Haploidentical Hematopoietic Cell Transplantation (HCT) Compared with Matched HCT from Family Donors: report of 216 cases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5160-5160
Author(s):  
Daopei Lu ◽  
Wei Han ◽  
Lujia Dong ◽  
Xiaojun Huang ◽  
Kaiyan Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Great Majority ◽  
Post Transplant ◽  
Unrelated Donors ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
First Time ◽  
Related Mortality

Abstract A total of 216 cases of matched and mismatched-haploidentical HCT from family donors have been performed since May 2002 in our Institute. The purpose of this analysis is to compare the GvHD, relapse rate and their risk factors for complications and survival. The feasibility of the present regimen can then be evaluated. In the arm of mismatched-haploidentical HCT, GIAC regimen (G-CSF priming hematopoietic cells collection; immunosuppression intensified and prolonged; ATG being used; combination use of BM + PB) was used for the first time. It was developed for patients without HLA matched related or unrelated donors. However, in HLA matched HCT, ATG was not used. The two groups were comparable in disease diagnoses, sex, and prophylaxis of GvHD, number of MNC/kg and use of G-CSF post-transplant. The great majority of recruited patients had hematological malignancies. A few were cases of SAA. There were significantly more patients in advanced stage or in high-risk status in mismatched-haploidentical HCT group. After median value of 9(2–260 months follow up, the results are shown in Table 1. Table 1. Survival and causes of Death (2-year Kaplan-Meire Estimates) Characteristics and Outcomes Matched Mismatched-haploidentical No. Of Patients 116 100 Age (yr.) 37 (12–62) 23 (3–52) Status of Patients Standard Risk 86 (74.8%) 44 (44%) High Risk 30 (25.2%) 56 (56%) Days post-transplant ANC>0.5x109/L 16.4 12 Platelets>20x109/L 16.9 17 Acute GvHD <100 days 0-I 48.6% 52% II 38.6% 35% III-IV 12.8% 13% Chronic GvHD 62.5% 63.3% Extensive 18.7% 18.3% Overall survival for 1 year 81.2% 72% Relapse related mortality 5.17% 6% Non-relapse related mortality 11.2% 16% In summary, compared to matched HCT, GIAC regimen for mismatche-haploidentical HCT is sufficiently safe for patients.

Long-Term Outcomes after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5534-5534
Author(s):  
Moaath Mustafa Ali ◽  
Donna M Abounader ◽  
Lisa A. Rybicki ◽  
Jamie Starn ◽  
Christina Ferraro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Long Term Outcomes ◽  
Post Transplant

Abstract Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for high-risk acute lymphoblastic leukemia (ALL). However, long-term outcomes after alloHCT for adult ALL have not been well described. We conducted a retrospective cohort study of 72 consecutive adult ALL patients who underwent a first myeloablative alloHCT at our institution from January 2000-December 2013. Median age at HCT was 38 yrs (range, 18-62), 40 (56%) were male, 18 (38%) had high HCT CI score, 14 (19%) had prior CNS leukemia and 35 (49%) had BCR-ABL+ disease. Donor source was HLA-matched related donor for 50% patients and 90% received PBSC as graft source. All patients were transplanted in CR (72% were in 1st or 2nd CR) and 92% received T-cell replete grafts. Median time from diagnosis to alloHCT was 5 months (range, 2-90). The incidences of grade II-IV and III-IV acute GvHD, chronic GvHD and extensive chronic GvHD were 43%, 13%, 51% and 36%, respectively. The median follow-up for our cohort is 76 months. At 6 years after HCT, probability of overall survival (OS) was 33% (95% CI, 21-44%) and relapse-free survival (RFS) was 30% (95% CI, 19-42%), and the cumulative incidence of relapse was 36% (95% CI, 25-48%) and non-relapse mortality (NRM) was 37% (95% CI, 26-49%). The most common causes of death were relapse (43%) and infection (21%); majority of relapses occurred within the first 2-years post-transplantation. There were no second cancer related deaths. In multivariable analyses, factors significantly associated with OS were HCT CI score (HR 2.69 for high vs. low/int., P=0.002) and CMV status (HR 2.62 for donor+ vs. others, P=0.05). HCT CI score was the only predictive factor for RFS (HR 2.26 for high, P=0.007). We also compared outcomes by BCR-ABL status. BCR-ABL+ patients were older (median age 42 vs. 36 yrs, p=0.02), had low HCT CI score (34% vs 22%, p=0.01), were more likely to be in CR1 (74% vs. 32%, p=0.002), and as a result, proceeded to HCT sooner after diagnosis (median 4 vs 7 months, p=<0.001). For BCR-ABL+ and BCR-ABL- patients, 6 year OS was 41% and 25%, RFS was 40% and 21%, relapse was 27% and 45% and NRM was 38% and 36% (P=NS for all comparisons). Myeloablative alloHCT can provide long-term survival for selected high-risk adult ALL patients. Relapses are relatively uncommon after 2 years post-transplant. Long-term NRM is high in this population and we did not observe a plateau in its incidence until 7.5 years post-transplant, suggesting the need for long-term follow up to prevent and manage late complications of alloHCT. Figure 1. Figure 1. Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

