Reduced-intensity Hematopoietic Stem Cell Transplantation Research Articles

Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial

DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency. To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT. We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day+30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis. A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.

Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis

Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. A total of 122 patients (median age: 8 years, range: 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day, days -9 to -6), cyclophosphamide (15 mg/kg/day, days -5 to -2), and in vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease prophylaxis with cyclosporine combined with methotrexate. We used the Kaplan-Meier method, log-rank test, and Cox proportional hazards models to analyze patient survival. Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched siblings in 48 (39.3%), matched other relatives in 56 (45.9%), and matched unrelated persons in 18 (14.8%) patients. With a median follow-up time of 24.25 months, graft rejection occurred in only one patient. The 1- and 5-year overall survival rates were 84.14% (95% confidence interval: 76.02-89.70) and 82.16% (95% confidence interval: 73.01-88.45), respectively. Of the patient characteristics documented before transplant, the presence of cardiopulmonary, genitourinary tract, central nervous system, and limb malformations significantly affected survival rates. Our results indicate excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable to aim at optimizing the outcome of HSCT in FA patients in future studies.

Assessment Of The Hematopoietic Cell Transplantation Comorbidity Index In Older Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for malignant and nonmalignant hematologic disorders. Reduced-intensity conditioning (RIC) regimens have expanded the use of HSCT to elderly and higher risk patients. However, HSCT still remains associated with a significant mortality and morbidity and the careful assessment of risks and benefits before transplantation is essential. Major factors which influence non-relapse mortality (NRM) and overall survival (OS) after HSCT are diagnosis, type of transplant, remission status and the patient's risk profile, which includes age and presence of comorbidities. The use of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been proposed to predict the probability of NRM and OS following HSCT. However, the HCT-CI usefulness for older patients receiving a reduced intensity allogeneic HSCT remains unclear. MethodsA retrospective medical record review was performed to collect data from patients who underwent an allogeneic HSCT at a large, urban, NCI Comprehensive Cancer Center during a five year period (January 2005 to December 2010). Patients 55 years and older who were transplanted using RIC for a hematologic malignancy were selected to be analyzed. Comorbidities and test results were collected to determine the HCT-CI score and other clinical data collected included disease and remission status at time of transplant. Results85 patients aged >55 years old who received a RIC HSCT for hematologic malignancies between January 2005 to December 2010 were analyzed. The median patient age at the time of transplantation was 63 years (range: 55-75 years). The patient diagnoses included AML (39%), NHL (29%), MM (9%), MDS (11%), CLL (8%), ALL (4%). The median pre-transplantation HSCT-CI score was 2 (range: 0-9). Among 85 patients, OS at 2 years was 44%. The 2 yr OS was 31%, 37% and 44% in the low-, intermediate-, and high-risk HSCT-CI groups (p = 0.61), respectively. The corresponding NRM at 2 years was 25%, 17% and 18% (p = 0.91). We found no predictive value of HSCT-CI for either OS or NRM in older patients having an allogeneic HSCT with reduced-intensity condition. Stratification of age (55-59, 60-64, and 65+) showed no significant impact on 2 yr OS or NRM. However, there was a trend towards a better 2 yr OS for patients who had achieved a CR versus no CR at time of transplant (48% vs 41%). ConclusionOlder patients with hematologic malignancies represent a highly selected cohort, with the prospect of an allogeneic HSCT often considered too high-risk. A method to reliably stratify these older HSCT candidates is greatly needed. However, the HCT-CI score in this retrospective analysis did not help predict their NRM or 2 year OS for patients 55 years and older with hematologic malignancies receiving a reduced intensity HSCT. Further research is warranted into what combination of factors may provide a reliable predictive score for older patients with hematologic malignancies. Disclosures:Mehta:Millennium: Speakers Bureau; Celgene: Speakers Bureau.

