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.

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.

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.

scholarly journals Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2141-2148 ◽  
Author(s):  
Junya Kanda ◽  
Masakatsu Hishizawa ◽  
Atae Utsunomiya ◽  
Shuichi Taniguchi ◽  
Tetsuya Eto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Leukemia ◽  
Graft Versus Host ◽  
Adult T Cell Leukemia ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.

Charlson Comorbidity Index (CCI) Not Hematopoietic Cell Transplantation Specific-Comorbidity Index (HCT-CI) Successfully Predicts Transplant Related Mortality and Post-Transplant Outcomes in Elderly Patients Undergoing Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3006-3006
Author(s):  
Tamila L. Kindwall-Keller ◽  
Mary J. Laughlin ◽  
Pingfu Fu ◽  
Hillard M. Lazarus ◽  
Paolo F. Caimi ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Median Time ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Comorbidity Index ◽  
Related Mortality

Abstract Abstract 3006FN2 Transplant related mortality (TRM), drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition, pre-transplant comorbidities can have significant impact on the transplant outcomes of elderly patients (pts). Two comorbidity measurement tools, the CCI and the HCT-CI have been inconsistent in predicting TRM and overall survival (OS) after conventional HCT. The HCT-CI and CCI scores have correlated less well with TRM and OS in UCB transplantation. These results may have been limited by the heterogeneity of the UCB transplantation study population in age, disease, disease-risk, comorbidities, and conditioning regimens used. This study was performed to explore the accuracy of the HCT-CI and CCI in predicting post-transplant outcomes in elderly pts with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 35 consecutive elderly (age ≥ 55 years (yrs)) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from each pt's CIBMTR pre-TED form and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. HCT-CI and CCI scores were distributed in the following comorbidity risk groups 0, 1, > 1. Between 2002 and 2011, 35 pts underwent UCB transplantation with the above regimen. Median age was 65 yrs (range 55–71), 21 were male (60%) and 14 female (40%). Most pts had advanced stage or high risk hematologic malignancies; 28 had MDS/AML (80%) and 7 had other hematologic malignancies. All pts had a PS ≤ 2. Twenty-seven pts were in CR ≤ 2, with 31 pts having received ≤ 2 prior therapies. Eight pts had received prior transplants, including 2 pts with prior UCB transplantations and 6 pts with prior autografts. UCB cell dose was calculated on actual body weight (median 84 kg, range 56.1–135.1 kg). A total of 66 UCB grafts matched at a minimum 3/6 (3/6 = 4, 4/6 = 34, 5/6 = 22, 6/6 = 6) were infused. Pts received a range of 1 to 5 UCB units (1 unit = 12 pts, 2 units = 19 pts, 3 units = 2 pts, 5 units = 2 pts). VNTR/FISH analyses confirmed engraftment with median time of 21 days (d) (95% CI: 14–40 d) to achieve > 60% chimerism. Nine pts failed to achieve chimerism > 60%, and 3 had secondary engraftment failure. Median time to ANC > 500/μL for 3 consecutive values was 27 d (95% CI: 21–32 d) and median time to platelets > 20, 000/μL on the first day of 7 consecutive days without a platelet infusion was 40 d (95% CI: 35–71 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 3/35 pts (9%) and chronic GVHD was seen in 6/27 pts (22%). To date 31% (n = 11) of pts have relapsed. Pre-transplant cardiac comorbidities, A-fib/flutter and coronary artery disease, were the most common. Six pts had prior solid tumor malignancies, not active at the time of HCT, including breast (n=2), prostate (n=2), bladder (n=1), and kidney (n=1). After a median follow up of 13 months (range 1–70), 1 yr OS and progression free survival (PFS) were 61% and 55%, respectively. Median PFS and OS were both 16 months (mos) (PFS 95% CI: 8–70 mos, OS 95% CI: 9–70 mos). CCI but not PS or HCT-CI was a significant predictor of OS and PFS (Table and Figure).OS (%)PFS (%)FactorN1 yr2 yr4 yrp-value1 yr2 yr4 yrp-valuePS    0175750330.885252350.81    1-218654534584538CCI    016805822675932    14100500.04100500.04    >115333333333333HCT-CI    012544314564415    1108069690.296969690.25    >113533535453636 TRM occurred in 8 pts (23%). CCI was associated with TRM (p=0.05): pts with CCI ≥ 2 had a 40% (6/15) TRM vs 10% (2/20) with CCI 0–1. PS (p=0.69) and HCT-CI (p=0.47) did not correlate to TRM. In conclusion, elderly pts undergoing RIC UCB transplantation for high risk hematologic malignancies, the CCI was a statistically significant predictor of TRM, PFS, and OS. This index and not HCT-CI or PS identified elderly pts undergoing RIC UCB transplantation at higher risk of TRM and poor post-transplant outcomes. Larger validation studies of the predictive capacity of these comorbidity indexes need to be performed in the multi-institutional setting. Disclosures: Cooke: Amgen:.

