Umbilical Cord Blood Transplantation in Patients with Hematological Malignancies Using a Non-ATG Containing Reduced Intensity Preparative Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1943-1943
Author(s):  
Fabiana Ostronoff ◽  
Filippo Milano ◽  
Ted Gooley ◽  
Jonathan Gutman ◽  
Peter A. McSweeney ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord Blood ◽  
Graft Rejection ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Comorbidity Score ◽  
Post Transplant ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Abstract 1943 Reduced intensity conditioning (RIC) regimens in umbilical cord blood transplant (UCBT) are increasingly utilized for older patients (pts) and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Incorporation of ATG into the conditioning regimen is thought to decrease the incidence of graft rejection, but it is associated with high incidence of infusion associated reactions and serum sickness, delayed T cell recovery, increased infections and higher risk of EBV post-transplant lymphoproliferative disorder (PTLD). We report the results of a non-ATG containing RIC regimen, in which ATG is replaced with a higher dose of TBI in pts considered to be at higher risk of graft failure. All pts received fludarabine (40mg/m2/day) from day −6 to day −2 and cyclophosphamide (50mg/kg) on day −6. Pts who had received a previous autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months previous to UCBT received a single fraction of 200cGy TBI on day −1. All other pts were considered at higher risk of graft rejection and received a single fraction of 300cGy of TBI on day −1. GVHD prophylaxis began on day −3 and consisted of cyclosporine A (CSA) and mycophenolate mofetyl (MMF). CSA was continued until at least day +100 and then tapered 10% per week starting on day +101 and discontinued no sooner than 6 months post-transplant. The duration of MMF was prolonged, with initiation of a taper on day+40 post transplant and then in the absence of GVHD, tapered by 12% per week and discontinued after day + 96. Thirty pts underwent double UCBT at 3 transplant centers using this protocol between February 2006 and January 2011. Median age and weight of the pts were 60 (range, 24–73) years and 78 (range, 55–141) kg, respectively. Disease status included AML-CR1 (n=11) and CR2 (n=5), ALL-CR2 (n=1) and refractory ALL (n=2), biphenotypic leukemia in 1st CR (n=1), MDS (n=1), relapsed/ refractory Hodgkin lymphoma (n=3), transformed DLBCL (n=1), primary PTCL (n=1) and very high grade B cell lymphoblastic lymphoma in 2nd CR (n=1). Nine pts (30%) had failed prior hematopoietic cell transplantation (HCT), of which 5 were auto, 3 were allo and 1 both auto and allo transplant. All pts received 2 cord blood units to achieve the required cryopreserved cell dose of 3.0×107 TNC/kg. The median cell doses infused were 4.92 × 107 (range, 3.12–8.3) TNC/kg and 0.26×106 (range, 0.02–2.85) CD34+ cells/kg. Among the 60 infused units, HLA matching was 6/6 in 3% (n=1), 5/6 in 30% (n=9) and 4/6 in 67% (n=20) of the pts. Twenty-two pts (73%) received 2GY and 8 (27%) received 3Gy of TBI. The median number of prior treatments and comorbidity score were 3 (range, 0–8) and 3 (range, 1–8), respectively. The median follow up was 183 days (range, 132 to 1303 days). Neutrophils engraftment occurred in all pts at a median of 13 (range, 6 to 40) days and platelet (PLT) engraftment (>50×109/L ) occurred at a median of 32 (range, 23 to 42) days, respectively. There was only one case of secondary graft rejection and no cases of primary graft rejection. The cumulative incidence of acute GVHD grade II-IV and III-IV were 60% and 24%, respectively; the cumulative incidence of chronic GVHD was 18%. Day 100 NRM was 17%. At one year, NRM, OS and PFS were 29%, 53% and 45%, respectively. Causes of death included relapse (n=6), multi-organ failure (n=2), sepsis (n=1), diffuse alveolar hemorrhage (n=1), necrotizing hemorrhagic meningitis (n=1), leukoencephalopathy (n=1) and intracranial bleed (n=1). There were no cases of CMV disease or PTLD. On multivariate analysis, only neutrophil