Safety and Efficacy of Yttrium-90-Labeled Anti-CD45 Antibody (90Y-DOTA-BC8) Followed By a Standard Reduced-Intensity Hematopoietic Stem Cell Transplant (HCT) Regimen for Patients with Refractory/Relapsed Leukemia or High-Risk Myelodysplastic Syndrome (MDS)

▪Although HCT offers the best potential for cure for patients with high risk leukemia and MDS, the procedure may not be an option for all patients due to the toxicity of the conditioning regimen. Reduced-intensity conditioning (RIC) allo-HCT regimens are associated with lower non-relapse mortality (NRM), but patients receiving these regimens have a higher risk of relapse. Radioimmunotherapy (RIT) can potentially deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When combined with RIC allo-HCT, RIT may improve responses without increasing toxicity associated with myeloablative conditioning.We evaluated the safety and efficacy of yttrium 90 (90Y)-anti-CD45 antibody (MAb; BC8) followed by a standard RIC regimen with fludarabine (Flu) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients. We used CD45 as a target due to its ubiquitous expression on hematopoietic stem cells including the leukemic blasts. We used the high-energy (2.2 MeVmax) beta-emitter 90Y, which has a relatively short half-life (2.7 days) to eliminate targeted malignant cells.This phase I dose-escalation trial (NCT01300572) was designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with Flu and 2 Gy TBI followed by HLA‐matched, related or unrelated allo-HCT for patients with high-risk leukemia or MDS. The MTD was defined as the radiation absorbed dose delivered by 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Inclusion required patients to have advanced leukemia or high-risk MDS (defined as primary refractory or relapsed AML/ALL, secondary AML, MDS expressed as RAEB or CMML). To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium (111In)-BC8-DOTA followed by gamma-camera imaging. On pre-HCT day -12, patients received 90Y-BC8-DOTA at a prescribed radiation dose calculated from the trace-labeled 111In-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to G-CSF mobilized donor PBSC infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine.Fifteen patients, median age of 62 (range 37-76), were treated (10 with advanced AML, 5 with high-risk MDS). At time of HCT, 9 patients had refractory active disease while 6 were in remission with minimal residual disease (Table 1). The patients received 22.8 to 151.2 mCi of 90Y, delivering an average of 10.5 Gy to marrow, 70 Gy to spleen, and 17 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no DLT was observed. Therefore, the MTD could not be estimated.Treatment led to complete remission in 13 patients (87%), 2 patients had persistent disease after HCT. All patients engrafted with a median donor-derived CD3 and CD33 chimerism both 100% by day 28 after HCT. Ten patients (67%) developed grade II-IV acute GVHD (grade II: n=7; III: n=2; IV: n=1). Five patients (33%) developed chronic GVHD. Six patients relapsed, 5 of whom subsequently died due to progression of disease. The median time to relapse among these 6 patients was 59 days (range, 6- 351 days). One patient died from stage IV steroid-refractory GVHD. One patient died in remission from acute renal failure at 7 months after HCT. Eight patients (53%) are surviving with a median follow-up of 1.8 (range, 0.9-5.9) years. Estimated overall survival at one and two years were 66% and 46%, respectively, with progression-free survival estimated to be 46% at each of these time points. The 1-year estimate of relapse was 41% (Fig. 1).The inclusion of 90Y-BC8-DOTA into a RIC allo-HCT regimen is feasible, tolerable and no DLTs were observed. The efficacy of this approach is promising considering the high-risk leukemia/MDS patients with active disease enrolled. Current studies are evaluating the use of an alpha emitter, astatine-211, which is short-lived (t ½ = 7.2 hours) and provides high-energy radiation, conjugated to anti-CD45 MAb BC8 as part of an HCT conditioning regimen for patients with advanced AML, ALL, or high-risk MDS, in place of 90Y with the goal of continuing to improve outcomes using RIT for allo-HCT (NCT03128034). [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Research Funding. Green:Juno Therapeutics: Patents & Royalties, Research Funding. Gopal:Incyte: Consultancy; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Teva: Research Funding; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Asana: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children

Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children

Allogeneic stem cell transplantation in acute lymphoblastic leukemia patients older than 60 years: a survey from the acute leukemia working party of EBMT.

