Allogeneic Peripheral Blood Hematopoietic Stem Research Articles

Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

Efficacy of Triple Prophylaxis for Prevention of Graft-Versus-Host Disease in Matched Sibling Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation in Pediatric Patients

BACKGROUND: Graft-versus-host disease (GVHD) continues to compromise the overall success of allogenic hematopoietic stem cell transplantation. It is the most important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation for malignant disease. In adults, post-transplant cyclophosphamide (Cy-PT) has been shown to be a feasible, economically accessible, and effective strategy to reduce the incidence of GVHD in matched sibling hematopoietic stem cell transplantation in combination with a calcineurin inhibitor plus mycophenolate mofetil (MMF). AIM: Demonstrate the clinical benefit of Cy-PT plus a calcineurin inhibitor combined with MMF for GVHD prophylaxis in HLA-matched, related peripheral blood stem cell transplants in pediatric patients with malignant hematologic neoplasms compared to standard therapy in historical controls. METHODS: A retrospective study was conducted on 22 pediatric patients with malignant hematologic neoplasms who underwent HLA-matched related peripheral blood allogenic stem cell transplantation (alloSCT) between July 2012 and December 2022. A comparison was made between two groups, one with triple prophylaxis using Cy-PT, cyclosporine (CsA), and MMF, and a historical cohort that received standard GVHD prophylaxis based on CsA and methotrexate (MTX). Patients were identified from a hospital registry. Descriptive and inferential statistics will be reported, using SPSS version 25 for analysis. RESULTS: Twenty-two patients received HLA-matched alloSCT from first-degree relatives genotypically identical in HLA-A, HLA-B, and HLA-DRB1 alleles. The demographic characteristics of both groups are summarized in the table. No patient experienced primary graft failure, sinusoidal obstructive syndrome, or hemorrhagic cystitis. Acute GVHD grade II-IV did not develop in patients who received Cy-PT, whereas in the CsA/MTX prophylaxis group, 1 (9%) grade IV patient was observed who died due to this cause before day 100. Two patients (18%) developed Moderate/Severe GVHD in the CsA/MTX group, and 1 (9%) had moderate GVHD in the Cy-PT group. Two-year overall survival was similar between the two groups (Cy-PT 53% and CsA/MTX 67%), as was event-free survival (PTCy 48% vs. CsA/MTX 61%). CONCLUSION: Peripheral blood represents a feasible option in our setting due to rapid graft engraftment, short hospital stays, and low incidence of primary graft failure, but with a higher incidence of GVHD as reported in the literature. We explored the efficacy and safety of triple prophylaxis for HLA-matched alloSCTs from peripheral blood using Cy-PT + CsA + MMF in a small group of patients, with outcomes slightly better than standard prophylaxis. These preliminary results motivate us to continue with this new regimen.

A Clinicopathological Study of Cytomegalovirus Lymphadenitis and Tonsillitis and Their Association with Epstein-Barr Virus.

IntroductionHistopathological characteristics of cytomegalovirus (CMV) lymphadenitis have been well described. Rare studies have reported the immune status and clinical features. Clinically, experts believed that CMV lymphadenitis develops in immunocompromised and immunocompetent patients. Infectious mononucleosis (IM)-like syndrome is the most well-known clinical presentation.MethodsWe reviewed archived CMV immunohistochemical stains on lymphoid tissues. The clinicopathological features of CMV-positive cases were studied.ResultsFor lymph nodes, we detected CMV in 29% (5/17) allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) recipients, 29% (4/14) post-autologous PBSCT patients, 13% (6/47) patients treated with intravenous chemotherapy, and 9% (9/96) immunocompetent patients. We detected CMV in 7% (2/24) of tonsils but not in the nasopharynx, tongue base, or spleen specimens. The patients with iatrogenic immunodeficiency ranged from 37 to 76 years old. CMV infections developed a few years after lymphoma treatment (median duration after allogeneic PBSCT, 932 days; after autologous PBSCT, 370 days; and after chemotherapy, 626 days). The most common clinical presentation was neck mass (13/25, 42%), followed by asymptomatic image finding (10/25, 40%). Positron emission tomography/computed tomography (PET/CT) scan showed increased uptake compared to the liver in all patients (11/11, 100%). Of 10 lymphoma patients, 8 (80%) had a Deauville score of 4–5; they accounted for 30% (8/27) of lymphoma patients with false-positive PET/CT scan results. All cases were self-limiting. 96% (23/25) cases had Epstein–Barr virus coinfection, and EBER-positive cells were predominantly in a few germinal centers.ConclusionsCytomegalovirus (CMV) lymphadenitis and tonsillitis were subclinical infections, not primary CMV infection with IM-like syndrome. The lymphadenopathy typically developed a few years after lymphoma treatments in the middle-aged and the elderly. The lesions mimicked lymphoma relapse in PET scans. Therefore, recognizing CMV infection in lymphoid tissues is of clinical importance.Graphic abstract

