Graft-Versus-Host Disease (GVHD) and Survival Outcomes after HLA-Haploidentical (Haplo) Bone Marrow Transplant (BMT) Compare Favorably with Matched Related Donor (MRD), and Matched Unrelated Donor (MUD) BMT Utilizing High-Dose Posttransplantation Cyclophosphamide (PTCy)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 730-730 ◽  
Author(s):  
Shannon R. McCurdy ◽  
Christopher G. Kanakry ◽  
Yvette L. Kasamon ◽  
Javier Bolanos Meade ◽  
Hua-Ling Tsai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
Lower Probability ◽  
Survival Outcomes ◽  
High Dose ◽  
Grade Ii ◽  
The Impact ◽  
Grade Iii

Abstract Background: High-dose PTCy has been shown to effectively reduce acute (a) and chronic (c) GVHD after MRD and MUD BMT and to enable the safe implementation of haplo BMT. However, GVHD-related risk factors and survival outcomes, the impact of donor type, and novel composite endpoints, such as cGVHD-free relapse-free survival (cGFRFS), have not been fully characterized in BMT with PTCy. Methods: We retrospectively analyzed 582 consecutive adult pts with advanced or poor-risk hematologic malignancies who received allogeneic BMT with PTCy at Johns Hopkins from 2002-2012. All pts received a T-cell replete bone marrow graft and PTCy (50 mg/kg/d IV) on D+3 and +4. Platforms consisted of: 1) myeloablative conditioning (MAC) with Busulfan/Fludarabine or Busulfan/Cy followed by MRD (n = 193; 33%) or MUD (n=119; 20%) allografting and PTCy as sole GVHD prophylaxis; or 2) nonmyeloablative (NMA) conditioning with Fludarabine/Cy/TBI followed by related haplo (n = 270; 46%) allografting and PTCy, mycophenolate mofetil D5-35, and tacrolimus D5-180. Results: The median follow up was 4 (range 0.3-11.4) years (y). The median pt age at time of BMT was 49 (range 18-66) in the MAC cohort and 54 (range 18-73) in the NMA cohort. On competing risk analysis, the D200 probability of grade II-IV aGVHD was 27% after haplo, 37% after MRD, and 50% after MUD BMT, and grade III-IV aGVHD was 4%, 11%, and 14% respectively. The 3-y probability of cGVHD was 12% after haplo, 8% after MRD, and 19% after MUD BMT. On multivariate analysis adjusted for age and original disease risk index (DRI), MRD and MUD BMT were associated with a statistically significantly higher risk of grade II-IV and grade III-IV aGVHD compared to haplo BMT (each p ≤ 0.001). Compared to haplo BMT, MUD, but not MRD, BMT was also associated with a significantly higher risk of cGVHD (p = 0.009). On multivariate analysis, female into male allografting was independently associated with a higher risk of cGVHD (p = 0.007), whereas age and CMV serostatus of the pt and donor were not statistically significantly associated with risks of acute or chronic GVHD. Pts with grade II-IV aGVHD or cGVHD had a lower probability of relapse, but a higher probability of nonrelapse mortality (NRM) at 3 y compared to pts without GVHD. Among pts with GVHD, an HCT-CI score ≥ 5 was associated with significantly inferior overall survival compared to lower HCT-CI scores. Although MAC matched BMT was associated with less relapse risk than NMA haplo BMT, the 3-y probabilities of NRM, DFS, and overall survival were comparable between the transplant platforms (Table). On multivariate analysis adjusted for pt age and DRI, there were no statistically significant differences in DFS, OS, or cGFRFS in MAC related or unrelated BMT compared to NMA haplo BMT. Conclusions: High-dose PTCy safely modulates acute and chronic GVHD across multiple BMT platforms. The apparently lower risk of aGVHD after NMA haplo BMT with PTCy likely reflects the reduced conditioning intensity and longer duration of immunosuppression utilized. Despite the limitations inherent to a retrospective analysis, these data suggest that key outcomes after BMT with PTCy are comparable across donor types and conditioning intensities. Notably, in all these settings, 3-y estimates of cGFRFS appeared to approach those of DFS. Thus, PTCy may minimize the late morbidity and mortality of cGVHD and allow earlier implementation of novel posttransplantation strategies for relapse prevention. TableOutcomes of BMT with PTCy3-y probabilitiesNMA HaploMAC MRD*MAC MUD*NRM141717DFS384144OS495856cGFRFS313533 * p = NS for all comparisons to haplo BMT on multivariate analysis Disclosures Off Label Use: High-dose posttransplantation cyclophosphamide.