scholarly journals HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies- Two-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2039-2039 ◽  
Author(s):  
Li Mei Poon ◽  
Yeh Ching Linn ◽  
Poh Lin Tan ◽  
Ziyi LIM ◽  
Balamurugan Vellayappan ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hla Antibodies ◽  
Day Range ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. GVHD, engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC product were divided into two fractions in 9:1 ratio, and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160 mg/m2 divided daily over 4 days, thiotepa 10 mg/kg divided twice daily for 1 day and melphalan 70-140 mg/m2 for 1 day, in combination with total lymphoid irradiation 6 Gy (n=23), or 7.5 Gy (n=12) over 3 equal fractions, or total body irradiation of 2 Gy (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 25 patients using tacrolimus and 2 patients using sirolimus. Results: We transplanted 37 patients, including 32 adults (median age 47 years, range 20 - 69) and 5 children (median age 13 years, range 7-15 years) with high risk AML (n=17), ALL (n=11), MDS (n=5), myeloma (n=1), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1) or NK/T lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 8.65 x 106 (range, 3.54 - 20.78) CD34+ cells/kg, 0.00 x 104 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 2.4 x 106 (range, 0.15 - 11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.19 x 104 (range 0 - 8.53) TCRαβ+ cells/kg, and 8.76 x 106 (range 1.73 - 30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC > 500 cells/µL at a median of 10 day (range, 8 - 22) and PLT > 20,000 cells/µL at a median of 12 day (range, 7 - 19). There was no secondary graft failure. Four patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab and immunoglobulin. Fourteen patients (38%) developed acute GVHD of grade II-IV (Gd II n=9 ; Gd III n=4 ; Gd IV n=1 ). Only one patient experienced chronic GVHD, giving 2 year cumulative incidence (CI) of chronic GVHD of 3.9 %. Day 180 CI of NRM and relapse were 22.7 % (95% 10.5-37.7%) and 12.0 % (95% CI 3.7-25.7%), respectively. NRM was attributed to aGVHD in 3 of the 13 deaths. Viral reactivation included CMV (n=13), HHV6 (n=4), EBV (n=3) and adenovirus (n=4), with no fatal viral infection occurred within 180 days. Seven patients died of infection, including 3 patients who had fatal blood stream infection (bacteria n=2; fusarium n=1) within 180 days. With a median follow up of 436 days (range 20- 916 days) in surviving patients, the 6 month and 2 year overall survival (OS) were 77.2% (95% CI 59.4-87.9%) and 57.7 % (95% CI 37.6-73.4%), respectively (Figure 1). The 2-year OS for patients with intermediate risk and high/very high risk disease risk index (DRI) were 60% and 24%, respectively (p=0.07) (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allows successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of donor-specific HLA antibodies. Acute GVHD was generally abortive, leading to chronic GVHD in <5% of the patients. Fatal viral infection was not observed. Further efforts are needed to lower the risk of death due to bacterial infection, and also relapse in patients with high risk DRI, such as antibiotic prophylaxis or repeated doses of memory-cell DLI. Disclosures Leung: Miltenyi Biotec: Employment.

HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies: Three-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Yang Liang Boo ◽  
Yeh Ching Linn ◽  
Rajat Bhattacharyya ◽  
Michelle Li Mei Poon ◽  
Zi Yi Lim ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Blood Stream Infection ◽  
Chronic Gvhd ◽  
Blood Stream ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T-cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK-cells, γδ T-cells, and CD45RO+ memory T-cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160mg/m2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70-140mg/m2 for 1 day, in combination with total lymphoid irradiation 6Gy (n=35) or 7.5Gy (n=12) over 3 equal fractions, total body irradiation of 2Gy (n=13) or antithymocyte globuline (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 50 patients using tacrolimus, and 2 patients using sirolimus. Results: We transplanted 62 patients, including 55 adults (median age, 47 years; range 20-69) and 7 children (median age, 13 years, range 7-17) with high risk AML (n=34), ALL (n=15), MDS (n=7), plasma cell neoplasm (n=2), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), and NK/T-cell lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 6.79 x 106 (range 3.54-20.78) CD34+ cells/kg, 0.00 x 104 (range 0-0.97) CD45RA+CD3+ cells/kg, and 1.09 x 106 (range 0.15-11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.20 x 104 (range 0-11.30) TCRαβ+ cells/kg, and 8.52 x 106 (range 0.62-30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC &gt; 500 cells/µL at a median of 10 days (range 8-22) and platelet &gt; 20,000 cells/µL at a median of 12 days (range 8-22). There was no secondary graft failure. Six patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab, and immunoglobulin. Twenty-two patients (35%) developed acute GVHD of grade II - IV (Gd II, n=15; Gd III, n=5; Gd IV, n=2). Three patients experienced chronic GVHD, giving 2-year cumulative incidence of 7 %. Day 180 cumulative incidence of NRM and relapse were 24.8% (95% CI 14.3-36.8%) and 14.9% (95% CI 6.3-27.0%), respectively. Four of the 16 NRM were attributed to aGVHD. Viral reactivation included CMV (n=25), HHV-6 (n=14), EBV (n=11), and adenovirus (n=7). Fourteen patients died of infection, including 5 patients who had fatal blood stream infection (bacteria, n=3; candidemia, n=2) and 1 patient from disseminated adenovirus infection within 180 days. With a median follow-up of 298 days (range 21-1298) in surviving patients, the 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 58% (95% CI 37.6-73.4%), 43% (95% CI 27-57%), and 39% (95% CI 24-54%), respectively (Figure 1). In multivariable analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 6.24; 95% CI 2.05-19.05; p=0.0013), EFS (HR 4.80; 95% CI 1.73-13.35; p=0.0027), and RRM (HR 6.49; 95% CI 1.44-29.25; p=0.015), whereas disease risk index (DRI) impacts risk of relapse (HR 4.50; 95% CI 1.39-14.52; p=0.012). The 2-year OS, EFS, and GRFS for the subset of 30 patients (adults, n=25; children, n=5) with HCT-CI score of 0 and low/intermediate risk DRI were 68%, 68%, and 60%, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allowed successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. The best outcome is seen in patients with favorable HCT-CI and DRI. Further efforts are needed to lower the risk of death due to blood stream infection, and relapse in patients with high risk DRI, such as optimisation of anti-microbial prophylaxis or repeated doses of memory-cell donor lymphocyte infusion (DLI). Disclosures No relevant conflicts of interest to declare.

Haploidentical Hematopoietic Cell Transplantation Using G-CSF Mobilized T-Cell Replete Grafts for for Acute Leukemia and MDS

