Cord Blood Allogeneic Stem Cell Research Articles

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia

Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.

Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (≥615/mm3; hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (≥395/mm3; HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony–stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure.

Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adultsPatients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100.Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%).In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series.In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD.Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT. DisclosuresNo relevant conflicts of interest to declare.

Human herpesvirus 6 reactivation before engraftment is strongly predictive of graft failure after double umbilical cord blood allogeneic stem cell transplantation in adults

Our main objective was to determine new factors associated with engraftment and single-unit predominance after double umbilical cord blood (UCB) allogeneic stem-cell transplantation. Engraftment occurred in 78% of cases in this retrospective study including 77 adult patients. Three-year overall survival, disease-free survival, relapse incidence, and nonrelapse mortality were 55 ± 6%, 44 ± 6%, 33 ± 5%, and 23 ± 4%, respectively. In multivariate analysis, Human herpesvirus 6 reactivation during aplasia (hazard ratio [HR] = 2.63; 95% confidence interval [CI]: 1.64-4.17; p < 0.001), younger recipient age (<53 years) (HR = 1.97; 95% CI: 1.16-3.35; p = 0.012), and lower human leukocyte antigen matching between the two units (3 of 6 or 4 of 6) (HR = 2.09; 95% confidence interval: 1.22-3.59; p = 0.013) were the three factors independently associated with graft failure. Also, factors independently predicting the losing UCB unit were younger age of the UCB unit (odds ratio [OR] = 1.01; 95% CI: 1-1.02; p = 0.035), lower CD34(+) cell dose contained in the UCB unit (≤ 0.8 × 10(5)/kg) (OR = 2.55; 95% CI: 1.05-6.16; p = 0.04), and presence of an ABO incompatibility between the UCB unit and the recipient (OR = 2.53; 95% CI: 1.15-5.53; p = 0.02). Thus, Human herpesvirus 6 reactivation during aplasia, lower unit-unit human leukocyte antigen matching, and younger UCB unit age, as new unfavorable predictive factors, may represent new parameters to take into account after double UCB allogeneic stem-cell transplantation in adults. These results need to be confirmed prospectively, as they may influence unit selections and patient outcomes.

Long-Lasting HHV-6 Reactivation in Long-Term Adult Survivors After Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation

Higher incidence of human herpesvirus 6 (HHV-6) infection has been documented after umbilical cord blood allo-transplant in adults. Here we demonstrate that HHV-6 reactivation persists for a very long time in half of the patients after this type of graft. Long-term immune reconstitution does not explain this event, which remains to be explained.

Plasmablastic Lymphoma: A Series of 16 Cases with the Largest Collection of 9 HIV-Negative Cases

AbstractAbstract 4162 Background:Plasmablastic lymphoma (PBL) is a distinctive B-cell lymphoma that shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts and having an immunophenotype of plasma cells. It was originally described as a rare variant of diffuse large B cell lymphoma involving the oral cavity and occurring in the clinical setting of HIV and latent EBV infection (Delecluse et al. 1997). However, the natural history of this disease in HIV-negative (HIV-) patients is poorly understood due to its rarity. Methods:Patients with a histologic diagnosis of PBL from January 1999 to June 2010 at Moffitt Cancer Center were identified and their charts were reviewed. Relevant clinical, pathologic, laboratory data and treatment variables were recorded and analyzed. Results:A total of 16 patients with PBL were evaluated including 9 HIV- cases, 5 HIV positive (HIV+) cases and 2 cases with unknown HIV status. The mean age at diagnosis was 39.8 and 58.4 years for HIV+ and HIV- patients (p=0.01) respectively. Flow cytometry and/or immunohistochemical staining analyses showed all cases phenotypically expressed at least one plasma cell marker (CD138 12/14; bright CD38 8/8; MUM1 8/8) and were negative for B-cell markers tested (CD20 16/16; PAX-5 3/3).All 5 HIV+ patients had CD4 count less than 100 (range 5–82). All 4 patients that had documented EBV status were positive. They all presented with advanced stages ranging from IIIB to IVB. Two patients received treatment, but did not have any response. All the HIV+ patients died within 6 months from diagnosis.HIV- cases (9) were more heterogeneous (summarized in Table 1). The stage at diagnosis varied from IE to IV. The list of common disease sites in the order of the frequency was following: oral-facial structures (5), lymph nodes (LN) (4), bone marrow (BM) (2), bone (1), GI tract (1). EBV was associated with 4 out of 7 cases while in 2 patients, the EBV status was unknown. Patient #5 developed PBL secondary to EBV reactivation 5 months post umbilical cord blood allogeneic stem cell transplant (HSCT) for MDS. Seven out of 9 patients received CHOP as a front-line therapy and 2 were treated with hyper-CVAD. Six out of 8 patients with assessed responses achieved complete response (CR), while one had very good partial response adequate for HSCT consolidation and the other one required salvage therapy. Four patients underwent autologous HSCT after achieving CR1. Three of them were stage IV at diagnosis and 1 was stage IIB. Two of these 4 patients were alive and disease-free (A-NED) at the end of the follow-up. The remaining 2 patients (#2 and #3) had disease recurrence at 2 and 14 months post HSCT, respectively. Interestingly, the patient #3 was treated with bortezomib/dexamethasone and achieved CR2. Despite consolidation with allogeneic HSCT, this patient recurred in 5 months post HSCT and died. The mean overall survival for our HIV- patients was 46.6 months with median survival not reached. Conclusion:Our study suggests that HIV- PBL is a heterogeneous disorder in terms of etiology and clinical course. A limited understanding of pathobiology and a lack of active biological agents for this subtype of B-cell lymphoma due to absence of cell surface CD20 expression might result in unfavorable prognosis in patients with advanced stages. Currently, more aggressive induction chemotherapy and consolidation with HSCT in CR1 have been offered to this group of patients at our center. A role of bortezomib in the front-line or relapse treatment settings needs to be tested on a larger cohort of patients. Disclosures:Off Label Use: Bortezomib use in this type of disease is considered off-label. Similarly, rituximab use is also off-label since CD20 is negative in this disease.