Outcome and Immune Reconstitution Following T Cell Depleted Nonmyeloablative Allogeneic Transplantation Using Matched Donors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2036-2036 ◽  
Author(s):  
David A. Rizzieri ◽  
Liang Piu Koh ◽  
Gwynn D. Long ◽  
Cristina Gasparetto ◽  
Jerald Z. Gong ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Allogeneic Transplantation ◽  
Stable Phase ◽  
Immune Recovery ◽  
Post Transplant ◽  
Donor Cells

Abstract To minimize toxicity and monitor immune recovery without interference of long term use of immunosuppressive agents, we have investigated T-cell depleted, nonmyeloablative allogeneic therapy using matched family member donors. Methods: Seventy five patients who were not candidates for ablative therapy due to age or comorbid diseases received fludarabine 30mg/sq m and cyclophosphamide 500mg/sq m IV qd x 4 with alemtuzumab 20mg IV qd x 5 followed by stem cell infusion. No other post transplant immunomodulation was provided. Results: Patient diagnoses included lymphoma/myeloma (20), leukemias/MDS (30), myelofibrosis/aplasia (7) and metastatic solid tumours (18). The median age was 50 (range 18–17) with a median follow up of 18 months. The median CD34+ cell dose collected was 13.4 x 106/kg. Engraftment occurred in 100% of patients with a median of 97% donor cells responsible for patient hematopoiesis by 3 months. Forty six also had a DLI (range 106–108 CD3+ cells/kg). Overall, Grade III–IV acute GVHD occurred in only 5/75 (7%) and 18 (29%) had grade II–IV. Four patients developed chronic GVHD. The transplant regimen was well tolerated with 4% 100 day treatment related mortality. In those with hematologic malignancies, only 7% started in remission, though 45 (60%) attained a CR. The most common cause of death in this group was progressive disease (28%), followed by infections (5%), and GVHD (5%). A subgroup of 21 of these older, more infirm patients who had high risk AML in 1–2nd CR or PR or ≥2 chronic stable phase CML, partially responding lymphoma, or severe myelofibrosis have been followed for at least 1 year. At 1 year, 13/21 (62%) remain alive and in continuing remission. Phenotypic analysis of lymphocyte subsets (measured by flow) revealed recovery at 6 months. Figure Figure T cell VBeta family recovery (spectratype analysis using PCR) revealed robust recovery by 6 months as well (first figure pre and second is 6 months post transplant), despite T depletion. Figure Figure TRECs analysis reveals little, if any, recovery in these patients for at least 12–18 months. Conclusions: Nonablative allogeneic transplantation using alemtuzumab for T cell depletion results in reliable engraftment with little acute GVHD or TRM. Immune recovery assays reveal that despite T cell purging, T cell subset and VBeta families have significant recovery by 6 months and TRECS results show the recovery is primarily from peripheral expansion of transplanted donor cells, not education of new T cells. These data possibly reflect the advantage of low dose donor lymphocyte boosts without planned long term use of immunosuppressive agents. The future challenge will to be to develop strategies to further improve immune recovery in this setting.

