HLA-identical Sibling Peripheral Blood Stem Research Articles

Graft-versus-host Disease–free, Relapse-free Survival After HLA-identical Sibling Peripheral Blood Stem Cell Transplantation With Tacrolimus-based Graft-versus-host Disease Prophylaxis in Japanese Patients

The ideal post-allogeneic hematopoietic cell transplantation recovery is not just the cure of hematologic malignancies but also freedom from ongoing morbidity. Recent studies have revealed that HLA-identical sibling peripheral blood stem cell transplantation (PBSCT) had been providing impaired graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) due to a higher risk of GVHD. Study on GVHD prophylaxis bears clinical reliance when focused on Japanese population because risk of GVHD differs among races. We identified 15 consecutive Japanese patients who received tacrolimus-based GVHD prophylaxis after myeloablative HLA-identical sibling PBSCT. No episode of grade ≥ II acute GVHD and only one episode of grade III toxicity were documented, with the control of mean weekly blood tacrolimus concentrations during the first 4 weeks at 13 to 17 ng/mL. An estimated 46.7% (95% CI: 21.4% to 71.9%) of the patients enjoyed their GRFS at 3 years after transplantation, and failure in the treatment of chronic GVHD was not reported during the median follow-up period of 1059 days (range, 784 to 1778 days) after the development of chronic GVHD. The results suggest that the application of tacrolimus with the optimization of its blood concentrations may effectively prevent ongoing morbidities after HLA-identical sibling PBSCT.

Comparison of unrelated cord blood transplantation and HLA-identical sibling peripheral blood stem cell transplantation for the treatment of adult hematological malignancies

目的比较单份清髓非血缘脐血移植（UCBT）与HLA相合同胞外周血干细胞移植（PBSCT）治疗成人恶性血液病的疗效。方法自2011年4月1日至2015年12月31日，共81例单份清髓UCBT与57例HLA相合同胞PBSCT患者入组进行比较。所有患者均采用清髓性预处理方案，环孢素A联合霉酚酸酯预防移植物抗宿主病（GVHD）。结果移植后42 d（+42 d）UCBT组中性粒细胞累积植入率为95.0%（95%CI 87.0%~98.1%），同胞PBSCT组为100%（P=0.863）。+100 d UCBT组血小板累积植入率低于同胞PBSCT组[87.3%（95%CI 76.8%~93.1%）对98.2%（95%CI 87.3%~99.7%），P=0.005]。+100 d UCBT组Ⅱ~Ⅳ度急性GVHD、Ⅲ/Ⅳ度急性GVHD的累积发生率分别为18.2%（95%CI 9.1%~26.4%）、10.4%（95%CI 3.3%~16.9%），同胞PBSCT组分别为8.9%（95%CI 1.1%~16.1%）、7.1%（95%CI 1.4%~13.7%），差异均无统计学意义（P=0.142，P=0.521）。UCBT组3年慢性GVHD、广泛型慢性GVHD累积发生率均低于同胞PBSCT组[14.9%（95%CI 5.2%~23.5%）对35.2%（95%CI 19.4%~47.8%），P=0.008；11.2%（95%CI 2.9%~18.7%）对31.4%（95%CI 16.2%~43.9%），P=0.009]。UCBT组、同胞PBSCT组3年移植相关死亡率（TRM）差异无统计学意义[30.1%（95%CI 19.2%~41.7%）对23.2%（95%CI 13.1%~35.0%），P=0.464]。UCBT组3年疾病复发率低于同胞PBSCT组[12.9%（95%CI 6.6%~21.5%）对24.3%（95%CI 13.5%~36.8%），P=0.039]。UCBT、同胞PBSCT组3年总生存率、无病生存率差异均无统计学意义[58.6%（95%CI 45.4%~69.7%）对54.8%（95%CI 39.9%~67.4%），P=0.634；57.0%（95%CI 44.0%~68.0%）对52.4%（95%CI 38.2%~64.9%），P=0.563]。UCBT组3年无GVHD及复发生存（GRFS）率高于同胞PBSCT组[55.7%（95%CI 44.1%~65.8%）对42.9%（95%CI 29.8%~55.3%），P=0.047]。结论对于成人恶性血液病，UCBT与HLA相合同胞PBSCT具有相似的急性GVHD发生率、TRM、总生存率和无病生存率，但UCBT组具有较低的慢性GVHD发生率及疾病复发率。

