Double Cord Blood Transplantation: Incidence, Organ Involvement and Risk Factors of Acute Graft Versus Host Disease. a Retrospective Analysis on Behalf of Eurocord, ALWP and Cqwp-EBMT

Abstract Double umbilical cord blood transplantation (dUCBT) has extended the applicability of UCBT for hematologic disorders especially to adult patients (pts) for whom the low cellular content of a single unit is a limiting factor. However the use of dUCBT has been, recently, associated with a higher incidence of acute graft-versus-host disease (aGVHD) when compared with single UCBT (sUCBT). Moreover, several retrospective and prospective studies have addressed risk factors for aGVHD with some conflicting results. Whether the number of total nucleated cells, HLA disparities, type of conditioning regimen or GVHD prophylaxis have an impact on aGVHD incidence in dUCBT is yet to be established in a larger series of patients. With this background, this report analyzed 921 adult recipients who underwent dUCBT for hematologic malignancies from 2005-2012 in EBMT centers. Median age was 46 (range, 18-72) years (yrs) and 59% were males. Diagnosis was acute leukemia in 56%, MDS/CML in 19% and lymphoid malignancies in 25%; 22% of pts received at least one prior autologous HSCT. Reduced-intensity conditioning (RIC) was used in 68% of pts and the most common regimen for both myeloablative conditioning (MAC) and RIC was Cyclophosphamide-Fludarabine-TBI (TCF) (40% and 78%, respectively). ATG was used in 30% of pts. GVHD prophylaxis consisted of a MMF based regimen in 774 pts (84%); cyclosporine±steroids in 103 (11%) and MTX-based regimen in 44 (5%). HLA incompatibilities were classified using the cord blood unit bearing the highest degree of mismatch with the recipient: 1% were HLA matched 6/6, 25% were 5/6, 67% were 4/6, and 7% <4/6. Median TNC collected was 4.8x10e7/kg. With a median follow-up of 26 months (range, 3-98) aGVHD was absent in 418 patients (46%), 169 pts developed grade I (18%), 194 grade II (21%), 103 grade III (11%) and 37 grade IV (4%). One-hundred day cumulative incidence (CI) of aGVHD grade II-IV was 36%±2% and III-IV 15%±2%, with a median time of onset of 28 days (range, 4-97). Of those pts with grade II-IV aGVHD, 82% had skin, 66% gastro-intestinal tract (GIT) and 25% liver involvement. The most common organ involvement in pts with grade III-IV aGVHD was GIT (89%) followed by skin (71%) and liver (39%). Treatment of grade II-IV aGVHD was steroid alone in 91% of pts. For pts with grade III-IV aGVHD steroid was used alone in 77% of pts, 11% received steroid+monoclonal antibodies, 3% steroid+MTX and 9% other treatments (figure 1). At day 60, CI of neutrophil engraftment was 84%. Out of the 712 pts at risk, 218 developed chronic GVHD (cGVHD) with a CI at 2 yrs of 25%±5%. Of these, 102 pts (47%) had previous aGVHD grade II-IV and 116 (53%) had de novo cGVHD. CI of early NRM (at day 100) was 13%. At 2 yrs, the probability of PFS was 37%, NRM 35% and relapse 28%. In multivariate analysis, the following factors were associated with an increased incidence of grade II-IV GVHD: use of MAC (HR: 1.45 (1.12-1.91), p=0.005), absence of ATG (HR: 2.39 (1.78-3.30), p<0.001) and ≥2 HLA mismatches (HR: 1.35 (1.01-1.81), p=0.048) – figure 2; whereas advanced stage disease at transplantation (HR: 1.76 (1.10-2.80), p=0.02) and absence of ATG (HR: 2.54 (1.56-4.13), p<0.001) were associated with increased incidence of aGVHD grade III-IV. Presence of 2 or higher HLA mismatches was associated with increased incidence of cGVHD (HR: 1.5 (1.1-2.05), p=0.01). In a time dependent model the presence of grade II-IV aGVHD was associated with lower relapse risk (HR: 0.71 (0.54-0.94), p=0.02), higher NRM (HR: 1.4 (1.1-1.76), p=0.005) and increased incidence of cGVHD (HR: 1.92 (1.59-2.63), p<0.001). Despite previous analysis showing increased incidence of acute and chronic GVHD after dUCBT, our study demonstrated that the GVHD incidence remains relatively low in dUCBT setting when compared to published data on HLA matched adult donor. In pts developing grade II-IV aGVHD, skin was the most common organ affected, followed by GIT and liver. Steroid alone was the backbone treatment of aGVHD and the association of steroid and other therapies (mainly monoclonal antibodies) was mostly seen in pts affected by grade III-IV aGVHD. Acute GVHD grade II-IV seems to be influenced by the intensity of the conditioning regimen, the use of ATG, and HLA compatibility; therefore prospective trials evaluating the role of these factors in dUCBT should be addressed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Acute Graft-Versus-Host Disease Following Umbilical Cord Blood Transplantation: Retrospective Survey Involving 2015 Japanese Patients.

