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

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.

Download Full-text

Excellent Disease-Free Survival after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Only Conditioning Regimen in a Diverse Adult Population.

Blood ◽

10.1182/blood.v106.11.2048.2048 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2048-2048 ◽

Cited By ~ 4

Author(s):

Karen K. Ballen ◽

Thomas R. Spitzer ◽

Beow Yeap ◽

McAfee Steve ◽

Bimalanghsu R. Dey ◽

...

Keyword(s):

Cord Blood ◽

Aplastic Anemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Free Survival ◽

Cord Blood Unit ◽

Disease Free ◽

Reduced Intensity

Abstract Umbilical cord blood is a useful 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 x 6 days, melphalan 100mg/m2/day x 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day x 4 days. Cord blood units were a 4/6 or better HLA match or better 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. Twenty-one patients, 15 males (71%) and 6 females (29%), median age 49 years (range 24–63 years) participated in a Phase I study. The diagnoses were AML (n=8), ALL (n=1), NHL (n=5), CLL (n=2), MDS (n=2), Hodgkins Disease (n=2), and aplastic anemia (n=1). Fifteen percent of patients were non Caucasian. The cell doses infused were a median of 4.0 x107 NC/kg (range 3.0–5.3 x107) and 2.0 X105 CD34+ cells/kg (range 0.6–10.0 x105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received successful second cord blood transplants using a different conditioning regimen. Among the remaining 19 patients, the median time to an absolute neutrophil count >500 was 20 days (range 15–34 days). The median time to a platelet count >20,000 unsupported were 41 days (range 21–125 days). One patient experienced a secondary graft failure, and is well following infusion of previously stored autologous cells. 4 patients (21%) experienced Grades II-IV acute GVHD, and only one patient (5%) experienced Grade III GVHD. There were no patients with Grade IV GVHD and no deaths from acute GVHD. Twelve patients were evaluable for chronic GVHD, and 3 patients (25%) had chronic GVHD of which one case was extensive disease. The 100 day transplant related mortality was 14%. The deaths were due to a CNS bleed, Epstein Barr virus lymphoproliferative disorder, and staphylococcal sepsis. Chimerism analysis showed predominance of one cord by Day +100 in 79% of patients evaluable for 100-day follow-up. In 85% of these patients the first cord blood unit infused predominated. One patient has had progressive disease. With a median follow-up of 7 months (range 2–16 months), the overall survival is 79% and the disease-free survival is 64%. The projected one year disease-free survival is 64%. In conclusion, 1) engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; 2) the risk of serious acute and chronic GVHD is low, 3) patients with aplastic anemia/MDS may require more intensive immunosuppression to allow engraftment, 4) GVL appears to be preserved despite the low T cell dose.

Download Full-text

Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients

Blood ◽

10.1182/blood.v118.21.1964.1964 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1964-1964

Author(s):

Saba Azarnoush ◽

Raphael Porcher ◽

Regis Peffault de la Tour ◽

Karima Yakouben ◽

Benedicte Bruno ◽

...

Keyword(s):

Bone Marrow ◽

Low Dose ◽

Acute Gvhd ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Secondary Malignancy ◽

Secondary Malignancies ◽

Reduced Intensity

Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v110.11.2016.2016 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2016-2016 ◽

Cited By ~ 1

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.

Download Full-text

Myeloablative Conditioning with Intravenous Busulfan In One Daily Dose and Fludarabine (BUF) for HLA-Identical Sibling Allogeneic HSCT In Myeloid Malignancies

Blood ◽

10.1182/blood.v118.21.3010.3010 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3010-3010

Author(s):

Javier De la Serna ◽

Jaime Sanz ◽

Arancha Bermudez ◽

Carlos Vallejo ◽

David Serrano ◽

...

Keyword(s):