Prevention of Chronic GvHD after HLA-Identical Sibling Peripheral Hematopietic Stem Cell Transplantation with or without Anti-Lymphocyte Globulin (ATG). Results from a Prospective, Multicenter Randomized Phase III Trial (ATGfamilystudy)

IntroductionAllogeneic stem cell transplantation is a curative and increasingly used treatment approach for a variety of hematological malignancies. Late complications such a chronic graft-versus-host disease (cGvHD) is a major risk factor, which significantly influences morbidity and mortality after allogeneic stem cell transplantation (ASCT). The incidence of cGvHD is higher when peripheral blood stem cells are used as stem cell source. There is a strong need for preventing cGvHD after ASCT without increasing the risk of relapse.Patients and MethodsWe performed a multicenter, multinational, open-label, randomized study comparing anti-lymphocyte globulin (ATG-Neovii®) 10mg/kg on day -3,-2 and -1 with no ATG in 155 patients with acute myeloid (n=110) or lymphoblastic leukemia (n=45) in 1st complete remission (CR; n= 139) or 2nd CR (n=16) who received peripheral blood stem cells from their HLA-identical sibling (n=148) or relatives (n=7) after standard TBI (12Gy)/Cyclophosphamide (120mg/kg) or Busulfan (16mg/kg)/Cy (120mg/kg) based myeloablative conditioning regimen and sufficient organ function. Standard GvHD prophylaxis consisted of cyclosporine A and a short course of MTX (10mg/m² on day +1,+3,+6 and +11). Major inclusion criteria were: acute myeloid or lymphoblastic leukemia in 1st or 2ndCR, age 18-65 years, HLA-identical sibling or relatives, peripheral blood stem cell as stem cell source, and a myeloablative conditioning regimen. The primary study aim was to compare the cumulative incidence of cGvHD at 2 years after ASCT.ResultsOut of 161 randomized patients from 27 centers and 4 nations, 6 were withdrawn before conditioning and ASCT due to leukemia progression, or cancellation of the donor. 155 patients were analyzed for safety and efficacy; 83 were randomized to ATG and 72 to non-ATG. The treatment groups were comparable regarding recipient and donor age and sex, CMV serostatus, disease (AML vs ALL), 1st or 2ndCR. The median time to leukocyte (>1.0x10e9/l) and platelet (> 20x 10e9/l) engraftment was significantly delayed in the ATG group (18 vs 15 days, p< 0.001 and 20 vs 13 days, p<0.001). The incidence of acute GvHD grade I-IV was 25% for the ATG arm and 36% for the non-ATG arm (p=0.32) and for severe grade III/IV acute GvHD 2% and 7%, respectively (p=0.2). Regarding the primary endpoint, the cumulative incidence of cGvHD at 2 years was 36% % (95% CI 26-51%) in the ATG and 73% (95% CI 63-84% ) in the non-ATG arm (p<0.0001). In the ATG group 74% of the patients with any cGvHD had only limited episodes and 26% had an extensive episode, compared to 49% and 51% for non-ATG (p=0.04). There was no higher rate of infectious complications (58% for ATG vs 54% for non-ATG), CMV reactivation (22 vs 24%) and of EBV reactivation (2.4 vs 1.4%). The cumulative incidence of therapy related mortality at 2 years was 13% (95% CI 7-22%) for the ATG arm and 10% (95% CI 5-20%) for the non-ATG arm (p=0.57), resulting in 2 year relapse-free and overall survival of 59%% (95%CI 49-70%) and 75% (95% CI 66-85%) for the ATG group and of 65% (95% CI 52-77%) and 79% (95% CI 69-89%) for the non-ATG group (p=0.44 and p=0.20, respectively).ConclusionThis randomized cGvHD prevention study provides evidence that ATG-Neovii® 3x 10mg/kg within a myeloablative preparative conditioning regimen for HLA-identical sibling peripheral blood stem cell transplantation is highly effective in preventing limited and extensive cGvHD without obvious increase of infectious complications and relapse, resulting in similar overall survival rates. DisclosuresKröger:Neovii: Research Funding.

Effective Prevention of Acute and Chronic Graft-Versus-Host Disease with Anti-Lymphocyte Globulin (ATG) without Increase of Relapse in HLA-Identical Sibling Peripheral Blood Stem Cell Transplantation.

