scholarly journals Graft Failure in Patients With Hematological Malignancies: A Successful Salvage With a Second Transplantation From a Different Haploidentical Donor

2021 ◽  
Vol 8 ◽  
Author(s):  
Yu-Qian Sun ◽  
Yu Wang ◽  
Feng-Rong Wang ◽  
Chen-Hua Yan ◽  
Yi-Fei Cheng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Graft Failure ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Second Transplantation ◽  
Neutrophil Engraftment

Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days−6 to−2) and cyclophosphamide (1,000 mg/m2/day) (days−5 to−4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8–55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35–120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95–12.51) × 108/kg and CD34 + cells 2.28 (0.75–5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10–20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.

Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7069-TPS7069
Author(s):  
Omer Hassan Jamy ◽  
Donna E. Salzman ◽  
Antonio Di Stasi ◽  
Racquel Innis-Shelton ◽  
Costa Luciano ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trial ◽  
Phase Ii ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
High Dose ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Number Of Patients

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.

Non-Myeloablative Hematopoietic Transplant with Sirolimus Immunosuppression: Determinants of Outcome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5462-5462
Author(s):  
David F. Claxton ◽  
Chuancai Wang ◽  
Michelle Carraher ◽  
Christopher Ehmann ◽  
Witold Rybka
Keyword(s):  
Graft Failure ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Logit Analysis ◽  
Risk Of Death ◽  
Increased Risk ◽  
Donor Cells ◽  
Alternative Donor ◽  
Disease Free

Abstract We added Sirolimus to an established conditioning regimen in an attempt to optimize engraftment and anti-tumor effects while minimizing GVHD. 55 patients patients with advanced hematological malignancies (median age 60) received cyclophosphamide (1gm/m2 days −7 and −6) and fludarabine (25mg/m2 days −7 through −3) prior to peripheral blood cell (51 patients) or marrow (4 patients) transplant. All received sirolimus with tacrolimus, both adjusted to 5–15ng/ml, and methotrexate (5mg/m2 days 1,3, 6) immunoprophyllaxis. Tacrolimus was tapered from days 30–45 in matched siblings (Msib -12 patients) and days 40–100 in (most) alternative donor recipients (AltD- unrelated donor or 5/6 matched related cells - 43 patients) without acute GVHD. Median follow-up is 313 days in AltD patients and 337 days for Msib patients. All Msib cells engrafted, whereas 3/43 AltD recipients showed primary graft failure or secondary graft failure (1/43). Msib recipients engrafted more rapidly than those with AltD transplants (p<0.01). For AltD recipients, the CD34 dose had a positive significant effect on donor engraftment - chimerism (p<0.05 for all points up to D100). Median overall and disease free survival was 287 and 230 days respectively for AltD patients and 303 and 167 days for Msib recipients. Amongst AltD patients, 17/43 survive progression free at D114-1167 (median D416), while in MSib patients only 1/12 survives progression free (p=0.0023 ). Two additional patients are disease free after donor lymphocytes (DLI) or withdrawal of immunosuppression in each group. No patient in the Msib group had transplant related mortality (TRM), but in the AltD group there were nine TRMs, including 7 from GVHD (NS). Multivariate analysis showed CD34 dose and donor types had no significant effect on development of progressive disease (PD). However, in general the odds ratio of any PD decreased exponentially as the level of chimerism increased. For example, at D100 the odds of developing PD decreased by 0.699 times when the level of chimerism increased by 0.1. Multinomial logit analysis showed that compared to GVHD death, the odds ratios for PD death decreased exponentially as the level of chimerism increased. In this series of patients with advanced hematological malignancy, Alternative donor cells provided a higher probability of control of disease, albeit with a trend to higher TRM. Higher CD34 cell doses were associated with improved donor engraftment (chimerism) in AltD recipients. For AltD recipients, risk of PD was reduced by increasing donor chimerism, but increasing chimerism is associated with increased risk of death from GVHD. Efforts to improve control of malignancy via more rapid engraftment of donor cells must be tempered with concern regarding potentially severe GVHD. Figure Figure

