HLA-Haploidentical TCR αβ/CD19-Depleted Hematopoietic Stem Cell Transplantation in Children with Fanconi Anemia

Abstract Introduction. Allogeneic HSCT currently represents the only consolidated curative approach for Fanconi anemia (FA) patients, with best results observed in the HLA-identical sibling setting. For patients lacking an HLA-matched related or unrelated donor, haploidentical HSCT virtually assures the opportunity for nearly all patients to benefit from HSCT, offering the advantage of immediate accessibility to the transplant procedure. In order to overcome the limitation of delayed immune recovery, historically associated with this type of allograft, in the last few years we developed a novel method of ex vivo graft manipulation, consisting of the negative depletion of T-cell receptor (TCR) αβ+ T-lymphocytes and CD19 B-cells from peripheral blood stem cells (PBSC) grafts (ClinicalTrial.gov identifier: NCT01810120) (Bertaina el al., Blood 2014). Here we report our analysis in a subgroup of FA patients given TCRαβ/CD19-depleted haploidentical HSCT at our Institution. Patients and methods. Ten consecutive FA patients (6 girls and 4 boys) underwent a TCRαβ/CD19-depleted HSCT from an HLA-haploidentical relative between September 2011 and July 2015. Median age at diagnosis was 6.6 (range 2.7-22.0) years and median age at time of transplantation was 8.1 (range 4.4-22.2) years. The conditioning regimen included Cyclophosphamide 300 mg/m2/day and Fludarabine 30 mg/m2/day for 4 consecutive days (days -6 to -3), with 200 cGy single-dose TBI. Pretransplantation Fresenius® ATG was administered at a dose of 4 mg/kg/day for 3 consecutive days (days -5 to -3) in order to prevent both graft failure and graft-versus-host disease (GVHD). All patients received Rituximab 200 mg/m2 to reduce the risk of Epstein-Barr virus-related post-transplant lymphoproliferative disorders. Selective removal of TCRαβ+ and B-cells was performed on G-CSF-mobilized donor PBSC through labeling with biotinylated anti-TCRαβ antibodies and anti-CD19 antibodies, followed by incubation with anti-biotin antibodies conjugated to paramagnetic beads (CliniMACS; Miltenyi Biotec, Bergisch Gladbach, Germany). No immunosuppressive therapy was administered as post-transplantation prophylaxis against GVHD. Results. The TCRαβ/CD19-depletedgrafts contained a median of 20.40 x106/kg (range 15.80-33.40) CD34+ cells, 5.60 x106/kg (range 1.78-69.60) CD3+ lymphocytes, 0.021 x106/kg (range 0.002-0.043) TCRαβ+ lymphocytes, 5.60 x106/kg (range 1.78-69.60) TCRγδ+ lymphocytes, 0.036 x106/kg (range 0.013-0.079) CD20+ lymphocytes, and 45.30 x106/kg (range 16.2-177.0) NK cells. Engraftment with sustained full donor chimerism was achieved in 9 out of 10 patients, the cumulative incidence of graft rejection being 10% (95% CI, 0-26.8). The patient who rejected his first allograft achieved a complete engraftment after a second HSCT from one-antigen mismatched unrelated donor. No secondary graft failures were observed. The median time for neutrophil and platelet engraftment was 12 days (range, 9-15) and 9 days (range, 8-12), respectively. No patient experienced acute or chronic GVHD in the follow-up period. No transplant-related deaths occurred in our cohort. With a median follow-up of 28 months (range 13.2-39.1), the Kaplan-Meier estimates of OS and DFS were both 100%, while the EFS probability was 90% (95% CI, 47.3-98.5). Discussion. These data suggest that haploidentical HSCT after removal of TCRαβ+ and CD19+ lymphocytes is able to guarantee engraftment with excellent OS and DFS in patients affected by FA. Moreover, given the very low incidence of both acute and chronic GVHD, which has been shown to contribute to the increased risk of developing late post-transplantation malignancies in FA patients, this approach can be considered a very attractive option for FA patients in need of an allograft and lacking an HLA-identical family donor. Disclosures No relevant conflicts of interest to declare.

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Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Severe Alpastic Anemia After Cyclophosphamide Plus Antithymocyte Globulin Conditioning Regimen,

Blood ◽

10.1182/blood.v118.21.4090.4090 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4090-4090

Author(s):

Johanna Konopacki ◽

Raphael Porcher ◽

Marie Robin ◽

Sabine Bieri ◽

Jean Michel Cayuela ◽

...