Long-term results of allogeneic peripheral blood hematopoietic stem cell transplantation for severe aplastic anemia

ObjectiveAplastic anemia (AA) is a life-threatening disorder and may be associated with significant morbidity and mortality Currently, the first treatment option is allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients younger than 40 years. Bone marrow is recommended as the stem cell source due to less graft versus host disease (GVHD) risk and better outcomes than peripheral blood (PB)-derived stem cell. The aim of this study is to share the data of AA patients who have underwent PB-derived allo-HSCT in our bone marrow transplantation center. MethodsTwenty-seven patients who underwent PB-derived allo-HSCT from human leukocyte antigen matched sibling donors were analyzed retrospectively. ResultsThe median follow-up time was 95.2 months (range, 4.8–235 months). The 10-year survival was 89 %. The median neutrophil and platelet engraftment time was 11 days (range, 9–16 days) and 13 days (range, 11–29 days), respectively. Primary platelet engraftment failure was observed in 1 patient (3.7 %). Acute and chronic GVHD observed in 2 (7.4 %) and 3 (11.1 %) patients, respectively. Neutropenic fever was observed in 13 (44.8 %) of patients until the engraftment after allo-HSCT. One patient died due to CMV infections, two died due to septic shock secondary to fungal infection. ConclusionAlthough there is no prospective data directly comparing BM with PB as stem cell source in AA, observational studies indicates better OS with BM. PB can be used in certain situations such as higher risk for graft failure and donor preference. This study demonstrated that PB-derived stem cell seems to be a reasonable alternative to BM.

Long-Term Results of the Treatment of Persons with Hodgkin's Lymphoma in a Resource-Constrained Setting: Real-World Data from a Single Center