Blood ◽

10.1182/blood.v110.11.1070.1070 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1070-1070

Author(s):

Shigesaburo Miyakoshi ◽

Takuhiro Yamaguchi ◽

Masahiro Kami ◽

Tomoko Matsumura ◽

Koichiro Yuji ◽

...

Keyword(s):

Cord Blood ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Event Free Survival ◽

Free Survival ◽

Graft Versus Host ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Acute Graft

Abstract BACKGROUND Limited information is available on incidences and clinical features of acute graft-versus host disease (GVHD) after cord blood transplantation and large-sized researches have been awaited. METHODS We investigated the incidences and clinical features of acute GVHD in 2,015 patients reported to the Japan Cord Blood Bank Network, who underwent cord blood transplantation between June 1997 and August 2006. RESULTS Of 2,015 patients, 1481 patients (73%) achieved neutrophil engraftment at a median of day 22 (range, 6–81). Cumulative incidence of neutrophil recovery at day 100 was 0.74 (95%CI, 0.73–0.76). Of 2015 patients, 708 patients developed grade II-IV acute GVHD: grade II (n=423), grade III (n=237), and grade IV (n=48). The median onset was day 19 (range, 4–190). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 0.35 (95% CI, 0.33–0.37) and 0.14 (95% CI, 0.12–0.15), respectively. Skin and gastrointestinal acute GVHD was documented in 1,006 and 405 patients, respectively, whereas liver GVHD was diagnosed in 149 patients. Multivariate analysis identified the following predictors of grade II-IV acute GVHD: the number of infused nucleated cells, transplantation from female donors to female recipients, TBI-containing preparative regimens, methotrexate-containing GVHD prophylaxis, and tacrolimus-based GVHD prophylaxis. Overall survival rates at three years of patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer were 0.58 (95%CI, 0.53–0.63), 0.61 (95% CI, 0.54–0.67) and 0.40 (95%CI, 0.31–0.49), respectively. CONCLUSIONS Acute GVHD following cord blood transplantation is mild and has graft-versus malignancy effects. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation.

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Preliminary Results of Combined Haploidentical-Cord Blood Transplantation for Patients Lacking HLA Identical Donors

Blood ◽

10.1182/blood.v112.11.3015.3015 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3015-3015 ◽

Cited By ~ 1

Author(s):

Elizabeth Shima Rich ◽

Andrew Artz ◽

Theodore Karrison ◽

Amittha Wickrema ◽

Loren Joseph ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Interstitial Pneumonitis ◽

