scholarly journals Enhancer Hijacking of BCL11B Defines a Subtype of Lineage Ambiguous Acute Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement_2) ◽  
pp. LBA-3-LBA-3
Author(s):  
Lindsey Montefiori ◽  
Sonja Seliger ◽  
Zhaohui Gu ◽  
Xiaotu Ma ◽  
Beisi Xu ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Leukemia ◽  
Research Funding ◽  
Noncoding Region ◽  
Chromosome 8 ◽  
Stem Cell Marker ◽  
Rna Seq ◽  
Cell Of Origin ◽  
Hematopoietic Stem

Lindsey Montefiori, Sonja Seliger, and Zhaohui Gu contributed equally. Acute leukemias of ambiguous lineage (ALAL), including those that express combinations of myeloid, T-lineage and stem cell markers such as T/myeloid mixed phenotype acute leukemia (MPAL) and early T cell precursor acute lymphoblastic leukemia (ETP-ALL), remain challenging to diagnose, classify and treat. To define the genomic basis of these leukemias, we conducted a large pan-acute leukemia analysis of 2,573 samples, including 774 T-ALL, 126 MPAL, 262 AML, and 1,411 B-ALL cases, with transcriptomic sequencing of all cases and whole genome sequencing of a subset. tSNE and hierarchical clustering analyses of RNA-seq data identified a new subtype of 60 samples with a distinct gene expression profile (Figure 1A) and immunophenotype (typically cCD3+ CD7+ CD1a- CD2+ CD5- CD8- cMPO+/- and myeloid/stem cell marker positive); of 55 cases with data, 25 (45.5%) were T/myeloid MPAL, 20 (36.4%) ETP-ALL, 8 (14.5%) AML and 2 (3.6%) undifferentiated leukemia; 80% of cases harbored FLT3 alterations. These cases exhibited monoallelic expression of BCL11B which encodes a T-lineage transcription factor that is repressed in hematopoietic stem and progenitor cells (HSPCs), a putative cell of origin for ALAL. WGS/RNA-seq identified recurrent BCL11B-deregulating structural variants (SVs) in 56/60 (93.3%) cases, including BCL11B fusion to RUNX1 or ZEB2 in 6 (10%) cases. Most SVs were noncoding and included rearrangement of BCL11B to a gene desert upstream of ARID1B on chromosome 6 (23 cases; 41%); rearrangement to the BENC enhancer at CCDC26, distal to MYC on chromosome 8 (9; 16%); rearrangement to an intronic region of CDK6 on chromosome 7 (4; 7%); a novel high-copy (~20x) tandem amplification of a 2.5 kb noncoding region 700 kb downstream of BCL11B on chromosome 14 which we term BCL11B Enhancer Tandem Amplification (BETA) in 12 cases (21%); and rearrangement to noncoding regions at the SATB1 and ETV6 loci, each observed in a single case (Figure 1B). BCL11B-deregulating SVs were otherwise not identified in WGS analysis of 5,550 pediatric and adult hematological malignancies, 344 pediatric brain tumors and 797 pediatric solid tumors. We hypothesized that these SVs result in enhancer hijacking and ectopic activation of BCL11B in a CD34+ HSPC. Accordingly, the ARID1B, CCDC26, CDK6, and ETV6 loci all harbor CD34+ super enhancers which are absent (ARID1B, CCDC26, ETV6) or diminished (CDK6) in committed T cell precursors (Figure 1C,D). The BETA region is nominally active in HSPCs; however, tandem amplification generates a ~50 kb chromatin domain which may transform this region into a potent transcriptional activator. To investigate this, we performed histone H3 lysine 27 acetyl (H3K27ac) chromatin conformation capture followed by high-throughput sequencing (HiChIP) on 5 primary samples (1 ARID1B, 1 CCDC26, 1 CDK6 and 2 BETA cases), normal cord blood CD34+ cells, and 2 T-ALL cell lines (Figure 1E,F). In each primary sample, HiChIP confirmed that the rearranged CD34+ enhancers are active and interact with BCL11B, supporting an enhancer hijacking mechanism. Moreover, in addition to looping to BCL11B, BETA also activates the T cell-specific ThymoD enhancer 1 Mb distal of BCL11B (Figure 1E). Thus, the tandem amplification of a short, inconspicuous noncoding region generates a powerful de novo enhancer that ectopically activates BCL11B, 700kb downstream, and co-opts a dormant T cell enhancer 300 kb in the opposite direction. These activation events likely collaborate to drive oncogenic BCL11B expression in HSPCs. In conclusion, this large-scale analysis has not only identified a new subtype-defining lesion in leukemia and a new mechanism of enhancer generation in cancer (BETA) but has also resolved two controversies. First, genotypic alterations transcend immunophenotype in the classification of lineage ambiguous leukemias, with BCL11B rearrangements unifying a subgroup of T/myeloid MPAL, ETP-ALL and poorly differentiated AML that often differ only by cMPO expression. This recapitulates prior observation of ZNF384-rearrangement defining a subtype of B-ALL and B/myeloid MPAL. Second, chromatin topology analysis demonstrates enhancer hijacking of BCL11B in a primitive stem/progenitor cell, and thus, at least for a subset of cases, a hematopoietic stem cell is the cell of origin for T/myeloid antigen-expressing lineage ambiguous leukemias. Disclosures Iacobucci: Amgen: Honoraria. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; AbbVie, Inc.: Research Funding.