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2278-2278
Author(s):  
Eric Huselton ◽  
Rizwan Romee ◽  
Michael Slade ◽  
Cory Jenson
Keyword(s):  
T Cell ◽  
High Risk ◽  
Relapse Rate ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Post Transplant ◽  
Active Disease ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract The use of T-cell replete grafts from MHC-haploidentical donors with post-transplant cyclophosphamide (PTCy) to selectively deplete alloreactive T cells is efficacious in patients who do not have ready access to an HLA identical donor. The Johns Hopkins group that pioneered this regimen used non-myeloablative (NMA) conditioning and bone marrow (BM) grafts to help mitigate the risk of GvHD. Their results showed low rates of GvHD and treatment related mortality but outcomes were limited by a high relapse rate. However, for patients with active disease or other high risk characteristics new approaches are needed to help mitigate post-transplant relapse. For other transplant modalities, peripheral blood stem cell (PBSC) grafts are associated with lower relapse rates, faster engraftment, and improved overall survival when compared to BM derived grafts. To date, there are few small studies evaluating the outcomes G-CSF mobilized PBSC grafts for haplo-HCT with PTCy. To report our experience with T cell replete PBSC grafts with PTCy for haplo-HCT, we retrospectively analyzed the outcomes of patients with leukemia and MDS who underwent this transplant regimen. Between 2009 and 2015, 124 patients were transplanted at Washington University School of Medicine with this transplant platform and their outcomes were measured by retrospective chart review through June 2016. Donors were mobilized with G-CSF 10 mcg/kg daily for 5 days prior to beginning pheresis and no grafts were subjected to ex vivo T-cell depletion. Myeloablative conditioning was used for 54 patients and NMA regimens were used for 70 patients, after which, patients were infused with a median of 5.0 x 106 CD34+ cells/kg and 18.0 x 107 CD3+ cells/kg. For GvHD prophylaxis, all patients received PTCy 50 mg/kg on days +3 and +4, tacrolimus from day +5 to 180, and mycophenolate mofetil from day +5 to 35, as previously described. The median age at time of haplo-HCT was 53 years (range 19-73). Ninety three patients were transplanted for AML, 16 for ALL, and 15 for MDS. This was a high risk population with a median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of 3.5 (≥3 indicates high risk). Thirty two patients had prior transplants and 49 patients had active disease prior to their transplant. Median follow up for surviving patients was 553 days. Neutrophil count recovery occurred after a median of 17 days and platelet recovery after 29 days. 74 patient deaths occurred by June 2016. Relapse accounted for 36 deaths, infection for 17, acute GvHD for 9, graft failure for 3, and 9 patients died from other causes. The 1 year overall survival (OS) was 47.5% (95% CI 38.2-56.2%) and 1 year event free survival was 40.2 (31.2-48.9%). For patients transplanted in remission, 1 year OS was 50.8% (38.7-61.6%), while for patients transplanted with active disease 1 year survival was 42.9% (28.4-56.5%). Treatment related mortality at 6 months and 1 year was 20.2% (13.7-27.8%) and 31.4% (23.1-40.0%). The relapse rate at 1 year was 39.5% (28.7-50.1%). For patients transplanted in remission, the 1 year relapse rate was 31.4% (18.7-44.9%) and for those transplanted with active disease it was 50.7% (32.5-66.3%). Univariate analysis showed increased risk of relapse when going into transplant with active disease or receiving NMA regimens. The 180 day cumulative incidence of grades II-IV acute GvHD was 39.3% (30.0-48.9%) and grade III-IV acute GvHD was 10.8% (3.1-23.7%). 1 year cumulative incidence of chronic GvHD was 49.0 (35.8-60.9%) and severe chronic GvHD was very low at 4.0% (1.0-10.4%). In conclusion, using G-CSF mobilized grafts from PBSC for haplo HCT with PTCy is feasible for patients with leukemia and MDS who do not have ready access to an HLA identical donor. The use of PBSC grafts with higher numbers of CD3+ cells led to rapid engraftment, low rates of graft failure, and acceptable rates of acute and chronic GvHD. The 1 year OS was almost 1 year, which is encouraging considering most patients had a HCT CI score > 3 and many had active disease at transplant or already failed a prior transplant. Disease relapse post-transplant remains the primary cause of post-transplant mortality for these leukemia patients. In this cohort relapse was associated with having active disease at time of transplant and receiving NMA conditioning. Our results show using PBSC may be a valid alternative to bone marrow grafts for haplo HCT with PTCy. Disclosures No relevant conflicts of interest to declare.

scholarly journals HLA-Haploidentical Hematopoietic Cell Transplantation of Ex Vivo Tcrαβ-Depleted Grafts with CD45RA-Depleted Memory T Cell Add-Back in Adults and Children with Hematological Malignancies: 4-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 555-555
Author(s):  
Ian Q Wu ◽  
Yeh Ching Linn ◽  
Yang Liang Boo ◽  
Rajat Bhattacharyya ◽  
Zi Yi Lim ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Grade Ii

