ALBERT

Description: Stage of the disease at transplant is critical for outcome after unrelated donor umbilical cord blood transplantation (UD-UCBT). The results of UD-UCBT in adults transplanted early in the course of their disease are unclear. Thus, UD-UCBT remains as the last resort for most patients. The major aim of this report was to study the outcome of a series of adult patients with hematologic malignancies undergoing UD-UCBT early in the course of their disease in a single institution. From May 1997 to May 2004, 40 patients in early disease stages underwent UD-UCBT. All patients received thiotepa, busulfan (orally in 29, intravenously in 11), cyclophosphamide, and antithymocyte globulin (Lymphoglobulin in 24 and Thymoglobulin in 16) as conditioning, cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis, and filgrastim to fasten engraftment. Diagnosis were chronic myeloid leukemia in chronic phase in 14 cases, high-risk acute lymphoblastic leukemia in 14 (12 in CR1, 1 in CR2, and 1 in CR3), high-risk acute myeloblastic leukemia in 8 (7 in CR1 and 1 in CR2), and high-risk myelodysplastic syndrome in 4 (3 untreated and 1 in CR1). Median age was 27 years (range, 16–46). The degree of HLA match (HLA-A and -B by serology and -DRB1 by high-resolution DNA typing) was 6/6 in 2 (5%), 5/6 in 18 (45%), and 4/6 in 20 cases (50%). The median number of nucleated and CD34+ cells infused was 1.8 x 107/kg (range, 0.9–4) and 0.8 x 105/kg (range, 0.1–5.7) respectively. Median time to PMN above 0.5 x 109/L and to platelets above 20 x 109/L was 22 days (range, 13–44) and 69 days (range, 32–188), and the cumulative incidence of myeloid and platelet engraftment was 90% (95% CI, 81–99%) and 70% (95% CI, 57–86%), respectively. Time to myeloid engraftment showed a direct relationship with the number of CFU-GM and CD34 cells cryopreserved (P = .02 and .01 respectively) and infused (P = .0001 and .0004 respectively). Platelet engraftment was faster in patients receiving grafts with a higher number of CFU-GM (P = .005) and CD34+ cells (P = .04), in those receiving Thymoglobulin (P = .02) and in those not developing acute GVHD above grade II (P = .04). Eight patients (20%) developed acute GVHD above grade II, and 9 of 25 patients at risk had extensive chronic GVHD. Patients receiving Thymoglobulin had a lower risk of acute GVHD (P = .0003). With a median follow-up of 33 months (range, 3–87), the probability of disease-free survival (DFS) at 3 years was 48% (95% CI, 30–66%) and was related directly to age (P = .004) and inversely to the development of acute GVHD above grade II (P = .004). The probability of DFS at 3 years was 66 % for patients younger than 31 years and 54% for those not developing acute GVHD above grade II. Cell dose, degree of HLA mismatch, and diagnosis did not clearly influence DFS. These results compare to those obtained after matched unrelated donor bone marrow transplantation, and suggest that UD-UCBT is a reasonable first-line option for adults with hematologic malignancies requiring transplantation and lacking a HLA-matched sibling donor.