Subsequent Hematopoietic Stem Cell Transplantation in Belinostat-Treated Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5438-5438
Author(s):  
Andrei R. Shustov ◽  
Haifa Kathrin Al-Ali ◽  
Gerald Wulf ◽  
Pamela Hsu ◽  
Mi Rim Choi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Hematopoietic Stem

Abstract Background: PTCL is a heterogeneous group of hematologic malignancies associated with a poor prognosis for most subtypes. In the relapsed setting, hematopoietic stem cell transplantation (HSCT) is the only potentially curative option for patients with PTCL. However, many patients are not able to achieve an adequate response to allow for HSCT. Belinostat (Beleodaq) is a potent pan-histone deacetylase inhibitor that was recently approved in the US for the treatment of patients with R/R PTCL. Approval was based on data from the pivotal Phase 2 BELIEF study that enrolled 129 patients with R/R PTCL (N = 120 evaluable), and demonstrated durable clinical benefit and tolerability. This analysis presents data for 12 of the enrolled patients (9 evaluable) who proceeded to HSCT following belinostat treatment. Methods: Patients with R/R PTCL received belinostat as a 1000 mg/m2IV infusion on Days 1-5 of a 21-day cycle. The primary endpoint of the study was Objective Response Rate (ORR; Complete Response [CR] + Partial Response [PR]) determined by an Independent Review Committee (IRC). We present efficacy and safety data for the subset of 12 patients who subsequently went on to HSCT. Results: Among 12 patients who subsequently proceeded to HSCT, 4 went on to receive an autologous HSCT and 8 received an allogeneic HSCT; 8 patients (67%) were female and 4 (33%) were male, and the median age was 54.5 (range 31-71) years. The median number of prior anticancer therapies was 2 (range 1-8), including 3 patients with prior autologous HSCT. The median number of belinostat treatment cycles was 2.5 (range 1-14) compared to the median of 2.0 (range 1-8) in the overall study population. Most patients in this subgroup had PTCL-Not Otherwise Specified (58.3%), angioimmunoblastic T-cell lymphoma (16.7%), or anaplastic large cell lymphoma (16.7%); 41.7% of patients had Stage IV disease. Three of the 12 patients were not evaluable for response due to insufficient histological material for confirmation by central pathologic analysis. The IRC-confirmed ORR for the 9 evaluable patients was 33.3% vs 25.8% in the study overall, and included 2 CRs, 1 PR, 2 patients with stable disease (SD) and 3 patients with progressive disease (PD). Duration of Response after transplant ranged from 41-261 days for the 3 belinostat responders. At last study contact, 2 patients had died from cardiac events (unrelated to belinostat) and 10 remained alive, with Overall Survival (OS) ranging from 8-23+ months. Most adverse events (AEs) were Grade 1-2, with two treatment-related Grade ≥3 AEs (neutropenia and prolonged QT interval); 3 serious AEs (arthralgia, lower limb fracture, and pyrexia) were reported in this subgroup. Conclusions: Belinostat was well tolerated in previously treated patients with R/R PTCL and enabled some patients to proceed to HSCT. Three patients responded and went on to HSCT following belinostat; the remaining patients had HSCT following SD (2), PD (4) or were not evaluable (3). OS was prolonged when compared to historical controls. Summary of Patients Treated with Belinostat Who Subsequently Went on to Hematopoietic Stem Cell Transplantation Sorted by Subtype and Response Table 1PatientSubtype(Stage)Prior RegimensECOGPSBelinostat CyclesIRC ResponseOS(months)DoR(days) Evaluable Patients931-003^PTCL-NOS (IIIB)3114CR11.56261907-006PTCL-NOS (IIA)5 + auto SCT02SD13.93-907-007^PTCL-NOS (IVA)402SD12.09-907-005^PTCL-NOS (IIIA)202PD13.63-140-002PTCL-NOS (IVA)817PD17.64-914-006PTCL-NOS (IIIA)4 + auto SCT02NE13.73-245-001AITL (UNK)106PR19.9141221-003ALCL ALK– (IA)2 + auto SCT011CR20.4173907-001ALCL ALK– (IVA)204PD22.87- Non-Evaluable Patients*914-002PTCL-NOS (IVB)102PD7.75-147-002^AITL (IIIB)221NE9.43-147-001Hepatosplenic TCL (IVA)103NE10.22- AITL = angioimmunoblastic T-cell lymphoma; ALCL = anaplastic large cell lymphoma; ALK = alkaline phosphatase; auto = autologous; CR = complete response; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; IRC = independent review committee; NE = not evaluable; NOS = not otherwise specified; OS = overall survival; PD = progressive disease; PR = partial response; PS = performance status; PTCL = peripheral T-cell lymphoma; SCT = stem cell transplantation; SD = stable disease; TCL = T-cell lymphoma *Lack of central pathologic confirmation resulted in exclusion from the evaluable population ^Autologous hematopoietic SCT Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Choi:Spectrum Pharmaceuticals: Employment. Allen:Spectrum Pharmaceuticals: Employment. Visser:Sanofi: Membership on an entity's Board of Directors or advisory committees. Horwitz:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jannsen: Consultancy.

scholarly journals Prior Use of Mogamulizumab to Allogenic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1940-1940 ◽  
Author(s):  
Takeshi Sugio ◽  
Koji Kato ◽  
Takatoshi Aoki ◽  
Takanori Ota ◽  
Noriyuki Saito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Research Funding ◽  
Acute Gvhd ◽  
Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract [Introduction] Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma (PTCL) with a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment in ATL patients. Mogamulizumab, a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is a novel immunotherapeutic agent, effective in treating patients with PTCL such as ATL, PTCL-not specified, and cutaneous T-cell lymphoma. However, in allo-HSCT setting, we should be careful to use mogamulizumab because CCR4 is expressed in regulatory T cells: The mogamulizumab treatment may accelerate GVHD by eradicating regulatory T cells in allo-HSCT patients. Here, we retrospectively analyzed the effect of mogamulizumab on GVHD development in ATL patients treated with mogamulizumab prior to allo-HSCT. [Patients and Methods] Data from the Fukuoka Bone Marrow Transplantation Group were retrospectively analyzed after the approval of mogamulizumab use in Japan. [Results] A total of 24 patients with ATL received mogamulizumab prior to allo-HSCT between April 2012 and April 2015 in our group. The median age at allo-HSCT was 58.5 years (range, 32-72). The median intervals from the last administration of mogamulizumab to allo-HSCT were 25 days (range, 9-126). The median total dose of mogamulizumab was 3 mg/kg (range, 1-8 mg/kg). After treatment with mogamulizumab, 18 patients (75%) had achieved in remission (CR in 4 patients and PR in 14) at allo-HSCT. Ten patients received unrelated bone marrow, 5 received related peripheral blood, and 9 received cord blood as stem cell sources. Eleven patients were treated with full-intensity conditioning and 13 received reduced-intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted of calcineurin inhibitors (cyclosporine or tacrolimus) with short-term methotrexate in 14 patients and mycophenolate mofetil in 9. The cumulative incidence (CI) of acute GVHD at 100 days was 66.6% in grade 2-4 and 33.3% in grade 3-4. The involved organs of acute GVHD were skin in 14 patients, gut in 10, and liver in 4. Among 14 patients who developed grade 2-4 acute GVHD, 5 had severe fluid retention such as pleural effusion or ascites associated with GVHD. Chronic GVHD was observed in 6 patients, and 5 of them were extensive disease. The CI of transplant-related mortality (TRM) and relapse at 1-year were 53.2% (95%CI, 29.3-72.3%) and 29.6% (95%CI, 12.6-48.9%), respectively. The leading cause of death was GVHD (n = 7). The 1-year overall survival and progression-free survival were 19.2% (95%CI, 5.7-38.8%) and 17.2% (95%CI, 4.9-35.7%), respectively. [Discussion] Use of mogamulizumab prior to transplantation in allo-HSCT patients has a merit to decrease the burden of ATL cells. However, it was associated with an increase of TRM due to severe GVHD. Although most of ATL patients achieved better disease status at allo-HSCT through mogamulizumab and the survival rate was expected to be 50% based on the previous data, the survival in the present study was ~20%. These data suggest that mogamulizumab administered before transplantation may have retained until an early phase of post-transplantation, and the donor or host-derived regulatory T cells might be eliminated, allowing the GVHD T-cell clone to expand. Since mogalizumab is a potent anti-ATL agent, we need to develop new treatment protocols integrating mogalizumab at a suitable dose or administration timing, to minimize the unwanted GVHD development in future studies. Disclosures Akashi: Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Generation of BCR-ABL Reactive CD4+ T Helper Cells By Reprograming and Redifferentiation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3424-3424
