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.

Successful Re-Engraftment after Second Allogeneic Transplantation for Graft Failure in Patients with Refractory Hematologic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5120-5120
Author(s):  
Don A. Gabriel ◽  
James Coghill ◽  
Thomas C. Shea ◽  
Terrance Comeau ◽  
Robert Irons ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
None None ◽  
Graft Failure ◽  
Fatty Infiltration ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Grade Ii

Abstract Graft failure (GF), either primary or after transient engraftment, following matched, related allogeneic hematopoetic stem cell transplantation (HSCT) without T-cell depletion is usually less than 3% for hematological diseases. Graft failure using non-T-cell depleted unrelated donors in chronic myelogenous leukemia (CML) as reported by the national marrow registry is approximately 9.7%. For aplastic anemia, the incidence of graft failure is estimated to be 10%. In this report, we present 3 patients (Pts) with GF following unrelated ablative allogeneic HSCT (two with peripheral blood stem cells and one with bone marrow). Pt. 1 had transient engraftment and Pts 2 & 3 had primary GF. Their relevant demographics are as follows: TABLE 1 Disease Unrelated Donor Age/Sex GVHD: BMT1 GVHD: BMT2 PTLD Pt1 CML, 1st Chronic Phase Matched 29/F None Grade II Yes Pt2 MDS Matched 57/M None None No Pt3 MDS/AML 1ag Mismatched 55/M None None No All patients were initially conditioned with alemtuzumab (A) 30mg/day on days −8 to −6, fludarabine (F) 30mg/m2/day on days −7 to −3, and busulfan .8mg/kg x 16 doses (two patients) or x 8 doses (one patient) on days −5 to −2. Conditioning for HSCT #2 included cyclophosphamide 50mg/kg/day, Mesna 50mg/kg/day, and thymoglobulin 2.5mg/kg/day on days −5 to −2. Graft versus host disease (GVHD) prophylaxis included tacrolimus for both HSCT transplants, and low dose methotrexate (3 doses) combined with prednisone (2mg/kg) on days 0–18 followed by a two week taper for HSCT #2. The stem cell product and engraftment kinetics are shown below. Significant toxicities after HSCT#2 have included successful resolution of PTLD in patient #1 (who also experienced infection with pulmonary respiratory syncitial virus, BK viruria, and fatty infiltration of the liver). BK viruria was noted in patient #2, as well as hypertension and a modest pericardial effusion with global hypokinesis (but with a normal ejection fraction). Hepatomegaly was documented, but no vaso-occlusive disease was established. Patient #3 developed a cardiac arrhythmia, hypertension, and BK viruria and remains Plt transfusion dependent. Patient #1 had grade II GVHD of the skin and gut, but patients 2 and 3 had none. GVHD has been <grade II. GF occurred in 3/17 Pts with MUD transplants that included alemtuzamab in the conditioning regimen. While GF is unacceptably high, it is encouraging that all 3 Pts. successfully completed 2nd MUD transplant with transfusion and cytokine independence using same donor preceded in Pts. 1 & 2 by depletion of anti-ABO incompatible antibodies in the recipient.[table2]

Haploidentical Peripheral Blood Stem Cell Transplantation Using Non-Myeloablative Conditioning With Post-Transplant Cyclophosphamide Regimen Is Safe and Is Associated With Very Encouraging Post-Transplant Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4532-4532
Author(s):  
Pavan Kumar Bhamidipati ◽  
John F. DiPersio ◽  
Keith Stokerl-Goldstein ◽  
Geoffrey L. Uy ◽  
Peter Westervelt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Cell ◽  
Conditioning Regimen ◽  
High Dose ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Post Transplant ◽  
Cell Sources