Iron Overload Strongly Correlates with Acute Graft-Versus-Host-Disease of the Liver and Treatment Related Mortality after Allogeneic Hematopoetic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1812-1812
Author(s):  
Ann-Kathrin Eisfeld ◽  
Ralph Burkhardt ◽  
Daniel Teupser ◽  
Sabine Schroeder ◽  
Rainer Krahl ◽  
...  
Keyword(s):  
Risk Factors ◽  
Iron Overload ◽  
Retrospective Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hfe Gene ◽  
Strongly Correlated ◽  
Body Iron ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Risk factors for morbidity and treatment related mortality (TRM) following HCT have been well defined in retrospective analysis and prospective validations. These include disease-, recipient- and donor-specific characteristics, but not treatment related factors. Considering that patients undergoing HCT usually receive multiple blood transfusions (BT) and that mutations of the HFE gene are common in the European population, we asked the question if iron overload and HFE mutations were risk factors for complications following HCT. Patients and methods: From January 2001 to December 2004, 265 consecutive patients (142 m/123 f; median age 47 y) received HCT at the University of Leipzig. Patients suffered from acute leukaemia (n=113; 43%), chronic leukaemia (n=75; 28%), lymphoma (n=37; 14%), multiple myeloma (n=21; 8%), and others (n=19; 7%). Preparative regimen consisted of Cyclophosphamid 120 mg/kg and 12 Gy TBI in 145 (55%) patients. The remaining 120 (45%) patients were conditioned with Fludarabin 30 mg/m2/day for 3 days and 2 Gy TBI. HCT was performed from matched related donors in 85 (32%) and matched unrelated donors (MUD) in 180 (68%) patients. Patients and donors were screened for mutant HFE genes by PCR using LightCycler, Roche. Serum ferritin (reference values 30–400 ng/ml) was measured at a median of 1 month after HCT. At the time of measurement, patients had to be in good clinical condition with normal C-reactive protein. Results: Elevated iron stores were present in 86% of patients (median ferritin 1697 ng/ml). At a median of 25 (range 7–55) months after HCT, 92 (35%) patients have died from relapse (n= 27; 29%) or TRM (n= 65; 71%). TRM occurred at a median of 4 months after HCT. Median ferritin in patients who died (measured at a median of 3 months prior to death) and in surviving patients were 3815 and 1146 ng/ml respectively (p&lt;0.0001). The median number of BT at HCT in the 2 groups were 34, and 16 unit respectively (p&lt;0.0001). MUD, CMV-serological status and the gender of the donor did not correlate with TRM. In multivariate analysis, ferritin and BT strongly correlated with TRM (p&lt;0.0001). Mutant HFE genes were found in 98 (37%) patients prior to HCT [heterozygous (het; n=82, 84%), compound (n=9; 9%), homozygous (homo; n=7; 7%). Similarly, 99 (37%) donors showed mutant HFE genes [het, n=86 (87%), compound, n=8 (8%), and homo, n=5 (5%)]. After HCT, all patients expressed donor HFE genotype. HFE genotype of patients and donors did not correlate with TRM. Acute GvHD &gt; grade II was significantly more in pts who died (p=0.0002). Acute GvHD of the liver strongly correlated with excess body iron (p=0.009). Interestingly, chronic GvHD of the skin and liver tended to be more frequent in patients with mutant HFE genes prior to HCT (p=0.03). Conclusions: This is, to our knowledge, the first retrospective analysis where excess body iron and the number of BT at HCT strongly correlated with acute GvHD of the liver and TRM after HCT. These data must be confirmed in prospective studies. Whether morbidity and TRM after HCT can be reduced by iron chelation needs to be evaluated.