Author(s):  
Norihiro Ueda ◽  
Yasusi Uemura ◽  
Rhong Zhang ◽  
Shuichi Kitayama ◽  
Yutaka Yasui ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
T Helper ◽  
Th Cells ◽  
Hematopoietic Stem ◽  
Chugai Pharmaceutical ◽  
Dc Maturation

Abstract Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder caused by BCR-ABL fusion protein that has constitutively active tyrosine kinase activity. Although the prognosis of the patient with CML in chronic phase has markedly improved by the advent of tyrosine kinase inhibiters, the management of the patients with CML in advanced phase remains to be the major challenge. Immunotherapy is considered to be one of the promising treatment strategies for refractory CML. BCR-ABL fusion region, b3a2 peptide, represents a neo-epitope that can induce CML-specific immune responses. The activation of b3a2 peptide-specific CD4+ T helper (Th) cells and their interaction with dendritic cells (DCs) can induce a robust cytotoxic T lymphocyte (CTL)-mediated anti-leukemic immunity through epitope spreading. However, current vaccination strategies cannot effectively induce the proliferation of antigen-specific Th cells in vivo, presumably due to the tumor-induced immunosuppressive milieu. In addition, ex vivo expansion of antigen-specific Th cells attenuates their effector functions by expansion-related cell senescence, and the procedure to establish antigen-specific Th cells for each patient's treatment is too complicated for the clinical application. The purpose of the present study is to establish a method to generate large amounts of functional b3a2-specific CD4+ Th cells enough for the treatment of the patients with refractory CML by using induced pluripotent stem cell (iPSC) technology. First, we established b3a2-specific CD4+ Th clone from peripheral blood mononuclear cells of a healthy donor positive for HLA-DRB1*09:01 and HLA-A*24:02. The Th clone recognized b3a2 peptide in the context of HLA-DR9 and exhibited a Th1 profile. Second, we established iPSCs from the Th clone and differentiated them into T cell lineage by coculture with OP9 stromal cells expressing Notch ligand Delta-like 1. The iPSC-derived T cells (b3a2-iPS-T cells) expressed the same T cell antigen receptor (TCR) as the original Th clone but not CD4 molecule. Because CD4 acts as a co-receptor in the TCR-mediated Th responses, we transduced b3a2-iPS-T cells with CD4 gene. The CD4-expressing b3a2-iPS-T cells (CD4+ b3a2-iPS-T cells) recognized b3a2 peptide in the context of HLA-DR9 as the original Th clone. Moreover, CD4+ b3a2-iPS-T cells activated by b3a2 peptide induced DC maturation, as indicated by the upregulation of CD86 on DCs. In the additional presence of HLA-A24-restricted Wilms tumor 1 (WT1) peptide, the mature DCs stimulated primary expansion of WT1-specific CTLs. The CTLs exerted cytotoxicity against WT1 peptide-loaded HLA-A24 positive cell lines. These data suggest that the CD4+ b3a2-iPS-T cells have a potential to induce effective anti-leukemic immunity via DC maturation and subsequent CTL responses. The current approach enable to provide large amounts of b3a2 specific CD4+ Th-like cells that would augment CTL-mediated anti-leukemic responses via DC maturation, which may contribute to the treatment of patients with refractory CML. Disclosures Kiyoi: Yakult Honsha Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Japan Blood Products Organization: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Teijin Ltd.: Research Funding. Naoe:Celgene K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; FUJIFILM Corporation: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding. Kaneko:AsTlym Co., Ltd: Other: founder, shareholder and scientific adviser.