The impact of postoperative complications on survival outcomes in patients with cT3/4a gastric cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4067-4067
Author(s):  
Masanori Tokunaga ◽  
Yukinori Kurokawa ◽  
Yuichiro Doki ◽  
Ryunosuke Machida ◽  
Shuji Takiguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Postoperative Complications ◽  
Infectious Complications ◽  
Survival Outcomes ◽  
Hazard Ratios ◽  
Grade Ii ◽  
The Impact ◽  
Grade Iii

4067 Background: Recently, the negative impact of postoperative complications on long-term survival outcomes has been reported in patients with gastric cancer. However, most are single center, retrospective studies with different definitions of postoperative complications. The objective of this study was to evaluate the impact of postoperative complications on long-term outcomes using the data of a multicenter randomized controlled trial (JCOG1001). Methods: This study included 1191 out of all 1204 patients enrolled in JCOG1001 which was aimed to confirm the superiority of bursectomy for patients with cT3/4a locally advanced gastric cancer. Complications were graded by Clavien-Dindo classification. The relationships between the grade (≥grade II or ≥grade III) or type (all or intraabdominal infectious (pancreatic fistula, anastomotic leakage, and intra-abdominal abscess.)) of complications and survival outcomes were evaluated. Results: The incidences of ≥grade II and ≥grade III all complications were 23.0% and 9.7%, and those of ≥grade II and ≥grade III intraabdominal infectious complications were 13.4% and 6.9%, respectively. The hazard ratios for overall survival (OS) of patients with ≥grade II and ≥grade III all complications and those of patients with ≥grade II and ≥grade III intraabdominal infectious complications were shown in Table. With whichever definition we adopted, postoperative complications were significantly associated with OS in both univariable and multivariable analysis. Conclusions: Postoperative complication was identified as an independent prognostic factor in patients with cT3/4a gastric cancer. Hazard ratios for overall survival by univariable and multivariable Cox proportional hazard model. Clinical trial information: UMIN000003688. [Table: see text]

Impact of Consolidation Radiotherapy in Patients With Advanced Breast Cancer Treated With High-Dose Chemotherapy and Autologous Bone Marrow Rescue

1999 ◽  
Vol 17 (3) ◽  
pp. 887-887 ◽  
Author(s):  
Dennis L. Carter ◽  
Lawrence B. Marks ◽  
Joseph M. Bean ◽  
Gloria Broadwater ◽  
Atif Hussein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Overall Survival ◽  
Advanced Breast Cancer ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
Advanced Breast ◽  
High Dose ◽  
Autologous Bone ◽  
The Impact

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994, 425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT−). The assignment of RT was not randomized. The RT+ and RT− groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT− patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT− groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT− groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

scholarly journals Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2017-2017 ◽  
Author(s):  
Eric Segal ◽  
Michael Martens ◽  
Hai-Lin Wang ◽  
Ruta Brazauskas ◽  
Daniel Weisdorf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Survival Outcomes ◽  
Unrelated Donor ◽  
Term Survival ◽  
Donor Source

Abstract Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Disclosures Sandmaier: Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

European MCL Network: An Update on Current First Line Trials.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 388-388 ◽  
Author(s):  
Martin H. Dreyling ◽  
Eva Hoster ◽  
Olivier Hermine ◽  
J.C. Kluin-Nelemans ◽  
Jan Walewski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Febrile Neutropenia ◽  
Elderly Patients ◽  
Response Rate ◽  
Response Rates ◽  
High Dose ◽  
High Dose Cytarabine ◽  
The Impact ◽  
Grade Iii