Bone Marrow Cells ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

Total Body

Abstract Background: Many patients (pts), particularly minorities, lack matched unrelated donors. Mismatched cord blood (CB) transplantation causes less graft versus host disease (GVHD), but is associated with delayed hematopoietic recovery. We studied an alternative donor regimen using T-cell depleted haploidentical stem cells and unrelated CB pioneered by Magro et al. (Haematologica2006;91:640–8) to confirm engraftment with acceptable rates of GVHD. Patients and Methods: We enrolled 15 pts (7 AML, 1 ALL, 2 MDS, 1 CML, 3 NHL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 28 years (range, 4–66) and median weight was 75 kg (range, 14–124). Twelve pts had active disease at transplant; 2 had prior autologous transplants. Eight pts were Caucasian; 7 other race or ethnicity. The haploidentical donor was the mother in 3; father in 1; child in 4; sibling in 5; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.41 × 106/kg (range, 1.25–6.26); CD3+ cells were 0.8 × 104/kg (range, 0.3–1.3). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 1 pt; 5/6 in 7 pts; 4/6 in 6 pts; 3/6 in 1 pt. Median cord total nucleated cells equaled 2.39 × 107/kg (range, 1.07–9.36); CD34+ cells were 0.14 × 106/kg (range, 0.04–0.75). The conditioning regimen for most pts was fludarabine (Flu) (30 mg/m2 × 5 days), thiotepa (5 mg/kg × 2 days), total-body irradiation (TBI) (12 Gy lateral opposed fields), and Thymoglobulin® (rATG) (1.5 mg/kg × 4 days). Five pts unable to tolerate TBI received Flu, melphalan (70 mg/m2 × 2 days), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Results: Two pts died early (sepsis, CVA). Twelve of the remaining 13 pts engrafted. One pt failed to engraft and died on day (d)36. Median time to ANC >500/mL was 9 days (range, 9–12). Median time to sustained platelets >20,000/mL was 24 days (range, 12–63). Early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0–100) on d14; 76% (range, 0–93) on d30; 36% (range, 0–83) on d55; 0% (range, 0–42) on d100; and 0% on d180. Median unfractionated cord chimerism was <5% (range, 0–100) on d14; 24% (range, 7–100) on d30; 64% (range, 17–100) on d55; 100% (range, 58–100) on d100; and 100% on d180. In the CD3+ compartment, median haploidentical chimerism was 94% (range, 0–100) on d14; 72% (range, 0–93) on d30; 24% (range, 0–76) on d55; 0% (range, 0–39) on d100; and 0% on d180. Median CD3+ cord chimerism was 6% (range, 0–100) on d14; 28% cord (range, 7–100) on d30; 76% (range, 24–100) on d55; 100% (range, 61–100) on d100; and 100% (range, 90–100) on d180. Four pts died of sepsis. One pt died of VOD; 2 pts who also received TBI developed interstitial pneumonitis, 1 fatal. Two pts relapsed and died. Cumulative d100 treatment-related mortality (TRM) was 44% (95% CI: 22 to 73%). Acute skin GVHD grade I–II occurred in 3 pts. No cases of chronic GVHD developed. Five pts are currently alive and in remission with complete CB chimerism. The median follow up for survivors is 207 days (range, 23–283). The median age of survivors is 27 years (range, 20–67). Conclusions: Combined haploidentical and CB transplantation is a promising strategy for those lacking HLA identical donors - even in the presence of low CB doses - leading to early haploidentical engraftment followed by durable CB predominance by d100. Acute and chronic GVHD are manageable. Complications such as interstitial pneumonitis may be related to the TBI-containing regimen. This donor combination, with further modifications to decrease TRM, warrants further study in pts lacking HLA identical donors.

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Intensified Mycophenolate Mofetil (MMF) Dosing Every 8 Hours Is Safe From The Standpoint Of Engraftment and May Ameliorate Severe Acute Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (CBT)

Blood ◽

10.1182/blood.v122.21.4600.4600 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4600-4600 ◽

Cited By ~ 1

Author(s):

Doris M Ponce ◽

Stephen J. Harnicar ◽

Sean Devlin ◽

Patrick Hilden ◽

Katherine L Evans ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Cord Blood ◽

Graft Versus Host Disease ◽

Calcineurin Inhibitor ◽

Cord Blood Transplantation ◽

Graft Versus Host ◽

Blood Transplantation ◽

Grade Ii ◽

Grade Iii ◽

Acute Graft

Background Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure. Methods We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those <12 years received 15 mg/kg/dose). From 9/2009, 91 patients (53%) received MMF at 1 gm IV q8 for patients both >12 years and ≥50 kg (or 15 mg/kg/dose if >12 years but <50 kg, or 20 mg/kg/dose if <12 years). The Gray's test compared the incidence of GVHD across the q12 and q8 dosing while the log-rank test was used to compare progression-free survival (PFS). Results Patient characteristics and infused viable CD34+ cell doses were similar in the q12 and q8 MMF groups. A comparison of transplant outcomes by MMF dosing is shown (Table). There were no differences in the time to neutrophil or platelet engraftment and the median time to count recovery was also similar. The incidences of grade II-IV aGVHD at day 100 were similar in the groups (46% vs 52%). However, there was a suggestion of decreased grade III-IV aGVHD at day 100 in the q8 MMF group (12%) versus the q12 group (21%), although this comparison did not reach significance. With a median follow-up of 41 months (range 3-94), the PFS in each dosing group was not significantly different. Conclusions We demonstrated that intensified q8 MMF dosing is safe from the standpoint of engraftment and toxicity. There was a suggestion of decreased severe grade III-IV aGVHD in recipients of 1 gm IV every 8 hours. While a larger analysis is needed to further investigate these findings, the results are encouraging. They suggest that, as with adult donor allografts, intensified q8 hour MMF dosing should be the dose investigated for the prevention of aGVHD in CBT recipients transplanted with CSA/ MMF prophylaxis without ATG. Finally, aGVHD prophylaxis could be further optimized in CSA/ MMF-based CBT by mycophenolic acid trough level drug monitoring, early post-transplant biomarker measurements such as ST2, and delayed taper post-transplant. Disclosures: No relevant conflicts of interest to declare.