Total Dose ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Leukemia Cell ◽

Disease Stage ◽

Allogeneic Hsct ◽

Myeloid Malignancies ◽

Daily Dose ◽

Related Mortality

Abstract Abstract 3010FN2 Background: There is a need to improve the conditioning regimens for allogeneic HSCT, both reducing the regimen related toxicity and improving the anti-leukemic effect. The myeloablative (MA) regimen consisting in intravenous (iv) busulfan (BU) with fludarabine (F) might be a better option than the conventional BU-CY (Cyclophosphamide) combination, since BU and F act synergistically against leukemia cell lines and previous studies with iv BU-F conditioning have reported an improved safety profile over BU-CY. Objective: We aimed to evaluate the efficacy and safety of the MA BU-F regimen, delivering iv BU in a one-daily dose after F infusion, since previous pharmacologic and clinical data supported its safety compared with the standard four-daily doses in the HLA identical sibling allogeneic HSCT setting. Patients: One hundred thirty seven consecutive adult patients with myeloid malignancies from nine Spanish institutions were recruited from 2005 to 2011. They had a median age of 47 years (range 19–74) and 60% were males. Diagnosis were AML: 80 (58.4%), AML secondary to MDS: 24 (17.5%), MDS: 23 (16.8%) and MPD: 10 (7.3%). At HSCT, the disease stage was 1st CR or untreated in 85 (62%) and more advanced stage in 52 (38%) cases. Patients having Karnofsky < 90% and Sorror CI >1 accounted for 11.7% and 38.3%. The conditioning regimen consisted in F, 40 mg/m2 daily for 4 days (total dose 160 mg/m2) followed by BU, one-daily IV 3.2 mg/kg infusion (total dose 12.8 mg/kg). GVHD prophylaxis consisted in cyclosporine and methotrexate. HSC infusion and post-transplant supportive measures and follow-up were made according each institution policies. Results: Donor graft source was peripheral blood (PB) in 93 (67.9%) and bone marrow (BM) in 44 (32.1%) cases. Median CD34+ cells infused were 4.5 millions/kg (range 0.6–17.8). All but one patient engrafted, with a median of 15 days (range 8–49) to >0.5 ×10E9 PMN/L and 13 days (range 7–149) to >20 ×10E9 platelets/L. The most frequent toxicity was mucositis, which was grade >1, in 68.8% cases. Three patients had hepatic SOS grade >1, and all of them resolved. Median hospitalization time was 30 days (range 17–114). Acute GVHD grade 2–4 incidence was 25% with a median of 32 days (range 12–87) to GVHD onset. The day-100 mortality was 4.8%. The chronic GVHD incidence in 114 patients at risk is 61.4%, with 37.7% of cases in extended form. At the time of this analysis, the median follow-up is 12 months (range 1–74). Crude survival data showed 106 (77.4%) patients remaining alive and 106 (77.4%) relapse free. Overall, 31 patients have died, 19 relapse-related (13.9%) and 12 (8.8%) due to transplant related mortality. Actuarial survival at 12 months is 79.4% and disease free survival is 71.3% in the whole series. Kaplan-Meier analysis showed that advanced age, comorbidities or advanced disease status at HSCT did not predict an inferior outcome. In conclusion, in the HLA identical sibling allogeneic HSCT setting, the BU-F regimen provides an adequate control of myeloid malignancies, with low regimen related toxicity and both reduced day-100 and non-relapse related mortality. Disclosures: Lahuerta: Janssen: Honoraria; Celgene: Honoraria.

Download Full-text

Fludarabine, Cytarabine, Busulphan, and Cyclophosphamide (FABC) as Conditioning Regimen in Hematopoietic Stem Cell Transplantation for Treatment of 92 Patients with Hematologic Malignancies.

Blood ◽

10.1182/blood.v114.22.1147.1147 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1147-1147

Author(s):

Jianyu Weng ◽

Xin Du ◽

Suijin Wu ◽

Zesheng Lu ◽

Chengwei Luo ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Chronic Myelomonocytic Leukemia ◽

