikh ◽  
Angela Granata ◽  
Claire Oudin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Progression Rate ◽  
Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

CD34-Selected, T Cell-Depleted Alternative Donor Stem Cell Transplantation For Children

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2064-2064 ◽  
Author(s):  
Andrew Gilman ◽  
Michael Eckrich ◽  
Stacy Epstein ◽  
Carrie Barnhart ◽  
Javier Oesterheld ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Primary Graft Failure ◽  
Alternative Donor ◽  
Mast Cell Leukemia ◽  
Grade Ii

Abstract Many children who need a hematopoietic stem cell transplant do not have a matched related or unrelated donor. The use of alternative donors including mismatched family members can provide a donor for almost all patients. The use of such donors is associated with a high risk of graft-versus-host disease (GVHD). We present the results of a prospective study using the CliniMACS® device for CD34-selection of peripheral blood stem cell (PBSC) grafts to prevent GVHD under BB-IND 14045. Patients did not receive immunosuppression after transplant. The approach was also used as a platform for a companion post-transplant immunotherapy study. The study included patients with malignant (MD) and non-malignant (NMD) disorders receiving unrelated donor (UD) and mismatched related donors (MMRD) to evaluate the broad applicability of this approach for GVHD prevention. The primary endpoint was acute GVHD incidence and there was a stopping rule for primary graft failure. Overall survival was a secondary endpoint. Between 2009-2013, 30 children underwent CD34-selected PBSC transplantation from an alternative donor. Fifteen patients had MD (ALL 4, AML 8, JMML 1, acute mast cell leukemia 1, Ewing’s sarcoma 1) and 15 had NMD (sickle cell 6, immunodeficiency 5, bone marrow failure 4). Twenty-three patients had MMRD and 7 had UD (all 7 had NMD). The conditioning regimen consisted of TBI 1200 cGy (MD) or melphalan 140mg/m2 (NMD), thiotepa 5mg/kg x2, fludarabine 40 mg/m2x5, and rabbit-ATG 1.5 (MD) or 2.5 (NMD) mg/kg x4. Seven patients with NMD received rituximab x1 during conditioning. Twenty-two patients received a planned (P) donor lymphocyte infusion (DLI) between days 30 and 42 with methotrexate GVHD prophylaxis on a companion study. Eight patients received a therapeutic (T) DLI for decreasing donor chimerism or viral infection. The median age at transplantation was 10 years (range 0.3-17). Median CD34+ dose was 21 x 10^6/kg (range 10-25) and all patients received < 1 x 10^4 CD3/kg. The ANC was > 500 at median 14 days (range 9-16). Acute GVHD prior to DLI occurred in 1 patient (3%; stage I skin which resolved with a brief course of prednisone). Primary graft failure occurred in 1 patient (3%). The patient subsequently engrafted after a CD34-selected transplant from the other parent. Two patients who had active disease at transplant (mast cell leukemia, Ewing’s) and early relapse are excluded from the following analyses. Twenty-one of 28 patients are alive with median follow-up of 2 years (range 1 mo-4 yrs). The Kaplan-Meier estimated 100 day and 1 year survival is 96% and 74%, respectively. Relapse occurred in 1/10 MD patients with at least 100 days follow-up. Grade II-IV acute GVHD and chronic GVHD occurred only after DLI. Acute GVHD grade II-IV occurred in 21% (3 P, 3 T) and chronic GVHD (3 P) in 11%. Viral reactivation was common, but viral disease was less common - CMV 12% and EBV-related PTLD 11% [at risk patients only] and adenovirus 11%. Invasive fungal infections occurred in 7%. All deaths were due to infection, with thrombotic microangiopathy present in 6/7. All outcomes were similar for MD and NMD and for MMRD and UD except for acute GVHD which occurred in 26% MMRD and 0% UD transplants and for EBV-PTLD which only occurred in NMD patients. EBV-PTLD has been reduced in NMD patients by using rituximab in the conditioning. The use of a CD34-selected, T cell-depleted alternative donor PBSC transplant successfully prevented acute GVHD without the need for post-transplant immunosuppression. The use of this approach and the conditioning regimens employed provided reliable engraftment and a very low incidence of Day 100 transplant-related mortality and relapse (for patients without active disease). Future efforts will focus on approaches for post-transplant immunotherapy to decrease morbidity and mortality due to viral infections. Disclosures: No relevant conflicts of interest to declare.