Description: BACKGROUND: Adult patients with high-risk ALL can benefit from allogeneic stem cell transplantation but most lack a suitable sibling or unrelated adult donor. Umbilical cord blood has emerged as an alternative source for stem cell transplantation. OBJECTIVES: The aim of the present study was to evaluate toxicity and efficacy of UD-UCBT for the treatment of high-risk ALL in adults as well as to identify by multivariate analysis factors affecting transplant outcome. PATIENTS AND METHODS: Thirty-seven consecutive patients (23 males, 14 females) with median age 26 yr (range, 15–47) who underwent UD-UCBT at a single institution from 1999 until 2006 were analyzed. Primary high-risk feature was Philadelphia-positive ALL (12), MLL rearrangement (3), primary refractory disease (3), salvage treatment for patients in second complete remission (CR2, 4) or beyond CR2 (6), and slow response to initial therapy or 2 cycles to achieve CR (9). Conditioning regimen consisted of thiotepa, busulfan (oral, 13; IV, 24), cyclophosphamide (24) or fludarabine (13), and anti-thimocyte globulin. Cyclosporine and prednisone were used for graft-versus-host disease (GVHD) prophylaxis. Most patients (95%) received an HLA-mismatched cord blood unit with 1 (35%) or 2 (60%) HLA disparities. At infusion, the median number of nucleated cells and CD34+ cells was 2.4 × 107/kg and 1.3 × 105/kg, respectively. RESULTS: Cumulative incidence (CI) of myeloid and platelet engraftment was 92% and 76% at a median time of 21 and 63 days respectively. CI of GVHD acute grades II-IV, III-IV and chronic extensive was 29%, 19% and 19% respectively. Transplant-related mortality at 180 days was 29% and was significantly increased in patients developing severe acute GVHD (96% vs 19%; p 〈 0.001). With a median follow-up of 23 months (range, 7–88), CI of relapse was 34% at 3 years and was higher in patients beyond CR1 (63% vs 28%; p 〈 0.001). 3-year event-free survival (EFS) and overall survival (OS) were 33% and 37%, respectively. Patients in CR1/2 had better EFS (41% vs 14%; p = 0.04) and OS (50% vs 14%; p = 0.04) while those who developed severe acute GVHD had a worse EFS (42% vs 0%; p = 0.004) and OS (49% vs 0%; p = 0.004). CONCLUSIONS: These results show that UD-CBT is a curative alternative for a significant number of patients with high-risk ALL. This option should be offered to patients early in the course of their disease to improve outcomes.

Description: Introduction Intensive consolidation chemotherapy in acute myeloid leukemia (AML) patients induces important hematologic toxicity with potential life-threatening infections that can lead to delays in further treatment or death in complete remission (CR). Recent single and multi-center studies (Guo et al. Blood 2011, JCO 2012, ASH 2015) have shown that the infusion of HLA-mismatched peripheral stem cell without immunosuppressive prophylaxis can accelerate hematologic recovery after chemotherapy, without developing graft versus host disease (GVHD). Objectives The primary objective of this phase I-II trial is to confirm the safety (absence of GVHD) and efficacy (reduction of neutropenia duration) of HLA-mismatched stem cells infusion after consolidation chemotherapy with idarubicine and cytarabine (3+7) in 50 younger patients with intermediate/high-risk AML. Herein we present the preliminary results of the phase I trial with 9 adult patients (safety cohort). Methods Patients younger than 65 years old with AML in CR after induction therapy that were assigned to receive consolidation course with idarubicin (12 mg/m2/day IV 1-3) and cytarabine (200 mg/m2/day IV 1-7) according to PETHEMA protocol were enrolled in this study in a single Spanish institution. To determine safety of HLA-mismatched stem cells infusion a standard 3+3 design was used in this preliminary study: cohorts of 3 patients were established with decreasing immunosuppressive prophylaxis, 3 additional patients would be enrolled with the same immunosuppression if limiting toxicity (LT) was observed in 1 out of 3 patients. LT was defined as global GVHD〉grade 2 or grade 4 infusion related reactions. The first cohort of 3 patients was assigned to receive immunosuppression with cyclosporine (1-1.5 mg/kg/bid) and prednisone (0.5 mg/kg/qid), the second cohort to receive only prednisone (0.5 mg/kg/qid), and the third would not receive immunosuppressive treatment. The immunosuppression resulting of this phase would be used in an expansion cohort. Stem cells were obtained after mobilization with G-CSF and apheresis from HLA-mismatched family-related donors and were infused the day 9 of the consolidation course. The donor and recipient HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 alleles were genotyped using a PCR-SSP method. Hematologic recovery was defined as days from start of chemotherapy to neutrophil count 〉0.5x109/L and to platelet count 〉50x109/L. G-CSF was administered only in case of severe infection. This study was approved by the Ethical Committee, and inform consent was obtained from all patients and donors. Results From March 2015 