Keyword(s):

Quality Of Life ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Increased Risk ◽

Long Term Follow Up

Abstract Abstract 4090 Background: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from an HLA- identical sibling is the treatment of choice for young patients with acquired severe aplastic anemia (SAA). Due to increased rates of secondary solid cancer in patients with SAA who received an irradiation-based conditioning regimen, we decided 2 decades ago to use the association of Cyclophosphamide (CY) and Antithymocyte globulin (ATG). We report here the long-term follow-up of patients who underwent HSCT from an HLA-identical related donor after this conditioning regimen. Patients and Methods: 61 consecutive patients with SAA who received a first transplantation from June 1991 to February 2010 in our center were included. Patients with Fanconi anemia or other congenital bone marrow failure were excluded. The conditioning regimen consisted in CY (200mg/Kg) and ATG (2.5 mg/kg/day × 5 days). The donors were HLA-identical siblings in 60 cases and family HLA-matched in 1 case. Graft-versus -host disease (GvHD) prophylaxis associated cyclosporine and methotrexate (days 1, 3, 6 and 11). Long-term clinical outcome, immune recovery and quality of life were assessed. Results: The median age was 21 years [range: 4–43], 41 being adults. Median duration of the disease before HSCT was 93 days. Most of the patients had idiopathic aplastic anemia (n=49, 80%). Median time from diagnosis to HSCT was 3 months (range, 1 to 140). All but 2 patients received bone marrow as source of stem cells and all but 2 engrafted (primary graft failure= 3.4%) with a neutrophils count > 0.5 G/L and a platelets count >20 G/L after a median of 23 (range, 19 to 43) and 21 days (range, 10 to 177), respectively. In patients who had achieved neutrophil recovery, no secondary graft failure was observed. Cumulative incidence (CI) of acute grade II-IV GvHD was 23% (95%CI, 13 to 34) and 18 patients developed chronic GvHD (CI: 32%, 95% CI, 20 to 46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic GvHD (p=0.017). With a median follow-up of 73 months (8 to 233), the estimated 6-year overall survival was 87% (95%CI, 78 to 97). At 72 months, the CI of secondary malignancies was 9%, 10 patients developed avascular necrosis (21% CI), 12 patients were diagnosed with endocrine dysfunctions (19% CI) and 5 presented cardiovascular complications (CI of 10%). The CI of bacterial, fungal and viral infections were 25% (95% CI, 15 to 36), 8% (95% CI, 3 to 17) and 61% (95% CI, 46 to 73) at 72 months, respectively. At 2 years post HSCT, the immune reconstitution was normal for CD3, CD8 T-cells, B-cell and NK-cell but still incomplete for CD4 T-cells. A FACT-BMT questionnaire of quality of life (QOL) was sent to all survivors (n= 53) of who 26 accepted to respond to the questionnaire. There was no evidence for a change in QOL perception with time after transplantation. Our data were compared with those obtained from HSCT recipients from a Swiss transplant center (n=125 patients), mainly transplanted for hematological malignancies. The perception of QOL in patients who were transplanted for SAA was similar to the group of patients who were transplanted for other reason than SAA. Conclusions: Our results confirm that HSCT from HLA-identical sibling donors after CY-ATG conditioning regimen is a curative treatment for patients with SAA, with an excellent long-term outcome. We found an increased risk of chronic GvHD associated with the number of infused CD3 cells. Furthermore, we also found non negligible late complications as well as a similar quality of life with patients transplanted for hematological malignancies. Improving long-term health conditions must thus be a priority field for research, exploring the use of new conditioning regimen as well as new GvHD prophylaxis to improve the quality of life post HSCT of such patients. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

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

Blood ◽

10.1182/blood-2021-152281 ◽

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 + < 4/µl, CD4 + < 1/µl, CD8 + < 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.

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HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽

10.1182/blood.v114.22.655.655 ◽

2009 ◽

Vol 114 (22) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Steven M. Devine ◽

Robert J Soiffer ◽

Marcelo C. Pasquini ◽

Shelly Carter ◽

Parameswaran N Hari ◽

...

Keyword(s):

T Cell ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

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KIT Blockade Is Sufficient to Sustain Donor Hematopoietic Stem Cell Engraftment in Fanconi Anemia Mice

Blood ◽

10.1182/blood.v126.23.1206.1206 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1206-1206

Author(s):

Shanmuganathan Chandrakasan ◽

Rajeswari Jayavaradhan ◽

Ernst John ◽

Archana Shrestha ◽

Phillip Dexheimer ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Fanconi Anemia ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Conditioning Regimen ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Increased Risk