Hematopoietic stem cell transplantation (HSCT) is being increasingly explored as a treatment modality for older patients with acute lymphoblastic leukemia (ALL). Yet, concerns regarding the long term outcome of transplantation in older patients limit the wide spread applicability of this approach. In this analysis we set out to determine the outcome of ALL patients over the age of 60 who underwent reduced intensity HSCT. Herein, we present the experience of the acute leukemia working party (ALWP) of the EBMT in this age group. We analyzed a cohort of 142 patients transplanted in first remission with a median age of 62 (range 60–76 years) and a median follow-up period of 36 months post-transplant. At 3 years, overall survival (OS) and leukemia-free survival were 42% and 35%, respectively. Multivariate analyses identified cytomegalovirus (CMV) donor-recipient matching (CMV D+/R+) to be significantly associated with inferior OS. Patients transplanted from unrelated donors experienced increased grade II-IV acute graft versus host disease compared to those receiving grafts from matched related donors [Hazard ratio (HR) of 3.7, 95% confidence interval (CI), 1.75–7.8; p = 0.0005). Outcome was not impacted by Philadelphia chromosome status. A select subset of older ALL patients will benefit from extended survival and a disease free state following HSCT.

Influence of a Moderate-Intensity Exercise Program on Early NK Cell Immune Recovery in Pediatric Patients After Reduced-Intensity Hematopoietic Stem Cell Transplantation.

Introduction: After allogeneic hematopoietic stem cell transplantation (HSCT), NK cell reconstitution, which is crucial for positive outcomes, is dominated by the CD56bright subset with low NK cell cytotoxicity (NKCC) activity. Moderate exercise has been described as a potent NK cell stimulus in adults with cancer. Purpose: To determine the effects of a moderate-intensity exercise program on NK cell recovery early after HSCT and the feasibility of this intervention. Methods: Six children undergoing allogeneic HSCT were randomized to an exercise program (EP) or control (CT) group. The EP group performed a 10-week training combining in-hospital and home-based EP. Results: We observed a significant increase in the posttraining/pretraining ratio of the CD56dim subset (EP = 1.27 ± 0.07; CT = 0.99 ± 0.08; P < .005) of the EP group. The ratio of NKCC was 8 times greater in the EP group. Conclusion: Data suggest that a moderate-intensity EP program performed early after HSCT is feasible and might redistribute the CD56dim/CD56brigh NK cell subset, improving NKCC. The results are still preliminary and must be interpreted with caution.

Research progress of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in treatment of myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is likely to be the optimum method to cure international prognostic scoring system (IPSS) intermediate and high-risk patients with myelodysplastic syndrome(MDS). However, patients suffered with MDS are usually too old to undergo myeloablative conditioning allogeneic stem cell transplantation(MAC-HSCT). On account of its advantages of higher efficiency and lower toxicity, reduced intensity conditioning allogeneic stem cell transplantation(RIC-HSCT) is widely applied in the treatment of MDS patients. Currently, fludarabine plus alkylating regimens are widely applied, but the clinical outcomes are different from each regimen. Although RIC-HSCT has unique advantages in treating intermediate and high-risk elder MDS compared with MAC-HSCT and non-HSCT therapy, whether the outcome is influenced by factors such as tumor burden, recipient age, IPSS risk stratification, type of allo-HSCT, and comorbidity before transplantation is still unclear. In this article, we review literatures on RIC-HSCT in treatment of MDS. Key words: Myelodysplastic syndrome; Transplantation conditioning; Hematopoietic stem cell transplantation

Longitudinal observation of serum anti-Müllerian hormone in three girls after cancer treatment

.Gonadal dysfunction and infertility are major endocrinological late effects among childhood cancer survivors. Chemotherapy and radiation have gonadotoxic effects and diminish the ovarian reserve. The serum concentration of anti-Müllerian hormone (AMH) is a useful marker of ovarian reserve in survivors. We conducted a longitudinal study to investigate the variations of AMH in evaluating the acute and chronic effects of cancer therapy on the ovary. Three young female patients with different hematological diseases were registered, and their medical records were reviewed. Patient 1 with myelodysplastic syndrome received reduced-intensity hematopoietic stem cell transplantation (HSCT) at 10 yr of age. Breast development and menarche occurred spontaneously after HSCT; however, AMH level became undetectable and gonadotropin did not increase. Patient 2 with acute lymphoblastic leukemia had been receiving chemotherapy since 11 yr of age. AMH level became undetectable but increased after chemotherapy and was associated with regular menstruation. Patient 3 with acute myeloid leukemia received chemotherapy at 13 yr of age and myeloablative HSCT at 14 yr of age. AMH level became undetectable after HSCT, and the patient developed amenorrhea. These different patterns in the recovery phase demonstrated that the AMH level immediately after the end of cancer therapy is inappropriate for the evaluation of the ovarian reserve.