and platelet engraftment were associated with mortality, with hazard ratios of 0.07 (95%, CI 0.009–0.61), p=0.01) and 0.11 (95%, CI 0.03–0.41, p=0.0009), respectively. Other variables, such as age, number of previous regimens, presence of minimal residual disease prior to transplant, dose of TBI (3Gy vs 2Gy), high-risk disease, comorbidity score and acute GVHD grade II-IV were not statistically significantly associated with poorer survival. In summary, results of this study to date demonstrate that this non-ATG containing conditioning regimen, with intensified immunosuppression and increased dose of TBI, provides a low incidence of graft rejection without increasing toxicity or the incidence of chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

Double Umbilical Cord Blood Transplantation with Reduced Intensity Conditioning and Sirolimus-Based GVHD Prophylaxis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2016-2016 ◽  
Author(s):  
Corey Cutler ◽  
Rachel Mitrovich ◽  
Grace Kao ◽  
Vincent Ho ◽  
Edwin Alyea ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Umbilical cord blood (UCB) is an alternative stem cell source for patients without related or unrelated donors. Single-unit UCB transplantation in adults is associated with high transplant-related mortality, largely due to delayed engraftment and infection. While double umbilical cord blood transplantation (DUCBT) is associated with faster engraftment, it is also associated with high rates of acute GVHD. We studied DUCBT using sirolimus and tacrolimus as GVHD prophylaxis to improve GVHD outcomes. Methods: Reduced-intensity conditioning consisted of fludarabine (30mg/m2×6 days), melphalan (100mg/m2× 1day), and rabbit ATG (1.5 mg/kg × 4 days). Cord blood units were ≥4/6 HLA-A, B, DR allele-matched with each other and the recipient, and contained a minimum combined dose of 3.7× 107 TNC/kg (pre-cryopreservation). GVHD prophylaxis consisted of tacrolimus (serum conc. 5–10 ng/ml) and sirolimus (serum conc. 3–12 ng/ml). Filgrastim was used routinely after transplantation, and subjects received prophylactic anti-fungal antibiotics as part of routine supportive care. Results: 27 patients (median age 49 years, range 19–67) with >100 day follow-up are reported. Diagnoses include AML(8), NHL(7), HD(4), MDS(3), CLL/PLL(2), ALL(1), MPD (1) and CML(1). The median total cell doses prior to cryopreservation were 5.25 ×107 TNC/kg (range 3.74–7.58 ×107) and 12.57 ×106 CD34+ cells (range 1.45–29.0 ×106). Neutrophil engraftment occurred at a median of 21 days (range 13–70) and platelet engraftment to 20 000/μL occurred at a median of 42 days (range 25–162) after DUCBT. Three subjects did not attain platelet transfusion independence by day 100 and there were 2 late graft failures. 3 patients developed Gr II–IV acute GVHD (2 Gr. II and 1 Gr. III). The rate of acute GVHD was lower when compared with a prior cohort that received the identical conditioning regimen, but with cyclosporine and MMF as GVHD prophylaxis (11.1% vs. 37.7%, p=0.05). 2 patients developed chronic GVHD at a median of 203 days from transplantation. The median follow up is 12 months (15 months among survivors, range 4–20 months). 100-day treatment-related mortality was 11.1%. There was no VOD or TMA. Relapse-free and overall survival at 1 year are 54.4% and 72.9% respectively. Causes of death include sepsis(4), relapse(2), and EBV-associated PTLD(2). Chimerism analysis at day 100 (n=22) revealed complete single cord chimerism in 13 subjects with mixed cord chimerism in 9. The first infused unit was the predominant unit at day 100 in 14/22 subjects. There was no correlation between cord dominance and HLA match, TNC/kg or CD34+ cell count prior to cryopreservation. Conclusions: This study demonstrates excellent engraftment after DUCBT in adult recipients after a reduced-intensity conditioning regimen. The risk of acute and chronic GVHD is low when sirolimus and tacrolimus are used as GVHD prophylaxis when compared with our prior experience with cyclosporine and MMF, and survival is comparable to historical unrelated donor cohorts.

Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 605-605
Author(s):  
Karen K. Ballen ◽  
Corey Cutler ◽  
Thomas R. Spitzer ◽  
Beow Yeap ◽  
Steve McAfee ◽  
...  
Keyword(s):  
Cord Blood ◽  
Total Dose ◽  
Aplastic Anemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cord Blood Unit ◽  
Reduced Intensity ◽  
Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count >500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count >20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3046-3046 ◽  
Author(s):  
Vincent T. Ho ◽  
Haesook Kim ◽  
Shuli Li ◽  
Corey Cutler ◽  
John Koreth ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Historical Cohort ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity

Abstract We have previously shown that the combination of tacrolimus and sirolimus (TAC/SIR) without methotrexate (MTX) is a safe and effective regimen for GVHD prophylaxis after myeloablative SCT. However, TAC/SIR has not been investigated in the RIC setting. We hereby report a prospective phase II trial testing TAC/SIR as GVHD prophylaxis after RIC SCT from matched related donors (MRD). All patients received fludarabine (FLU) 30 mg/m2 IV and intravenous busulfan (BU) 0.8 mg/kg IV daily × 4 days (day -5 thru day -2) as conditioning, followed by transplantation of filgrastim mobilized peripheral blood stem cells. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Tacrolimus and sirolimus were started on day-3, and doses were adjusted to maintain target serum trough levels 5–10 ng/ml and 3–12 ng/ml, respectively. Twenty-six patients have been transplanted, with a median age of 52 years (range 29–64 yrs). Diagnoses include NHL (8), AML (6), HD (5), CLL/SLL (3), CML (2), MDS (1), MM (1). Median CD34+ cells infused was 8.06 × 106 cells/kg (range: 2.96–38.0 × 106 cells/kg). All patients had sustained hematologic engraftment. Only 4 (15%) patients developed neutropenia below ANC 500, and 6 (23%) had platelet counts below 20K. One patient had late graft failure at 7 months post transplant. Grade II-IV acute GVHD incidence was 20%, with grade III-IV incidence of 12%. No hepatic VOD or thrombotic microangiopathy was observed. Day +100 transplant related mortality (TRM) was 0%. The cumulative incidences of TRM and relapse at 1 year were 4% and 38%, respectively. The cumulative incidence of chronic GVHD at 1 year was 74%. A high level (>90%) of donor-derived hematopoiesis was achieved in 68% by 1 month post transplant. Median donor chimerism at between day 20–50 post transplant was 93.5% (range 32%-99%), and 94% (range 22%-100%) at day 85–115. With a median follow-up of 13.5 months among survivors (range 5.5–19 months), progression-free survival (PFS) and overall survival (OS) at 1 year were 58% and 79%, respectively. Compared to a historical cohort of 47 MRD transplant recipients treated with the same FLU/BU conditioning regimen and using TAC/SIR ± mini-MTX (5 mg/m2 IV day +1,3,6) as GVHD prophylaxis, there was no statistical difference between TAC/SIR vs. TAC/SIR/MTX in the incidence of grade II-IV acute GVHD (20% vs 11%, p= 0.48), cumulative incidence of relapse at year (38% vs. 57%, p= 0.25), 1-yr PFS (58% vs. 41%, p= 0.33), or 1-yr OS (79% vs. 73%, p= 0.79). These results demonstrate that omission of mini-MTX is permissible, and that the combination of TAC/SIR alone as GVHD prophylaxis following reduced intensity conditioning with FLU/BU is associated with low rates of acute GVHD, TRM, and high levels of donor chimerism after MRD SCT.

Unrelated Cord Blood Transplantation (UCBT) in Children with Sickle Cell Disease (SCD): US Centers Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2044-2044 ◽  
Author(s):  
Tom V. Adamkiewicz ◽  
Ann Haight ◽  
Melissa A. Mazur ◽  
K. Scott Baker ◽  
Paul Szabolcs ◽  
...  