Abstract Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donors. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications are main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells will permit hematopoietic engraftment while effectively reducing GVHD and providing donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labelling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany) respectively. All except 6 patients received the standard conditioning regimen of fludarabine 160mg/m 2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70 - 140mg/m 2 for 1 day, in combination with either total lymphoid irradiation 6Gy (n=53) or 7.5Gy (n=12) over 3 equal fractions, or total body irradiation of 2Gy (n=17), or thymoglobulin (n=2). Short term GVHD prophylaxis was given for 30 days to 1 patient using MMF, 73 using tacrolimus, and 2 using sirolimus. Results: Between January 2017 and July 2021, we transplanted 85 patients, including 78 adults (median age, 48 years; range 20 - 70) and 7 children (median age, 13 years, range 7 - 17), with high risk AML (n=44), ALL (n=19), MDS (n=9), plasma cell neoplasm (n=4), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), CMMoL (n=2), CML (n=1) and lymphoma (n=2). Patients were infused with TCRαβ and CD45RA depleted grafts containing median of 6.19 x 10 6 (range 3.54 - 20.78) CD34+ cells/kg, 0.00 x 10 4 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 1.10 x 10 6 (range 0.15 - 11.67) CD45RO+CD3+ cells/kg. TCRαβ depleted graft fraction contained a median of 0.42 x 10 4 (range 0 - 11.30) TCRαβ+ cells/kg, and 7.61 x 10 6 (range 0.62 - 31.84) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure with no secondary graft failures. All others had engraftment of ANC &gt; 500 cells/µL at median of 12 days (range 8 - 22) and PLT &gt; 20,000 cells/µL at median of 11 days (range 7 - 17). 6 patients with high donor-specific HLA antibodies (DSA) titres engrafted successfully after desensitisation with plasma exchange, rituximab, and immunoglobulin. 29 patients (34%) developed acute GVHD of grade II - IV (Gd II, n=20; Gd III, n=5; Gd IV, n=4), with a cumulative incidence (CI) of grade II-IV and grade III-IV of 31% (95% CI 21-42%) and 11% (95% CI 5-19%) respectively, at 100 days. Chronic GVHD was seen in only 4 patients at a 2-year CI of 6% (95% CI 2-13%). 1-year CI of non-relapse mortality (NRM) and relapse were 22.7% (95% CI 13.9 - 32.9%) and 15.7% (95% CI 8.3 - 25.3%) respectively. 4 of the 17 NRM were attributed to aGVHD. Viral reactivation included CMV (n=32), HHV-6 (n=22), EBV (n=15), and adenovirus (n=8). 15 patients (17.6%) died of infection within 180 days, including 6 patients with fatal bacteraemia (bacteria, n=4; candidemia, n=2) and 1 patient from disseminated adenovirus infection. At a median follow up of 448 days (range 16- 1648) in surviving patients, 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 64.2 %, 54.0 %, and 49.0%, respectively (Figure 1). In multivariate analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 3.38; 95% CI 1.42 - 8.02; p=0.0059), EFS (HR 2.62; 95% CI 1.18 - 5.76; p=0.0017), and NRM (HR 4.92; 95% CI 1.79 - 13.58; p=0.0021). Disease risk index (DRI) showed a trend in higher risk of relapse (HR 2.83; 95% CI 0.96 - 8.33; p=0.059). 2-year OS, EFS, and GRFS for the subset of 58 patients (adults, n=52; children, n=6) with HCT-CI score of 0 were 76.6 %, 63.4%, and 57.5 %, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allow successful allograft in high-risk patients lacking suitable matched donors, including patients with high levels of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. Best outcomes are seen in patients with favourable HCT-CI. Further efforts are needed to reduce the risk of infection-related death in patients with high risk HCT-CI, and relapse in patients with high risk DRI, through optimization of anti-microbial prophylaxis or prophylactic infusion of memory-cell DLI. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4389-4389
Author(s):  
Oscar Gonzalez-Llano ◽  
Elias Eugenio Gonzalez-Lopez ◽  
Ana Carolina Ramirez-Cazares ◽  
Edson Rene Marcos-Ramirez ◽  
Guillermo J. Ruiz-Arguelles ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Children And Adolescents ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Post Transplant

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

A Prospective Study of G-CSF Primed Bone Marrow from Pediatric Donors as a Stem Cell Source for Allogeneic Bone Marrow Transplant: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1964-1964 ◽  
Author(s):  
Haydar Frangoul ◽  
Ann Woolfrey ◽  
Shakila Khan ◽  
Michael Pulsipher ◽  
John Levine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Chronic Gvhd ◽  
Marrow Transplant ◽  
Allogeneic Bone ◽  
Post Transplant ◽  
Cell Dose ◽  
Pediatric Donors ◽  
Standard Risk