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Low-Dose Methotrexate Could Reduce Severe Early Immune Reactions but Probably Increase Garft Failure in Umbilical Cord Blood Transplantation

Blood ◽

10.1182/blood-2019-131524 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5679-5679

Author(s):

Liu Huilan ◽

Xiaoyu Zhu ◽

Kaidi Song ◽

Xiang Wan ◽

Guangyu Sun ◽

...

Keyword(s):

Cord Blood ◽

Graft Versus Host Disease ◽

Low Dose ◽

Cord Blood Transplantation ◽

Immune Reactions ◽

Graft Versus Host ◽

Blood Transplantation ◽

Dose Methotrexate ◽

Gvhd Prophylaxis

Early immune disorders, including preengraftment syndrome (PES)and acute graft-versus-host disease(aGvHD)are problematic in cord blood transplantation (CBT), and optimal prophylaxis has not been established. Here, we prospectively investigated whether intensive GvHD prophylaxis by adding low-dose methotrexate (MTX)at day 3 after CBThas a prognostic impact on CBT. 16 consecutive single-unit CBT recipients treated for high-risk hematologic malignancies (10 cases) and non-malignancies (6 cases) between February 2019 and March 2019. The patients, 6 female and 10 males, had a median age of 9 years (range 4-40) and a median weight of 26 kg (range 14-68). Myeloablative preparative regimen comprised fludarabine, busulfan and cyclophosphamide for malignancies and reduced-intensity-conditioning comprised fludarabine, cyclophosphamide and total-body irradiation (4 Gy) for non-malignancies. Graft-versus-host disease (GvHD) prophylaxis was cyclosporine and mycophenolate mofetil plus MTX 3 mg/m2 on day+3. 14 patients achieved engraftment at a median of day 19 and had more than 95% (complete) donor chimerism on day+14.Two patients without hematopoietic reconstitution were engrafted after a second CBT. PES was characterized by high-grade fever, rash, pulmonary edema, weight gain, liver and renal dysfunction developed on a median of day 8 in 11 of the 16 evaluable patients, including 2 who did not achieve engraftment. The PES patients received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 2 patients were requiredBasiliximab to improve clinical symptoms. Grade I to IV and aGvHD developed in 4 and only 1 patient developed severe aGvHD with Grade Ⅲ. Follow-up so far, one death occurred at day 103 because of pneumonia. 15 patients are alive well at a median follow-up of 135 days (131-163). Adding low-dose MTX at day +3 may be offer one optimal regimen to reduce severe early immune reactions and improve outcomes in CBT. Disclosures No relevant conflicts of interest to declare.

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Outcomes after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia. An Eurocord-Netcord Survey.

Blood ◽

10.1182/blood.v106.11.304.304 ◽

2005 ◽

Vol 106 (11) ◽

pp. 304-304 ◽

Cited By ~ 1

Author(s):

Vanderson Rocha ◽

Gerard Michel ◽

Nabil Kabbara ◽

William Arcese ◽

Juan Ortega ◽

...

Keyword(s):

Cord Blood ◽

Cumulative Incidence ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Cord Blood Transplantation ◽