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Post Transplant ◽  
Elevated Liver Enzymes ◽  
Unrelated Cord Blood ◽  
Reduced Intensity ◽  
Grade Iii

Abstract UCBT may be curative in patients (pts) with high-risk SCD. Unrelated cord blood units matched at >4/6 HLA are acceptable for UCBTs and available to most pts. We reviewed UCBTs in 7 children with SCD and cerebrovascular accidents performed in 4 centers (1998 to 2003): 4 pts were conditioned with conventional myeloablative regimens, and 3 pts with reduced-intensity regimens. The former received busulfan (BU), cyclophosphamide (CY) and anti-thymocyte globulin (ATG) (3 pts) or BU/CY/ATG plus fludarabine (FLU) (1 pt). Of 3 pts who received 4/6 HLA-matched UCBTs after BU/CY/ATG and GVHD prophylaxis with methylprednisone (MP) and cyclosporine (CSP) or tacrolimus (TAC), 2 have durable engraftment, 1 had autologous reconstitution (BMT2004; 34:405–11). A 5 yr old (yo) female with transfusion-induced alloimmunization received a 5/6 HLA-matched UCBT (6.2 X 10^7/kg nucleated [NC] cells) after BU/CY/ATG/FLU, followed by CSP and MP post-transplant. PMN engraftment and VNTR > 98% of donor origin were documented 24 and 37 days, respectively, after UCBT. Complications included elevated liver enzymes during conditioning, grade IV GVHD of skin, GI and liver, grade III mucositis, VOD, parainfluenza 3 infection, candidemia and adenovirus viremia. Pt died of severe acute GVHD and multi-organ failure 73 days after UCBT. Two different reduced-intensity regimens were used in the other 3 pts. An 8 yo male received a 4/6 HLA-matched UCBT (3.2 X 10^7/kg NC) after conditioning with alemtuzumab, rituximab, hydroxyurea, thiotepa and TBI (600cGy, with 300 cGy total dose to liver and kidneys) and received TAC and mycophenolate mofetil (MMF) post-transplant. This patient failed UCBT 8 months earlier (FLU/CY/ATG/TLI, 4/6 HLA). PMN engraftment and VNTR > 98% of donor origin was documented within 18 days after UCBT. Complications included grade I skin GVHD, grade 1 mucositis and parainfluenza 1 infection. This pt remains engrafted and fully active 1.6 ys after UCBT. A 4 yo female and a 16 yo male received 4/6 or 5/6 HLA-matched cord units, respectively, after BU or CY, ATG, FLU and total lymphoid irradiation (200 or 500 cGy) and received CSP and MMF post-transplant. Neither had evidence of donor engraftment, and autologous reconstitution was documented within 2 weeks after UCBT. Sustained donor engraftment occurred in 3/4 pts (75%) who underwent UCBT after myeloablative conditioning and 1/3 pts (33%) who underwent UCBT after reduced-intensity conditioning. Two of the 3 pts who engrafted after myeloablative preparative regimens developed acute grade III–IV GVHD, and 1 of these pts developed extensive chronic GVHD. The 1 pt who engrafted after a reduced-intensity preparative regimen developed grade I acute GVHD only. Significant viral infections (CMV 1 pt, adenovirus, parainfluenzavirus 2 pts each) occurred in 4 pts. In this limited experience, following various conditioning regimens, optimal GVHD and infection prevention remains a challenge. Both apparent lesser risk and documented durable engraftment may justify further development of non-myeloablative strategies for UCBT in children with high-risk SCD.