Abstract Higher bone marrow cell dose has been associated with improved survival after allogeneic BMT. Although PBSC provides higher cell dose, it also provides a higher number of T cells which increases the risk of GVHD and may negatively impact the outcome in pediatric patients. A prospective multi-center trial was conducted to evaluate the safety and feasibility of G-CSF primed bone marrow in children receiving HLA-identical sibling bone marrow transplantation (BMT). Thirty eight children at 9 different centers, 17 female and 21 male with a median age of 9.8 years (range 0.8–17) were enrolled between May 2003 and May 2005. Fifteen patients had high risk diseases (ALL ≥CR2=4, AML≥ CR2/refractory=5, Advanced MDS=3, JMML=1, NHL=2) and 23 had standard risk disease (SAA=6, Red Cell Aplasia=1, Sickle cell disease=1, CML-CP=2, AML CR1=9, ALL CR1=2, MDS-RA=2). Five patients had undergone a prior allogeneic transplant. All patients received myeloablative preparative regimens (Cy/TBI±VP-16=12, BU/Cy±other=20 and Cy/ATG=6) and 32 (84%) received CSP/FK506 with MTX as GVHD prophylaxis. Donors were HLA identical siblings except for one who was syngeneic. Donors with median age of 9.2 y (range 1.1–22) received 5 mcg/kg/day of GCSF SQ for 5 consecutive days. Bone marrow was collected on the fifth day with a median volume of 14.5 cc/kg (range 5.2–25). No donor experienced any complications related to G-CSF administration or harvest, up to the time of last follow-up at one month after the harvest. The absolute CD34 cell count at the day of the harvest was measured in 28 patients and it was significantly higher in bone marrow compared to peripheral blood, median of 50/μl (8–247) vs 513/μl (116–156) respectively (p <0.0001). Median nucleated and CD 34 cells infused was 8.4x108/kg (range 2.4–60.9) and 8.7x106/kg (range 2–27.6) respectively. No G-CSF was administered post transplant. All patients had neutrophil engraftment at a median of 19 days (13–28), and all but one patient with early post-transplant relapse had platelet engraftment at a median of 20 days (9–44). Thirteen patients (35%) developed grade 2 GVHD and 4 of 34 evaluable patients (12%) developed chronic GVHD (3 limited and 1 extensive). There was no transplant related mortality. Among 30 patients with malignant disorders 9 (30%) relapsed (6 with high risk and 3 with standard risk disease). The EFS and OS of patients with standard disease at 1 year is 84% (95% CI 68–100%) and 95% (95% CI 87–100) respectively. With a median follow up of 1 year the estimated EFS and OS of all patients at one year is 76% (CI 62–93) and 92% (95% CI 83–100) respectively. We conclude that G-CSF primed bone marrow from pediatric donors is safe and can result in high NC and CD34 cell dose that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD. A prospective randomized trial comparing G-CSF primed bone marrow to unstimulated marrow is planned.

Pre-Transplant 5-Azacitidine (Vidaza®) May Improve Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3664-3664 ◽  
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Melissa Alsina ◽  
Ernesto Ayala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
High Dose ◽  
Unrelated Donor ◽  
Conditioning Treatment ◽  
Risk Of Relapse ◽  
Related Mortality