New insights into cord blood stem cell transplantation

To review the available clinical and biological advances of umbilical cord blood allogeneic stem cell transplantation in pediatric and adult patients. Recent large international studies suggested that allogeneic umbilical cord blood transplantation may potentially emerge as the frontline stem cell source for pediatric patients with hematopoietic malignancies because of its ability to confer superior overall and relapse-free survival compared with matched marrow stem cells. In adults, umbilical cord blood transplantation, double umbilical cord blood units and nonmyeloablative engraftment strategies have attracted further attention in clinical practice with the advantages of possible stronger graft-versus-leukemia effect and expanding transplantation indications. Additional advances in the basic biology of umbilical cord blood also appear very promising in development of enhanced engraftment approaches for limiting hematopoietic stem cell numbers or expansion of repopulating cells. Umbilical cord blood is a valuable alternative source of hematopoietic stem cells for patients that require allogeneic transplantation in the absence of readily available human leukocyte antigen matched marrow or blood hematopoietic stem cells. The current advances in clinical and biological research will further expand its application in pediatric and adult hematopoietic stem cells transplantation for treating hematologic disorders.

Infection à BK Virus après allogreffe de celluleshématopoïétiques. A propos d'un cas

Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. Significant clinical manifestationscan be seen in immunocompromised patients. We report a case of haemorragic cystitis likely due to BKV in a child after allotransplantation of hematopoietic stem cells. A 10-year old boy with poor-prognosis acute T lymphoblastic leukaemia underwent cord blood allogeneic stem cell transplantation while in his first relapse. Macroscopic haematuria and low back pain occurred by day 95, in the context of acute graft versus host disease and pulmonary aspergillosis. Histopathologic examination showed a cytopathogenetic effect consistent with the diagnosis of BKV infection. Urinary PCR was positive for BKV. Treatment with cidofovir was followed by a marked improvement of urinary symptoms. The current understanding, diagnosis, and treatment of BKV-associated infection is discussed.

High levels of antiphospholipid antibodies are associated with cytomegalovirus infection in unrelated bone marrow and cord blood allogeneic stem cell transplantation.

Antiphospholipid antibodies (APA) are a family of autoimmune and alloimmune immunoglobulins recognizing protein-phospholipid complexes in in vitro laboratory test systems. These antibodies have been associated with several conditions (malignancies, autoimmune diseases, infections, use of drugs); moreover, a syndrome capable of inducing thromboembolic disease has recently been associated with the presence of these antibodies. The aim of this prospective study was to investigate the levels of APA in subjects affected by haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation (ASCT). Between March 1996 and December 1997, 32 patients undergoing ASCT were studied prospectively until day +180 from transplant. The mean values of IgG and IgM anticardiolipin antibodies (ACA) increased in recipients of stem cells from anunrelated donor, and a statistically significant difference inACA IgG mean value between unrelated and related transplanted patients was demonstrated between days +95 and +180. All of the subjects who received stem cells from an unrelated donor had APA levels higher than the mean normal value +3 SD vs. 35% of those receiving stem cells from a related donor (P < 0.01). The reason for such a difference may be a result of the different incidence in documented cytomegalovirus (CMV) infection in the two groups (83% vs. 23%; P < 0.01), as indicated by the significant correlation between APA positivity and CMV infection (P < 0.05). No relationship was found between APA, conditioning regimen and acute or chronic graft vs. host disease (GVHD). Moreover, we did not observe any thromboembolic disorder or veno occlusive disease (VOD).