Abstract Background: Fanconi anemia (FA) is the most common cause of inherited bone marrow failure (BMF). Currently, the only curative option for the BMF in FA is an allogenic hematopoietic stem cell transplant (HSCT). However, due to the underlying DNA repair defect, FA patients poorly tolerate alkylating chemotherapy or irradiation based conditioning, which is necessary for donor engraftment. However, this results in significant short and long term morbidity/mortality and augments the inherent increased risk of malignancies in FA patients. To overcome the adverse effects associated with alkylating conditioning agents, alternate experimental approaches exploiting the inherent hematopoietic stem cell (HSC) defect in FA are of utmost clinical necessity. Objective: To develop a safe KIT blocking antibody (KIT-Ab) based HSCT conditioning regimen for FA that does not involve chemotherapy or irradiation. Method: High purity KIT-Ab was made from the ACK2 hybridoma and its specificity to KIT binding was validated using mast cell assay. Baseline peripheral blood cells and the bone marrow hematopoietic stem and progenitor cell (HSPC) compartment (Lin-Kit+Sca+ and Lin-Kit+Sca+CD150+CD48- cells) of FANCA-/- and FANCD2-/- murine models were analyzed. Mechanistic studies using sorted FA bone marrow HSPC were performed ex vivo. This was followed by definitive primary and secondary transplants experiments following injection of KIT-Ab. Results: Several features of FA hematopoietic stem/progenitor cells (HSPC) suggested their susceptibility to KIT-Ab blockade-mediated killing: (a) Expression of KIT was significantly lower in FANCA-/- HSPC, while expression of its ligand was higher in bone marrow stroma; (b) Moreover, genes associated with apoptosis/senescence, stress and inflammatory signaling that were upregulated in WT-HSPC following KIT-Ab blockade, were upregulated in FANCA-/- HSPC at baseline; (c) Furthermore, FANCA-/- HSPC demonstrated increased susceptibility to KIT-Ab mediated apoptosis and had a reduced proliferative capacity. In-vivo studies following ACK2 injection showed a marked reduction of colony-forming units (CFU-C) from both FANCA-/- and FANCD2-/- mice one week following injection, when compared to WT mice (48% and 76% decrease in CFU-C, respectively). Based on these findings, we evaluated the role of ACK2 as a sole HSCT conditioning regimen in FANCA-/- and FANCD2-/- mice. Indeed, definitive HSCT in both FANCA-/- and FANCD2-/- mice using KIT-Ab based conditioning resulted in donor HSC engraftment with multi-lineage chimerism, which progressively increased to 22-24% by 4-months, and was sustained in secondary transplants. Overall, we show that KIT-blockade alone is an adequate non-genotoxic HSPC-targeted conditioning in FA mice, and its clinical translation could circumvent the extensive transplant-related morbidity/mortality in this disease. Disclosures No relevant conflicts of interest to declare.

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Clinical Outcome Associated with Cytomegalovirus (CMV) Infection/Disease in CMV-Seropositive Adult Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-112151 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3382-3382

Author(s):