Experience of hematopoietic stem cell transplantation (HSCT) in the patients infected with either hepatitis B or hepatitis C virus

BackgroundHematopoietic stem cell transplantation (HSCT) is challenging in Hbs-Ag positive or HCV-Ab positive patients due to fear of delaying engraftment and transplant-related mortality (TRM). Very few data are published internationally till date. We had done HSCT (allogenic/autologus) of 19 hepatitis B and hepatitis C positive malignant and nonmalignant patients at our institute during the years 1999–2013. Design and methodsWe performed a retrospective analysis of the patients who were either hepatitis B or hepatitis C virus seropositive at the time of HSCT (n=19). All the positive patients (Hbs-Ag positive or HCV-Ab positive) who underwent HSCT for malignant or nonmalignant causes during 1999–2013 were selected. A total of 13 patients underwent autologus HSCT and 6 patients underwent allogenic HSCT. All the included patients had performance score 1, normal liver function test, and noninfectious state of Hbe antigen before HSCT. ResultsThe median age of the seropositive patients was 25 years (range 7–54); 16 patients were Hbs-Ag positive and 3 were HCV-Ab positive. Most common indication of HSCT was lymphoma (n=12), in which 7 patients were of Hodgkin disease and 5 patients were of non-Hodgkin disease (NHL). Three patients were acute myeloid leukemia, 2 patients of thalassemia major, 1 patient was of chronic myeloid leukemia-chronic phase, and 1 of multiple myeloma. We had used high-dose chemotherapy for induction with carmustine, etoposide, cytarabine, and melphalan (BEAM) for autologus HSCT and busulfan, cyclophosphamide (BUCY), busulfan, cyclophosphamide-thymoglobulin (BUCY-THYMO), and reduced intensity HSCT (RIST) for allogenic HSCT. All the patients underwent successful engraftment except one NHL patient. The median duration of neutropenia was 14 and 11 days in the allogenic HSCT and autologus HSCT, respectively. Median duration for engraftment of neutrophils was achieved on +Day 17 with 3 consecutive absolute neutrophil counts of more than 500cumm/dL. Median duration for engraftment of platelets was achieved on +Day 19 with 3 consecutive platelet counts of more than 50,000cumm/dL without any component support. Out of 6 allogenic HSCT patients, 4 developed graft versus host disease (GVHD) (2 – liver, 1 – colon, 1 – both skin and liver). Three patients died due to liver GVHD (2 – acute, 1 – chronic). Grades of GVHD in allogeneic HSCT patients are as follows, for liver (grade 3 in 2, grade 4 in 1), colon (grade 2 in 1), and skin (grade 2 in 1). Out of the 8 patients, one patient developed grade 3 veno-occlusive disease. Median at 100 days, 1-year overall survival (OS), and 5-year OS were 89.4%, 94.1%, and 81.1%, respectively. ConclusionsHSCT is a rugged job in Hbs-Ag positive or HCV-Ab positive patients due to more complications in the form of more neutropenia, GVHD, drug toxicity of chemotherapy, acute fulminant liver failure, fear of delaying of engraftment, and TRM. Careful evaluation before embarking on HSCT and intensive assessment against complications are warranted in Hbs-Ag positive and HCV-Ab positive recipients.

CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

AbstractCytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R+)/seronegative donor (D−) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-cell-depleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R+/D− and R+/seropositive donor patients. We show that in R+/D− patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R+/D− setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity.