to June 2016, 9 patients were enrolled in this study. Median age was 46 (28-64) and 6 were male. All were in CR after induction therapy, 6 had intermediate risk cytogenetic, and 3 high risk cytogenetic/molecular AML. All the donors were family-related and HLA compatibility was 3/6 for 8 patients and 5/6 in one patient. HLA-mismatched stem cells infusion characteristics were: median number of mononuclear cells, CD34+ and CD3+ T cells infused per course was 4.5 (2.1-6.6)x108/kg, 3.3 (0.7-4.9)x106/kg and 1.7 (0.8-2.3)x108/kg, respectively. LT was not reached and no diagnosis of GVHD was made. Two patients developed cytarabine related rash and other 2 patients infectious diarrhea. No patient needed further immunosuppressive treatment. Median duration of neutropenia and thrombocytopenia was 30 (27-50) and 44 (22-51) days, respectively. 3 patients received G-CSF and 2 developed severe infections. Median blood cell unit and platelet units transfused was 4 (2-20) and 8 (2-32). These results are similar to those observed in a historical cohort (non-matched) of 59 patients with AML who received consolidation with 3+7 at the same institution between January 2010 to January 2015 (median duration of neutropenia and thrombocytopenia was 29 (17-57) and 36 (18-206) days, respectively). Conclusion The infusion of HLA-mismatched stem cell is safe after consolidation with idarubicin and cytarabine in younger patients. The methodology and in consequence the results of our safety cohort (with immunosuppressive prophylaxis) are not comparable to the previous experience reported by other groups. The reduction of hematologic recovery remains to be confirmed with this schedule in a larger cohort without immunosuppressive prophylaxis. Research granted by IIS La Fe (2014/0368) Disclosures Boluda: Instituto de Investigación Sanitaria La Fe: Employment.

Description: The major aim of this study was to update our preliminary report on the results of single-unit UCBT for adults with hematologic malignancies (Sanz GF et al, Blood2001; 98:2332). From May 1997 to June 2006, 92 patients underwent single-unit UCBT with a myeloablative conditioning that included thiotepa (TT), busulfan (BU; oral, 43; iv, 49 - iv single daily dose, 20), cyclophosphamide (72) or fludarabine (FLU; 20), and antithymocyte globulin (Lymphoglobulin, 32; Thymoglobulin [THY], 60). All received cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis and filgrastim to fasten engraftment. Diagnoses were acute lymphoblastic leukemia in 34, acute myeloblastic leukemia in 25, chronic myelogenous leukemia (CML) in 21, myelodysplastic syndrome in 5 and lymphoid malignanices in 7. The stage of the disease at transplant was advanced in 32 cases (35%). Median age and weight were 31 yr (range, 16–47) and 71 kg (range, 41–112). HLA match (HLA-A and -B at antigen and -DRB1 at allelic level) was 6/6 in 5 (5%), 5/6 in 33 (34%), and 4/6 in 54 cases (59%). The median number of nucleated cells (NCs) and CD34+ cells infused was 2.1 x 107/kg (range, 0.9–4.9) and 1 x 105/kg (range, 0.1–5.7) respectively. Median time to neutrophils 〉 0.5 × 109/L and platelets 〉 20 × 109/L was 22 days (range, 11–57) and 88 days (range, 27–188), and the cumulative incidence of myeloid and platelet engraftment was 90% at 60 days and 64% at 180 days, respectively. The cumulative incidence of grade II–IV acute GVHD was 36% (grade III–IV, 18%) and 28 of 55 patients at risk (51%) developed chronic GVHD (extensive in 19). The cumulative incidence of non-relapse mortality (NRM) at 30 days, 100 days, and 3 years was 8%, 25%, and 40% respectively. With a median follow-up of 26 months (range, 2–111), the cumulative incidence of relapse and the probability of disease-free survival (DFS) at 3 years were 21% and 39% (95% CI, 27–51%). Multivariate analyses showed that the absolute number of CD34+ cells in the UCB unit was the most important predictor of myeloid and platelet engraftment (P 〈 0.0001). The use of THY was related to faster platelet engraftment (P 〈 0.01) and lower incidence of acute GVHD (P 〈 0.0001). The development of grade II–IV acute GVHD was associated with slower platelet engraftment (P 〈 0.01) and greater NRM (P = 0.03). A higher age predicted for greater NRM (P = 0.005) whereas conditioning with TT, FLU, iv BU as a single daily dose, and THY (P = 0.004) and higher numbers of CD3+ cells infused (P = 0.0024) were associated with a lower NRM. Risk of relapse was lower for patients with CML (P = 0.02) and higher for those transplanted in advanced disease stage (P = 0.02). The only variable independently associated with DFS was the stage of the disease at transplant (P = 0.001). For patients transplanted in early stages DFS at 3 years was 52% (95% CI, 37–67%). The number of NCs and HLA mismatches did not impact any outcome. These results confirm that single-unit UCBT is a clear alternative for adults with high-risk hematologic malignancies, especially if transplanted in early stages. They also show that the universally accepted criteria for selecting the best UCB unit for transplantation in adults need to be modified.