Abstract Background: Conventional chemotherapy achieves only short term remission despite high initial response rates of 70%–80%. In the current study generation, the European MCL Network investigates the impact of various combined immuno-chemotherapy regimens. Additionally, in elderly patients the role of rituximab maintenance is being evaluated, whereas in younger patients dose-intensified regimens with implementation of high dose cytarabine are investigated based on the excellent results of the HyperCVAD regimen. Methods: In MCL elderly, patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either an PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan). Results: In MCL elderly, 222 of 263 patients were evaluable based on the annual interim analysis. Median age was 70 years with 66% of patients displaying an intermediate high/high risk IPI. Induction was well tolerated with mainly hematological toxicity (grade III/IV in R-CHOP/R-FC): Leukocytopenia 62/72%, thrombocytopenia 13%/40%, but only rare febrile neutropenia (23%/7%) or infections (19%/23%). Despite the poor risk profile, combined immuno-chemotherapy (total group) achieved a remarkable 84% response rate (51% CR/CRu). Although the impact of maintenance is not yet evaluable, both progression-free and overall survival were encouraging with 77% and 86% at 12 months, respectively. In MCL younger, 247 of 271 patients were evaluable. Again, toxicity (grade III/IV in R-CHOP/alternating R-DHAP) was mainly hematological: leukocytopenia 58/77%, thrombocytopenia 14%/74%, but only rare febrile neutropenia (11%/22%) or infections (5%/7%). Combined immuno-chemotherapy achieved a 93% response rate (60% CR/CRu) before subsequent high dose consolidation. Again, both progression-free and overall survival are remarkable with both 90% at 12 months, respectively. Discussion: Combined immuno-chemotherapy results in high response rates in two prospective international trials. Further recruitment and follow-up will determine the role of rituximab maintenance and high dose cytarabine in this distinct subtype of malignant lymphoma.

scholarly journals Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1259-1259
Author(s):  
Doris M. Ponce ◽  
Rodney Sparapani ◽  
Junfang Chen ◽  
Vanderson Rocha ◽  
Daniel H. Fowler ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Disease Status ◽  
Free Survival ◽  
Grade Ii ◽  
Disease Free ◽  
Grade Iii

Abstract Background: Cord blood (CB) is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of disease-free survival (DFS). However, one controversial issue in pediatric CB transplantation is the role of anti-thymocyte globulin (ATG) as immunoprophylaxis. While inclusion of ATG in the conditioning may decrease the risk of graft-versus-host disease (GVHD), it could potentially abrogate graft-versus-leukemia effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with acute lymphoblastic leukemia (ALL) who underwent myeloablative CB transplantation with or without ATG. Methods: Patients with ALL in morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose total body irradiation-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient and had CB unit with cryopreserved total nucleated cell dose of ≥ 2.5 x107/kg/unit. Cox regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was 3-year DFS. Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95%CI: 21-40) versus 54% (95%CI: 47-61), p = 0.0002] and 3-year chronic GVHD [22% (95% CI: 14-31) versus 43% (95% CI: 36-50), p = 0.0008] were decreased in ATG recipients. However, day 100 grade III-IV aGVHD was comparable: 11% (95%CI: 5-18) in ATG versus 17% (95%CI: 12-23) in non-ATG recipients, p = 0.15]. The 3-year TRM was similar in both groups: 16% (95%CI: 10-25) in ATG versus 17% (95%CI: 13-23) in non-ATG recipients (p = 0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95%CI: 10-23) versus 27% (95%CI: 21-34, p = 0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95%CI: 0.30-0.98), p = 0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95%CI: 1.22-3.89), p = 0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3-year DFS was 66% (95%CI: 56-76) and 55% (95%CI: 48-62) in ATG and non-ATG recipients, respectively (p = 0.23, Figure 1). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p = 0.24) (Table 1). Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in 3-year DFS in each group and multivariate analysis revealed ATG inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults. Table 1 Hazard ratio(95% confidence interval) p-value ATG use Conditioning without ATG Conditioning with ATG 1.00 0.78 (0.52 – 1.18) 0.24 Disease status CR1 CR2, CR3 1.00 2.01 (1.31 – 3.08) 0.001 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Graft-Versus-Leukemia Effect after Haplo-Identical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with AML- No Association with Graft-Versus-Host Disease: A Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4586-4586
Author(s):  
Avichai Shimoni ◽  
Myriam Labopin ◽  
Emanuele Angelucci ◽  
Didier Blaise ◽  
Fabio Ciceri ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Grade Ii ◽  
Landmark Analyses ◽  
Subsequent Relapse ◽  
Grade Iii