scholarly journals Novel Improvement of Haploidentical Hematopoietic Stem Cell Transplantation for Advanced Refractory/Relapsed Acute Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4593-4593
Author(s):  
Fei Pan ◽  
Peihua Lu ◽  
Zhijie Wei ◽  
Rong Yang ◽  
Shuquan Ji
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Median Time ◽  
Mononuclear Cells ◽  
Chronic Gvhd ◽  
Hematopoietic Stem

Introduction The advanced refractory/relapsed acute leukemia has a very dismal prognosis even with the salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT). To develop a novel transplant protocol to achieve a rapid engraftment and quick graft-versus leukemia (GVL) effect is crucial. Based on previous observation, the G-CSF primed bone marrow (BM) plus peripheral blood mononuclear cells (PBMNCs) could not only increase mononuclear cells and CD34 cells, but also change T-cell biology by down-regulating the expression of adhesion and CD28/B7 molecules and increase the absolute number of D2APCS, which promotes a T-cell shift from T1 to T2 subset to secrete a higher anti-inflammatory cytokines of IL-4 and IL-10. After going through a rigorous conditioning, the recipients' T-cells are incapable to attack host. We propose that reinfusion of G-CSF primed donor PBMNCs to recipient on transplant day + 6 may cross mismatched MHC barrier thus accelerating engraftment. Patients and Methods From April 2018 to June 2019, 30 advanced-stage patients with refractory/relapsed acute leukemia were enrolled and underwent a salvage haploidentical (haplo)-HSCT. The median age was 12 (2-63) years with M/F ratio of 17/13. There were 21 patients with acute myelocytic leukemia (AML, 70%), 4 -cell acute lymphoblastic leukemia (B-ALL, 13%), 2 biphenotypic acute leukemia (BAL, 7%), 1 juvenile myelomonocytic leukemia (JMML, 3%), and 2 T-lymphoblast leukemia (T-LBL, 7%). The median BM blasts were 40% (5%-90%). Twenty-eight patients received a conditioning regimen including fludarabine 30mg/m2/d×4 day, cytarabine 2.0g/m2/d×4 days, busulfan 3.2mg/kg/d Q6h×4days, cyclophosphamide 1.5g/m2/d×2 days and melphalan 110mg/m2/d×1 day. Two patients with T-LBL received BCNU+Etoposide+Cytarabine+Melphalan (BEAM) regimen. Graft-versus-host disease (GVHD) prophylaxis contained methotrexate (MTX), cyclosporine A (CsA) and mycophenolate mofetil (MMF), plus ATG (Rabbit anti-human thymocyte immunoglobulin, Sangstat) 1.5mg/kg/d iv daily from day -4 to -1 and additional 1.5mg/kg on day +7 (total dose of 7.5 mg/kg). In addition, anti-CD25 monoclonal antibody (basiliximab) 20 mg on day+1 and +4 was given iv. Donors were primed with G-CSF at 3-4 ug/kg/d sq d1-5. On day 4 of G-CSF, donor BM cells were harvested and were infused unmanipulated on the same day to patient on transplant day 01. On day 5 of G-CSF injection, donor primed PBMNCs were harvested, part of which were immediately infused unmanipulated to recipient on transplant day 02. Part of the cells were cryopreserved and stored in the liquid nitrogen, which were then thawed and reinfused unmanipulated to recipient on day +6 (Table 1). Results All patients achieved a trilineage engraftment with a median time of 13.5 (5-16) days. The median neutrophil and platelet engraftment were 13 (11-19) days and 10 (5-22) days respectively (Fig.1). Among 29 evaluable patients, acute GVHD occurred in 10 (34.5%, Fig. 2) with a median time of 32 (14-60) days, including 5 cases (17%) of grade Ⅱ, 3 (10%) of grade Ⅲ and 2 (7%) of grade Ⅳ. Among the 28 evaluable patients for chronic GVHD, only 6 (21.4%, Fig.3) developed limited chronic GVHD with a median time of 103 (90-180) days. Twenty seven out of thirty (90%) patients achieved disease-free survival (DFS) with a median follow-up time of 6 (5-14) months. Three patients died from transplant related complication, including infection for 2 and GVHD for 1 respectively. Conclusion In this study, with an intensive myeloablative condition and salvage haplo-HSCT, by reinfusing additional unmanipulated donor PBMNCs to recipients on day +6 during their transplantation, a short engraftment time without engraftment failure, low lethal GVHD incidence, and a lower infection rate were able to be achieved. More importantly, most patients remain DFS at a median follow-up time of 6 months. Despite short-term follow-up. the outcomes are particularly encouraging. Disclosures No relevant conflicts of interest to declare.