Background: Hodgkin's lymphoma (HL) is the model of curative care with radiation therapy, combination chemotherapy, staging approaches, peripheral blood stem cell transplantation, and immunotherapy. However, the value of the novel anti cancer drugs has been recently analyzed and questioned in view of the results in the real improvement of overall survival (OS). Material and methods: All consecutive patients seeking medical care after 1986 in our institution as a result of HL and followed for at least 3 months were entered in the study. A diagnosis of HL was based on the histological study of a pathology specimen, mainly a lymph node; the same pathologist analyzed all the specimens and defined the histological subtype. Clinical stage was defined according to the Ann Arbor classification. Bone marrow biopsies were done only in patients with clinical stages III or IV. Computed tomography (CT) scans were done in all cases, prior to starting the treatment. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed since 2002. Between 1986 and 1997, patients were treated with MOPP, and after 1997 with ABVD as frontline therapy. For stages I and II, four cycles of chemotherapy were delivered and a computerized tomography (CT) scan was performed; if lymph node enlargement were present at this point in time, four additional cycles were given, whereas two additional cycles were given if the CT scan was negative. For stages III and IV, the CT scans were performed at the end of six cycles and two or four more cycles. Mediastinal radiotherapy was delivered only to persons with a positive FDG-PET scan at the end of the treatment. Patients showing activity after these treatments were considered as refractory and treated with four courses of ICE (ifosfamide, carboplatin and etoposide). Autologous or allogeneic peripheral blood hematopoietic stem cell transplants (HSCT) were given to refractory patients after achieving a complete remission (CR): High-dose melphalan (200mg/m2) was employed in autologous transplants, whereas cyclophosphamide, fludarabine and busulfan were employed in allogeneic transplants, all of them from HLA-identical siblings. After the completion of the treatment, patients were every two months for one year and every four months later on. No FDG-PET scans were done during the follow up, unless clinically indicated. Results: Among 91 patients with HL identified between 1986 and 2020, 88 were followed three months or more and were included in the analysis. There were 37 females and 51 males. The median age was 29years (range5-73years). There were 62 patients with nodular sclerosing HL (70%), 19 mixed cellularity (HL), 2 lymphocyte depleted HL, and one lymphocyte predominant HL; in 4 cases the histologic variant could not be defined. According to Ann Arbor classification, 5 patients were found in stage I, 48 in stage II, 19 in stage III and 16 in stage IV. Ten patients presented with a mediastinal mass larger than 10 cm. in the chest X-ray film. Three cases presented with relapsed disease. Patients have been followed for a median of 114 months (range4-402). 44 patients are alive, 10 have died and 34 were lost to follow-up. Median OS for all the patients has not been reached, being above 402 months, the OS at 310 months is 88% and at 402 months 77%. Median OS has not been reached and is above 94, 109, 90 and 98 months for stages I, II, III and IV, respectively (p=0.2). The 310-month OS was 83% for patients treated with MOPP and 88% for those treated with ABVD (HR:0.76, 95% CI 0.2-2.8; p=0.6).Sixteen patients (18%) were refractory to the treatment and 9 (10%) relapsed; they were treated with ICE followed by HSCT (autologous 15 patients and allogeneic 10 patients). Patients who underwent auto-HSCT had a median survival of 329.1 months and an OS of 92.3%, whereas those given allo-HSCT had a median survival of 59.3 months and an OS of 45.7% (HR0.2, 95%CI 0.04-1.3, p=0.057). The OS of patients given or not HSCT was 73.5% and 92.9% at 266 and 404 months, respectively (HR4.09, 95%CI 1.0-16.6, p=0.01). The OS was similar. The causes of death were breast carcinoma in 2 cases, liver carcinoma in one and uncontrolled lymphoma activity in the remaining. Conclusion: HL may be less aggressive in Mexican population than in Caucasians. Combined chemotherapy renders acceptable results, irrespective of clinical stage. Disclosures No relevant conflicts of interest to declare.

Long-term results of allogeneic peripheral blood hematopoietic stem cell transplantation for severe aplastic anemia

Abstract Objective Aplastic anemia (AA) is a life-threatening disorder and may be associated with significant morbidity and mortality Currently, the first treatment option is allogeneic hematopoietic stem cell transplant (allo-HSCT) for patients younger than 40 years. Bone marrow is recommended as the stem cell source due to less graft versus host disease (GVHD) risk and better outcomes than peripheral blood (PB)-derived stem cell. The aim of this study is to share the data of AA patients who have underwent PB-derived allo-HSCT in our bone marrow transplantation center. Methods Twenty-seven patients who underwent PB-derived allo-HSCT from human leukocyte antigen matched sibling donors were analyzed retrospectively. Results The median follow-up time was 95.2 months (range, 4.8–235 months). The 10-year survival was 89 %. The median neutrophil and platelet engraftment time was 11 days (range, 9–16 days) and 13 days (range, 11–29 days), respectively. Primary platelet engraftment failure was observed in 1 patient (3.7 %). Acute and chronic GVHD observed in 2 (7.4 %) and 3 (11.1 %) patients, respectively. Neutropenic fever was observed in 13 (44.8 %) of patients until the engraftment after allo-HSCT. One patient died due to CMV infections, two died due to septic shock secondary to fungal infection. Conclusion Although there is no prospective data directly comparing BM with PB as stem cell source in AA, observational studies indicates better OS with BM. PB can be used in certain situations such as higher risk for graft failure and donor preference. This study demonstrated that PB-derived stem cell seems to be a reasonable alternative to BM.