Abstract Introduction . Allogeneic stem-cell transplantation (SCT) is a curative approach in acute myeloid leukemia (AML) by providing dose-intensive chemo-radiotherapy and enhancing a graft-versus-leukemia (GVL) effect. The GVL effect is provided by alloimmune T- cells and is usually closely associated with graft-versus-host disease (GVHD). Patients with GVHD have a lower incidence of relapse, but at high grades a higher incidence of non-relapse mortality (NRM). However, GVL can also occur independently of GVHD. The use of haplo-identical SCT is rapidly increasing over the last decade due to the introduction of non-T depleted methods, in particular with post-transplant cyclophosphamide (PTCy), with expected outcomes that are similar to other donor sources. The GVL effect after T- depleted haplo-identical SCT is mostly related to natural-killer cell alloreactivity and is not necessarily associated with GVHD. However, there is no definite data whether GVL after SCT in the non-T depleted setting is similarly associated with GVHD as in the matched donor setting. Methods . We assessed the impact of acute and chronic GVHD on SCT outcomes in patients with AML following non-T depleted haplo-identical SCT with PTCy, by using a series of landmark analyses. Results . The study included 605 patients with AML in CR1 (73%) or CR2 (27%) after non-T depleted haplo-identical SCT with PTCy, given during the years 2009-2016. The median age was 53 years (range, 18-76). 71% had myeloablative conditioning and 29% had reduced-intensity conditioning . The overall rate of acute GVHD grade II-IV and III-IV was 28.4% and 8.0%, respectively. The rates of chronic GVHD all grades and extensive were 32.7% and 12.3%, respectively. The rate of relapse and NRM were 21.8% and 18.2% and the rates of leukemia-free survival (LFS) and overall survival, 2 years after SCT were 59.9% and 64.1%, respectively. 509 patients were alive and leukemia-free 100 days after transplant. 366 had no prior acute GVHD at this landmark, 107 had acute GVHD grade II and 36 had grade III-IV. The overall rate of subsequent relapse was 20.3%, 18.3% and 11.9%, respectively (P=0.60). The overall rates of subsequent NRM were 10.3%, 19.0% and 35.7%, respectively (P<0.001). The rates of LFS were 69.4%, 62.6% and 52.4%, respectively (P=0.01). Multivariate analysis showed that acute GVHD grade II before day 100 was not associated with subsequent relapse (Hazard ratio (HR) 1.02, P=0.93), had borderline association with NRM (HR 1.79, P=0.09) and no association with LFS (HR 1.28, P=0.27). Acute GVHD grade III-IV before day 100 was not associated with subsequent relapse (HR 0.92, P=0.87), while it was associated with higher NRM (HR 5.23, P<0.001) and inferior LFS (HR 2.35, P=0.003). Both acute GVHD grade II and grade III-IV were associated with subsequent extensive chronic GVHD, HR 2.02 (P=0.04) and 6.93 (P<0.001), respectively. 393 patients were alive and leukemia-free 6 months after transplant. Out of them 316 had no prior chronic GVHD at this landmark, 55 had limited and 22 extensive chronic GVHD. The overall rate of subsequent relapse was 14.3%, 9.2% and 23.9%, respectively (P=0.60). The overall rates of subsequent NRM were 7.3%, 10.4% and 31.7%, respectively (P=0.003). The rates of LFS were 78.4%, 80.4% and 44.4%, respectively (P=0.01). Multivariate analysis showed that limited grade chronic GVHD occurring before 6 months was not associated with subsequent relapse (HR 0.69, P=0.44), NRM (HR 1.43, P=0.55) or LFS (HR 0.88, P=0.74). Extensive chronic GVHD was not associated with subsequent relapse (HR 1.44, P=0.56) but was associated with higher NRM (HR 5.77, P=0.004) and inferior LFS (HR 2.75, P=0.01). Similar results were seen for prior chronic GVHD at the 1 year landmark. Conclusions. By a series of landmark analyses at 100 days, 6 months and 1 year after SCT, we did not find any association of acute GVHD grade II or III-IV or chronic GVHD (limited or extensive) with subsequent relapse. Acute GVHD grade III-IV was associated with a higher NRM and lower LFS rates after day100. All grades of acute GVHD were associated with a higher incidence of chronic GVHD. Previous extensive chronic GVHD was also associated with a higher NRM and a lower LFS. GVL is thus not associated with GVHD after non T-deleted haplo-identical SCT with PTCy. Future novel strategies for prevention of significant GVHD are warranted. Disclosures Angelucci: Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board. Mohty:MaaT Pharma: Consultancy, Honoraria.

scholarly journals Post-Transplant High Dose Cyclophosphamide and Bortezomib As Graft-Versus-Host Disease Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3892-3892
Author(s):  
Benedetto Bruno ◽  
Frank Cirrone ◽  
Kelli Cole ◽  
Kelsey Stocker ◽  
Maher Abdul-Hay ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
High Dose ◽  
Graft Versus Host ◽  
One Year ◽  
Grade Iii

Abstract Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin®) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year . Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention

Megadose CD34-Selected Haplocompatible Donor Stem Cell Transplantation in Children.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5417-5417
Author(s):  
Barbara S. Sleight ◽  
Morton J. Cowan ◽  
Biljana Horn ◽  
Jennifer Jaroscak ◽  
Joseph McGuirk ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract We report a retrospective review of 18 children receiving haplocompatible related donor hematopoietic peripheral blood SCT and consecutively enrolled at four U.S. transplant centers. The median age was 8 yrs (range 1–20). Patients with malignancy (n=13) included: AML-CR1 (primary induction failure, failed cord blood transplant) [1], CR2 [3]; MDS-RA/RARS [2], RAEB [2]; AML and Fanconi anemia [1]; CML-CP2 [1]; ALL-CR3 [2]; NHL-CR2 [1]. Patients with non-malignant diseases included severe aplastic anemia [n=4] and Wiskott-Aldrich syndrome [n=1]. Thirteen donors were a 3/6 HLA match and 5 were a 4/6 match. CD34 positive selection was used to select stem cells and deplete T lymphocytes. Conditioning for 13 of the patients consisted of TBI 12–14 Gy in 6 fractions, thiotepa, fludarabine and ATG. Fractionated TBI was replaced by single fraction TBI (n=2) or melphalan (n=3). Cyclophosphamide replaced thiotepa for 1 patient with FA. No post-transplant graft-versus-host disease (GVHD) prophylaxis was given. Patients received a median of 18 × 106 CD34+ cells/kg (range 6–28) and 3 × 104 CD3+ cells/kg (range 0.3–11). Sustained primary engraftment occurred in 15/18 (83%) patients. Primary graft failure occurred in one patient. Two patients had immunological rejection following HHV-6 reactivation. Both engrafted after a second transplant; therefore the overall engraftment success was 94%. The median time to an ANC >0.5 × 109/L was 12 days (range 9–21). Platelet recovery occurred in 16/18 at a median of 17 days (range 9–22). Primary (occurring after SCT but prior to DLI) grade II acute GVHD was seen in 4/17 patients (24%). Grade III-IV GVHD was seen in 1 patient (6%) manifest as overlap syndrome in association with HHV-6 reactivation. One pt had primary extensive chronic GVHD. Of nine patients who received DLI and/or stem cell boosts, 4 had grade II GVHD (3/4 had prior acute GVHD), none had grade III-IV GVHD, 2 developed chronic GVHD and 1 developed overlap syndrome. Infections were common but manageable. All patients were at risk for CMV reactivation based on CMV serology: recipient/donor +/+ (9), +/− (3), −/+ (6). Seven patients (39%) reactivated CMV. All cases were responsive to anti-viral therapy and/or DLI. No CMV disease was seen. Seven patients had adenovirus reactivation and 6 had HHV-6 reactivation. EBV reactivation occurred in 5/18 (28%) patients. Rituximab (5) and DLI (2) yielded rapid resolution of EBV in all patients. Four of 13 (31%) at risk patients have relapsed: 1 pt with cytogenetic relapse remains in CR2 > 6 mo later and another who recently relapsed is undergoing salvage therapy. The 100 day and 1 year transplant-related mortality was 11% and 19%, respectively. The overall survival is 72% with a median follow-up of 31 months (range 7–89). Among patients transplanted for malignant diseases (13) and non-malignant diseases (5), overall survival is 69% and 80%, respectively. The K-M 2 year survival was 70% +/− 22%. All survivors were complete donor chimeras by DNA methods. The use of megadose CD34-selected PBSC without post-transplant GVHD prophylaxis yielded rapid engraftment, low 100-day mortality and incidence of severe GVHD, and excellent survival. The overall survival compares favorably with MSD and MUD HSCT.

Salvage Autologous Hematpoeitic Stem Cell Transplants (AHSCT2) for Myeloma: Single Center Experience.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4591-4591
Author(s):  
Bishoy Faltas ◽  
Jane L. Liesveld ◽  
Michael Becker ◽  
Jainulabdeen J. Ifthikharuddin ◽  
Gordon L. Phillips
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Median Overall Survival ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
High Dose ◽  
The Impact