Sequential Intensified Conditioning Followed By Tapering Of Prophylactic Immunosupressants and Donor Lymphocyte Infusions In Allogeneic Hematopoietic Stem Cell Transplantation For Refractory Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 702-702
Author(s):  
Qifa Liu ◽  
Li Xuan ◽  
Yu Zhang ◽  
Hongsheng Zhou ◽  
Fen Huang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Research Funding ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Leukemia Relapse ◽  
Ebv Viremia ◽  
Donor Lymphocytes

Abstract Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is perceived as the only curative option for refractory acute leukemia. However, the relapse rate exceeds 50% in these patients undergoing allo-HSCT with standard myeloablative regimen. To improve outcomes of allo-HSCT for refractory leukemia, we previously introduced a strategy of sequential intensified conditioning and early rapid tapering of prophylactic immunosupressants for graft-versus-host disease (GVHD). The results indicated this strategy could improve outcomes of refractory leukemia, with 5-year overall survival (OS) and disease-free survival (DFS) of 44.6% ± 8.1% and 38.2% ± 7.7%. However, the 3-year cumulative incidence of leukemia relapse reached to 33.3%. To reduce the relapse rate but without increasing regimen-related toxicities (RRT), we increased the dose of etoposide (VP-16) in conditioning and infused donor lymphocytes (DLI). The aim of this prospective study was to assess the feasibility and efficacy of this modified strategy in patients with refractory acute leukemia. Methods A total of 123 patients with refractory acute leukemia undergoing allo-HSCT from January 2009 to December 2012 were enrolled. Ninety-four patients received related (73 sibling and 21 family donors), 29 unrelated donor transplants; 73 were HLA locus matched, 50 mismatched. Modified sequential intensified conditioning regimen was: fludarabine (30 mg/m2/day, -10 to -6 days) + cytarabine (2.0 g/m2/day, -10 to -6 days) plus TBI (total body irradiation, 4.5 Gy/day, -5, -4 days) + cyclophosphamide (60 mg/kg/ day, -3, -2 days) + VP-16 (15 mg/kg/day, -3, -2 days). Cyclosporine A (CsA) was withdrawn rapidly in a stepwise fashion (total dose reduced by 20%/week) if patients who did not experience acute GVHD (aGVHD) by day +30 post-transplantation. Donor lymphocytes (1.0×108/kg, once a month, 4 doses totally) would be infused in patients without II° or more than II° aGVHD by day + 60 post-transplantation. Results All patients achieved hematopoietic engraftment, except for two who died of infections and one who died of RRT during conditioning. All 120 evaluable patients achieved complete remission (CR) at the time of neutrophil engraftment and achieved complete donor chimerism by day +30 post-transplantation. The incidence of total RRT was 100%, and III-IV RRT was 22.0%. Within the first 100 days post-transplantation, 67 patients developed 95 episodes of infections. Twenty-one had bacterial infections, 7 had invasive fungal infections, 9 had viral infections except cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia, 24 had mixed infections and 6 had infections of unknown etiology. Moreover, 48 patients had CMV viremia, 3 developed CMV pneumonia; 41 had EBV viremia, 13 developed EBV-associated diseases. Of the 120 evaluable patients, aGVHD occurred in 31 cases by day +30. Of