scholarly journals Use of Thymoglobulin with Lower Dose of Busulfan Results in Less Acute Gvhd Following Unrelated Donor Allogeneic Stem Cell Transplantation for AML without Affecting Relapse-Free and Overall Survival

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4488-4488
Author(s):  
Dipenkumar Modi ◽  
Vijendra Singh ◽  
Seongho Kim ◽  
Abhinav Deol ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Advisory Board ◽  
Unrelated Donor ◽  
Hla Matching ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Reduced Intensity

Introduction: Post-transplant relapse and GVHD are two major barriers of success of allogeneic hematopoietic stem cell transplantation (AHSCT) for AML. These outcomes are often dependent on the complex interaction between the post-transplant immunosuppression and the conditioning regimen. We as well as others have used rabbit thymoglobulin for the reduction of both acute and chronic GVHD in unrelated transplant in AML. The interaction between different conditioning regimens and thymoglobulin may play an important role in the outcomes, but it has not been fully investigated. In this study, we compared outcomes of patients undergoing unrelated donor AHSCT for AML using thymoglobulin with either a myeloablative or reduced intensity conditioning regimen. Patients received busulfan/fludarabine (Bu/Flu)-based myeloablative conditioning (MAC) regimen with 4 days of busulfan or reduced intensity conditioning (RIC) regimen using 2 days of busulfan with fludarabine. Since 2 days of busulfan as RIC may have a higher relapse rate, we added low dose TBI (200cGY) to the RIC regimen (Bu/Flu/TBI). Methods: We retrospectively evaluated outcomes of adult AML patients who underwent unrelated donor AHSCT utilizing tacrolimus, mycophenolate (MMF) and thymoglobulin as GVHD prophylaxis. All patients received either a Bu/Flu/TBI-based RIC or a Bu/Fu-based MAC regimen. Thymoglobulin was administered at a total dose of 4.5mg/kg in divided fashion (0.5mg/kg on day-3, 1.5mg/kg on day -2, 2.5mg/kg on day -1). Tacrolimus and MMF were started on day -3. The objectives were to determine the rates of acute and chronic GVHD, overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM) using Cox proportional hazard regression and competing risk models. Results: One hundred twenty-two patients with AML received unrelated donor AHSCT between January 2005 and December 2017. Of these, 88 (72%) patients had de-novo and 34 (28%) had secondary AML. Sixty-four patients received Bu/Flu/TBI-based RIC, and 58 received Bu/Flu as MAC regimen. All patients received peripheral blood stem cells. The patients receiving RIC regimen were older (median age 66 vs 53 years, p<0.001), had higher proportion of patients with normal cytogenetics (47% vs 31%, p=0.02) and 8/8 HLA match (88% vs 64%, p=0.004) as compared to MAC regimen. The 6-month cumulative incidence rate (CIR) of grade III-IV acute GVHD (aGVHD) was 6% in RIC and 26% in MAC regimen (p=0.004). The 2-year CIR of chronic extensive GVHD was 35% and 29% in RIC and MAC regimen, respectively (p=0.50). Median follow-up of surviving patients after RIC and MAC regimen was 4.4 years and 4 years, respectively. Two-year OS after RIC and MAC regimen was 50% and 49%, respectively (p=0.69). Two-year relapse rate with RIC and MAC was 37% and 24%, respectively (p=0.25), whereas two-year NRM with RIC and MAC was 21% and 31%, respectively (p=0.41). Two-year RFS was 43% with RIC and 45% with MAC regimen (p=0.80). In all, CMV and EBV reactivation rates were 34% and 7%, respectively. Eight patients (7%) developed gastrointestinal CMV disease. Multivariable analysis revealed that relapsed and refractory AML at AHSCT was associated with adverse OS (HR 1.71, p=0.04), RFS (HR 1.84, p=0.01) and higher NRM (SHR 2.96, p=0.006) compared to first complete remission. Secondary AML was associated with higher NRM (HR 2.44, p=0.02). No impact of HLA matching and conditioning regimen on OS, relapse, NRM and RFS was observed. Subgroup analysis showed that HLA matching had an interaction with the conditioning regimen for RFS (p=0.03). Otherwise, none of the factors appeared to have any significant interaction with the conditioning regimen for survival outcomes. Conclusion: Our study shows that thymoglobulin when used with lower dose of busulfan (in the form of Bu/Flu/TBI-based RIC regimen) provided significantly lower rate of acute GVHD compared to Bu/Flu-based MAC in AML patients undergoing unrelated donor AHSCT without affecting leukemia-free and overall survival. Disease status at transplant remains a significant predictor of post-transplant outcomes. Disclosures Deol: Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board.

Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sézary Syndrome (SS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2544-2544 ◽  
Author(s):  
Wen-Kai Weng ◽  
Randall Armstrong ◽  
Sally Arai ◽  
Laura Johnston ◽  
Ginna G. Laport ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advanced Stage ◽  
Molecular Remission ◽  
Curative Therapy ◽  
Post Transplant ◽  
Preparative Regimen ◽  
Grade Ii

Abstract Introduction: The majority of patients with refractory, advanced stage MF or SS have a life expectancy less than 5 years. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed allogeneic transplant in 29 patients as a prospective clinical study using a novel non-myeloablative preparative regimen to provide prolonged disease control. Patient and Transplant Regimen: This cohort included 11 patients with MF and 18 patients with SS. The median age was 62 years (range 20-75). These patients were heavily treated with a median number of prior systemic therapies of 5 (range 2-13). The median time from diagnosis to transplant was 33 months (range 9-147). Five patients had stage IIB disease and 24 patients (83%) had stage IV disease (21 with IVA and 3 with IVB). All 11 patients with MF had evidence of large cell transformation. All patients had active disease at the time of preparative regimen (skin: 100%, blood: 62%, lymph node: 62%). The patients received total skin electron beam therapy (TSEBT, 24-36 Gy) as part of preparative regimen for skin disease control, immediately followed by total lymphoid irradiation (TLI, 8 Gy) and rabbit anti-thymocyte globulin (ATG). All patients received G-CSF mobilized peripheral blood hematopoietic cells from either an HLA-matched related (n=11), HLA-matched unrelated (n=13) or HLA-mismatched unrelated (n=5) donor. Cyclosporine or tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. The entire protocol required only a 5-day inpatient stay during the infusion of ATG. Results: As planned, all patients received their allograft infusion as outpatient. Patients tolerated the immediate post-transplant period extremely well. Fifteen patients required hospital admission within 100 days after transplant, with a median length of hospital stay of 4 days. The most common cause for admission was delayed ATG reaction. At day +90, full donor chimerism (donor CD3+ > 95%) was achieved in 10 patients (34%) and mixed chimerism was found in 14 patients (48%). Of these 14 patients, 9 of them subsequently achieved full donor chimerism and 1 had secondary graft rejection. Five patients (17%) had primary graft rejection (donor < 5%). Three of the 6 with graft rejection received a second transplant after experiencing disease progression. The incidence of GVHD in our study was considerably lower than reported in other studies using reduced intensity regimens. The cumulative incidence of grade II-IV acute GVHD was 21%. Five patients had grade II acute GVHD (4 skin, 1 GI) and 1 had fatal grade IV acute GVHD (GI). The cumulative incidence of extensive chronic GVHD at 1 and 2 years was 13% and 23%, respectively. One death was attributed to complications of chronic GVHD. At 3-month post transplant, 19 patients achieved a complete response and 7 had a partial response (ORR 90%). Two patients experienced disease progression immediately after transplant, and 1 patient had stable disease. The median post-transplant follow-up for the entire cohort was 22.2 months and for the surviving patients was 24.5 months. The 2-year OS and PFS were 76% (95% CI, 54–88%) and 50% (95% CI, 28–68%), respectively. Among the surviving 21 patients, 81% (n=17) were in CR at last follow-up (16 with durable CR lasting >1 year). Of the 8 deaths in this study cohort, 3 were from NRM, each due to acute GVHD, complications related to chronic GVHD, or secondary malignancy (B-cell acute lymphoblastic leukemia). The 1-year cumulative NRM was 3%. High-throughput sequencing (HTS) of TCRß CDR3 was used for minimal residual disease (MRD) monitoring (Sci. Transl. Med.5:214ra171, 2013) (ImmunoSEQ, Adaptive Biotech). Of the 24 patients assessed, 11 patients (46%) achieved molecular remission in the blood after transplant. The median time to achieve molecular remission in the blood was 60 days (range 30-540). Of these 11 patients, 10 of them also achieved molecular remission in the skin. The 2-year OS and PFS for patients who achieved molecular remission were 86% (95% CI, 34–98%) and 71% (95% CI, 26–92%), respectively. Conclusion: We have developed an effective novel preparatory regimen with low transplant related mortality for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. Using the utmost sensitive TCRß HTS method to assess MRD, we were able to demonstrate a potentially curative therapy with molecular remission in this patient population. Disclosures No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 825-825 ◽  