Introduction The availability of HLA matched donors remains a major obstacle for successful allogeneic hematotopoietic cell transplantation. The use of HLA-mismatched alternate donors such as cord blood and haploidentical donor stem cell sources have allowed for greater access for those patients who need an allo-HSCT but lack a suitable matched sibling or unrelated donor. Introduction of high dose cytoxan in the early post-transplant period has significantly improved the outcomes of patients undergoing haploidentical transplantation and has eliminated the need for expensive and labor-intensive ex-vivo T cell depletion. Encouraging results have been reported using this platform with bone marrow as the source of stem cells. However, there have been only limited reports using this transplant platform with G-CSF mobilized peripheral blood stem cells (PBSC) as a source of stem cells for haloidentical transplantation. Here we report the outcomes of 18 patients who underwent haploidentical transplant for hematological malignancies from single institution treated on the Hopkins non-meloablative conditioning regimen but with G-CSF mobilized PBSC as a source of stem cells from a haplo-identical family donor. Patients and Methods A total of 18 patients (median age 41 years, range 22-73 years, 11 males and 7 females) between July 2009 and June 2013 underwent haploidentical transplant at Washington University School of Medicine in St Louis using the Hopkins non-myeloablative conditioning regimen with post transplant cytoxan (fludarabine (30 mg/m2/day on days -6 to -2), cytoxan (14.5 mg/kg/day on days -6 and -5) and TBI (single dose at 200cGy on day -1) and all these patients received two doses of post-transplant cytoxan (50mg/kg on D+3 and D+4). G-CSF mobilized PBSC from parents (n=9) or siblings (9) were used as a graft source with median CD34+ cell dose of 5.0 x 106/kg and median CD3+ T cell dose of 19.7 x 107/kg. GVHD prophylaxis regimen included MMF plus tacrolimus (16/18 patients) or MTX plus tacrolimus (2/18 patients). Median follow-up of all patients was 251 (range 17-1174) days. Diagnoses included AML (n=12), ALL (n=2), NHL (n=2), CLL (n=1) and aplastic anemia (n=1). 7 out of 12 AML patients underwent transplant with active disease (not in remission) and 4/18 of these patients had prior history of allogeneic HCT. Results 16 patients (89%) engrafted (> 95% donor chimerism), median time to neutrophil engraftment was 15 days (range: 12-28 days) and median time to platelet engraftment was 18 days (range: 11-40 days). None of these patients had secondary graft failure. 1-year overall survival (OS) for all patients was 62% and 100-day and 1-year non-relapse mortality (NRM) rates were 11% and 17% respectively. Both 1-year and 2-year relapse free survival (RFS) rates were 53%. Despite very high CD3+ T cell doses, cumulative incidence of grade II-IV aGVHD was 40.7% while grade III-IV aGvHD occurred in only 3 patients (17%). Cumulative incidence of cGVHD at 1 and 2 years were both at 8% (extensive in only 1 patient). CMV reactivation occurred in 11 patients (61%) but did not significantly impact their survival or relapse rates and none of these patients developed CMV disease. Conclusions Here we report the outcomes of 18 patients with hematologic malignancies or marrow failure states undergoing haploidentical transplant using the published Hopkins NMA conditioning platform with post-transplant high dose cytoxan and with G-CSF mobilized PBSC as a source of donor stem cells. In spite of the limited numbers of patients transplanted, our results suggest that this approach is both safe and effective and associated with rapid multilineage engraftment, low rates of both aGvHD and cGvHD and encouraging overall and disease-free survival rates and low rates of NRM. Based on these results, 1) G-CSF mobilized PBSC from haploidentical donors should be considered as an alternative source of haploidentical stem cells to BM and 2) future randomized trials using this platform to test the role of haploidential G-CSF mobilized PBSC with other unrelated donor stem cell sources (cord blood and matched unrelated could also be considered in the future. Disclosures: Abboud: Alexion: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Teva: Speakers Bureau.

scholarly journals Rapid and Safe T Cell Immune Reconstitution By T Cell Progenitor Injection Following Haploidentical Transplantation for Severe Combined Immunodeficiency (SCID)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1752-1752
Author(s):  
Despina Moshous ◽  
Elisa Magrin ◽  
Sarah Winter ◽  
Benjamin Fournier ◽  
Martin Castelle ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Post Transplantation ◽  
Historical Cohort ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors

Abstract Severe Combined Immunodeficiencies (SCID) are defined by a complete absence of T lymphocytes in the blood and lymphoid organs, with variable defects in other WBC subsets depending on the gene defect. From a clinical perspective SCIDs are characterized by early development of life-threatening infections accounting for early death if untreated. The treatment of choice is allogeneic HSCT with very high success rates if a HLA identical sibling (MRD) or unrelated donor (MUD) is used. However, due to the scarcity of matched-related donors, SCID can benefit from haploidentical HSCT. In contrast to the continuous improvement of HLA compatible donor transplantations, no significant improvements have been obtained over the last twenty years for haploidentical HSCT. The profound immunodeficiency during the first months following haploidentical HSCT exposes patients to opportunistic viral, bacterial and fungal infections, which account for approximately 30-40% of the transplant related mortality (TRM). The rapid restoration of the T-cell compartment is the main aim of stem cell therapy in this setting. To this end we have recently set up a phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT03879876) aiming to accelerate the immune reconstitution by injection of ex vivo generated Human T lymphoid progenitors (ProTcell TM) following haploidentical HSCT. T cell progenitors in this trial are generated in vitro within 7 days from mobilized peripheral blood (mPB) CD34 + hematopoietic stem and precursor cells (HSPCs) using our Notch ligand Delta-like 4 GMP culture platform so called SMART Immune's SMART101 product. This open-label, non-randomized study evaluates safety and efficacy of the SMART101 injection following CD34 + selected, haploidentical HSCT in SCID patients and is designed as a dose-escalation study comprising 6 doses of the SMART101 product obtained from the patient's haploidentical stem cell graft. The aim of this protocol is to define the highest efficacy dose without any toxicity. The conditioning regimen is based on Busulfan and Fludarabine according to IE-WP/EBMT guidelines with upfront administration of ATG to prevent graft rejection. Tight monitoring of ATG serum levels is applied in order to assure injection of SMART101 when ATG is below the lymphotoxicity threshold. Here we report the results of the first two SCID patients. P1 presented a homozygous Artemis deficiency. At diagnosis he had an ALC of 341/µl, with complete absence of T cells (CD3 + &lt; 4/µl, CD4 + &lt; 1/µl, CD8 + &lt; 2/µl) and B cells (CD19 + 0/µl). NK cells were present in the normal range for age (CD16 +CD56 + 331/µl). In the absence of an HLA compatible donor, the patient`s father was chosen as haploidentical stem cell donor. P1 received upfront ATG (5 mg /kg total dose), Busulfan (AUC of 16058 microM.min) and Fludarabine (160 mg/m²). He received Defibrotide prophylaxis from D0 until D+21, as well as Ursodeoxycholic acid until D+80. The CD34 + immunoselected graft contained 1.04 x 10 8 nucleated cells/kg with 24.15 x10 6 CD34 + cells/kg and 4000 CD3 + cells/kg on D0. After ATG monitoring 0.12x10 6 Smart101 cells were administered at D+14 post- HSCT. In the follow-up P1 didn't develop any acute or chronic SAEs, no acute or chronic GVHD, and no infection. He was discharged at D+121 post HSCT. The day +100 post transplantation CD4 + cell count/microliter exceeded 10 times the CD4 + count of our historical cohort of RAG1/2 or Artemis deficient patients transplanted with haploidentical HSCT alone following the same conditioning regimen. At 6 months post HSCT this difference remains important (851 versus 300 CD4 + cells/µl); Ig replacement therapy could be stopped as early as 9 months post transplantation and vaccinations have been started. At last follow up; almost 14 months post HSCT P1 is alive and well. P2 had an undefined molecular SCID diagnosis. She has been treated with the same conditioning regimen and received the second dose of 0.2x10 6 CD7 + cells, but unfortunately died from severe VOD emphasizing the need to replace chemotherapy with less toxic myeloablative agents. The preliminary results obtained after injection of Human T lymphoid progenitors in P1 are encouraging. While deserving confirmation in larger numbers of patients they could represent an important step forward in improving the outcome of haploidentical HSCT for SCID. Disclosures Cavazzana: Smart Immune: Other: co-founder.

Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 879-885 ◽  
Author(s):  
Kanchan Rao ◽  
Persis J. Amrolia ◽  
Alison Jones ◽  
Catherine M. Cale ◽  
Paru Naik ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract The optimal approach to stem cell transplantation in children with immunodeficiency who lack a matched family donor is controversial. Unrelated donor stem cell transplantation gives equivalent outcome to mismatched family donor stem cell transplantation in severe combined immunodeficiency, whereas unrelated donors may be preferable in non–severe combined immunodeficiency children. However, unrelated donor stem cell transplantation with conventional conditioning regimens has been associated with significant treatment-related toxicity, particularly in non–severe combined immunodeficiency patients with preexisting organ dysfunction. We report the outcome of a series of 33 consecutive unrelated donor transplantations performed at our center in children with primary immunodeficiency using a reduced-intensity conditioning regimen between 1998 and 2001. We have compared these outcomes with a retrospective control cohort of 19 patients who underwent transplantation with myeloablative conditioning between 1994 and 1998. All children in both groups had primary engraftment. There was no statistical difference in the speed of immune reconstitution or incidence of graft-versus-host disease between the 2 groups. Overall survival was significantly better in the reduced-intensity conditioning group: 31 (94%) of 33 patients survived, compared with 10 (53%) of 19 in the myeloablative conditioning group (P = .014). We conclude that the reduced-intensity conditioning regimen results in improved survival and reduced transplantation-related mortality compared with myeloablative conditioning in high-risk patients undergoing unrelated donor transplantation.

scholarly journals Allogeneic Peripheral Blood Stem Cell Transplantation Using Reduced-Intensity Conditioning Regimen with Fludarabine and Busulfan from HLA-Matched Related Donor for Elderly Adult T-Cell Leukemia/Lymphoma: Results of Multicenter Phase II Study (ATL-NST-3)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2580-2580
Author(s):  
Ryuji Tanosaki ◽  
Ilseung Choi ◽  
Mototsugu Shimokawa ◽  
Atae Utsunomiya ◽  
Masahito Tokunaga ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Marrow Transplant ◽  
Term Survival ◽  
Adult T Cell Leukemia ◽  
Reduced Intensity Conditioning Regimen ◽  
Related Donor

Abstract Background: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type 1 (HTLV-1) infection and commonly affects individuals at an average age of 67 years. Since the prognosis of aggressive ATL patients (pts) treated with conventional chemotherapy has been dismal, we had so far conducted two clinical trials to evaluate the feasibility of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HLA-identical sibling donor using reduced-intensity conditioning regimen (RIC) consisting of fludarabine and busulfan. We reported that allo-PBSCT using RIC provided a long-term survival in about one third of ATL pts and that it exerted not only graft-versus-ATL effects but also graft-versus-HTLV-1 effects (Okamura J, et al. Blood 2005; Tanosaki R, et al. Biol Blood Marrow Transplant 2008; Choi IL, Bone Marrow Transplant 2011). To confirm these promising results in a larger number of ATL pts, we conducted a phase II study (UMIN C000000409). Patients and Methods: Between September 2006 and July 2011, 20 pts were registered in this study. Because ATL is a rare disease affecting elderly people, their siblings were also old and were not appropriate for donors, and the enrollment of pts needed much more time than we had expected. Therefore, though we had originally planned to enroll 35 pts, we had to close this study incompletely. The conditioning regimen consisted of fludarabine 30 mg/m2/day intravenously days -8 to -3, and busulfan 3.2 mg/kg/day intravenously or 4 mg/kg/day orally days -6 and -5. GVHD prophylaxis was CsA alone from day -1 and PBSCs (CD34+ cells >2x106/kg) were infused on day 0. Primary endpoint was 2-year overall survival (OS). Engraftment, adverse events such as graft-versus-host disease (GVHD) and infectious events, and progression free survival (PFS) were also evaluated as well as donor chimerism by STR-PCR analysis, HTLV-1 proviral load, and Tax-specific cytotoxic T lymphocytes (CTL) by tetramers. The eligibility criteria at registration included acute- or lymphoma-type ATL, pts with an HLA-matched related donor, age between 50 and 70, disease status of CR, PR or NC with stable disease, no uncontrollable active infections, no major organ dysfunction, and no active CNS involvement. Results: Median age was 54 years (range 50-68), genders were 10 males and 10 females, ATL types were 13 acute and 7 lymphoma, and disease status at transplantation was 9 CR, 8 PR, and 3 NC. 13 donors were HTLV-1 positive. Engraftment as confirmed by donor chimerism analysis was achieved in all pts. OS and PFS were 95% (95%CI, 86-100%) and 60% (95%CI, 39-82%) at day 100, 74% (95%CI, 55-94%) and 45% (95%CI, 23-67%) at 1 year, and 53% (95%CI, 31-76%) and 40% (95%CI, 19-62%) at 2 years. Acute GVHD occurred in 13 pts (grade I in 2, II in 5, III in 6 pts), and chronic GVHD developed in 12 pts (63%) out of 19 evaluable pts. Eleven pts died at the time of analysis; ATL 6, GVHD 3, IP 1, PCP 1. There was no significant relationship between OS and grades of acute GVHD. While HTLV-1 proviral load decreased as early as 1 month after transplantation and became undetectable level in 14 pts (70%) out of 20, the increase of A2- or A24-restricted Tax-specific CTLs in HLA-A2 or A24-positive pts, respectively, were observed in some pts after 3 months or later, and there was no clear relationship between them. With a median follow-up of 36 months (range 24-86), 9 pts (5 CR and 4 PR at transplantation) were alive without disease. Conclusions: It was confirmed that allo-PBSCT using RIC consisting of fludarabine and busulfan was relatively safe and effective, and provided a long-term survival at least in chemo-sensitive aggressive ATL pts. Disclosures Nakamae: Novartis: Honoraria, Research Funding, Speakers Bureau, Travel/accomidations/meeting expenses Other.