Imatinib Combined with Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Versus Imatinib Alone for Young Patients with Chronic Myeloid Leukemia in Chronic Phase

Background and AimsThe relative merits of reduced intensity hematopoietic stem cell transplantation (RIST) for chronic myeloid leukemia (CML) in the first chronic phase (CP) in the imatinib (IM) era have not previously been evaluated. This prospective clinical trial was designed to compare the medical outcomes, with combination therapy of RIST plus imatinib versus imatinib alone in treating young patients with first CP including the early CP (ECP; a CML duration < 12 months) and the late CP (LCP; a CML duration ∼12 months).Patients and methodsFrom January 2005 to January 2013, Patients aged ¡Ü 49 years, who were treated consecutively at the First Affiliated Hospital of Zhejiang University, were non-randomly assigned to treatment with imatinib alone or RIST group according to whether the patient had an HLA-matched donor; those with an HLA-matched donor were assigned to the RIST group, and the others were assigned to the imatinib group. In the RIST group, the conditioning regimen was based on busulfan, fludarabine and anti-thymocyte globulin, combined with pre-transplant imatinib for 3-12 months and post-transplant imatinib for 12 months.ResultsIn total, 130 patients with the age from 11 to 49 years old were recruited, 42 patients were assigned to the RIST group and 88 patients were assigned to the imatinib group, respectively. Based on an eight-year follow-up period, the overall survival (OS) and event-free survival (EFS) were comparable between RIST and IM group (8 year-OS: 85.5% vs 89.0%, p=0.186; 8 year-EFS: 78.2% vs 73.9%, p=0.59). Interval from diagnosis to imatinib treatment more than 12 months (Late CP), high socal score, and no complete cytogenetic response at 3 month to IM were the adverse prognostic factors for EFS and OS, but only the time from diagnosis to imatinib was an independent predictor after multivariate analysis (OS: estimated HR=5.8, P=0.009; PFS:estimated HR=4.7, P=0.01).Among the ECP patients, imatinib alone was superior to RIST, with 8-year EFS rates of 92.3% vs 83.4% (p=0.05) and OS rates of 96.6% vs. 90% (P=0.03), respectively. Among LCP patients, both treatments resulted in similar survival (8-year OS rate: 62.6% vs 64.8%, p=0.53), but more LCP patients in the imatinib alone group experienced events as defined for 8-year EFS rate of 25.6%, compared with those in RIST group, with 8-year EFS rate of 48% P=0.047).The outcome of RIST was also released in the study. Primary graft failure occurred in two patients. Eleven (26.2%) developed grade I–II aGVHD, and one (2.4%) developed grade III–IV aGVHD. cGVHD could be evaluated in 39 patients, of whom 13 (33.3%) developed limited cGVHD and only 4 (10.2%) developed extensive cGVHD. The 100-day treatment-related mortality (TRM), one-year TRM and 8-year TRM was 2.5%, 10% and 12.7%, respectively. The patients were treated with 12-month imatinib for relapse prophylaxis, and the 2-year relapse rate was 10.5%. There was no late relapse (relapse after two year post-transplantation ) case. The patients with higher EBMT risk scores (3-5) had an inferior survival than those with lower EBMT risk scores ( 69.2% vs 92.9%, P = 0.04), and the EBMT risk score was an independent risk factor for OS with an odds ratio of 5.1 in multivariate analysis.ConclusionsWe concluded that imatinib alone confers significant survival advantages for young patients with CML in the ECP. For those in the LCP, both treatment arms resulted in similar overall survival, but RIST plus IM group resulted superior EFS, compared with IM alone. Thus, imatinib is superior to transplantation as the first-line therapy for young patients in the ECP, as for LCP, RIST should be considered to combined with pre-transplant and post-transplant IM as the treatment choice, especially when the patient get low EBMT risk scores. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Absolute Lymphocyte Count Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome

To determine the impact of absolute lymphocyte count (ALC) recovery on clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) and to determine the threshold value of ALC, we conducted a retrospective study of 1109 adult patients who underwent a first allogeneic HSCT from 2003 through 2009, excluding patients who died or relapsed before D30. The median age was 51 years (range: 18-74) with 52% undergoing reduced intensity HSCT and 48% myeloablative intensity HSCT with T-replete PBSC (93.7%) or marrow (6.4%) grafts; 41% receiving HLA-matched related donors, 51% HLA-matched unrelated donors, and 8.5% HLA-mismatched transplantation. The median follow-up time was 6 years (range: 2.5 – 9.8 years). To determine the threshold value, we randomly split the entire cohort into a training set and a validation set in a 1:1 ratio stratified by conditioning intensity, and then applied a restricted cubic spline (RCS) smoothing method to obtain relative hazard estimates of the relationship between ALC at 1 month and log hazard of progression-free survival. Based on this approach, ALC was categorized as low (≤0.2x 109 cells/L) or normal (>0.2x109 cells/L). For patients with low ALC at 1, 2, or 3 months after HSCT, excluding relapse or death prior to each time point to rule out the direct influence of relapse on the ALC, the overall survival (OS) (p≤0.0001) and progression-free survival (PFS) (p≤0.0002) were significantly lower and non-relapse mortality (p≤0.002) was significantly higher compared to patients with ALC >0.2x109 cells/L at each timepoint, but there was no difference in relapse. Since patients with newly low ALC at 2 or 3 months post HSCT had equally poor outcome as those whose ALC was low at 1 month post HSCT, we combined patients who had low ALC at 1, 2 or 3 months post HSCT and compared their outcome to that of patients who had ALC>0.2x109 cells/L at 1, 2, and 3 months after HSCT. The 5-year OS for patients with low ALC was 28% vs 46% for patients without low ALC (p<0.0001); the corresponding 5-year PFS were 21% vs 39%, p<0.0001 and NRM 40% vs 18%, p<0.0001 (Figure A-C). This result was consistent when other prognostic factors, including occurrence of grade II-IV acute GVHD, were adjusted for in multivariable Cox models stratified by conditioning intensity: HR for OS was 1.52 , p≤0.0001; for PFS, 1.42, p=0.0008; and for NRM, 2.4 p<0.0001 for patients with low ALC within 3 months of HSCT. Low ALC was not significantly associated with relapse (HR 1.01, p=0.92) in the multivariable model. Low ALC early after HSCT is an independent risk factor for increased NRM and poor survival independent of grade II-IV acute GVHD. ALC assessment early after HSCT may be useful to identify high-risk patient cohorts that may benefit from additional therapeutic interventions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donor lymphocyte infusion is an effective therapy for relapsed Hodgkin lymphoma after reduced-intensity allogeneic hematopoietic stem cell transplantation

A 3-year-old boy with Hodgkin lymphoma relapsed only 2 months after completion of first-line therapy. He received reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT), but relapsed again. To treat the second relapse, donor lymphocyte infusions were performed four times. He showed no evidence of disease and his quality of life was maintained for 500 days after stem cell transplant. However, his condition worsened and he died 3 years and 3 months after onset. In high-risk patients fully intolerant to myeloablative regimens, RIC allo-HSCT followed by subsequent donor lymphocyte infusions must be considered an effective therapeutic approach.

Spontaneous Alleviation Of Growth Impairment In Tyrosine Kinase Inhibitor-Treated Chronic Myeloid Leukemia Children

Although tyrosine kinase inhibitor (TKI) is popular in controlling chronic myeloid leukemia in the chronic phase (CML-CP), its long-term adverse effects in children are an issue of concern. One such concern is the negative impact on growth in these children. We previously demonstrated that growth impairment was a major adverse effect in imatinib-treated CML children. However, severity of impairment was not completely elucidated because of the short follow-up period.The Japanese Pediatric Leukemia/Lymphoma Study Group CML committee reviewed the clinical records of 107 Japanese children diagnosed with CML-CP (<18 years of age) between 2001 and 2011, and treated with TKI for more than a year with no history of hematopoietic stem cell transplantation. Concurrent hydroxyurea administration was permitted (n = 7). Cumulative change in height was assessed using the height standard deviation score (height-SDS) and converted height data from age- and sex-adjusted Japanese norms. Children who reached final height at the time of diagnosis (n = 5), those afflicted by a chronic disease (n = 10), those treated for a disease that could affect growth (n = 7), and those without height data (n = 8) were excluded.In total, 77 children (47 boys and 30 girls) met these criteria. Median age at diagnosis was 10 years (2 to 15 years) and median observation period was 38 months (12 to 119 months). Median height-SDS at diagnosis and during the study was −0.14 SD (−2.3 to 2.3 SD) and −0.75 SD (−3.2 to 1.9 SD), respectively. Decrease in height-SDS (change in height-SDS from initiation of TKI till last follow-up point) was observed in 84.4% of children, which was >1 SD in 21 children (27.2%). Decrease in height-SDS was more severe in prepubertal children than in pubertal children (0.85 vs. 0.36, p< 0.01). However, in prepubertal children median annual change in height-SDS significantly decreased 2 years after TKI initiation, and was<0.1 SD 3 years after TKI initiation. There was no significant difference in median height-SDS at 3 years and thereafter from TKI initiation. Similar tendency was observed in pubertal children, with median annual change in height-SDS shifting to an increasing trend since 3 years after TKI initiation.Because of the possibility of TKI discontinuation, growth impairment is assumed to be a huge issue particularly in children who are inevitable of prolonged exposure to TKI. We previously discussed the possibility that growth velocity may recuperate in prepubertal children as they reach pubertal age, suggesting that imatinib had less impact on growth during puberty. However, this updated study data demonstrated that period of TKI treatment may influence alleviation of growth impairment by TKI to a greater extent than puberty. We suggest that severity of growth impairment could be mitigated 2 years after TKI initiation. Thus, therapeutic intervention, such as reduced-intensity hematopoietic stem cell transplantation and discontinuation of TKI, may not be necessary for improvement of growth in TKI-treated CML children. Disclosures:No relevant conflicts of interest to declare.