Blood Transplantation ◽

Advanced Phase ◽

Unrelated Cord Blood

Abstract Unrelated cord blood transplantation (UCBT) is an alternative option to treat children with haematological diseases without an HLA-identical donor. We have analyzed a total of 323 children with ALL receiving an UCBT, from 1994 to 2004 in 99 transplant centres in 24 countries, mostly in Europe. Cumulative incidence with competing risk and KM estimates were used to calculate outcomes. Seventy six children were transplanted in CR1, 136 in CR2 and 111 in more advanced phase of the disease. Among those children poor cytogenetics were observed in 89% of children in 1CR, 33% in 2CR and 42% in advanced phase. Twenty percent of children transplanted in advanced phase had been previously autografted. The median age was 6.5 years at UCBT, median cell dose infused was 4.1x107/kg and the median follow time was 22 months (3–96). The cord blood was HLA identical (6/6) in 12% of the cases, 5/6 in 46%, 4/6 in 39% and 3/6 in 3%. All children received myeloablative conditioning regimen (TBI in 66%) and the majority (67%) received CsA+corticoids as GVHD prophylaxis. Cumulative incidence of neutrophil recovery at day 60, platelets recovery (>20.000) at day 180, acute (grade II–IV) and chronic GVHD were 76±5%, 54±5%, 42±3%, 14±2%, respectively. Overall 2 year-LFS was 36±3%. In a multivariate analysis, only CR1 or CR2 were associated with better LFS (HR=1.8; p<0.0001). Outcomes CR1 (n=76) CR2 (n=136) Advanced (n=111) TRM at day 100 22+/−5% 25+/−4% 34+/−5% Relapse at 2 years 34+/−8% 37+/−5% 48+/−7% LFS at 2 years 42+/−6% 41+/−4% 24+/−4% For those patients transplanted with poor cytogenetics, LFS at 2 years was 32±6% and it was 37% for CR1, 43% for CR2 and 0% for advanced phase of the disease. In conclusion, in these large series of high risk ALL patients, these results show that UCBT should be proposed as alternative source of allogeneic transplantation for children lacking an HLA identical donor, in earlier status of the disease.

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Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.

Blood ◽

10.1182/blood.v110.11.2023.2023 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2023-2023

Author(s):

Koji Kato ◽

Ayami Yoshimi ◽

Etsuro Ito ◽

Kentaro Oki ◽

Jun Hara ◽

...

Keyword(s):

Cord Blood ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

Disease Status ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

Cd34 Cells ◽

Advanced Stages ◽

Grade Ii

Abstract Cord blood transplantation (CBT) became one of the important alternatives in allogeneic stem cell transplantation for children with hematological malignancies. We have analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified risk factors of transplant outcome, when they had no prior transplant. From 1997 to 2006, total 332 children with ALL have undergone CBT from unrelated donor and 270 of them had no prior transplant. They are 0–15 yrs (median 5) and 4 to 60kg of body weight (median 18). Serological disparities of HLA for graft-versus-host disease (GVHD) direction were 0(n=54), 1(n=168) and 2(n=47), and disease status at transplant were 1st complete remission (CR) (n=120), 2nd CR (n=71), and more advanced stages (n=75). The median number of nucleated cells in cord blood unit was 4.93×107/kg (1.35–24.9), and that of CD34+ cells was 1.53×105/kg (0.17–15.0). As preconditioning, total body irradiation (TBI) was given in 194 patients and methotrexate (MTX) was given as GVHD prophylaxis in 159 patients. The neutrophil engraftment was achieved in 88.5% (95%CI: 84.1–91.8%) of patients and platelet engraftment (>50k) was obtained in 72.6% (95%CI: 66.8–77.7). The incidence of grade II–IV and III–IV acute GVHD was 45.6% (95%CI: 39.5–51.4) and 20.4% (95%CI: 15.8–25.4) respectively. Non-relapse mortality was observed in 22.6% (95%CI: 17.7–27.8) and 35.2% (95%CI: 29.2–41.3) of patients relapsed after CBT. The five year event free survival (EFS) of all patients was 38.1% (95%CI: 34.9–41.3); 47.4%(95%CI: 42.4–52.4) in 1st CR, 45.5%(95%CI: 38.9–52.1) in 2nd CR and 15.2%(95%CI: 10.8–38.9) in more advanced stages, respectively. The multivariate analysis revealed that the larger number of CD34+ cells (p<0.01) and administration of granulocyte colony stimulating factor after CBT (p<0.01) were associated with earlier neutrophil engraftment. Preconditioning with TBI (p<0.01) and absence of MTX (p=0.037) significantly affected the development of grade II-IV acute GVHD. Advanced disease at transplant was the most predominant factor for leukemic relapse (p<0.01). GVHD prophylaxis with MTX (p=0.042), less allele mismatches (p=0.013) and disease status of 1st and 2nd CR at transplant (p<0.01) were significantly associated with better EFS. Our results showed the favorable effect of MTX for the development of acute GVHD and EFS. In conclusion, GVHD prophylaxis including MTX is important in CBT for children with ALL.

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Allogeneic Hematopoietic Cell Transplantation From Combined Haploidentical Family Members and Unrelated Cord Blood (CB) Can Benefit High Risk Patients Lacking HLA-Identical Donors.