Abstract Abstract 4591 Although the role of AHSCT1 is well established in multiple myeloma therapy, the role of the salvage (not “tandem”) AHSCT2 is less clear. However, most pts. undergo initial stem cell harvests with plans for eventual AHSCT2. To clarify the indications, the prognostic factors and the outcomes of AHSCT2 in relapsed myeloma, we analyzed our experience in 19 pts. (pts.) who underwent salvage AHSCT2 between the 1994–2008. Mean age at AHSCT1/2 was 54.58 (SD 7.96)/57.03 (SD 8.10) respectively; 15 (79.0%) were males. At the time of diagnosis, 7 (36.8%) pts. had ISS stage I, 6 (31.6%) stage II, 3(15.8%) stage III and in 3 (15.8%) the ISS stage could not be determined. Isotypes: IgG 11 (57.9%), IgA 4 (21.1%), 1 (5.3%) pt. had IgM and 3 (15.8%) had light chain myeloma. Cytogenetics were normal in 6 (31.6%), abnormal in 5 (26.3%) and unavailable for 8 (42.1%) pts. The most common therapy received prior to AHSCT1 was Vincristine/Adriamycin/Dexamethasone in 11 (57.9%) pts.; 7 pts. were exposed to novel agents. One pt. achieved complete response (CR), 15 (79.0%) pts. achieved partial response (PR) and 3 (15.8%) pts. had stable or progressive disease after receiving the initial treatment. All pts. proceeded to receive high dose therapy with Melphalan (MEL), 2 pts received fTBI in addition to MEL. Mean MEL dose was 190.00 mg/m2 (SD 23.01); 15 pts. received 200 mg/m2. All pts. received >2×10e6/kg of CD34+ cells in the first and second transplants. At D+100 after AHSCT1, responses were: 4 (21.1%) CR, 1 (5.3%) VGPR, 8 (42.1%) PR and 6 (31.6 %) with lesser responses. Therapy to prolong response or for salvage after AHSCT1 was given in all pts before AHSCT2, including Thalidomide in 6 (31.6%), Bortezomib in 4 (21.1%) and Lenalidomide in 2 (10.5) pts. Median time to progression after AHSCT1 was 318 days [95 % CI 110– 573]. Median interval between AHSCT1 and AHSCT2 was 896.74 days (SD: 698.34 days). At the time of AHSCT2, 4 (21.1%) were in PR, 15 (79.0%) had progressive disease. For AHSCT2, all pts. Received MEL, one pt. received MEL + Cytoxan and one pt. received MEL + Bortezomib. The median MEL dose/m2 was 175.56 (52.04).All pts. survived AHSCT2 to D+100, responses were as follows: 3 (15.8%) VGPR, 9 (47.4%) in PR; 7 (36.9) pts. had lesser responses. After AHSCT2, nine (47.4%) pts. had grade III toxicity and only one pt. had grade IV toxicity (avascular necrosis). Maintenance therapy after AHSCT2 included Bortezomib in 7 (36.8%) pts., Lenalidomide in 5 (26.3%) pts. and Thalidomide in 4 (21.1%) pts. After AHSCT2, the median overall survival (OS) was 658 days [95 % CI 326–1330] and progression free survival (PFS) after AHSCT2 was 237 days [95 % CI 121– 397] (Figure 1). OS probability at 6, 12, 24 months after AHSCT2 was 81.3, 75.0, 39.3 % respectively. For all pts., the median OS time (i.e. time from diagnosis to death or last follow-up) was 2187 days [95% CI 1413– 4126]. At the end of the follow up period, a total of 14 pts. had died. Causes of death were progression in 12 (63.2%) and sepsis in 2 pts. (10.5%). The number of previous lines of chemotherapy, interval between transplants, disease status at the time of AHSCT1/2, type of myeloma and MEL dose were not predictive of OS and PFS. In the multivariate analysis, only age by decade at AHSCT2 and male gender were independent predictors of OS after AHSCT2 (HR 4.037, P= 0.01), (HR 3.74, P=0.07) respectively. Similarly, in the multivariate analysis for PFS after AHSCT2, age at AHSCT2 was an unfavorable independent predictor (HR 3.48, P=0.009) whereas relapse free response more than 18 months after AHSCT1 was an independent favorable predictor (HR 0.198, P=0.007).Our results are consistent with the few studies examining the impact of salvage transplants for myeloma which report a median overall survival ranging from 20.7 to 38.1 months from the time of AHSCT2.We conclude that salvage AHSCT2 can positively impact PFS and OS but efforts to improve outcomes are mandatory.FigureSEQ Figure ≂,* ARABIC 1Figure. SEQ Figure ≂,* ARABIC 1 X-axis represents time from AHSCT2 in days. Y axis represents survival distribution. Blue line = OS, Red = PFS. Disclosures: No relevant conflicts of interest to declare.

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