Myelogenous Leukemia ◽

Hematopoietic Stem ◽

Myelomonocytic Leukemia ◽

Related Mortality

Abstract Abstract 1147 Poster Board I-169 In the past twenty years, allogeneic hematopoietic stem cells transplantation (Allo-HSCT) has been accepted as the most effective treatment for many hematologic malignancies. However, the successful rate of allo-HSCT has been limited by transplantation-related mortality and malignancies relapse, no matter using traditional intensity conditioning or reduced-intensity conditioning. In this study, we presented ninety-two patients with hematopoietic malignancies received fludarabine combinasion with modified Bu/Cy (FABC) conditioning regimen before allogeneic hematopoietic stem cell transplantation. Ninety-two patients with hematological malignancies (58 males, 34 females) ranged in age from 14 to 50 (median 28) years. These patients were diagnosed with acute lymphoblastic leukemia (ALL, n=30), acute myelogenous leukemia(AML, n=24), chronic myelogenous leukemia (CML, n=33; CP, n=27; CML-AP, n=5; CML-BC, n=1), myelodysplastic syndrome ( MDS, n=3), chronic myelomonocytic leukemia (CMML, n=1), and one patient coexisted chronic myelomonocytic leukemia and T lymphoblast cell lymphoma. Fifty-five (59.8%) patients were at high risk. From June 2004 to October 2008, 92 patients gave their informed consent and received conditioning regimen with fludarabine-based modified Bu/Cy (FABC conditioning regimen) in allo-HSCT. The FABC regimen consist of cytarabine 2.0 g/ m2 on day -9, busulphan (Bu) 3.2 mg/kg per day for intravenous on days -8 to day-6, followed by cyclophosphamide (Cy) 60 mg/kg per day on days -5 and day-4, combined fludarabin 30 mg/m2 per day for three consecutive days, on days -6 to day-4, and Me-CCNU (1-(2-Chloroethyl)-3-(4-ethylnitrobiphenyl Cylohexyl4)-1- Nitrosourea) 250 mg/m2 on day -3. Graft-versus-host-disease(GVHD) prophylaxis consisted of cyclosporine A, short-term MTX and Mycophenolate Mofefil (MMF 1.0g/day, on d-8 to d-1). Anti-T-lymphocyte globulin (2.5 mg·kg-1·d -1, on d-3 to d-1) was added to patients with mismatched sibling or unrelated donors. Follow-up was performed on 30 December, 2008. Ninety-two patients engrafted successfully, the median time for ANC >0.5×109/L was 12 (8 to 22) days, and for BPC > 20×109/L was 12 (7 -32) days. Detected by short tandem repeat (STR)-PCR, complete donor chimerism was comfirmed in all patients on day +21 or day+30. The incidence of acute GVHD was 25% (23/92), and grades 3 to 4 acute GVHD developed in 8 (8.7%) of 92 patients with in 100 days after HSCT. Chronic GVHD developed in 40(47.6%) of 84 patients who were alive more than 100 days after HSCT, and the incidence of extensive cGVHD was 35.7%(30/84). The transplant related mortality (TRM) was 19.6% (18/92), mainly from severe infection (n=7), acute or chronic GVHD (n=5), transplant associated-microangiopathy (n=2), diffusion alveolar hemorrhage (n=2), and post-transplant lymphoproliferative disorders (n=2). With a median follow-up of 16.2(1.5 to 54.5) months, 70 (76.1%) of the 92 patients were alive and 67(72.8%) were disease-free. The probabilities of OS at 1 year and 2 years was 80% and 72.5%, and DFS was 79.1% and 71.4%, respectively. These results suggest that the fludarabine-based modified Bu/Cy conditioning regimen (FABC) should reduce severe acute GVHD and accelerate hematopoietis resconsition without increasing chronic GVHD and lower leukemia relapse rates even in high-risk patients. Footnotes Corresponding author Disclosure No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v118.21.1943.1943 ◽

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.

Download Full-text

HLA-Haploidentical HSCT with Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Blood ◽

10.1182/blood.v120.21.4510.4510 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4510-4510

Author(s):

Yuelin He ◽

Chunfu Li ◽

Xuedong Wu ◽

Xiaohui Zhou ◽

Xiaoqin Feng ◽

...

Keyword(s):

Aplastic Anemia ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Donor Lymphocyte Infusion ◽

Severe Aplastic Anemia ◽

Platelet Recovery ◽

Graft Versus Host

Abstract Abstract 4510 Objective To investigate the effect of pretransplantation donor lymphocyte infusion (DLI) and posttransplantation cycolphosphamide (CY) to prevent graft rejection and graft-versus-host disease (GVHD) after bone marrow transplantation plus peripheral blood stem cell transplantation from HLA-haploidentical mismatched related donors. Methods Four patients (median age, 11 years; range, 8–15 years) with severe aplastic anemia and all of them had HLA-haploidentical donors more than or equal to 2/8 HLA (HLA-A, B, C and DRB1) mismatched at antigen level. The conditioning regimen consisted of pretransplantation DLI (Lymphocytes, 1×10e7/kg at day -9); 40mg/m2/day of fludarabine (day-6 to -2); 3.2mg/kg/day of Busulfex (day-6 and -5); 10mg/kg/day of Thiotepa (day -4) and 50mg/kg/day of Cy on day -7, 14.5mg/kg on day-3,-2 and 40mg/kg on day +3,+4, respectively. The prophylaxis of acute GVHD consisted of tacrolimus and mycophenolate mofetil. The median follow-up time is 5 (rang: 3–6) months. Results The median times to neutrophil (>500/ÌL) and platelet recovery (>20,000/ÌL) were 21 and 23.5 days, respectively. No acute GVHD and Chronic GVHD were, so far, observed for all patients and were survive without SAA. Conclusion Posttransplantation cyclophosphamide for the prophylaxis of acute GVHD was safe and effective. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Bone Marrow Transplantation ◽

10.1038/s41409-021-01323-9 ◽

2021 ◽

Author(s):

Michael H. Albert ◽

Mehtap Sirin ◽

Manfred Hoenig ◽

Fabian Hauck ◽

Catharina Schuetz ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Reduced Intensity

AbstractGraft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

Download Full-text

Primary Graft Failure (GF) after Unrelated Donor Cord Blood Transplants (UCBT): Risk Factors and Management.