Efficacy of autologous versus allogeneic peripheral blood hematopoietic stem cell transplantation in non-high-risk acute myeloid leukemia patients in first complete remission

Efficacy of autologous versus allogeneic peripheral blood hematopoietic stem cell transplantation in non-high-risk acute myeloid leukemia patients in first complete remission

Influencing Factors and Prevation of Infection in Leukemia Patients after Allogeneic Peripheral Blood Stem Cell Transplantation

To explore the influencing factors and countermeasures of infection in leukemia patients after allogeneic peripheral blood hematopoietic stem cell transplantation. A total of 126 patients with leukemia admitted in our hospital from August 2016 to March 2018 were selected. The number of infected patients after transplantation was recorded, and the causes of infection were analyzed. Among the 126 patients, 43 were positive for infection, and the infection rate was 34.13%. A total of 89 pathogens were detected, of which bacteria accounted for 64.05%; virus accounted for 22.47%, and fungi accounted for 13.48%. The patient's age, donor type, pre-transplant infection, prophylactic use of antibiotics and aGVHD all were factors influencing the patient's infection (P＜0.05). The follow-up results showed that the incidence of infection in the intervention group significantly decreased after intervention with prevention program (P＜0.05). After reasonable nursing intervention, the incidence of infection in the intervention group after follow-up for 12 months was lower than that in the control group (P＜0.05). Pre-transplant infection and prophylactic use of antibiotics are factors influencing the infection after allogeneic hematopoietic stem cell transplantation. The incidence of infection can be reduced by reasonable infection prevention.

Clinical and Pathological Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm

To explore the clinical manifestation, pathological features and treatment regimen of blastic plasmacytoid dendritic cell neoplasm (BPDCN). The clinical and pathologic features, diagnosis, treatment and prognosis of 5 BPDCN patients were analyzed retrospectively. 5 patients had skin lesions, and bone marrow involvement. The immunohistochemical staining showed that the CD56 expression was observed in 5 patients, CD4 and CD123 in 4 patients, and CD43 expressed in 3 patients. After initial treatment, 3 patients achieved complete remission and 1 patient did not. One patient showed disease progression after partial remission for 1 month. Two young patients underwent sibling allo-PBHSCT, and then achieved long-term survival. BPDCN often presents skin lesions as the first symptom, moreover, soft tissues, lymph nodes and bone marrow were involved, which suggested the disease progresses. There is currently no uniform treatment protocol for this disease. Active allogeneic peripheral blood hematopoietic stem cell transplantation in the CR1 phase for appropriate patients may increase their chances for long-term survival.

Comparable Outcomes of Allogeneic Peripheral Blood versus Bone Marrow Hematopoietic Stem Cell Transplantation in Major Thalassemia: A Multivariate Long-Term Cohort Analysis

Allogeneic hematopoietic stem cell transplantation (HSCT) currently is the only available curative option for transfusion-dependent thalassemia. Peripheral blood is a more convenient source for HSCT in comparison with bone marrow. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. The aim of this study was to evaluate the pros and cons of using peripheral blood instead of bone marrow as the graft source in thalassemia transplantation. We analyzed the transplant results of 567 transfusion-dependent thalassemia patients who received a transplant between 1998 and 2015 considering their stem cell source as a comparative variable. In multivariate Cox analysis the survival advantage for bone marrow compared with peripheral blood was not significant after adjusting for sex, age, and hepatic fibrosis presence. Rejection incidence was significantly lower in patients who used peripheral blood as their graft source. Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants, but the difference was not statistically significant. This study shows that peripheral blood could be an alternative stem cell source in patients undergoing allogeneic HSCT for thalassemia.

Clinical Characteristics, Treatment and Prognosis of PTLD after allogeneic Hematopoietic Stem Cell Transplantation

To study the clinical characteristics of patients with post-transplantation lymphoproliferative disease (PTLD) after allogeneic peripheral blood hematopoietic stem cell transplantation, and to improve the understanding and diagnosis of PTLD. The clinical data of 244 patients underwent allogeneic hematopoietic stem cell transplantation in the General Hospital of PLA from May 2014 to April 2017 were analyzed retrospectively. The follow-up time was up to November 30, 2017. The incidence, risk factors, treatment and survival of patients with PTLD were statistically analyzed. Among the 244 cases the PTLD occurred in 22 cases, the incidence rate was 9.02%, 5 of them were diagnosed by pathology, and 17 were diagnosed clinically. All of them had EB virus infection. They were all ATG user, either underwent related haploidentical hematopoietic stem cell transplantation or unrelated hematopoietic stem cell transplantation, 20 cases were treated with rituximab or rituximab combined with γ-globulin, glucocorticoid, ERV+CTL, chemotherapy and 17 showed the effective response, with a total effective rate of 85%. The median follow-up time was 122 days, the median survival time was 5 months (1-22 months) and the total survival rate was 50%. The incidence of PTLD after allogeneic peripheral blood hematopoietic stem cell transplantation closely relates with EB virus infection. The application of ATG in the preconditioning scheme is a high risk factor for the onset of PTLD. In the case of no pathological diagnosis, clinical and laboratory examinations should be actively combined so as to define clinical diagnosis. The riturimab should be used more and more for patients with PTLD.