Abstract Most patients with MDS are older than 60 yrs and, because of age, many have previously been excluded from HCT due to the high risk of transplant related mortality. Reduced intensity conditioning has decreased regimen related mortality in HCT and has increased the age of patients for whom this treatment is offered. There remains substantial risk of relapse after HCT especially in patients with > Int-1 MDS who benefit the most from immediate HCT. One strategy to suppress leukemia burden and potentially decrease the risk of relapse is pre-transplant treatment with 5-azacitidine (Vidaza®). This DNA hypomethylating drug is FDA approved for the treatment of MDS. We analyzed the outcome for 34 MDS patients who received a myeloablative HCT from an HLA compatible sibling or unrelated donor from July 2004 through June of 2006, to investigate the potential impact of pre-transplant 5-azacitidine on response and post-transplant relapse. Fourteen of thirty-four patients received a median of 2 (1–7) cycles of 5-azacitidine prior to HCT. Median age was 59 (49 – 69) yrs. Diagnosis and IPSS category included MDS (8) [Int-1 (1) and Int-2 (7)], MDS-AML (5) and CMML (1). Two patients had induction chemotherapy with residual MDS prior to 5-azacitidine. Subsequent to 5-azacitidine: ten responded [CR (2), PR (1) improvement (7)] three progressed and one was not evaluable. The IPSS category after 5-azacitidine treatment and prior to HCT was Int-2(1), Int-1 (4), and Low (5; 3 in CR) in addition to AML (2) and CMML (1). One was unable to assess. The median follow-up in the survivors is 191 (47 – 524) days. Of the fourteen 5-azacitidine treated patients, none have relapsed post-HCT including patients who progressed on 5-azacitidine. Four have died from non-Hodgkins lymphoma (1), DAH (1), adenovirus pneumonia (1) and chronic GVHD (1). Ten are alive in remission, two for greater than one year. Twenty patients did not receive 5-azacitidine. Diagnosis and IPSS category included MDS (9) [Int-1 (3) and Int-2 (6)], MDS-AML (9) and CMML (1) and one not determined due to lack of cytogenetics. Their median age was 53 (33 – 68) yrs. Treatment included supportive care, induction chemotherapy (9) and SCIO-469 (1). IPSS distribution prior to HCT was Int-2 (7), Int-1 (5) Low (5; 4 in CR); in addition to AML (1) and CMML (1). One was unable to assess. The median follow-up in the survivors is 420 (21 – 742) days. Ten of twenty are alive without relapse and eight have relapsed. Five have died, with relapse (3), fungal pneumonia (1) or multi-organ failure (1). The 1 year K-M estimates of overall and progression free survivals are 64% (SEM 15%) and 64% (SEM 15%), respectively for 5-azacitidine group and 70% (SEM 11%) and 51% (SEM 13%) for non-5-azacytidine group. We conclude from this preliminary analysis that pre-HCT conditioning treatment with 5-azacitidine may reduce the risk for MDS relapse after allogeneic transplant in higher risk patients. In addition to its direct anti-tumor effect, 5-azacitidine may sensitize neoplastic cells to the effects of high dose chemotherapy or promote the expression of antigens critical to effective graft-vs-tumor response. This treatment strategy will be evaluated in a prospective trial to investigate the role of pre-transplant 5-azacitidine on transplant outcomes in patients with higher risk MDS.

Hematopoietic Cell Transplantation After Reduced Intensity Conditioning for Severe Paroxysmal Nocturnal Hemoglobinuria:

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2047-2047 ◽  
Author(s):  
Rafic Farah ◽  
Georg Franke ◽  
Tara B. Gregory ◽  
Mark W. Brunvand ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Failure ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Graft Versus Host ◽  
Pnh Clone ◽  
Reduced Intensity

Abstract Abstract 2047 Objectives: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disease. Patients may present with intermittent hemolysis, thrombotic events or cytopenias. The manifestations can be life threatening. Hematopoietic Cell Transplantation (HCT) is still the only curative therapy. Hegenbart et al reported early results in 7 patients with PNH with high risk features who received transplants from matched related (n=2) or unrelated donors (n=5) after conditioning with a fludarabine / total body irradiation (TBI) based regimen (Biol Blood Marrow Transplant 2003; 9: 689–697). Here we update the data and report outcomes in 12 additional patients. Patients: Nineteen patients diagnosed with severe PNH underwent allogeneic HCT after a reduced intensity conditioning (RIC) regimen. Patients were treated at 9 centers. Eighteen patients had at least 1 high-risk feature (Table), 1 patient had none but underwent transplant because of severe hemolysis prior to the era of eculizumab. Conditioning consisted of fludarabine (30 mg/m2/d) on days −4 to −2 before HCT and 2 Gy (n=16) or 4 Gy (n=3) of TBI on day 0 (n=16) followed by treatment with mycophenolate mofetil and cyclosporine or tacrolimus. All patients received peripheral blood stem cells (PBSC). Donors were HLA-matched related (n=3), HLA-matched unrelated (n=12) or HLA-mismatched unrelated (n=4). Results: The follow-up period ranges between 2 months and almost 10 years (median 27.5 months) after HCT. Neutropenia (absolute neutrophil count<500/μl) developed in 15 of 19 patients after transplantation. The median time to neutrophil recovery in patients who engrafted was 16 days (range 0–29) with a median duration of neutropenia of 12 days (range 0–17, n=12). The median duration of thrombocytopenia (platelet count <20,000/μl) was 3 days (range, 0 to 10 days, n=12). All but 2 patients (89.5%) had a sustained engraftment. One patient experienced primary graft failure and remained neutropenic. He received a second nonmyeloablative HLA-matched unrelated PBSC transplant, 47 days after the first transplant, from a different donor, with 3 Gy TBI and 90mg/m2 fludarabine, and had sustained engraftment. The second patient experienced after engraftment, late graft failure 6 months after HCT. She underwent, 7 months after the first transplant, a second nonmyeloablative, HLA- matched unrelated PBSC transplant, from a different donor, with 4 Gy TBI and 150mg/m2 fludarabine, and had sustained engraftment. Eighteen patients were assessable for acute graft-versus-host disease (GvHD). The incidence of grades 2, 3, and 4 acute GvHD were 22% (4/18), 17% (3/18), and 5% (1/18), respectively. Chronic GvHD developed in 78% (14/18) of evaluable patients. Fifteen patients (78.9%) are alive at the time of last follow-up (Fig.). None of the 15 patients still alive has any evidence of relapse, clinically nor by flow cytometry. Four patients died (21.1%) of complications (necrotizing pancreatitis of unknown cause, pseudomonas infection during treatment of chronic GvHD, hemorrhage after liver biopsy with subacute/chronic liver GvHD, intracerebral bleed). All 15 surviving patients have an ECOG performance status of 0 or 1. Conclusion: The RIC regimen reported here is well tolerated and leads to a high rate of successful engraftment. The graft-versus-host effect seems to be sufficient to eradicate the PNH clone. This regimen may be equally effective in medically fit PNH patients to eradicate the PNH clone while reducing treatment related complications of higher intensity conditioning regimens. Note: 1st 3 authors contributed equally. Disclosures: No relevant conflicts of interest to declare.