Author(s):  
Vincent Ho ◽  
Glenn Dranoff ◽  
Haesook Kim ◽  
Matthew Vanneman ◽  
Mildred Pasek ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Leukemia Cell ◽  
Sustained Remission ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Studies have shown that leukemia specific donor immune responses can be elicited by cancer vaccination after allogeneic SCT. Given the likelihood of disease progression in patients with active leukemia at the time of transplant, potential anti-tumor vaccines must be administered early post-transplant if they are to exert a meaningful effect. Early vaccination after SCT could capitalize upon the rapid homeostatic lymphoid expansion associated with post conditioning lymphopenia. However, there is concern about the efficacy of vaccinations early after allogeneic transplant when patients remain on immune suppression to prevent GVHD. GVAX, a cancer vaccine composed of leukemia cells genetically modified to secrete GM-CSF, has demonstrated activity in MDS and AML. We completed a trial investigating the feasibility and safety of administering GVAX early after allogeneic HLA matched reduced intensity conditioning (RIC) SCT for patients with MDS-RAEB or active AML. Prior to SCT, autologous myeloblasts were harvested and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Conditioning consisted of fludarabine 30mg/m2/d IV × 4, and busulfan 0.8mg/kg IV q12H × 8 doses prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. Vaccination started between day +30 to +45 post SCT if there was adequate count recovery and no grade II–IV acute GVHD. GVAX was administered SC/ID weekly × 3 doses, then q2 wks × 3 doses. Taper of tacrolimus began after vaccine completion (» d+120). Twenty four patients (13 URD, 11 MRD) were transplanted: 16 AML, 6 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 62 (range, 41–71 years). Median marrow blast content at transplant was 22% (range, 6–91%). GVAX was successfully generated for all patients. Of the 24 patients transplanted, 9 could not start vaccine due to rapid leukemia progression (4); acute GVHD requiring systemic steroids (3); sepsis (1) and IPS (1); Among the 15 patients who started vaccination per protocol, 10 completed all 6 vaccines. Mild injection site reaction with induration, erythema, and pruritus was the only common side effect. After vaccination, 3/15 patients developed grade II acute GVHD and 7/15 had cGVHD. Relapse free (RFS) and overall survival (OS) at 2 years for patients who started GVAX were 46% and 56%, respectively. This is superior to the 2-yr DFS and OS of 12% and 16% (p=0.02), respectively, in a matched cohort of 34 patients with the same disease receiving RIC SCT during the same time period. Among the patients who completed all 6 vaccines, 9/10 remain in complete remission (6 AML, 3 MDS-RAEB) with median follow-up of 22.5 months post SCT (range, 7–38 mos). Three patients with disease relapse/progression early post SCT entered CR after vaccination and taper of tacrolimus. Pathologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils in all patients who responded. Concordant with prior studies showing that anti-cancer activity after GM-CSF secreting tumor cell vaccines is associated with NKG2D-target-cell interactions mediated by NK and NK-T cells, our immunologic studies revealed progressively decreasing levels of soluble NKG2D ligands in patients with sustained remission after GVAX. Our results demonstrate that GVAX vaccination early after RIC SCT elicits important biologic activity despite administration during full immune suppression with tacrolimus. Given that all of the patients had active disease at transplant and received a reduced intensity conditioning regimen, we would have expected few to enter complete and sustained remission. Our encouraging results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after allogeneic SCT.

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