Multiple Giant Mushroom-like Tumors Inside the Stomach

Question: A 63-year-old woman presented with abdominal fullness and dizziness for 1 month. She had a history of acute myeloid leukemia (AML), M2, and received chemotherapy followed by allogeneic matched unrelated donor peripheral blood hematopoietic stem cell transplantation 5 years ago. She remained in complete hematologic remission upon bone marrow examination 6 months ago. The physical examination showed epigastric tenderness. The blood tests were unremarkable except for macrocytic anemia (hemoglobin, 11.0 g/dL; mean corpuscular volume, 104.9 fL). The vitamin B12 and folic acid levels were within normal limit (vitamin B12, 707 pg/mL; folic acid, 3.16 ng/mL). Esophagogastroduodenoscopy showed multiple 2to 6-cm mushroom-like tumors over the fundus and body, with hyperemic mucosa, superficial ulceration, and easily touch bleeding in some of them (Figure A). Biopsies were obtained. Abdominal computed tomography scan revealed multiple mass lesions up to 6 cm over the fundus and gastric body (Figure B). Positron emission tomography scan showed focal hot area at stomach, which was suspected to be inflammation or a malignancy (Figure C). What is the most likely diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Therapeutic Efficacy Analysis of Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation for 14 Adult Patients with T Lymphoblastic Lymphoma

To investigate the therapeutic efficacy of allogeneic peripheral blood hematopoietic stem cell transpdantation (allo-HSCT) for T lymphoblastic lymphoma (T-LBL). The clinical data of 14 adult patients with T-LBL treated with allo-HSCT were collected, the hematopoietic reconstruction, survival and relapse, as well as overall survival (OS) rate, event-free survival (EFS) rate of 1, 3 and 5 years were analysed retrospectively. All the patients were engrafted with neutrophil successfully, the median time of absolute neutrophil count >0.5 × 10(9)/L was 13 (10-19) d; 13 patients were engrafted with platelets successfully, the median time of Plt count >20 × 10(9)/L was 17 (12-62) days. The acute GVHD occurred in 6 patients, but among them only 1 case with 3 grade of aGVHD; out of 14 patients, 5 developed chronic GVHD. The transplant-related mortality at 100 days was 7.1% (1/14), mainly from coronary heart disease and pulmonary infection. The median follow-up time was 26.5 months, the estimated 1, 3 and 5 year OS rate was 85.7%, 47.6% and 38.1%, respectively, and estimated 1, 3 year EFS rate was 85.7%, 34.4% and 34.1%, respectively. The relapse rate was 42.8% (6/14) and the median relapse time was 22.5% months after transplantation. Up to now, 7 patients still survive, 1 patient out of them have survived for 103 months. The allo-HSCT is a safe and effective method for treatment of T-LBL.

Post-Transplantation B Cell Activating Factor and B Cell Recovery before Onset of Chronic Graft-versus-Host Disease

Excessive levels of B cell activating factor (BAFF) are found in patients with active chronic graft-versus-host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplantation factors and subsequent development of cGVHD, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow hematopoietic stem cell transplantation (HSCT) and censored data at time of cGVHD onset. In patients who did not develop cGVHD, we affirmed a temporal pattern of gradually decreasing BAFF levels as B cell numbers increase after myeloablative conditioning. In contrast, after reduced-intensity conditioning, BAFF levels remained high throughout the first post-HSCT year, suggesting that the degree of myeloablation resulted in delayed B cell recovery associated with persistence of higher BAFF levels. Given that high BAFF/B cell ratios have been associated with active cGVHD, we examined differences in early BAFF/B cell ratios and found significantly different BAFF/B cell ratios at 3 months post-HSCT only after myeloablative conditioning in patients who subsequently developed cGVHD. In addition to HSCT conditioning type, the use of sirolimus was significantly associated with higher BAFF levels after HSCT, and this also was potentially related to lower B cell numbers. Taken together, our results are important for interpreting BAFF measurements in cGVHD biomarker studies.

Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens

Anti-human leukocyte antigen (HLA) antibodies are associated with several complications in solid organ transplantations, but their impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not yet well defined. To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allo-HSCTs after reduced-intensity conditioning regimen between 2005 and 2010. Acute myeloid leukemia and multiple myeloma were the most frequent malignancies in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Anti-HLA antibodies were present in 24 patients (22%). There was no significant impact of anti-HLA antibodies on engraftment, incidence of relapse, and incidence of acute graft-vs-host disease. The presence of anti-HLA antibodies was associated with significantly worse overall survival (p = 0.006) and event-free survival (p = 0.024) after stratification on sex. The 3-year probability of overall survival was 34% without anti-HLA antibodies and 16% in their presence. Patients with anti-HLA antibodies had a higher transplant-related mortality associated with life-threatening vascular complications. Our study supports that anti-HLA antibodies should be tested and considered as an important impacting factor for transplantation outcomes after reduced-intensity conditioning allo-HSCT. We recommend its consideration before allo-HSCT in the donor-recipient selection parameters.

Patterns of Serum Free Light Chain (FLC) Recovery After Reduced Intensity Conditioning (RIC) Allogeneic Transplant for Multiple Myeloma (MM) Predict Long Term Outcomes

AbstractAbstract 1301 Introduction:Allogeneic transplantation in MM is pursued in the hope of establishing an immune mediated graft vs. MM effect (allogeneic effect) in order to prevent relapse. After RIC allogeneic transplantation, donor immune function (donor chimerism) is established over time in the recipient. Long term B lymphocyte recovery may be delayed by graft vs. host disease (GVHD). GVHD may also be associated with the beneficial graft vs. MM effect. The recovery pattern of the original light chain associated with MM clone (involved free light chain) and the alternate light chain (uninvolved in MM and donor derived after allotransplant) serve as markers for MM progression vs. establishment of donor derived B cell function respectively after allotransplant. The serum FLC assay is a marker for both the progression of the recipient's original MM clone (rising involved FLC) as well as establishment of donor derived immune recovery (restoration of uninvolved FLC to normal).We hypothesized that the FLC assay is influenced by the competing effects of progression of the MM clone vs. the beneficial impact of alloimmunity/GVHD on relapse. Methods:Forty seven RIC allogeneic peripheral blood hematopoietic stem cell transplant recipients (45 matched sibling donors) for MM at the Medical College of Wisconsin (2005-2009) were studied. Conditioning regimen was,(200 cGY TBI +/− fludarabine). Median follow up was 2 years. Baseline and follow-up serum free light chain assay results at 3 monthly intervals were correlated with outcomes. The light chain associated with MM clone was designated as “involved” (IFLC) and the complementary light chain designated as the “uninvolved” (UFLC). Results:Overall (OS) and progression free (PFS) survival of cohort at 4.5 years was 54% (CI 36 – 72%) and 38% (CI 15– 61%) respectively. Treatment related mortality was 14.5%. All patients, except those with rapidly progressive MM (group 1 below), had suppression of both IFLC and UFLC immediately after RIC. Based on pattern of recovery of UFLC we identified 3 distinct groups. Group 1(n=12) – those who did not have any UFLC recovery, Group 2(n=10) those UFLC returned to normal levels within 6 months of RIC (early recovery) and a group 3 (n=25) where the UFLC recovery was delayed beyond 6 months (late recovery). Outcomes for all the three groups are shown in the table 1. The incidence of clinical GVHD was similar across the groups. Median PFS was significantly superior in the late recovery group (not reached at 5 years, vs. 4.6 mo and 11.8 mo in the other groups) (p=0.0001). In order to eliminate “survival by response” bias, we performed a landmark analysis, restricting the analysis to those alive at 6 mo after RIC and confirmed these findings (Fig 1.).Table:Outcomes and UFLC recovery after RIC allografts for MMGroupUFLC Response GroupAny GVHDMedian PFSPFSRelapsed DeathRelapsed AliveN47231071No Recovery (12)9 (75%)4.6 mo0602Early Recovery (10)8 (80%)11.8 mo4323Late Recovery (25)18 (72%)NR @ 5 yrs1915P=NSP=0.0001 [Display omitted] Conclusion:Our data suggest that after RIC, with immunosuppressive conditioning, late recovery of UFLC is a marker of the efficacy of the allogeneic effect. The antineoplastic effect of donor alloimmunity likely explains the delayed recovery of UFLC (mediated by clinical/subclinical GVH activity) and paradoxically, better anti-MM effect in the late UFLC recovery group. Rapid progression of MM clone and non-establishment of a donor anti-MM effect explains the rapid relapse in those with no UFLC recovery. In the early recovery group, a higher risk of relapse is likely mediated by the absence of an alloimmune effect sufficient enough to delay B cell recovery and also insufficient for beneficial graft vs. MM effect. Since GVHD rates were similar across groups, the beneficial “allo immune effect” is likely independent of clinical GVHD. The FLC assay may be a sensitive marker of donor B cell recovery after allotransplant and needs further validation as a measure of donor derived antineoplastic effect in MM and other malignancies. Disclosures:No relevant conflicts of interest to declare.