Abstract 3055Acute and chronic graft versus host disease (GvHD) are severe complications after allogeneic stem cell transplantation but occurrence of GvHD is associated with reduced risk of relapse. Therefore, strategies to prevent GvHD without increasing the risk of relapse are urgently needed.We investigate retrospectively whether anti-lymphocyte globulin (ATG Fresenius®, Fresenius Biotech, Graefelfing, Germany) as part of the conditioning regimen may reduce the risk of GvHD without increasing the risk of relapse after peripheral blood stem cell transplantation from HLA-identical siblings or HLA-compatible relatives. Out of 462 patients who received HLA-identical stem cell transplantation between 1990 and 2011 in our institution, we selected 238 consecutive patients who received allogeneic peripheral blood stem cell grafts after the year 2000. The median age of the patients was 48 years (r.,18–73y) and diagnosis were: AML (n=93), ALL (n=24), CML (n=25), MDS (n=23) or lympho-proliferative disorders (n=73). Patients were classified as good risk (n=95) or bad risk (n=143). 79 patients did receive ATG within the conditioning regimen with a median dose of 30mg/kg (r., 20–90mg/kg) and 159 patients did not receive ATG. In the ATG group there were more HLA mismatch donors (6% vs. 1%, p=0.02), more bad risk patients (70% vs. 50%, p=0.04), more reduced intensity conditioning regimens (65% vs. 34%, p< 0.001) and older patients (median age 50 vs. 46 years, p=0.03). Acute GvHD grade I to IV was less observed in the ATG group (27% vs. 40%, p= 0.04), but the difference in severe GvHD grade III and IV did not show statistical significance (10% vs. 18%, p=0.1). Chronic GvHD was less observed in the ATG group (30% vs. 52%, p=0.002), which was most obvious for extensive chronic GvHD (14% vs. 40%, p<0.001). After a median follow up of 57 months in the non-ATG and 63 months in the ATG group the cumulative incidence of non-relapse mortality at 5 years was 20% for the ATG and 34% for the non-ATG group (p=0.06) and the cumulative incidence of relapse at 5 years was 34% for the ATG group and 29% for the non –ATG group (p=0.2), resulting in a comparable 5 year progression-free (ATG: 46% and non-ATG 37%, p=0.5) and overall survival (ATG: 54% and non-ATG 46%, p=0.4).This retrospective study shows that ATG can prevent severe chronic GvHD without obvious risk of relapse and similar PFS and OS in HLA identical sibling transplantation. A randomized trial including QoL measurement comparing ATG vs. no ATG in HLA identical sibling transplantation is ongoing (registered NCT 00678275). Disclosures:Kröger:Fresenius Biotech: Honoraria, Research Funding. Off Label Use: ATG in HLA identical sibling transplantation.

Experience of Therapy for Pneumonia In Hematopoietic Stem Cell Transplant Recipients Infected by Influenza 2009 H1N1.