Hematopoietic Stem Cell Transplantation (HSCT) from Alternative Donors for Acute Leukemia at High-Risk of Relapse. The Haploidentical Option.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 441-441
Author(s):  
Franco Aversa ◽  
Antonio Tabilio ◽  
Adelmo Terenzi ◽  
Stelvio Ballanti ◽  
Alessandra Carotti ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Leukemia ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Post Transplant ◽  
Leukemia Relapse

Abstract Despite advances in chemotherapy for acute leukemia, survival is poor when patients have unfavourable prognostic features at diagnosis, when they do not achieve CR after the first induction cycle and when they are in second or later remission. In these circumstances an allogeneic HSCT is preferred. The chance of finding a matched unrelated donor depends on the HLA diversity and although molecular analysis achieves closer matches it reduces the probability of finding a donor. Furthermore, many patients relapse while waiting for transplant. Transplantation of HSCs from a one-haplotype mismatched family member offers an immediate source of HSCs to almost all leukemia patients who urgently need an allogeneic transplantation because of the high-risk of leukemia relapse and who do not have a matched, either related or unrelated, avaible donor. Over the past decade, our group has shown the two major obstacles to mismatched transplants, that is severe acute GVHD in T-cell-replete transplants and graft rejection in T-cell-depleted transplants, can be overcome by infusing a megadose of extensively T-cell-depleted HSCs after an immuno-myelo-ablative conditioning regimen. Since our first reports (Aversa et al. Blood 1994 and NEJM 1998), the main modifications to our original approach were: a) in October 1995, fludarabine was substituted for cyclophosphamide in our TBI-based conditioning regimen; b) peripheral blood cells were positively selected by using initially the Ceprate device and then, since January 1999, the Clinimacs instrument which ensures a 4.5 log T-cell depletion in a one-step procedure with no E-rosetting; c) in the 138 patients transplanted since January 1999 post-transplant G-CSF administration was stopped so as to improve immune recovery. The patient population included 90 AML and 48 ALL, median age 28 years (range 9–62), 40 (29%) in bad-risk CR I, 43 (31%) in second or later CR and 55 (40%) in relapse at transplant. Primary full-donor engraftment was achieved in 125/134 evaluable patients (93%); 8 patients engrafted after second transplants. Overall engraftment was achieved in 133 patients (96%). Without any post-transplant immunosuppressive prophylaxis, grade II-IV acute GvHD occurred in 7/133 evaluable patients and 5/106 developed chronic GvHD. Cumulative incidence (C.I. 95%) of non-leukemia mortality was 36% (19%–53%) and 40% (19%–66%) for patients who were respectively in CR or in relapse at transplant. 38/51 deaths were infection-related. Disease status was the major risk factor for relapse and EFS. Cumulative incidence of leukemia relapse was 27% (12%–45%) and 60% (30%–80%), p=0.006, for ALL patients in CR and relapse respectively; 17% (8%–29%) and 46% (29%–61%), p=0.0001, for AML in CR and relapse respectively. ALL and AML patients transplanted in relapse have, respectively, a 6% and 13% probability of surviving event-free. For those transplanted in remission, EFS is respectively 38% and 50% for ALL and AML patients in any CR at transplant. These results indicate the mismatched transplant should be offered to high-risk acute leukemia patients without a HLA-identical donor not as a last resort, but as a viable option in the early stages of the disease.