Donor Cell-derived Acute Myeloblastic Leukemia After Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia

Despite its rarity, donor cell leukemia (DCL) is a most intriguing entity. We report here the case of a 5 year-old girl with juvenile myelomonocytic leukemia and normal female karyotype who developed acute myeloblastic leukemia with a karyotype of 46, X, t(X; 7) (p21; p11.2), der(7) t(3; 7) (q13.3; q22) 5 months after peripheral blood hematopoietic stem cell transplantation from her HLA-matched sister. We performed the analysis of short tandem repeat sequence markers to DNA obtained from donor peripheral blood, patient's peripheral blood including leukemic blasts and patient's hair root. This analysis showed that the leukemic blood DNA matched the donor blood DNA and not the patient's DNA, thus confirming DCL. To our knowledge, this is the first case of DCL after peripheral blood SCT for juvenile myelomonocytic leukemia.

Clinical relevance of NK, NKT, and dendritic cell dose in patients receiving G-CSF-mobilized peripheral blood allogeneic stem cell transplantation

To analyze the relationship between the cellular composition of peripheral blood allografts and clinical outcome, we performed a prospective study in 45 adult patients who underwent allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from a histocompatibility leukocyte antigen identical sibling donor for different hematological malignancies. The dose of CD34+, CD3+, CD4+, CD8+, and CD19+ lymphocytes, natural killer (NK) cells, natural killer T (NKT) cells, type 1 and type 2 dendritic cells (DC1 and DC2), as well as regulatory T (Treg) lymphocytes was analyzed. All patients were conditioned with busulphan and cyclophosphamide (BuCy2) +/- VP-16 and received a short course of methotrexate and cyclosporin-A as graft-versus-host disease (GVHD) prophylaxis. Acute GVHD (aGVHD) was present in 9 of 43 (21%) patients, and chronic GVHD (cGVHD) developed in 18 of 39 (46%) patients. There was a significantly higher incidence of aGVHD in patients receiving more than 6x10(6)/kg CD34+ cells. In univariate analysis, variables associated with better survival were as follows: a dose of less than 1.5x10(7)/kg NKT cells and less than 1.7x10(6)/kg DC2 for disease-free survival (DFS), and a dose of less than 3x10(7)/kg NK cells, less than 1.5x10(7)/kg NKT cells, less than 3x10(6)/kg DC1, and less than 1.7x10(6)/kg DC2 for overall survival (OS). In the Cox regression analysis, the dose of NKT cells was the only variable associated with better DFS, while the doses of NK, NKT, and CD34+ cells (less than 8x10(6)/kg) were associated with better OS. In conclusion, different circulating cell populations, other than CD34+ cells, are also of relevance in predicting the clinical outcome after allogeneic peripheral blood HSCT.

Reduced-Intensity Conditioning Versus Conventional Regimen for Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia.

