Efficacy of bortezomib to intensify the conditioning regimen and the graft-versus-host disease prophylaxis for high-risk myeloma patients undergoing transplantation

2019 ◽  
Vol 55 (2) ◽  
pp. 419-430
Author(s):  
T. Caballero-Velázquez ◽  
◽  
C. Calderón-Cabrera ◽  
L. López-Corral ◽  
N. Puig ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Host Disease ◽  
Graft Versus Host

Long-Term Outcomes of Myeloablative Conditioning and Matched-Related Donor Hematopoietic Cell Transplantation for Patients with High-Risk and Advanced-Stage Hematolymphoid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4383-4383
Author(s):  
Jonathan E. Benjamin ◽  
Ginna G. Laport ◽  
Laura J. Johnston ◽  
Sally Arai ◽  
Wen-Kai Weng ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Donor

Abstract Patients with high-risk hematolymphoid malignancies who relapse or who do not achieve a complete remission to induction chemotherapy generally do not achieve long-term survival when treated with the best available non-transplant therapies. The benefit of allogeneic hematopoietic cell transplantation has been well described for patients in first complete remission, but less so for patients with advanced disease. We report the long-term follow-up of 131 patients with leukemia or lymphoma who received an HLA-matched related donor transplant following myeloablative conditioning with fractionated total body irradiation (1320cGy), etoposide (60mg/kg), and cyclophosphamide (60mg/kg). Eligibility for transplantation under this protocol included induction failure or high-risk disease that was beyond first remission. All patients were treated at a single institution. Diagnosis at the time of transplantation included ALL (n=57), AML (n=38), NHL (n=20), CML (n=10), MDS (4), JMML (n=2). Of the 95 patients with acute leukemia, 62 (65%) were not in remission at the commencement of the conditioning regimen. The median age at transplantation was 29 years (range 2–55). Seventy-four (56%) patients received unmanipulated bone marrow and the remainder received filgrastim-mobilized peripheral blood. Median follow-up of surviving patients was 8 years (range 0.3–17). The estimated five-year overall survival and event-free survival were 34% (95% confidence interval: 22–42%) and 32% (95% confidence interval: 24–39%), respectively. Leading causes of death included relapse (n=43), infection (n=11), acute graft-versus-host disease (n=8), respiratory failure (n=5) and hepatic veno-occlusive disease (n=4). Grade II–IV acute graft-versus-host disease occurred in 26% of patients. The cumulative incidence of extensive chronic graft-versus-host disease among those patients who survived beyond day 100 was 32%. These results indicate that patients with high-risk or advanced disease can experience long-term disease-free survival following an aggressive conditioning regimen that combines radiotherapy, etoposide, and cyclophosphamide. Relapse remains the most significant cause of mortality, and future efforts should focus on augmenting the graft-versus-malignancy effect.

scholarly journals Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5647-5647
Author(s):  
Yuan Li ◽  
Qing Ya Wang ◽  
Ze Yin Liang ◽  
Yue Yin ◽  
Wei Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Relapse Time ◽  
Risk Patients ◽  
Grade Ii ◽  
Acute Graft

Objective: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate- and high-risk patients with MDS or AML. Methods:Retrospective analysis of data pertaining to 76 intermediate and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabine containing conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine. Results: Overa median follow up of 40 months(range, 1 to 155), the incidence of grade II to IV acute graft versus host disease was 12.5% in the Decitabine group and 41.7% in the non-Decitabine group (P=0.003). On multivariate analysis, Decitabine containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.275, 95% confidence interval 0.098-0.770,P=0.014). Incidence of respiratory infection in the Decitabine and non Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.837, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2 to 12) versus 3 months (range, 2 to 4), P=0.171]. Decitabine containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the between-group difference was not statistically significant (P=0.085). Conclusions: Inclusionof Decitabine in the conditioning regimen for allo-HSCT in intermediate- and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

scholarly journals CD52‐negative T cells predict acute graft‐versus‐host disease after an alemtuzumab‐based conditioning regimen