Bone-targeted therapy in patients with renal cell carcinoma bone metastases undergoing palliative surgery.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16572-e16572
Author(s):  
Benjamin Garmezy ◽  
Ava Brozovich ◽  
Lei Feng ◽  
Lorenzo Deveza ◽  
Robert L. Satcher
Keyword(s):  
Targeted Therapy ◽  
Bone Metastases ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Palliative Surgery ◽  
Open Reduction Internal Fixation ◽  
Rank Test ◽  
Cancer Center ◽  
Kaplan Meier ◽  
Md Anderson

e16572 Background: RCC bone metastases (RCCBM) are found in 20-39% of patients and are becoming more prevalent. RCCBM cause significant morbidity and often require surgical intervention. Current bone-targeted therapies include bisphosphonates and denosumab. Previous literature has suggested that bisphosphonates do not improve survival or reduce skeletal related events and little has been published about the effect of denosumab. Here we present experience describing outcomes and therapeutic effect in patients with RCCBM following palliative surgery for bone metastasis. Methods: We performed a retrospective analysis of 226 patients with RCCBM who underwent orthopedic surgery at MD Anderson Cancer Center between 11/2005 – 8/2019. The Kaplan-Meier method and log-rank test were used to estimate and evaluate survival differences. Results: Patient characteristics included: median age 58.2, male 66.4%, clear cell histology 93.5%, metastatic at presentation 57.9%, nephrectomy 79.8% (63.9% prior to orthopedic intervention), received radiation to the surgical site (pre-op: 13.0%, post-op: 41.4%). First orthopedic intervention: resection arthroplasty 37.2%, curettage and intramedullary nailing (IMN) 18.6%, IMN 16.4%, open reduction internal fixation 15.0%, amputation 2.7%, 10.2% other. Pre-op therapy: bisphosphonate 12.4%, denosumab 5.8%, both 2.7%, none 79.2%. Post-op therapy: bisphosphonate 18.1%, denosumab 13.7%, both 0.9%, none 67.2%. With a median follow up of 3.1 years after first orthopedic intervention, median overall survival (OS) was 2.7 yr (95% CI 2.1 – 3.6). Progression free survival (PFS) was calculated from time of first surgery to either first progression or death; median PFS was 5.2 months (95% CI 4.6 – 7.5). Pre-op or post-op bone-targeted therapy was not significantly associated with PFS (yes vs no: Pre-op: median 3.4 vs 6.3 mth, p=0.42; Post-op: median 4.3 vs 5.8 mth, p=0.61) or OS (Pre-op: 2.1 vs 2.9 yr, p=0.45; Post-op: 2.4 vs 3.2 yr, p=0.18). Post-op denosumab compared to bisphosphonate was associated with increased PFS (9.6 vs 3.8 mth, p=0.03) and OS (3.3 vs 1.6 yr, p=0.02). However, post-op denosumab vs no bone-targeted therapy was not significantly associated with increased PFS (9.6 vs 5.8 mth, p=0.42) or OS (3.3 vs 3.2 yr, p=0.85). Of note, post-op bisphosphonate vs no bone-targeted therapy was associated with reduced PFS (3.8 vs 5.8 mth, p=0.04) and OS (1.6 vs 3.2 yr, p=0.01). Conclusion: Addition of bone-targeted therapy did not significantly improve PFS or OS in patients with RCCBM undergoing orthopedic intervention. Post-op denosumab was associated with better PFS and OS compared to bisphosphonates and bisphosphonates were associated with worse PFS and OS compared to no bone-targeted therapy. Patient selection for therapy may be an important source of bias. Prospective research is needed to clarify the role and selection of bone-targeted therapy in RCCBM patients.

Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) for Refractory Waldenstrom’s Macroglobulinemia (WM): Evidence for a Graft-Versus-WM Effect.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3034-3034 ◽  
Author(s):  
Larry D. Anderson ◽  
Brenda M. Sandmaier ◽  
Michael B. Maris ◽  
Dietger Niederwieser ◽  
Edward Agura ◽  
...  
Keyword(s):  
Median Time ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Peripheral Blood Mononuclear ◽  
Allogeneic Hct