Blood ◽

10.1182/blood.v108.11.44.44 ◽

2006 ◽

Vol 108 (11) ◽

pp. 44-44 ◽

Cited By ~ 2

Author(s):

Ka Wah Chan ◽

Michael S. Grimley ◽

Candace Taylor ◽

Donna A. Wall

Keyword(s):

Risk Factors ◽

Cord Blood ◽

Aplastic Anemia ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Viral Reactivation ◽

Unrelated Donor ◽

Cell Dose

Abstract Primary GF is recognized as a major risk in UCBT. Both graft (cell dose and quality of the cord blood unit) and recipient (diagnosis of aplastic anemia, prior chemotherapy exposure) characteristics have been reported as being associated with non-engraftment. Here we present a large series of UCBT patients from a single institution and analyze the risk factors and management of this complication. Between 3/2001 and 7/2006, 106 consecutive patients (pts), of median age 5.3 (range 0.1–18.4) years and weight median 22 (range 4–85) kg, received UCBT at Texas Transplant Institute. 13 did not achieve donor engraftment as documented by recovery of ANC< 500/μl by day + 42, and lack of donor cells on ≥2 RFLP analysis of the bone marrow. Failure to attain engraftment occurred in 5/27 with a non-malignant disorders, and 8/79 with hematologic malignancies (p< 033). Non-engraftment was less common in better HLA matched transplants (≥5/6 HLA match: 1/45 vs ≤ 4/6 HLA : 12/61; p< 0.02). Preliminary analysis showed no difference in cord blood TNC/kg, CD34/kg and pre thaw CFU/kg in pts who had primary GF compared to the rest of the cohort. A post thaw CFU/pre-freeze ratio of <20% was more common in primary GF. Among the 79 pts with hematologic malignancies (HM), 8 did not engraft. 4 died early; 1 from persistent leukemia, and 3 from transplant-related complications (TRM). Of the remaining 4 pts with HM, 2 were ALL children in CR1. The other primary GF occurred in 2/5 children with HLH (both with active disease at UCBT), 2/8 the children transplanted for aplastic anemia, and one pt with CD40L deficiency who had primary GF. The 9 pts who had not relapsed or died of TRM went on to second (2nd) UCBT 33 to 95 (median 55) days after first transplant (1st UCBT). Conditioning regimen for 2nd UCBT was fludarabine 175mg/m2, cyclophosphamide 50mg/kg, TBI 2 Gy, ± ATG in 7/9 patients. Median cell dose for 2nd UCBT were 3.6 × 107/kg. HLA matching was similar to 1st UCBT. There was one TRM (respiratory failure) but the rest (8/8) engrafted; with ANC >500/μl at a median of 15 (range 5–64) days, and platelets > 20000/μl at a median of 92 (range 24 to 137) days. All became transfusion-independent, and as of 8/1/2006, 7 of 9 pts are alive. All have complete donor chimerism 164–1616 (median 672) days after 2nd UDCBT. EBV-lymphoproliferatve disorders developed in 2 patients and it was fatal in one. Other viral infections encountered were BKV(1), HHV-6(1), CMV(3) in the blood; adenovirus(1) and enterovirus(1) in the stool; and BKV (1) in the urine. Acute graft-versus-host disease (GVHD) was diagnosed in 2/8 pts. 7/8 pts surviving >100 days had chronic GVHD, and it was extensive in 5 pts. It is important that primary GF be recognized as a risk of UDCBT and a back-up donor source be identified prior to transplant. Children with intact/active immune systems prior to transplant are at greater risk. Early 2nd UCBT, before patient’s condition deteriorates, is a feasible treatment alternative. This immunosuppressive preparative regimen is well tolerated early post first UCBT and can result in reliable engraftment, albeit a greater risk of chronic GVHD and viral reactivation post transplant.

Download Full-text

Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Blood ◽

10.1182/blood.v114.22.4328.4328 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4328-4328

Author(s):

Karen K Ballen ◽

Steven L McAfee ◽

Bimalangshu R Dey ◽

Christine Dube ◽

Eyal C Attar ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Total Dose ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Acute Myelogeneous Leukemia ◽

Reduced Intensity

Abstract Abstract 4328 The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures: Spitzer: Genzyme: Consultancy.

Download Full-text