Unrelated Donor (URD) or Partially Matched Related Donor (PMRD) Peripheral Stem Cell Transplant (PSCT) with CD34+ Selection and CD3+ Addback for Pediatric Patients with Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2159-2159
Author(s):  
Nancy Bunin ◽  
Stephan Grupp ◽  
Giuliana Pierson ◽  
Robert Iannone ◽  
Dmitri Monos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Increased Risk ◽  
Related Donor ◽  
Cd34 Selection

Abstract PSCT is becoming increasingly more common, as large doses of PSCs may result in faster engraftment than bone marrow, and high PSC doses may be advantageous in decreasing graft rejection. PSCs contain several logs more T cells than bone marrow, and most studies have shown an increased risk of extensive chronic GVHD with unmodified PSCs. However, purified CD34+ cells may be associated with increased graft failure (Bornhauser, et al. Br J Haematol118:1095, 2002) or relapse. To decrease the risks of both chronic GVHD and graft failure, and maintain potential graft vs. leukemia effect, we used CD34+ selection with a defined dose of CD3+ cells in the product at the time of infusion for URD or PMRD PSCT. We report on the first 23 patients (pts) on this IRB approved study. Conditioning was thiotepa 10mg/kg, cyclophosphamide 120 mg/kg and TBI 12 Gy/6 fractions. Lung shielding after 8 Gy and methylprednisolone 1 mg/kg at day+8 were initiated when it became apparent that engraftment syndrome was being observed in the first 10 patients. GVHD prophylaxis was cyclosporine, followed by oral tacrolimus, which was weaned by 120 days in the absence of GVHD. CD34+ selection was accomplished with the Isolex 300i device and resulted in an average T cell depletion of 4.2 logs. The positive fraction had an average purity of 94%, and T cells obtained from the negative fraction were added to the positively selected product at the time of infusion to achieve the defined T-cell dose of 5 x 105/kg CD3+. The remaining portion of the negative fraction was cryopreserved in multiple aliquots for DLI, if needed. There were 12 males; median age was10 yrs (range, 3–22). Diagnoses included: ALL: 6, AML/MDS:12, CML: 3, JMML: 2. URDs were used for 22 patients, and related donor for 1. This was the second transplant for one pt with MDS. Donors were matched by high resolution typing for13 pts; mismatches included A for 5 pts, B and C loci for 3 pts, DQB1 for 2 pts. The median CD34+ dose infused was 6.6 x 106/kg (1.3–12.4). Engraftment occurred in all pts, with ANC>500 at a median of 14 days (10–19), and platelets >20K in 15 pts at a median of 22 days (13–33). Eleven patients (48%) are alive in remission 7–25 months post SCT (med, 18). Grades I-II GVHD occurred in 15 pts, grade III in 1, and grade IV in association with HHV6 in 1 pt. Limited chronic GVHD occurred in 8 of 12 evaluable pts (67%), and has resolved in all but one. Two pts with AML relapsed at 3 and 18 months. Ten pts died at d 32–85 from CMV (2), ARDS (5), HHV6/infection (2), bacterial sepsis(1). Both pts who developed CMV pneumonitis were seropositive, with seronegative donors; one developed pneumonitis at day +20, with negative antigenemia. Pts with CML were negative for bcr-abl by PCR <6 months post SCT and have remained negative without GVHD. There was a trend toward higher mortality with mismatched donors (RR 2.6, p=0.06). This study demonstrates that PSC engineering with CD34+ positive selection with a defined dose of CD3+ cells results in prompt engraftment. With this approach, the risk of extensive chronic GVHD with URD or PMRD PSCs may be reduced.