Busulfan Area-under-the-Curve Finding Study within a Busulfan/Fludarabine (BuFlu) Conditioning Regimen before Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2939-2939 ◽  
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Melissa Alsina ◽  
Ernesto Ayala ◽  
Karen Fancher ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Systemic Exposure ◽  
Pharmacokinetic Analysis ◽  
Event Free Survival ◽  
Free Survival ◽  
Unrelated Donors ◽  
M Estimates ◽  
Related Mortality

Abstract Relapse of malignancy is frequent in patients transplanted with advanced diseases. There is a relationship between higher Bu exposure and lower risk of relapse, but also higher transplant-related mortality, and data indicated the maximum tolerated daily Bu AUC is < 6000 microMol/min when Bu is used in combination with cyclophosphamide (Cy). To reduce transplant-related mortality, Flu has been substituted for Cy in many transplant centers. We hypothesized that pharmacokinetics-targeting of IV Bu, which results in a predictable systemic exposure, would produce values of tolerable Bu AUC that are higher for BuFlu than for BuCy. Our standard HCT regimen since July 2004 consists of once daily IV BuFlu where fludarabine 40 mg/m2 is given intravenously daily for four days and each infusion is followed immediately by an initial IV Bu dose of 130 mg/m2. Pharmacokinetic analysis is performed after the first infusion of busulfan; the goal is to adjust the busulfan doses for days 3 and 4 to achieve an average exposure targeted to an AUC of 4500–5600 microMol/min. Outcomes for the first sixty-nine patients were analyzed. Thirty-nine of 63 (62%) evaluable patients had their Bu doses adjusted, 30 increased [median adjustment 50% (8 – 175%)], and 9 decreased [median 30% (11 – 60%)], while 24 (38%) pts had an AUC within the desired range without adjustment. Most of the patients (98%) had hematological malignancies and 73% had high CIBMTR risk, median age was 48 (22–68) years, donors were HLA-identical siblings (33), matched (23) or mismatched unrelated donors (13). With a median patient follow-up of 392 (248 – 707) days, the non-relapse mortality was 4% at 100 days and 17% at one year. The K-M estimates of survival and event-free survival are 88%±4% and 83%±5% at 100 days, and 61%±6% and 51%±6% at 1 year, respectively. Subsequently, as part of a prospective, targeted AUC-dose finding trial, 20 patients received an initial Bu dose of 170 mg/m2 with subsequent doses targeted to achieve a 4-day average AUC of 5400–6600 microMol/min. Pharmacokinetic analysis was performed after the first and fourth infusion of busulfan. All patients had hematologic malignancies, 65% had high CIBMTR risk, median age was 48 (22 – 61) years, donors were HLA-A, B, C, DRB1, DQB1 matched siblings (11) or matched unrelated donors (9). Thirteen (65%) patients had their doses adjusted, six had it increased [median 37.1% (35.6 – 61.9 %)] and seven decreased [median 41.6% (18.3 – 55.2%)], while seven patients had an AUC within the desired range without adjustment. With a median follow-up of 111 (range 21–312) days, the 100-day K-M estimates of survival are 88%±8% and event-free survival 83%±9%. The complete observation of 100-day safety, relapse and survival will be presented at the meeting and data will determine further AUC escalation.

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