Regis Peffault De Latour ◽

Patrice Chevallier ◽

Didier Blaise ◽

Aurore Clement ◽

Thierry Allavoine ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

First Year ◽

Unrelated Donor ◽

Cmv Infection ◽

Hematopoietic Stem ◽

Increased Risk ◽

Infection Disease

Abstract Recipients of allogeneic hematopoietic stem cell transplant (HSCT) who have positive cytomegalovirus (CMV) serology are at increased risk for morbidity and mortality after HSCT. However, the exact correlation between early CMV infection and post-HSCT outcomes, notably relapse, is still a source of conflicting data, especially in the era of viral surveillance through polymerase chain reaction (PCR) and preemptive antiviral therapy. We thus decided to retrospectively investigate the clinical impact of early, post-HSCT CMV infection/disease, in a large multi-center cohort of French patients. All consecutive CMV-seropositive adults (≥ 18 years old) who received a first HSCT in 3 French centers between January 1st 2010 and December 31th 2014 were eligible. Cord blood transplantation or a second HSCT were not considered here, as these procedures are associated with a significantly higher risk of morbidity and mortality. Study data were primarily derived from existing electronic health records. The study was conducted in accordance with the Declaration of Helsinki. CMV infection/disease was defined by the initiation of a preemptive and/or a curative anti-CMV treatment in the presence of a CMV viremia detected by a quantitative PCR. The primary objective of this study was to assess the association between CMV infection/disease and overall mortality within the first-year post-transplantation. Secondary clinical endpoints addressed the association between CMV infection/disease and the following outcomes within the first-year of HSCT: graft failure, relapse of the underlying disease, non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host disease (GvHD), and the occurrence of infections other than CMV. Relapse was considered as a competing risk for non-relapse mortality, and death for other events of interest (relapse, incidence of acute and chronic GvHD, and occurrence of infections). Models were adjusted for disease type, disease status at HSCT, age at HSCT, sex, donor type, stem cell source, and conditioning regimen (MAC versus RIC, use of total body irradiation or anti-thymocyte globulin). Five hundred seventy-two patients (54.5% male, 71.2% with Karnofsky >90, and median age 54 years) met the inclusion criteria. Underlying diseases were acute leukemia (33.9%), lymphoid neoplasms (25.9%), and myelodysplastic/ myeloproliferative neoplasms (22.6%). The disease was generally in complete remission at the time of HSCT (56.5%) or stable at the time of HSCT (16.4%). The majority of patients had received a reduced intensity conditioning regimen HSCT (72.5%), and peripheral blood stem cells (71.3%). Donor type was as follows: HLA-matched unrelated donor, 34.1%; HLA-matched relative donor, 46.5%; mismatched unrelated donor, 16.3% and mismatched related donor, 3.10%. CMV infection/disease was observed in 227 patients (39.7%) at a median time of 39.5 days (range, 3-295 days) post-transplant. Overall survival rate as per Kaplan-Meier analysis was 70.9% at 1-year post-HSCT. After adjusting for significant risk factors and considering CMV infection/disease as a time-dependent variable in a Cox model, overall mortality at 1-year was significantly increased in patients developing CMV infection/disease (HR 1.86, [95%CI 1.16 - 3.00], p=0.011). The Fine and Gray competing risk model showed that CMV infection/disease during the first-year post-transplant was significantly associated with higher risk of infections other than CMV (HR 2.34, 95%CI [1.63 - 3.37], p<0.0001) and, consequently, an increased risk for NRM (HR 2.62, 95%CI [1.59 - 4.30], p=0.0001). We did not find any significant association between CMV infection/disease and acute or chronic GvHD, as well as with relapse. In this large cohort of 572 consecutive CMV-seropositive adults undergoing allo-HSCT, and who were monitored with a PCR-based strategy according to routine clinical practice, we identified that CMV infection/disease were significantly associated with an increased risk of 1-year overall and non-relapse mortality, related to higher rates of infections other than CMV. Therefore, post-HSCT CMV infection/disease seemed to be a major concern in the recent healthcare setting, affecting mortality and morbidity. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Clement:MSD: Employment. Allavoine:MSD: Employment. Tadmouri:ClinSearch: Employment. Blomkvist:ClinSearch: Employment.

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Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Bone Marrow Transplantation ◽

10.1038/s41409-021-01323-9 ◽

2021 ◽

Author(s):

Michael H. Albert ◽

Mehtap Sirin ◽

Manfred Hoenig ◽

Fabian Hauck ◽

Catharina Schuetz ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Reduced Intensity

AbstractGraft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

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Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Blood ◽

10.1182/blood-2012-04-423822 ◽

2012 ◽

Vol 120 (2) ◽

pp. 473-476 ◽

Cited By ~ 110

Author(s):

Maria Ester Bernardo ◽

Eugenia Piras ◽

Adriana Vacca ◽

Giovanna Giorgiani ◽

Marco Zecca ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem

Abstract Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

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Unrelated Donor Hematopoietic Cell Transplantation after Non-Myeloablative Conditioning for Patients with High Risk Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3158.3158 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3158-3158

Author(s):

Roberto Sorasio ◽

Luisa Giaccone ◽

Francesca Patriarca ◽

Vittorio Montefusco ◽

Stefano Guidi ◽

...

Keyword(s):

Disease Progression ◽

Initial Treatment ◽

Response Rate ◽

Treatment Plan ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

High Response ◽

High Dose ◽

Unrelated Donor

Abstract Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p<0.025), and 90% and 28% respectively (p<0.005). Unrelated donor non-myeloablative allografting is feasible with relatively low TRM and high response rate. Graft-versus-myeloma effect appears to be more efficient when patients are treated soon after diagnosis. Longer follow-up is needed to assess response duration.

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Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.

Blood ◽

10.1182/blood.v114.22.195.195 ◽

2009 ◽

Vol 114 (22) ◽

pp. 195-195

Author(s):

Arnon Nagler ◽

Myriam Labopin ◽

Avichai Shimoni ◽

Liisa Volin ◽

Donald W. Bunjes ◽

...

Keyword(s):

Conflicts Of Interest ◽

Conditioning Regimen ◽

Disease Status ◽

Post Transplantation ◽

Allogeneic Hsct ◽

Reduce Relapse Rate ◽

Conditioning Regimens ◽

Wbc Count ◽

Transplantation Outcomes

Abstract Abstract 195 TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable. Disclosures: No relevant conflicts of interest to declare.

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Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽

10.1182/blood.v114.22.4326.4326 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4326-4326

Author(s):

Malek Benakli ◽

Redhouane Ahmed nacer ◽

Amina Talbi ◽

Rachida Belhadj ◽

Farih Mehdid ◽

...

Keyword(s):

Complete Remission ◽

Hodgkin Lymphoma ◽

Median Time ◽

Conflicts Of Interest ◽

Late Onset ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Lymphoid Leukaemia ◽

Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

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