Abstract While toxicities and transplant related mortality (TRM) have limited the use of conventional allogeneic HCT to younger patients (pts) without significant medical comorbidities, WM is a disease that affects primarily older pts with a median age of 63 years at diagnosis. Here we examined the safety and efficacy of nonmyeloablative (NM) HCT for patients with refractory WM, where anti-tumor effects are provided by graft-versus-tumor immune responses rather than from conditioning therapy. Twelve pts with refractory WM were treated within the institutions of the Seattle Consortium using HLA-matched related donor (n=7) or unrelated donor (URD) (n=5) HCT. NM conditioning consisted of 2 Gy TBI with (n=8) or without (n=4) fludarabine (30 mg/m2/day x 3 days). Eleven pts received unmodified G-CSF-mobilized peripheral blood mononuclear cells, and 1 pt received URD bone marrow. Post-grafting immunosuppression consisted of mycophenolate mofetil and either cyclosporine or tacrolimus. The median age was 58 (range 44–65) years and median time from diagnosis to allogeneic HCT was 6.6 (range 1.5–20) years. Pts had received a median of 4.5 (2–8) prior regimens. The median follow-up after HCT was 14 (range 1–85) months overall, and median follow-up for surviving pts (n=7) was 17 (range 4–85) months. All pts except 1 have stably engrafted with &gt;95% donor CD3+ T cell chimerism. Acute GVHD grades II, III, IV, and extensive chronic GVHD occurred in 50%, 8%, 0%, and 58% of pts, respectively. TRM was 17%. Responses (4 CR and 6 PR) were seen in 10 of 11 (91%) evaluable pts while 1 had progressive disease. The non-evaluable pt died from early non-relapse causes. The median time to CR was 12 (6–32) months for the 4 CR pts, and 1 of the PR patients still has a declining IgM at 10 months. Only 1 of the 10 responders has had WM progression, though 1 pt in CR died from relapsed diffuse large B-cell lymphoma (DLBCL) 16 months after allografting despite no longer having a monoclonal IgM spike. This pt had been allografted in tandem following an auto transplant with BEAM conditioning for transformation of WM to DLBCL. Of the 7 sibling transplants, all had a response (3 CR and 4 PR). Of 5 pts receiving URD allografts, 1 had a CR, 2 had a PR, 1 was not evaluable due to TRM on day 29, and 1 pt failed to respond and died of progressive IgM myeloma 12 months after HCT. One pt with a PR had heavily pretreated disease (pancytopenic pre-HCT) and died of host-derived AML 10 months after HCT. The Kaplan-Meier estimates of 5 year overall and progression free survival were 59% and 61%, respectively. In summary, graft-versus-tumor effects that develop slowly following NM allogeneic HCT have been observed in the majority of pts with refractory WM. These graft-versus-WM effects occurred in the absence of serious GVHD and with low TRM. NM allogeneic HCT provides a new treatment option for WM pts and may result in long-term disease control. Figure Figure

Prevention of Graft-Versus-Host Disease (GVHD) with Tacrolimus after Allogeneic Grafting for Hematological Malignancies Following Sub-Myeloablative Conditioning.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5321-5321
Author(s):  
Joseph Fay ◽  
Giovanna Saracino ◽  
Edward Agura ◽  
Brian Berryman ◽  
Luis Pineiro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
P Value ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant

Abstract Severe acute or chronic GVHD following allogeneic hematopoietic stem cell transplantation therapy (HSCT) has a deleterious effect on the successful treatment of hematological malignancies. We have retrospectively studied mycophenolate mofetil (MMF) and tacrolimus (FK) or cyclosporine (CSA) following allogeneic HCST in the prevention of GVDH and the induction of immune tolerance in 93 patients with hematological malignancies using non-myeolablative pre-transplant conditioning. In the current study, there were 35 patients with leukemia, 36 patients with lymphoma, 12 patients with myelodysplastic syndrome or a myeloproliferative disorder and 10 patients with multiple myeloma. There were 63 women and the median age was 42 (15–75) years. Twenty patients had relapsed after previous autologous or allogeneic HSCT and 45 patients were older than 59 years. The remaining patients had co-morbid medical conditions that precluded the use of chemotherapy/radiotherapy dose-intensive pre-conditioning. Conditioning prior to allogeneic HSCT (94 blood stem cell grafts and 1 marrow graft) was fludarabine (90 mg/m2 in three daily doses) and TBI (200cGy) in 86 patients, fludarabine (120 mg/m2 in 4 daily doses) and cyclophosphamide (50mg/kg) in 5 patients, and TBI (200 cGy) only in 4 patients. Forty-three patients received sibling and 50 unrelated grafts. Median follow-up post transplant is 3.0 (0.2–6.1) years. Five (5.3%) patients did not experience sustained hematological chimerism post-transplant. MMF and FK were administered to 33 recipients and MMF and CSA to 60 recipients. The dose and schedule of MMF, CSA and FK have been published (Laport et al. Blood, 2006 and Fay et al. Blood, 1996.) There was no difference in the degree of HLA mismatching between the two groups of patients. Cumulative incidences were used to estimate the incidence of acute and chronic GVHD, all deaths and disease progressions not related to GVHD being considered as the competing events. The Gray test was used to compare cumulative incidences between groups. The unadjusted cumulative incidence of grade III–IV acute GVHD that required oral or systemic corticosteroid therapy, was 54% (95% CI, 40%–68%) in evaluable patients who received CSA in contrast to 38% (95% CI, 18%–58%) in patients who received FK (p-value=0.25). Furthermore, the unadjusted cumulative incidence of extensive chronic GVHD at 1 year was 45% (95% CI, 32%–58%) for CSA versus 34% (95% CI, 14%–54%) for FK (p-value=0.48). Progression-free survival between patients who received FK or CSA at the time of the analysis of this study is similar (p-value=0.6191). The progression-free survival at 1 year was 43% (95% confidence interval [CI], 24%–62%) for CSA versus 43% (95% CI, 31%–55%) for FK. Analyses of the overall morbidity and the incidence of infectious complications between the 2 groups are ongoing. FK combined with MMF may be superior to CSA and MMF in the prevention of GVHD post sub-myeloablative allogeneic HSCT therapy for hematological malignancies and FK may result in improvement of treatment outcome. We believe further study is warranted.

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