Are Back-Up Bone Marrow Harvests of Value in Unrelated Donor Allogeneic Transplants?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5023-5023
Author(s):  
Christy Stotler ◽  
Edward Copelan ◽  
Ronald Sobecks ◽  
Lisa Rybicki ◽  
Robert Dean ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Graft Failure ◽  
Clinical Status ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
The Other ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Allogeneic Transplant

Abstract In June 2007 four members of the University of Michigan Cardiothoracic transplant team died in a plane crash while transporting organs to an expectant transplant recipient. Matched Unrelated Donor Stem Cell transplants (MUDs) require that patients receive the preparative regimen before the hematopoeitic stem cells are transported. Our transplant program performs a “back-up” autologous harvest prior to administration of the conditioning regimen for use if the donor graft fails to arrive or if graft failure occurs. However, this practice is not uniform and insurers sometimes balk at payment. To evaluate the value of their routine collection, we reviewed the results of our center’s use of back-up marrows. 215 MUD transplants were performed at CCF from 1/95 to 12/05 and 146 recipients underwent back-up marrow collection. All recipients of adult MUD or Cord Blood transplants with hematologic malignancies in complete remission were harvested. Of 146 back-up marrows harvested, 15 patients (10%) had their back-up harvest infused. All 15 patients received their rescue marrow infusion for graft failure (adult MUD, n=12; Cord, n=3) 0.7–7.6 (median 1.1) months after the original transplant. Seven of the 15 (46%) patients had undergone full molecular matching, the other 8 (54%) patients being matched by serology for class I antigens and DNA typing for class II antigens. 9 patients were 6/6 serologic or molecular matches, 3 patients were 5/6 matches, and the 3 cord transplants were 4–5/6 matches. Deteriorating clinical status and a need for rapid engraftment was the rationale for infusion of autologous back-up marrow, as opposed to seeking additional donor cells (which potentially takes several weeks). Five patients (33%) are alive and in complete remission 14.6 to 137 (median 91) months from back-up infusion. Of these, two were bridged to a second MUD transplant. These two patients are alive and well at days 4200 and 1950 respectively. The other three have shown surprisingly durable disease free survival without repeat allogeneic transplant. Survivors Following Rescue Autologous Stem Cell Infusion Patient No. Primary Disease Transplant Material - all MUD Day of rescue infusion HLA typing of 1st transplant Second transplant Outcome 1 CML BM +29 Serologic 6/6 Yes (+560) Alive last f/u (+4200) 2 CML BM +33 Serologic 5/6 No Alive last f/u (+3363) 3 NHL BM +62 Serologic 8/8 No Alive last f/u (+2833) 4 AML Adult PBSC +230 Molecular 8/8 Yes (+1581) Alive and well (+1950) 5 AML Cord +38 Molecular 5/6 No Alive last f/u (+482) In total, 5 patients went on to a second transplant, all from adult MUD donors. Three patients died following second transplant - two from relapse and the 3rd from ARDS. Ten patients died following back-up infusion: 4 (36%) from relapse, 5 (54%) from infections and 1 from graft failure before rescue cells could engraft. Within this group, patients lived a mean of 114.5 (4–357) days from autologous rescue. Five patients were discharged from the hospital and lived a mean of 7.1 (1–12) months from discharge. In conclusion, a rescue autograft following graft failure may allow for rapid hematopoeitic recovery providing an opportunity for a second allogeneic transplant if another donor is available. In some cases it can directly result in durable remission. This procedure has saved the lives of 5 patients and should be more widely employed.

scholarly journals Results of Unrelated Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe on Behalf of Paediatric Diseases (PDWP) and Inborn Errors Working Parties (IEWP) of the EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4583-4583 ◽  
Author(s):  
Eliane Gluckman ◽  
Josu de la Fuente ◽  
Barbara Cappelli ◽  
Graziana M. Scigliuolo ◽  
Fernanda Volt ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Hematopoietic Stem Cell Transplantation ◽  
Graft Failure ◽  
Median Number ◽  
Unrelated Donor ◽  
Cell Disease ◽  
Hla Matching ◽  
Hematopoietic Stem ◽  
Neutrophil Engraftment