AbstractAbstract 4553In March 2009, a novel influenza H1N1 2009 virus was firstly detected in Mexico and then spread throughout the world rapidly. Till now, data about severe cases infected by 2009 H1N1 following allogeneic hematopoietic stem cell transplantation (allo-HSCT) are sparse, with only 11 anecdotal cases reported. We first describe three cases of influenza A/H1N1 2009 infection following allo-HSCT in China, including the first report in a haploidentical allo-HSCT recipient. The main clinical presentation in all cases are classic pneumonia-like symptoms and H1N1 virus was isolated from throat swabs in all patients. All patients received oral oseltamivir 75 mg twice a day, broad-spectrum antibiotic and anti-fungi drugs were given at the same time for co-infection. Two patients achieved complete resolution with this treatment regimen, the haploidentical HSCT recipient finally died of ARDS. Our cases suggest combination of oseltamivir, more effective of prophylaxis of co-infections and better supportive care is an effective treatment for influenza A/H1N1 2009 pneumonia in immunodeficient patients. The first case, a 16-year-old male, was diagnosed with acute lymphocytic leukemia (ALL-L2) in April 2008. He received HLA-identical sibling peripheral blood stem cells transplantation (allo-PBSCT) in October 23, 2008. Acute and chronic GVHD were not observed. He was admitted to our hospital for pharyngodynia, rhinobyon, exacerbated cough accompanied by pricked dyspnea on November 2009. Broad-spectrum antibiotic were administered for 3 days and no significant clinical improvement was observed. High-solution chest CT showed bilateral multiple flaky infiltrating. Influenza 2009 H1N1 virus was subtyped in his throat swab by real-time quantitative PCR (RT-PCR) analysis using validated CDC published primer/probe sets septic for variant 2009 H1N1 virus. The second case, a 25-year-old female, was diagnosed with acute lymphocytic leukemia (ALL-L2, B-cell, Ph-) in August 2008. She received HLA-identical unrelated donor (10/10 alleles matching) allo-PBSCT in April, 2009. She developed dermatosclerosis-like extensive cGVHD (skin) but the symptom was not improved after being treated with prednisone, thalidomide and tacrolimus. She was admitted to our hospital for palm infection in December, 2009. Chest CT showed lung infection and round lesion near the pleura. She was diagnosed with H1N1 influenza by RT-PCR analysis in throat swabs. The third case, a 42-year-old male, was diagnosed with acute lymphocytic leukemia (ALL-L2) with positive Bcr/Abl P190 fusion gene in October 2008. He received HLA-haploidentical sibling (his daughter) allo-PBSCT in April 2009. The patient developed grade II aGVHD (skin) on day 14 after transplantation, He achieved excellent response by being treated with prednisone and FK506. He was admitted to our hospital for skin rush and hyperglycemia in December, 2009. His oxygen saturation was 93.3% on room air. Chese CT showed interstitial ground glass-like changes in both lungs, and consolidation in both lobus inferior pulmonis. The patient developed progressive tachypnea after 4 days and was diagnosed with H1N1 influenza by RT-PCR analysis in throat swabs. All patients were nursed in H1N1-ICU ward for further treatment as soon as being diagnosed. Oseltamivir (75 mg twice a day) was given with broad-spectrum antibiotic and anti-fungi drugs. The first and second patients' symptoms were improved after 2 weeks, and recurrent throat swab examination was negative. The third patient was continued mechanical ventilation, Chest CT show infection was progressive and infiltrating in the whole lung. In January 7, 2010, the patient's oxygen saturation decreased to 50% and malignant ventricular arrhythmias were observed. Although with cardio pulmonary resuscitation for more than 1 hour, the patient died of ARDS. Our experience highlights on the severity of 2009 H1N1 infection in post-transplantation recipients. Haploidentical transplantation is an independent adverse prognostic factor. Oseltamivir is an effective therapy for pneumonia infected by 2009 H1N1, broad-spectrum antibiotic and anti-fungi drugs should be given at the same time. Disclosures:No relevant conflicts of interest to declare.

T-Cell Depleted PBSCT Mitigates Acute GVHD, but Preserves Protective Chronic GVHD. Long Term Follow up of 138 Patients.