Treosulfan Based Myeloablative Regimen Provides High Rate Of Allogeneic Engraftment and Low Toxicity In Patients With Advanced Myelofibrosis,

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5504-5504
Author(s):  
Simone Claudiani ◽  
Francesca Lunghi ◽  
Fabio Giglio ◽  
Giorgia Levati ◽  
Maria Teresa Lupo Stanghellini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Median Time ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Graft Function ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Full Dose ◽  
Low Toxicity

Abstract Abstract 5504 Backgroud Allogeneic transplantation (HSCT) is the only potentially curative therapy for myelofibrosis, even in the era of new drugs that only impact on selected manifestations of disease. The time to evolution of myelofibrosis in advanced phases is variable (months to several years). The choice to proceed to allogeneic transplantation is based on several clinical variables; conditioning regimen and time to transplantation may influence the outcome of HSCT. Here we present our experience in a group of patients with myelofibrosis transplanted in Our Center with a myeloablative regimen based on full dose of treosulfan. Methods We retrospectively evaluated 20 patients (15 male) with primary myelofibrosis (14) and post-ET (essential thrombocythemia) myelofibrosis (6) who underwent HSCT at our institute from July 2005 to February 2013. In this cohort we included 4 patients in blast phase, 3 of which received a brief course of chemotherapy prior to transplant; 4 patients who underwent a second allogeneic transplantation for disease relapse (2) or graft failure (1); 1 patient referred at our Institute in graft failure 3 months after first HSCT.  Only 1 patient had splenectomy before HSCT. Results The median age at diagnosis was 59 years (range 41-76). JAK2 V617F mutation was positive in 7 and unknown in 3 patients. In post-ET MF patients, the median time to transformation in MF was 134 months (60-144). The median time from diagnosis to transplant was 14 months (4-101 months). The median age at transplant was 62 years. DIPSS score at transplant was low in 1, int-1 in 3, int-2 in 13 and high in 3 patients.  We adopted myeloablative regimen based on treosulfan 42 gr/ms and fludarabine 150 mg/ms, plus TBI 4 Gy in 7 patients. GvHD prophylaxis was based on ATG, Rituximab and CSA/MTX (8 pts) or rapamycin (11 pts). The graft was PBSCs (19) and BM (1) from related HLA-identical donor (7 pts), matched unrelated donor (5 pts) and haploidentical donor (8 pts).  The incidence of graft failure and poor graft function was 5% and 20% respectively. The median time to neutrophils engraftment was 20 days. The incidence of acute and chronic graft versus host disease was 50% and 40% respectively. Cumulative incidence of TRM (transplant related mortality) was 45 %; day 100 OS (overall survival) was 70% while 2 year OS was 40%. In multivariate analysis there was no statistically significant correlation between individual factors (including WBC, hemoglobin, platelets, ferritin, beta2-microglobulin, IgA, IgG, IgM, LDH, psuedocholinesterase levels, age, Sorror comorbidity score, donor match, bone marrow kariotype) and survival. However, we found that a linear composition of level of peripheral blasts  (0%, ≥1%, ≥5%), bone marrow CD34+ cells (<5%, ≥5%, ≥20%), spleen size and number of red blood cells units transfused pre-HSCT is able to predict the outcome (p-value 0.03), even if each factor alone is not strongly correlated with survival. There was no statistical significant correlation between the outcome and DIPSS score, Bacicalupo score and Lille score. Conclusions A myeloablative regimen based on full dose treosulfan provide a 95% rate of primary allogeneic engraftment and 40% overall survival in myelofibrosis at advanced stage, with low extra-hematological toxicity in frail patients. Allogeneic transplantation after myeloablative low-toxicity regimens may be offered in myelofibrosis in early chronic phase of disease and for younger patients, two conditions usually linked with durable engraftment, low toxicities and low rate of relapse. Disclosures: No relevant conflicts of interest to declare.

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