2020 ◽  
Vol 191 (2) ◽  
pp. 253-262
Author(s):  
Pascal Woelfinger ◽  
Katharina Epp ◽  
Lukas Schaefer ◽  
Diana Kriege ◽  
Matthias Theobald ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals Increased Mac-2 binding protein glycan isomer in patients at risk for late nonrelapse mortality after HSCT

2019 ◽  
Vol 3 (21) ◽  
pp. 3287-3296
Author(s):  
Yu Akahoshi ◽  
Hideki Nakasone ◽  
Koji Kawamura ◽  
Machiko Kusuda ◽  
Shunto Kawamura ◽  
...  
Keyword(s):  
At Risk ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Binding Protein ◽  
Liver Graft ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Key Points ◽  
Patients At Risk

Key Points M2BPGi is increased in patients with liver graft-versus-host disease, especially in those at high risk for late NRM after allogeneic HSCT. WFA+-M2BP–positive macrophages are found in liver graft-versus-host disease, supporting these cells as a responder of this glycoprotein.

Keratinocyte Growth Factor Ameliorates Acute Graft-versus-Host Disease in a Novel Nonmyeloablative Haploidentical Transplantation Model.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3060-3060
Author(s):  
Gerard M.J. Bos ◽  
Ariane Vanclee ◽  
Ellis Oving ◽  
Ludy Lutgens ◽  
Nicolaas Deutz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Keratinocyte Growth Factor ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Host Disease ◽  
Graft Versus Host ◽  
Haploidentical Transplantation ◽  
Before And After ◽  
Total Body

Abstract Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and non-malignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To meet these requirements, we have developed a nonmyeloablative conditioning regimen in a haploidentical F1 → F1 mouse model. These mini-transplantations, consisting of low dose total body irradiation and cyclophosphamide-based chemotherapy, resulted in stable full donor chimerism, but also in the development of GVHD. Administration of keratinocyte growth factor (KGF) before and after SCT resulted in reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis than in saline-treated controls. KGF preserved plasma citrulline and TNF-a levels, both indicative for reduced radiation-induced injury to the gastrointestinal tract. Citruline has recently been described as a new marker for gastrointestinal toxicity. Six months after transplantation, survival rates were significantly higher in KGF-treated animals (57% as compared to PBS-treated controls (5.3%). Figure Figure These data indicate that nonmyeloablative haploidentical transplantations might be feasible and that KGF might contribute substantially to reduction of lethal GVHD, also after nonmyeloablative procedures. For clinical transplantation such an effect would be significant if intensive T cell depletion might be prevented in haploidentical transplantation protocols and therefore reduced infection rates can be obtained.

Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) for Hematologic Malignancies (HM) Using Pentostatin/Low-Dose Total Body Irradiation (TBI).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3671-3671
Author(s):  
R. Gregory Bociek ◽  
James E. Talmadge ◽  
James C. Lynch ◽  
Charles A. Enke ◽  
Charles A. Kuszynski ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background/Patients and Methods: NST is increasingly being used as a means of establishing a graft-versus-malignancy (GVM) effect with less regimen related toxicity. Between 9/01 and 7/04, 39 patients (pts) with high risk/relapsed/refractory HM who were not candidates for full intensity allogeneic stem cell transplantation underwent NST using Pentostatin/TBI. The median age of pts was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous stem cell transplantation in 22 pts. Diseases transplanted included chronic lymphocytic leukemia/indolent non-Hodgkin’s lymphoma (NHL, n=6), aggressive NHL (n=8), mantle cell lymphoma (n=3), Hodgkin’s disease (n=6), myeloproliferative disorders (n=4), myelodysplastic syndromes (n=4), and acute myelogenous leukemia (AML, n=8). Conditioning consisted of Pentostatin 4 mg/m2 daily on day −21, −20, and −19, followed by 200 cGy TBI on day −1. Post-grafting immunosuppression consisted of cyclosporine/mycophenolate mofetil. Results: Stem cell transplantation was from matched related (n=14) or unrelated (n=25) donors. Death prior to 100 days post transplant occurred in 7 patients. Grade III/IV toxicities included hematologic (n=10 pts), infectious (n=5) and other non-infectious (n=4). The median nadir values (day −21 to day 0) for hemoglobin, neutrophil count and platelet count were 10.7 g/dl (range 7.8–12), 1056/mm3 (range 0–5336), and 174/mm3 (range 24–523) respectively. Three pts failed to engraft; two patients with myelofibrosis (both of whom had autologous reconstitution) and one patient with high risk AML (who died of complications of fungal sepsis without hematologic recovery). The median chimerism values for CD3+ cells and WBC at day 28 are 80% and 95% donor cells respectively. The median chimerism values for CD3+ and WBC at day 70 are 95% and 95% respectively. There have been no late graft failures. The cumulative incidence of all grades of acute graft-versus-host disease at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%, P=0.012). Chronic graft-versus-host disease has developed in 69% of patients. The cumulative incidence of relapse for all patients is 30%, and is lower for unrelated donor transplants than matched related donor transplants (46% vs. 20%, P=0.02). The probability of event-free and overall survival at two years is 52% and 56% respectively. Conclusions: This regimen is associated with acceptable toxicity. Engraftment has not been an issue with the exception of two pts with myelofibrosis. Pts receiving unrelated donor grafts have a higher incidence of graft-versus-host disease and a lower relapse rate. This represents indirect support for the presence of a GVM effect. A prospective study using a modified Pentostatin schedule (starting at day − 10) is ongoing based on the nadir of host T-cells identified in this study.

Submyeloablative Cord Blood Transplant Corrects Clinical Defects Seen in IPEX Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5414-5414
Author(s):  
Kenneth G. Lucas ◽  
Melanie A. Comito ◽  
David R. Ungar ◽  
Brandt P. Groh
Keyword(s):  
Cord Blood ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Cord Blood Transplant

Abstract IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) is a disorder of regulatory T cell function caused by mutations in the FOXP3 gene. This disorder is generally associated with a fatal outcome early in life from complications related to bleeding, infection, or enteritis. Allogeneic stem cell transplant (SCT) can be curative for this disorder, but pre-transplant disease-related complications may preclude a full myeloablative conditioning regimen. We report a seven year old boy with IPEX whose pre-transplant course was complicated by recurrent laryngeal papillomas and severe airway obstruction, frequent pulmonary infections, and recurrent gastrointestinal hemorrhage. Due to these problems he underwent a submyeloablative conditioning regimen consisting of fludarabine 30 mg/m2/day for 6 days, Busulfan 0.8 mg/kg/dose every 6 hours for 2 days, then anti-thymocyte globulin 2.5 mg/kg/dose for 4 days. Mycophenylate and cyclosporine were used for graft versus host disease (GVHD) prophylaxis. This patient received an HLA 5/6 matched (A,B,DR) unrelated donor cord blood transplant with 1.1 ×108 total nucleated cells/kg and 3 × 105 CD34+ cells/kg. His diarrhea and airway issues resolved following the conditioning regimen. The patient achieved myeloid engraftment on day 14, and was platelet and red cell transfusion independent by day 29 and 56, respectively. He had 81% and 98% donor chimerism at 2 and 9 months post-transplant, respectively. While tapering cylcosporine he developed graft versus host disease of the lower GI tract, which was sucessfully treated with a course of corticosteroids. He also experienced reactivation of EBV and was treated with 4 weekly doses (375 mg/m2) of anti-CD20 monoclonal antibody. This patient has had full resolution of his clinical symptoms and is currently 17 months post-transplant, with no signs of GVHD. For those children who do not respond or have only partial improvement following immunosuppressive therapy, allogeneic SCT using a submyeloablative approach can be well tolerated and result in sustained donor chimerism.

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