Umbilical Cord Blood as an Alternative Source of Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Epstein-Barr Virus–Associated T or Natural Killer Cell Lymphoproliferative Diseases

Chronic Epstein-Barr virus–associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor.

Irreversible Leukoencephalopathy After Reduced-intensity Stem Cell Transplantation in a Dyskeratosis Congenita Patient With TINF2 Mutation

Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.

Spontaneous Subcapsular Splenic Hematoma Associated with Filgrastim in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

To report the development of a spontaneous subcapsular splenic hematoma following filgrastim administration in a patient undergoing an allogeneic hematopoietic stem cell transplant. A 60-year-old female with myelodysplastic syndrome was admitted for a reduced-intensity allogeneic hematopoietic stem cell transplant from an unrelated donor. She received filgrastim 5 μg/kg starting on day 1 to accelerate neutrophil recovery. On day 5, she began reporting severe left chest-wall pain. Contrast-enhanced computed tomography of the abdomen/pelvis revealed a spontaneous subcapsular splenic hematoma. Upon discontinuation of filgrastim, the pain fully resolved. The patient was subsequently rechallenged with filgrastim, which led to recurrence of the left-sided chest-wall pain. Filgrastim was discontinued and the patient reported resolution of the pain. Filgrastim has been associated with splenic hematoma and splenic rupture, predominantly in healthy donors undergoing mobilization of peripheral blood stem cells. Although splenic rupture attributed to filgrastim in a patient undergoing allogeneic hematopoietic stem cell transplantation has been reported, to our knowledge, this is the first case report to establish causality. Using the Naranjo probability scale, an objective causality assessment revealed that the adverse drug event was highly probable. Although filgrastim-induced splenomegaly, splenic hematomas, and splenic rupture are rare, clinicians working in the bone marrow transplant setting should be cognizant of the potential of growth factors to cause these adverse events.

Successful Treatment With Third Stem Cell Transplant From an Allogeneic Donor for a Patient With Relapsed Diffuse Large B-Cell Lymphoma

High-dose chemotherapy with autologous stem cell transplant is commonly used for diffuse large B-cell lymphoma that recurs after successful salvage chemotherapy. However, in patients in whom the disease recurs again, the prognosis is poor. A 40-year-old woman who underwent allogeneic stem cell transplant 4 years after autologous stem cell transplant developed recurrent diffuse large B-cell lymphoma 3 years after the initial autologous stem cell transplant. She then underwent reduced-intensity hematopoietic stem cell transplant from a human leukocyte antigen-matched, unrelated donor who was not the previous autologous stem cell transplant donor. She achieved a long survival (328 days after the reduced-intensity hematopoietic stem cell transplant and 1844 days after the first allogeneic transplant). A second allogenic transplant may provide survival benefits in a proportion of patients with malignant lymphoma recurring after allogeneic transplant, although careful consideration is required because of the high risk of treatment-related mortality with second allogenic transplant.