Between 1997 and 2004, 138 patients with hematological malignancies had an HLA-identical sibling peripheral blood stem cell transplant (PBSCT). Preparative regimen was TBI (12–13.6Gy), cyclophosphamide 120mg/kg +/− fludarabine 125mg/m2. T-cell dose was adjusted to 0.2-1 x 105 CD3+ cells/kg. CD34 dose was 2.7 – 15.9 x 106/kg (median 5.9). Patients without ≥ grade 2 acute GVHD received 1 or 2 donor lymphocyte infusions (DLI) of 107 CD3+ cells/kg between days 45 and 100. For GVHD prophylaxis, all patients received cyclosporine (CSA) following the DLI for a minimum of 6 months. In addition 72 patients received CSA in the first 6 weeks post PBSCT and 66 received no CSA immediately post-transplant. Patients were aged between 10–56 (median 34 years). Seventy-seven patients with CML-CP (42), acute leukemia in first remission (22) or MDS RA (10) were designated as standard risk (SR) for transplant outcome. Sixty-one patients with more advance or refractory disease were designated as high risk (HR) for transplant outcome. Seven patients, distributed in both groups had CLL, NHL, MM and CMML. Overall survival, relapse and TRM were 58 ± 4.5%, 40.2 ± 5.5% and 18.4 ± 3.4% respectively after a median follow up of 4 years. Twenty-two patients did not receive DLI, 70 received one and 46 received two DLI. Twenty-three patients had TRM, 2 from graft failure, 5 from acute or chronic GVHD. Fifty two (37%) developed ≥ grade II, and 21 (15%) patients grade III-IV acute GVHD. Forty two (30%) had limited and 30 (22%) extensive chronic GVHD. In univariate Kaplan-Meier analyses standard risk disease, cGVHD, single DLI and day 30 lymphocyte count (LC30) above median, favorably affected overall survival (DLI p=0.002; LC30 p=0.0002, all other variables p<0.0001). Risk status was the strongest factor predicting relapse (28.8 ± 8% and 58.4 ± 7% in SR and HR patients respectively p<0.0001). Fludarabine, degree of T-cell depletion, age, cyclosporine schedule and CD34 dose were not significant.In a Cox regression analysis, only cGVHD (RR, 4.268; p=0.001; 95% CI=1.77–10.25) and standard risk (RR, 0.146; p<0.001; 95%CI=0.06–0.35) remained as independent predictive factors for outcome (Figure A). On landmark analysis after day +120, cGVHD was associated with better OS (p<0.0001) and DFS (p=0.0006) (Figure B), and relapse (21.7± 6% and 51.5 ± 11% in patients with and without cGVHD p= 0.002).Aggressive T-cell depletion, combined with relatively high doses of CD34+ cells had proven to be a key strategy to minimize TRM and severe aGVHD. Similar to unmanipulated PBSCT this approach appears to provide a protective effect of chronic GVHD, but with low late mortality. [Display omitted]

HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents.

Allogeneic peripheral blood stem cell transplantation (PBSCT) was performed in children and adolescents for the treatment of malignant (n = 49) and nonmalignant hematological disease (n = 8). Granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs were apheresed from 57 HLA-matched siblings aged 9 months to 24 years (median, 8 years) without any serious adverse, effects. No abnormalities were found in these donors for a median follow-up of 25 months (range, 6-56 months). Patients were conditioned with a TBI-containing regimen (n = 17) or a non-TBI regimen (n = 40). GVHD prophylaxis consisted of methotrexate (MTX) plus cyclosporine A (CSP) for 23 patients, CSP plus methylprednisolone (mPDN) for 22 patients, MTX only for 7 patients, CSP only for 4 patients, and MTX plus CSP plus mPDN for 1 patient. Engraftment was prompt, with a median number of days to reach an absolute neutrophil count (ANC) above 0.5 x 10(9)/L of 13 days (range, 8-23 days), with 1 graft failure. Acute GVHD (grades II-IV) occurred in 8 (16%) of 49 evaluable patients, and chronic GVHD developed in 23 (64%) of 36 evaluable patients. Notably, two thirds of chronic GVHD was extensive. The Kaplan-Meier estimate of 3-year disease-free survival was 0% for refractory disease (n = 6), 37.2% +/- 11.8% for high-risk malignancies (n = 25), 81.4% +/- 9.7% for standard-risk malignancies (n = 18), and 100% for nonmalignant disease (n = 8). The estimated 100-day nonrelapse mortality rate was 9.9% +/- 4.2%. In conclusion, allogeneic PBSCT is feasible in a pediatric population. Although the grade of acute GVHD was set low, as in Japanese BMT studies, the incidence and severity of chronic GVHD appears to be relatively high. For nonmalignant disease, the question arises of whether the higher incidence and severity of chronic GVHD is a drawback of this procedure. For high-risk malignancies, whether or not a graft-versus-leukemia effect prevents relapse needs to be clarified in future comparative studies with BMT.

Adverse side-effects associated with G-CSF in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation

Administration of the myeloid growth factor G-CSF after allogeneic hematopoietic stem cell transplantation is usually well tolerated, and associated with rapid hematopoietic engraftment. We report a high incidence (50%) of side-effects associated with post-transplant G-CSF in patients with chronic phase chronic myeloid leukemia undergoing allogeneic HLA-identical sibling peripheral blood stem cell transplantation. One or more of the following signs and symptoms were observed shortly after the subcutaneous injection of G-CSF: dyspnea, chest pain, nausea, hypoxemia, diaphoresis, anaphylaxis, syncope and flushing. These reactions led to discontinuation of G-CSF in the majority of patients. Predictive factors could not be identified, and the underlying mechanism leading to these reactions is unknown.