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because a human leukocyte antigen (HLA) matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. The likelihood of finding a 10/10 (HLA-A, B, C, DRB1 and DQB1) matched donor varies among ethnic groups, with the lowest probability among individuals of African descent. To date, few series of SCD patients transplanted with an unrelated donor (UD) have been reported, but the high rates of rejection and chronic graft versus host disease (cGvHD) have limited its widespread application. Patients and methods: We report the results of a retrospective, registry based, survey on 70 UD HSCT performed in patients (pts) with SCD from UD in 22 European Society for Blood and Marrow Transplantation (EBMT) centers between 2005 and 2017. Data were collected from the EBMT database and missing information was updated by the centers. Median follow up was 38 (range 2-154) months. Most pts were HbSS (n=54; 78%), had positive serology for CMV (80%), and a Karnofsky score >80% (98%). Eighteen pts had a major ABO incompatibility. Recurrent vaso-occlusive crisis (n=58), cerebral vasculopathy (n=23) and acute chest syndrome (n=24) were the main indications for HSCT. Red blood cell (RBC) transfusions pre-HSCT were reported in 97% of pts of whom 53% received more than 20 transfusions; 14% of the transfused pts had RBC alloantibodies. Hydroxyurea pre-HSCT was used in 65% of pts. Median age at HSCT was 9.6 years (range 2-43) with 87% of pts being ≤ 16 years. Stem cell source was bone marrow (BM) in 55 pts (79%) and peripheral blood (PBSC) in 15 (21%). The median number of infused TNC /kg was 3.6 x 108 for BM and 7.1 x 108 for PBSC; the median number of infused CD34/kg was 4.4 x 106 for BM and 8.3 x 106 for PBSC. HLA matching at high resolution typing was 10/10 (HLA-A, B, C, DRB1 and DQB1) in 31, 9/10 in 17 and 8/10 in 4 of the patient-donor pairs; intermediate resolution typing was available for 10 (10/10 or 9/10) and the HLA information was missing for the remaining 8 patient-donor pairs. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) and busulfan- cyclophosphamide (12%). GvHD prophylaxis was cyclosporine plus methotrexate in 59%. Anti-thymocyte globulin was used in 90% and alemtuzumab in 9% of pts. Results: The cumulative incidence (CI) of neutrophil engraftment at 60 days was 93% (95% CI 76-100), with median time to engraftment of 18 days; platelet engraftment at 180 days was 90% (95% CI 83-98) with a median time of 20 days. Ten pts had graft failure (5 primary and 5 secondary) of whom 6 had a second transplant and were all alive at last FU (median 9.5 months after second HSCT). The CI of grade II-IV aGVHD at 100 days was 23% (95% CI 15-36), and 8 pts (11%) had grade III-IV. Acute GVHD was more frequent in patients who received PBSC (PBSC 42.9%, BM 18.2%, p=0.062). Three-year CI of cGVHD was 23% (95% CI 15-36), 7 pts (10%) had limited and 9 (13%) extensive cGvHD. Three-year overall survival (OS) was 90±4%; three-year event free survival (EFS) (considering death and graft failure as events) was 76±6%; HLA matching between donor and recipient was the most important factor for OS and EFS. Considering only pts-donor pairs with high resolution HLA typing available (n=52), 3-year OS was 96±4% in 10/10 group compared to 77±11% in 9/10 plus 8/10 group (p 0.065), 3-year EFS was 85±7% vs 62±12% (p 0.040), respectively. No significant differences between the groups were observed in CI of neutrophil engraftment, aGVHD and cGVHD. Conclusion: UD HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor. Nevertheless, efforts are still needed to improve outcomes after UD HSCT. Our results indicate that using a 10/10 HLA matched UD improves both OS and EFS compared to donors with 1 or more mismatches; so, when such a matched unrelated donor is not found, using an haplo relative or an unrelated cord blood as donor source should be evaluated. A prospective trial is in preparation to evaluate the use of haploidentical donors for HSCT in SCD (EudraCT number: 2018-002652-33). Disclosures No relevant conflicts of interest to declare.

scholarly journals Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplant for Hyperinflammatory Inborn Errors of Immunity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Rebecca A. Marsh ◽  
Soyoung Kim ◽  
Kyle Hebert ◽  
Christopher C. Dvorak ◽  
Victor Aquino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Graft Failure ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Inborn Errors ◽  
Free Survival ◽  
Inborn Errors Of Immunity ◽  
Conditioning Regimens