Description: BACKGROUND: Adult patients with high-risk AML can benefit from allogeneic stem cell transplantation but most lack a suitable sibling or unrelated adult donor. Umbilical cord blood has emerged as an alternative source for stem cell transplantation. OBJECTIVES: The aim of the present study was to evaluate toxicity and efficacy of UD-UCBT for the treatment of high-risk AML in adults as well as to identify, by multivariate analysis, factors affecting transplant outcome. PATIENTS AND METHODS: Forty-four consecutive patients (27 males, 17 females) with a median age of 34 yr (range, 16–52) who underwent UD-UCBT at Hospital Universitario La Fe from 2000 until 2007 were analyzed. Primary high-risk feature was high risk cytogenetics (13), therapy-related AML (3) and two or more cycles to achieve first complete remission (CR1, 10) for patients transplanted in CR1 and salvage treatment for patients in second complete remission (CR2, 6) or more advanced stage of the disease (12). Five patients had failed a previous autologous stem cells transplant (ASCT). Conditioning regimen consisted of thiotepa, busulfan (oral, 8; IV, 36), cyclophosphamide (16) or fludarabine (28), and anti-thymocyte globulin. Cyclosporine and prednisone (37) or cyclosporine and mycophenolate mofetil (7) were used for graft-versus-host disease (GVHD) prophylaxis. Most patients (93%) received an HLA-mismatched cord blood unit with 1 (43%) or 2 (50%) disparities. The median number of total nucleated cells (TNC) and CD34+ cells infused was 2 ×107/kg (range, 1–4.4) and 1.2 ×105/kg (range, 0.1–6), respectively. RESULTS: Cumulative incidence (CI) of myeloid and platelet engraftment was 98% and 72% at a median time of 20 and 54 days respectively. Higher CFU-GM counts at infusion accelerated neutrophil recovery and higher CD34+ cell dose at infusion as well as being in first complete remission (CR1) improved platelet engraftment. CI of acute GVHD grades II–IV and III–IV was 20% and 9%, respectively. CI of chronic and chronic extensive GVHD was 47% and 21%, respectively. CI of non-relapse mortality at 2 years was 38% and was significantly increased in patients transplanted beyond CR1 (53% vs 29%; p = 0.01). With a median follow-up of 19 months (range, 7–75), CI of relapse was 20% at 2 years and was higher in patients beyond CR1 (35% vs 18%; p = 0.02) and in patients receiving a lower TNC dose (39% vs 9%; p = 0.02). Event-free survival (EFS) at 2 years was 42% and was significantly higher for patients in CR1 (53% vs 19%; p 〈 0.01). CONCLUSIONS: These results show that UD-CBT is a curative alternative for a significant number of patients with high-risk AML. This option should be offered to patients early in the course of their disease to improve outcomes. Apart from disease status, cord blood cell dose affected engraftment and could also influence relapse incidence.