Objective To explore the significance of reduced-intensity conditioning allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) in the treatment of chronic myeloid leukemia.Patients and Methods Twenty-six consecutive patients received reduced-intensity conditioning (Flu 30mg/m2.d−1×5d+BU 4mg.kg−1.d−1×3d or CTX 100mg.kg−1+TBI≤6.0Gy) PBSCT(RIC group). Among them, 21 were male and 5 female with median age of 36 (23~49). Twenty three of them were in chronic phase and 3 in progressive phases. The median time from diagnosis to transplantation was 12 (3~84) months. Twenty-four consecutive patients received standard conditioning (CTX 120mg.kg−1+ TBI≥7.0Gy) prior to PBSCT (STAND group) were used as historic controls. In this group of patients, 22 were in chronic phase and 2 in progressive phases. Twenty patiens were male and 4 female with median age of 35 (18~49). The median time from diagnosis to transplantation was 13 (3~48) months. All patients received PBSC from HLA matched related donors. Mycophenolate mofetil (MMF),CsA and MTX were given for prophylaxis of acute graft-versus-host-disease (aGVHD).Results All patients were successfully engrafted and achieved a complete cytogenetic remission. One patient developed graft rejection 6 months post-transplantation in RIC group. The median time when granulocyte exceeded 0.5 ×109/L and platelets exceeded 20 ×109/L was 15(12–23) days and 19(12–32) days in STAND group and 13(11–18) and 17(11–30) days in RIC group, respectively. The cumulative incidence of aGVHD was 45.83% (11/24) in STAND group and 23.08% (6/26) in RIC group(P>0.05). The incidence of Grade III–IV aGVHD in STAND group and RIC group was 16.67% and 0%, respectively(P<0.05). Chronic GVHD (cGVHD) occurred in 15 out of 20 patients (75%) lived longer than 6 months post-transplantation in STAND group and 18 out of 25 patients (72%) in RIC group(P>0.05). The incidence of extensive cGVHD in STAND group and RIC group was 35% and 0%, respectively(P<0.01). Median follow-up for survivors was 34(14–89)and 18(6–39)months in the STAND and RIC groups, respectively. Relapse occurred in 12.5%(3/24)of the patients in STAND group and 11.54%(3/26)in RIC group (P>0.05). 4 patients experienced a cytogenetic relapse, which was successfully treated with donor PBSC infusions. The Cumulative incidence of TRM was 41.67% (10/24) for the STAND group and 19.23% (5/26) for the RIC group, respectively (P>0.05). GVHD copplicated with interstitial pneumatitis or severe infection were the main causes of death. The estimated 3-year probabilities of disease-free-survival (DFS) was 62% in STAND group and 76% in RIC group, respectively (P>0.05).Conclusion Our results indicate that reduced-intensity conditioning allogeneic peripheral blood stem cells transplantation is a safe, less toxic and curative approach for patients with chronic myeloid leukemia.

Allogeneic Peripheral Blood Stem Cell Transplantation Using Reduced Intensity Versus Myeloablative Conditioning Regimens for the Treatment of Leukemia

Reduced intensity conditioning (RIC) have allowed the application of transplantation to older patients and to patients with underlying medical problems. Between October, 1999, and June, 2003, 61 patients with acute leukemia or chronic myeloid leukemia received allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings. Thirty-four were conditioned with myeloablative protocols and twenty-seven with RIC regimens. The patients in the myeloablative group were younger (29 vs. 37 years; p < 0.0003), most of them were transplanted in complete remission (74% vs. 59%; p < 0.03), had a shorter interval between diagnosis and HSCT (12 vs. 21 months; p < 0.02) and a greater proportion belonged to standard-risk prognosis (68% vs. 48%; p < 0.1). The median times to neutrophil, platelet and red blood cell engraftment for the myeloablative and RIC groups were 14 versus 11 days (p < 0.009), 17 versus 9 days (p < 0.0001), and 19 versus 12 days (p < 0.007), respectively. Transfusion requirements were lower in the RIC group. Severe mucositis was present in 32% and 7%, respectively (p < 0.01). The proportion of patients having acute graft versus-disease (GVHD), chronic GVHD, and infections was the same, as well as early and late mortality, disease-free survival, and overall survival. Analyzing all the patients together, three factors significantly influenced overall survival: standard risk patients, complete remission at transplant, and the absence of severe acute GVHD. In conclusion, our data suggest that even in high-risk patients, RIC transplantation seems to be as useful as ablative HSCT.