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged <21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism <5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p<0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p<0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

scholarly journals Investigation of donor KIR content and matching in children undergoing hematopoietic cell transplantation for acute leukemia

2020 ◽  
Vol 4 (7) ◽  
pp. 1350-1356 ◽  
Author(s):  
Michael R. Verneris ◽  
Jeffrey S. Miller ◽  
Katherine C. Hsu ◽  
Tao Wang ◽  
Jennifer A. Sees ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Entire Cohort

Abstract Multiple models of donor killer immunoglobulin receptor (KIR) alloreactivity or KIR genotype have been reported to be protective against leukemia relapse after allogeneic transplantation. However, few studies have addressed this topic in the pediatric population. Here, we assessed the outcomes of allogeneic transplantation in children with acute lymphoblastic leukemia (ALL; n = 372) or acute myeloid leukemia (AML; n = 344) who received unrelated donor (URD) transplantation and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005 to 2016. As expected in this pediatric population, most patients underwent myeloablative conditioning while in remission and with bone marrow as a stem cell source. We tested KIR ligand mismatch, KIR gene content (centromeric [Cen] B), KIR2DS1 mismatching, and Cen B/telomeric A using Cox regression models and found that none were significantly associated with either relapse or disease-free survival when considering the entire cohort of patients (ALL and AML), AML, or ALL separately. Moreover, there was no significant association with outcomes in the in vivo T-cell–depleted (ie, serotherapy) cohort. This study, which is the largest analysis of donor KIR in the pediatric acute leukemia population, does not support the use of KIR in the selection of URDs for children undergoing T-replete transplantation.

A Myeloablative Conditioning Regimen Is Required to Produce Durable Engraftment and Immune Reconsitution in Related and Unrelated Multi-Antigen HLA Mismatched Pan-T-Cell Depleted Limited T-Cell Add-Back Transplants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5185-5185
Author(s):  
Jack W. Hsu ◽  
Scott D. Rowley ◽  
Stuart L. Goldberg ◽  
David S. Siegel ◽  
Robert A. Preti ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Failure ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Graft Function ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
Donor Graft ◽  
Related Donor

Abstract Multi-antigen HLA mismatched transplantation is associated with a high risk of graft failure and graft-vs.-host disease (GVHD), particularly in the unrelated setting. Strategies used to overcome these barriers include high CD34+ dose and T-cell depletion respectively. However, this often results in increased relapse rates and delayed immune reconstitution. We previously reported on four patients without matched donors who were transplanted using a multi-antigen mismatched, pan T-cell depleted donor graft with limited (1x105 CD3+ cells/kg unrelated donor, 1x106 CD3+ cells/kg related donor) T-cells added back on the day of transplant. Two additional patients have been transplanted using this strategy. The results are summarized in the table below. Post-graft immunosuppression consisted of tacrolimus and prednisone with short course methotrexate. Patients who received a full myeloablative conditioning regimen demonstrated neutrophil engraftment (ANC > 500/uL) at day +15, +15, +16 and +21. One patient had secondary graft failure attributed to resistant herpes infection, and promptly recovered graft function after an additional infusion of CD34+ cells. Of the patients who received a reduced intensity conditioning regimen, one never attained neutrophil engraftment while the other had neutrophil recovery at day +32, but had secondary graft failure at day +107. None of the patients receiving an unrelated donor graft developed GVHD. Of the six patients, there are two survivors at 12 months and 29 months. Analysis of the immune reconstitution of these patients reveal persistent graft function with recovery of T-cell function with absolute CD4+ counts of 225 and 472 cells/μL respectively. Both patients remain in complete remission. In summary, limited T-cell add-back at the time of immune reconstitution in pan T-cell depleted, multi-antigen HLA mismatched grafts can result in engraftment without GVHD, adequate disease control, and immune reconstitution. However, a requirement for this effect is a fully myeloablative conditioning regimen. We postulate that the degree of immuosuppression provided by a reduced intensity conditioning regimen is not enough to overcome the host-vs.-graft reactions, resulting in graft rejection. Further study is warranted among patients requiring mismatched donor transplantation. Diagnosis Mismatch Stem Cell Source Conditioning WBC > 500 Plt >20k Complications Pt. Status Notes: BC= blast crisis, CR= complete remission, R= relapse, U= unrelated donor, R= related donor, BM= bone marrow, PBSC= peripheral blood stem cell, Bu= busulfan, CY= cyclophosphamide, ATG= rabbit ATG, Flu= fludarabine, Mel= melphalan 2° AML-CR1 B/DR/DQ U-BM Bu/CY/ATG D+14 D+104 EBV, Influenza Alive @ 19 Mo ALL-CR2 B/C U-BM TBI/CY/ATG D+21 - CMV Pneumonia Died D+110, CMV CML-BC A/DQ U-BM Bu/CY/ATG D+25 −/D+17 after CD34 boost Graft failure 2° HSV, CD34 boost D+128 Alive @ 12 Mo 2° AML-CR1 DR/DQ R-PBSC Flu/Bu/ATG D+15 D+24 GVHD gut D+40, Relapse D+118 Died D+212, relapse 2° AML-CR1 B/C U-PBSC Flu/Mel/ATG - - 1° graft failure Died D+42, graft failure AML-R1 A/C U-PBSC Flu/Mel/ATG D+32 - 2° graft failure D+107, melanoma Died D+148, graft failure