Description: Abstract 1339 There is conflicting data on the capacity of single-unit UD-UCBT to achieve stable engraftment. Moreover, criteria for UCB unit selection in adults with hematologic malignancies undergoing sUCBT are mainly based on registry studies that in most cases lack homogeneity in patient selection and management, analyse pooled data from adults and children with benign conditions and malignant disorders, and lack of specific information on potentially relevant characteristics of the UCB unit. The aim of the present study was to identify by multivariate analysis relevant prognostic factors of myeloid engraftment in a large series of adults with high-risk hematologic malignancies undergoing sUCBT after myeloablative conditioning at a single institution. One hundred and seventy-eight consecutive patients (112 males, 66 females) with median age 32 yr (range, 15–52) who underwent single-unit UD-UCBT after myeloablative conditioning at Hospital Universitario La Fe from 1997 until 2010 were included in the analysis. One hundred and twenty-four patients (70%) had acute leukemia (62 AML, 62 ALL) while the remaining 54 patients (30%) had a variety of high-risk hematological malignancies. Disease stage at transplantation by CIBMTR criteria was early in 75 (42%), intermediate in 44 (25%) and advanced in 59 (33%). Conditioning regimen consisted of thiotepa, busulfan (oral, 43; IV, 135), cyclophosphamide (72) or fludarabine (106), and anti-thymocyte globulin. Cyclosporine and prednisone (128) or cyclosporine and mycophenolate mofetil (50) were used for graft-versus-host disease (GVHD) prophylaxis. Most patients (94%) received an HLA-mismatched single UCB unit with 1 (29%), 2 (64%) or 3 (1%) mismatches with the recipient. The median number of total nucleated cells (TNC) was 2.9 × 107/kg (range, 1–7.5) at cryopreservation and 2.4 × 107/kg (range, 1–5.9) at infusion. Median number of CD34+ cells was 1.6 × 105/kg (range, 0.2–6.6) at cryopreservation and 1.2 × 107/kg (range, 1–5.9) at infusion. Eight patients died early without engraftment and five had primary graft failure. The remaining 165 patients experienced myeloid engraftment with full donor chimerism at a median time of 22 days (range, 11 – 57) and the cumulative incidence (CI) of myeloid engraftment at 57 days was 93%. Disease stage at time of transplantation was the only transplant or patient-related characteristic affecting engraftment. The CI of myeloid engraftment for patients transplanted in advanced and non- advanced stage was 86% and 96%, respectively (P = 0.002). All other variables with an influence on neutrophil recovery were related to UCB unit cell content. Cell dose information at time of freezing offered by UCB banks and that obtained at time of infusion were analyzed separately. For variables considered at time of UCB unit selection (data provided by UCB banks), only CD34+ cell dose with a best cut-off at 1.5 × 105/kg had a statistically significant and independent impact on multivariate analysis. CI rates of myeloid engraftment for patients receiving UCB units with CD34+ cells above and below 1.5 × 105/kg, were 96% and 90% respectively (P = 0.003). At time of infusion, cell dose measurements showing a significant and independent influence on myeloid engraftment in multivariate analysis were CD34+ cell dose with a best cut-off at 1 × 105/kg (P 〈 0,01), CFU-GM with a best cut-off at 2 × 104/kg (P 〈 0,01) and lymphocyte dose with a best cut-off at 1 × 107/kg (P 〈 0,01). Neither TNC dose at cryopreservation or at infusion nor degree of HLA disparity between the UCB unit and the recipient had any impact on myeloid engraftment.These results confirm that sUCBT after busulfan-based myeloablative conditioning offers high rates of myeloid engraftment in adults with hematological malignancies. UCB cell dose, especially CD34+ cell dose, is the most important predictor of engraftment in adults with hematologic malignancies undergoing sUCBT. CD34+ cell dose at cryopreservation provided by UCB banks, although not fully standardized, offers more valuable information than TNC dose and should be used for UCB unit selection. Disclosures: No relevant conflicts of interest to declare.