Blood ◽

10.1182/blood.v114.22.3378.3378 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3378-3378 ◽

Cited By ~ 1

Author(s):

Elizabeth Shima Rich ◽

Andrew Artz ◽

Theodore Karrison ◽

Lucy A Godley ◽

Olatoyosi Odenike ◽

...

Keyword(s):

High Risk ◽

Cord Blood ◽

Median Time ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Bone Marrow Cells ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Blood Transplantation

Abstract Abstract 3378 Poster Board III-266 Introduction: Haploidentical-cord blood transplantation is a promising approach for patients (pts) who lack HLA donors and may improve rates of early engraftment while allowing long term cord blood reconstitution with low rates of GVHD. We enrolled 29 pts (17 AML/MDS, 4 ALL, 3 CML, 4 NHL/HL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 40 years (range, 4-67), and median weight was 75 kg (range, 14-125). Twenty-two (76%) pts had active disease at time of transplant; 6 had prior autologous transplants. 14 pts were Caucasian; 15 were other race or ethnicity. The haploidentical donor was the mother in 4; father in 3; child in 10; sibling in 10; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.51 × 106/kg (range, 1.25-10.95); CD3+ cells were 1.0 × 104/kg (range, 0.3-3.7). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 2 pts; 5/6 in 18 pts; 4/6 in 9 pts. Median cord total nucleated cells equaled 1.93 × 107/kg (range, 1.07-9.36); CD34+ cells were 0.08 × 106/kg (range, 0.03-0.75). The conditioning regimen for 18 pts was fludarabine (Flu) (30 mg/m2 on d-7 through -3), melphalan (Mel) (70 mg/m2 on d -3 and -2), and Thymoglobulin (rATG) (1.5 mg/kg on d-7, -5, -3, -1). Eleven pts received Flu, thiotepa (5 mg/kg on d -7 and -6), total-body irradiation (TBI) (12 Gy lateral opposed fields in 2 Gy fractions BID on d-3 through -1), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Engraftment: Two pts died early (sepsis, CVA). Three other pts failed to engraft with either haploidentical or CB and died of infection on d36, 43, and 63. One of these had anti-donor HLA antibodies. 24 pts engrafted with a median time to ANC >500/mL of 10 days (range, 9-31) and median time to sustained platelets >20,000/mL of 20 days (range, 15-63). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. However, 3 pts had persistent hematopoiesis associated with only the haploidentical donor, while a fourth pt engrafted with only CB on day 31. Late graft failure and death from sepsis occurred in one of the patients with haploidentical engraftment. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0-100) on d14; 76% (range, 0-95) on d30; 6% (range, 0-87) on d100. Median unfractionated cord chimerism was <5% (range, 0-100) on d14; 20% (range, 0-100) on d30; 85% (range, 0-100) on d100. In the CD3+ compartment, median haploidentical chimerism was 95% (range, 0-100) on d14; 86% (range, 0-95) on d30; 6% (range, 0-79) on d100. Median CD3+ cord chimerism was 5% (range, 0-100) on d14; 26% (range, 0-100) on d30; 90% (range, 1-100) on d100. Toxicities and outcome: Other fatal toxicities included VOD (1), EBV-associated PTLD (1), ARDS (1), cardiac arrest (1), intractable seizures (1). Two patients developed TTP and later died of complications related to sepsis. Five pts relapsed of whom 4 have died. Acute GVHD (aGVHD) grade II occurred in 3 pts, one of whom developed the only case of chronic GVHD after failing to continue prograf. No aGVHD grade III-IV was seen. Twelve pts are currently alive; 11 are without disease. The median follow up for survivors is 186 days (range, 16-642). Estimated one year survival is 26% (95%CI, 6-46), and PFS is 19% (1-36). Conclusions: Combined haploidentical and CB transplantation results in early haploidentical engraftment followed by durable CB predominance in a majority of pts. The median times to neutrophil engraftment are considerably shorter - and the range narrower - than with other methods of cord blood transplantation. Early haploidentical engraftment failed in four patients; cord blood engraftment also failed in three of these pts and in three others. Rates of acute and particularly of chronic GVHD are low. Durable remissions can be achieved even in high risk pts regardless of age or remission status at the time of transplant. Disclosures: Rich: Genzyme: Research Funding. Odenike:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. van Besien:Genzyme: Research Funding.