Allogeneic Transplantation after an Alemtuzumab-Containing Myeloablative Conditioning Regimen for CD52 Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1135-1135
Author(s):  
Partow Kebriaei ◽  
Rima M. Saliba ◽  
Carrie Ma ◽  
Cindy Ippoliti ◽  
Daniel R. Couriel ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Median Time ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Donor Graft

Abstract Alemtuzumab is an effective agent in the treatment of various B- and T-cell malignancies that express CD52. Patients with advanced or refractory ALL have poor outcome after allogeneic stem cell transplantation (SCT). We investigated whether the addition of alemtuzumab to a standard myeloablative conditioning regimen would have any additional therapeutic effect and improve outcome after SCT in CD52+ ALL. Patients and Methods: Patients were eligible if their disease expressed CD52 in >20% blasts by flow cytometry. The conditioning regimen consisted of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions). Alemtuzumab at 10 mg was intravenously administered daily on days -6 to -2 prior to day of stem cell infusion. Patients received additional graft versus host disease (GVHD) prophylaxis with tacrolimus and methotrexate. Results: Fifteen patients (9 M/6 F) with median age 33 years (range 22–57) were studied. Twelve patients had B-lineage and 3 had T-lineage disease. Cytogenetic data were available for 12 patients; all had high-risk cytogenetics, including 5 with Ph+ disease. The median number of prior chemotherapy regimens was 3 (range 1–6). At time of study entry, 3 patients were in CR1, 3 were in ≥ CR1, and 9 were in primary or refractory relapse. Five patients received a matched related donor transplant and 10 received an unrelated donor graft. The source of stem cells was bone marrow (n=7) or peripheral blood (n=8). The median CD34+ cell dose infused was 4.67 x 106/kg (range 1.85–6.43). Median time to ANC ≥ 0.5 x 109/L was 15 days (range 11–20). Median time to platelet count ≥ 20 x 109/L was 19 days (range 13–34). The cumulative incidence of non-relapse mortality at 2 years was 13% (95% CI, 4%–43%). The incidence of grade II-IV acute GVHD was 7% (95% CI, 1%–38%); no grade III/IV acute GVHD was observed. The incidence of chronic extensive GVHD was 20%. Overall survival at 2 years was 16% (95% CI, 3%–40%). Failure was related mainly to progression; thirteen of 15 patients had disease progression at a median time of 4 months (range 1–22). Conclusion: These data suggest that alemtuzumab can be safely added to the standard transplant conditioning regimen for ALL without delayed engraftment or increased regimen-related toxicity. However, any potential direct antileukemia effect in CD52+ ALL patients with advanced disease appears to be negated by in-vivo T-cell depletion of the donor graft. Strategies to restore the graft-versus-leukemia effect in this setting are needed.

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