HLA-Haploidentical Familial Donor Hematopoietic Cell Transplantation without Ex Vivo- T Cell Depletion after Reduced-Intensity Conditioning of Busulfan, Fludarabine, and Anti-Thymocyte Globulin: A Preliminary Report.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3077-3077
Author(s):  
Kyoo-Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Ho-Jin Shin ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Animal hematopoietic cell transplantation (HCT) models and several small clinical trials showed that successful engraftment can be achieved across HLA-haplotype difference after reduced-intensity conditioning (RIC). Furthermore, decreased graft-versus-host disease (GVHD) and transplantation-related mortality (TRM) after RIC was shown in a swine leukocyte antigen-haploidentical HCT experiment. Therefore, a protocol investigating the role of RIC in HLA-haploidentical familial donor HCT was initiated in April 2004 and 20 patients [13 male and 7 female; median age 26.5 years (16–65)] without HLA-matched donor enrolled until June 2007. The diagnosis were AML (n=9), ALL (n=4), acute biphenotypic leukemia (n=1), MDS (n=4), and SAA (n=2), and all patients had high-risk features, i.e. first complete remission (CR) but with high-risk chromosomal abnormality (n=1), first CR after salvage (n=1), second CR (n=6), recurrent/refractory state (n=7), immunotherapy failure (n=4), and high-risk MDS (RAEB-1, n=1). The RIC included iv busulfan 3.2 mg/kg × 2, fludarabine 30 mg/m2 × 6, plus anti-thymocyte globulin [Thymoglobuline 3 mg/kg (n=17) or Lymphoglobuline 15 mg/kg (n=3)] × 4. After receiving G-CSF, the donors (13 mothers; 5 offsprings; and 2 HLA-haploidentical siblings) underwent 2 or 3 daily leukapheresis, and the collected cells were given to patients without T cell depletion [medians of; 7.9 (3.7–12.1)×108/kg MNC, 6.9 (3.6–73.5)×106/kg CD34+ cells, and 4.6 (1.8–8.5)×108/kg CD3+ cells]. GVHD prophylaxis was cyclosporine 3 mg/kg/day iv from day -1 and a short course of methotrexate. As a part of separate phase 1 study, the two most-recently enrolled patients received additional donor CD34+ cell-derived NK cells 6 weeks after HCT. Except one patients with SAA who died due to K. pneumoniae sepsis on day 18, all 19 evaluable patients engrafted with ANC> 500/μl median 17 days (12–53) and platelet> 20,000/μl median 23 days (12–100) after HCT. Eight patients experienced acute GVHD (grades I, II, III, and IV; 2, 3, 2, and 1, respectively). Cumulative incidences (CI) of overall and grade II-IV acute GVHD were 40 and 30%, respectively. Eight patients experienced chronic GVHD (limited, 4; extensive, 4; CI, 51%). Fourteen showed positive CMV antigenemia, while 2 suffered CMV colitis, which resolved after treatment. As early as 2 weeks after HCT, 15 of 16 evaluable patients, and, by 4 weeks, all of 17 evaluable patients showed donor chimerism ≥95% on STR-PCR, which was maintained until 24 weeks in all 11 patients tested. Thirteen patients are alive after median follow-up of 13.6 months (1.5–37.9; Kaplan-Meier survival, 55.6%). Of 16 patients with acute leukemia and high-risk MDS, 8 remain alive without recurrence (event-free-survival, 40.9%). Two patients died of K. pneumoniae sepsis and grade IV acute GVHD, respectively (CI of TRM, 11%). Immune recovery in 10 patients without relapse for > 6 months showed robust lymphocyte contents and immunoglobulin levels at 6 months (means of; 1,060/ul CD3+, 222/ul CD4+, 767/ul CD8+ cells, and 1,317 mg/dl IgG) and 12 months. After RIC, consistent engraftment and durable complete donor hematopoietic chimerism can be achieved from HLA-haploidentical familial donor. The frequencies of GVHD and TRM were low.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2305-2305 ◽  
Author(s):  
Robert J Soiffer ◽  
Jennifer LeRademacher ◽  
Vincent T Ho ◽  
Fangyu Kan ◽  
Andrew Artz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Cell Depletion ◽  
P Value ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3034-3034
Author(s):  
Andrea P Bacigalupo ◽  
Anna Maria Raiola ◽  
Alida Dominietto ◽  
Maria Teresa Van Lint ◽  
Francesca Gualandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Active Disease ◽  
Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

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