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Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽

10.1182/blood.v116.21.223.223 ◽

2010 ◽

Vol 116 (21) ◽

pp. 223-223 ◽

Cited By ~ 4

Author(s):

Vanderson Rocha ◽

Myriam Labopin ◽

Annalisa Ruggeri ◽

Marina Podestà ◽

Dolores Caballero ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

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Reduced Intensity Conditioning Regimen Prior to Unrelated Cord Blood Transplantation In Patients with Acute Myeloid leukemia : Preliminary Analysis of a Prospective Phase II Multicentric Trial on Behalf of Societe Française De Greffe De Moelle Osseuse Et Therapie Cellulaire (SFGM-TC) and Eurocord

Blood ◽

10.1182/blood.v116.21.911.911 ◽

2010 ◽

Vol 116 (21) ◽

pp. 911-911 ◽

Cited By ~ 1

Author(s):

Bernard Rio ◽

Sylvie Chevret ◽

Stephane Vigouroux ◽

Patrice Chevallier ◽

Sabine Furst ◽

...

Keyword(s):

Cord Blood ◽

De Novo ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Blood Transplantation ◽

Reduced Intensity Conditioning Regimen ◽

Prospective Phase ◽

Grade Ii ◽

Unrelated Cord Blood

Abstract Abstract 911 Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of CB in elderly patients(pts) and those with co-morbidities without an HLA identical donor. To evaluate RIC-UCBT in pts with Acute Myeloid Leukemia (AML), we conducted a prospective phase II multicentric trial in France, whose primary objective was to show a reduction in non-relapse mortality (NRM) from 40% (based on registry data) to 20%. We calculated that at least 76 pts should be enrolled (for controlling type I and type II error rates both at 5%). Inclusion criteria were: 1) de novo and secondary AML, 2) lack of HLA identical unrelated donor (10/10 or 9/10), 3) cord blood units (CBU) with less than 3/6 HLA disparities, 4) a nucleated cell dose before freezing of more than 3×107/Kg within 1 or 2 CBU. The conditioning regimen consisted of cyclophosphamide (50mg/kg) +fludarabine (200mg/m2)+ TBI(2Gy), CsA +MMF as GVHD prophylaxis and GCSF from day +1. Supportive care and infections prophylaxis were given according to the EBMT recommendations. Patients were enrolled in 23 centers from Oct. 2007 to Sept. 2009. This preliminary results include 65 pts, 55% female, median age at diagnosis of 49.7 years (range, 13–65), mostly with de novo AML, extramedullary leukemic involvement of AML in 8%. Cytogenetics was normal in 33 pts (52%), of those 10/33 were FLT3 positive, and abnormal in 48%, including 36% with a complex karyotype and/or abnormality of chr 5, 7, 11 and inv 3. Nine (14%) pts had been previously transplanted. 57% of the pts were transplanted in 1st complete remission (CR1), 40% in CR2 and 3% in non-remission. Median time from diagnosis to transplant was 6.6 months (range, 3.7–24) in pts transplanted in CR1 and was 21 months (range, 5.1–93) for pts transplanted in CR2. Median age was 51 years (14-65), median weight was 65 kg (49-105), 51% were CMV-seropositive. The median follow-up for survivors was 20 months (range 9–30). 51% of the pts had no comorbidity. The Sorror score was 1 in 17%, 2 in 8 and 3 or more in 24%. 60% of the pts received 2 CBU. The median number of nucleated cells (NC) and CD34 infused after thawing were 3.4 x107/kg (0.5-6) and 1.1 x105/kg (0.10-3.1), respectively. Patients transplanted with a single CBU received a median of 2.92 NC x107/kg and of 0.92 CD34 x105/kg. Those transplanted with 2 CBU received 3.5 x107/kg and 1.1 x105/kg, respectively; 3% of the units were HLA matched, 23% 5/6 and 74% 4/6 (HLA defined as low resolution for HLA-A and B and high resolution for HLA-DRB1; the highest HLA disparity between CB and pts was taken into consideration in double CBT). ABO major incompatibility was observed in 40% of the pts (in double CB, the highest incompatibility was considered). Results: Median time to cell recovery was 15 days (95CI: 11–20) for neutrophils and 43 days for platelets. Cumulative incidence (Cum Inc) of neutrophil recovery at day 60 was 86% (95CI: 78–95%); 85% (95CI: 69–99) after 1 CBU and 87% (95CI: 76–98) after 2 CBU (p=ns). Twenty-three pts developed grade II-IV acute(a) GVHD (grade II: n=8; grade III n=14; grade IV n=1); Cum Inc of aGVHD (II-IV) at day 100 was 37% (95CI: 24–47%)(38% (95CI: 20–57) for 1 and 34% (95CI: 19–49) for 2 CBT (p=ns)). At 1 year post-transplant, Cum Inc of chronic GVHD was 13% (95CI: 3–23%) and Cum Inc of NRM was 18% (95CI: 8–28%), with variations according to patient status (20% for pts transplanted in CR1 and 13% for pts transplanted in CR2) or number of CBU (21% for 1 CBU and 16% for 2 CBU). At 1 year, Cum Inc of relapse was 30% (95CI : 19–42%); it was 37% for patients transplanted in CR1 and 19% for patients transplanted in CR2 (p=ns), 32% for those transplanted with one CBU and 29% for those transplanted with 2 CBU (p=ns). At 1 year, overall survival was 60% (95CI: 48–74%) and LFS was 52% (95CI: 41–66%). LFS was 43% (95CI: 29–63%) for pts transplanted in CR1, 68% (95CI: 52–89%) for those transplanted in CR2 (p=0.05). According to number of graft, LFS was 48% (95CI: 31–73%) for those transplanted with 1 CBU and 55% (95CI: 41–74%) for those transplanted with 2 CBU (p=ns). In conclusion, the preliminary results of this prospective trial show the interest of RIC-UCBT in patients with AML without a HLA identical donor. A decreased NRM was observed, based on data with a median follow-up of 20 months. We have observed better LFS in patients transplanted in CR2, probably related to the very high risk group of patients transplanted in CR1. These results will be confirmed in the whole enrolled cohort. Disclosures: No relevant conflicts of interest to declare.