Description: Prophylactic antiviral treatment for prevention of CMV infection and disease could be valuable after UCBT, where the incidence of CMV infection is very high. The purpose of this study was to evaluate the efficacy and safety of a strategy of prophylaxis of CMV infection and disease in patients undergoing UCBT. From May 1997 to May 2005, 52 CMV-seropositive adults with hematologic malignancies (15 in advanced phases) underwent UCBT at our institution. CMV prophylaxis consisted of high-dose intravenous acyclovir from day −5 until engraftment followed until day +100 by intravenous ganciclovir (GAN, 5 mg/kg per day 3 to 7 days per week) in the first 38 patients and by oral valganciclovir (VALGAN, 900 mg per day as a single daily dose) in the last 14 patients. All patients received thiotepa, busulfan, cyclophosphamide and antithymocyte globulin as conditioning, cyclosporine and prednisone as GVHD prophylaxis, and filgrastim from day +7 until engraftment. All 52 patients were considered as evaluable for efficacy and those actually receiving the scheduled CMV prophylaxis with GAN or VALGAN were considered evaluable for toxicity. Median age was 33 yr (range, 18–47), HLA match was 6/6 in 2 (4%), 5/6 in 19 (37%), and 4/6 in 31 cases (60%), and median number of nucleated and CD34+ cells infused was 2.1 x 10E7/kg (range, 0.9–5) and 0.9 x 10E5/kg (range, 0.1–5.7) respectively. The cumulative incidence of CMV infection was 46% at day 100 and 54% at days 180 and 365, and the cumulative incidence of CMV disease was 2% at day 100, 8% at day 180 and 15% at day 365. No clear differences between patients taking GAN or VALGAN were observed in the cumulative incidence of CMV infection (45% and 50% at day 100 and 53% and 57% at days 180 and 365, respectively; P=0.89) and CMV disease (3% and 0% at day 100, 10% and 0% at day 180 and 16% and 14% at day 365, respectively; P=0.75). Twenty-two patients assigned to receive GAN and 8 patients assigned to receive VALGAN experienced 31 and 11 episodes of other severe infections respectively. GAN was withdrawn in 2 patients due to renal toxicity and VALGAN in 2 patients due to neutropenia. Ten patients (7 receiving GAN and 3 receiving VALGAN) experienced at least one episode of recurrent CMV infection. Two of the 8 patients who developed CMV disease, both with GAN, died from CMV. Higher doses of nucleated (P=0.008) and CD3+ (P=0.04) cells infused, presence of acute GVHD below grade II (P=0.01), and use of Thymoglobulin (P=0.008) were associated with a lower risk of CMV infection. The CD3+ cell dose was inversely associated with the risk of CMV disease (P=0.01). These results suggest that CMV prophylaxis with intravenous GAN or oral VALGAN is both safe and effective to reduce and/or delay the occurrence of CMV infection and disease after UCBT. Further, these data show, for the first time, the importance of the CD3+ cell dose infused and of other characteristics in the development of CMV infection and disease after UCBT.

Description: The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults remains unclear. This study reports the results of UD-CBT in 22 adults with hematologic malignancies following conditioning with thiotepa, busulfan, cyclophosphamide, and antithymocyte globulin in 21, with thiotepa, fludarabine, and antithymocyte globulin in 1, and graft-versus-host disease (GVHD) prophylaxis with cyclosporine and prednisone. Median age was 29 years (range, 18-46 years), and median weight was 69.5 kg (range, 41-85 kg). HLA match was 6 of 6 in 1 case, 5 of 6 in 13 cases, and 4 of 6 in 8 cases. Median number of nucleated cells infused was 1.71 × 107/kg (range, 1.01 × 107/kg to 4.96 × 107/kg). All 20 patients surviving more than 30 days had myeloid engraftment, and only 1, who received the lowest cell dose, developed secondary graft failure. Median time to reach an absolute neutrophil count of at least 0.5 × 109/L was 22 days (range, 13-52 days). Median time to platelets numbered at least 20 × 109/L was 69 days (range, 49-153 days). Seven patients (32%) developed acute GVHD above grade II, and 9 of 10 patients at risk developed chronic GVHD, which became extensive in 4 patients. Twelve patients remained alive and disease-free 3 to 45 months after transplantation. Disease-free survival (DFS) at 1 year was 53%. Age strongly influenced DFS (P = .01). For patients aged 30 years or younger, the DFS at 1 year was 73%. These preliminary results suggest that UD-CBT should be considered a reasonable alternative in young adults with hematologic malignancy and no appropriate bone marrow donor.