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Phase II Multicenter Study of Busulfan-Fludarabine Conditioning Regimen for cord Blood transplantation in Pediatric Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.1928.1928 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1928-1928

Author(s):

Hee Young Ju ◽

Hyoung Jin Kang ◽

Ji Won Lee ◽

Hyery Kim ◽

Kyung Duk Park ◽

...

Keyword(s):

Cord Blood ◽

Myeloid Leukemia ◽

Graft Failure ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Once Daily ◽

Pediatric Acute Myeloid Leukemia ◽

Blood Transplantation

Abstract Abstract 1928 Introduction. Cord blood transplantation (CBT) has become an alternative transplantation for various diseases. CBT has comparable efficacy with unrelated transplantation, but higher transplantation related mortality (TRM) rate upto 50% in early results has been a major obstacle. To reduce TRM, we studied reduced toxicity myeloablative conditioning regimen with busulfan and fludarabine for CBT in pediatric acute myeloid leukemia (AML) patients. Patients and methods. This study was a phase II prospective multicenter clinical trial (NCT01274195) and 27 patients were enrolled who underwent CBT with upto 2 HLA mismatch cord blood. Conditioning regimen was composed of fludarabine (40 mg/m2 once daily iv on days -8 ∼ -3), busulfan (0.8 mg/kg every 6 hours iv on days -6 ∼ -3) and rabbit thymoglobulin (2.5 mg/kg once daily iv on days -8 ∼ -6). For GVHD prophylaxis, cyclosporine and MMF were used. Results. Nine patients received single unit cord blood, and 18 patients received double unit cord blood. Median dose of nucleated cells and CD34+ cells were 4.23×107/kg (0.5–16.4) and 2.58×105/kg (0.33–6.77), respectively. Primary graft failure developed in 5 patients, and secondary graft failure occurred in 1 patient. Acute and chronic GVHD occurred in 16 patients (59.3%) and 10 patients (37%), respectively. TRM developed in 5 patients (cumulative incidence 22.2%), which included chronic GVHD-associated complication (n=1), post-transplantation lymphoproliferative disease (n=2), pneumonia (n=2), and diastolic cardiomyopathy (n=1). Relapse incidence was 30.9%. The 5-year overall and event-free survival were 46.3% and 40.0%, respectively. Patients who received single unit cord blood showed survival rate of 44.4%, and those who received double unit cord blood showed survival rate of 50%. Univariate analysis revealed that low nucleated cell count (P=0.011), low CD34+ cell count (P=0.002) were independent prognostic factor for survival. Conclusion. Reduced intensity conditioning regimen containing fludarabine and iv busulfan showed lower TRM rate than previous studies with myeloablative conditioning regimens. However graft failure and relapse rate were not satisfactory, and further study for optimization of conditioning regimen is warranted. Disclosures: No relevant conflicts of interest to declare.

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