the 89 patients who did not develop GVHD by day +30, 28 developed aGVHD after CsA withdrawal. Of the 66 patients who received DLI by day +60, 20 developed aGVHD, and 43 developed chronic GVHD (cGVHD, including 13 migrating from aGVHD). cGVHD occurred in 65 of 102 patients who survived more than 100 days, including 43 after DLI. Twenty-three patients experienced leukemia relapse (hematologic in 16, genetic in 4, central nervous system in 2 and extramedullary in 1) at a median time of 165 (range, 28 to 479) days post-transplantation. The 3-year cumulative incidence of relapse was 25.3 ± 4.8%. Of the 23 patients who relapsed, 6 abandoned treatment and 17 received treatment, including 9 with chemotherapy and DLI, 6 only with chemotherapy, 1 only with DLI, and 1 with chemotherapy and radiotherapy. Only two of the 17 cases achieved CR after treatment, and the others all died of disease progress. With a median follow up of 316 (range, 7 to 1589) days post-transplantation, 75 patients survived and 48 died. Causes of death included leukemia relapse (n=21), infections (n=12), GVHD (n=8), EBV-associated diseases (n=5), cerebral hemorrhage (n=1) and secondary dyshematopoiesis (n=1). The 3-year OS and DFS was 58.8% ± 4.7% and 57.0% ± 4.8%. Conclusions For patients with refractory leukemia undergoing allo-HSCT, the modified strategy of sequential intensified conditioning followed by tapering of prophylactic immunosupressants and DLI not only improves OS and DFS, but also reduces leukemia relapse. Disclosures: Liu: It was supported by 863 Program (No. 2011AA020105).: Research Funding; It was supported by National Public Health Grand Research Foundation (Grant No. 201202017), National Natural Science Foundation of China (Grant No.81000231, No.81270647).: Research Funding; It was supported by Science and Technology Program of Guangzhou of China (11A72121174). : Research Funding.

scholarly journals Personalized Risk-Profiling for Acute Leukemia Patients Undergoing Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Acute Leukemia Working Party of the EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Joshua A Fein ◽  
Roni Shouval ◽  
Myriam Labopin ◽  
Fabio Ciceri ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Research Funding ◽  
Prediction Interval ◽  
Disease Status ◽  
Training Set ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Gvhd Prophylaxis

Background: Prediction of patient outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) remains a tenacious problem. An important limitation of current prediction models is the heterogeneity in outcome even among similar cases. We introduce a novel approach to individualizing estimates of leukemia-free survival (LFS) in acute leukemia patients undergoing haploidentical (haplo) HSCT. Methods: Data were obtained from the registry of the European Society for Blood and Marrow Transplantation for all cases of haplo HSCT for acute leukemia performed between 2011 and 2017. Patients receiving ex-vivo T-cell depleted grafts were excluded. Acute myeloid leukemia patients were classified by clinical disease ontogeny (de novo vs. secondary), cytogenetics, and FLT3-ITD/NPM1mut status; acute lymphoblastic leukemia patients by disease status and the presence of the Philadelphia chromosome. Common patient and transplantation parameters including recipient age, Karnofsky performance status (KPS), time from diagnosis to transplantation, conditioning and graft-versus-host disease (GvHD) prophylaxis were included. Data were split into training and geographic validation sets. Results: A total of 2,001 patients was included in the training set and another 270 in the validation cohort. In the training set, the median age was 50 years; 68% of patients were in complete remission, and 69% had a KPS ≥ 90; 87% received post-transplant cyclophosphamide and 13% antithymocyte globulin for GvHD prophylaxis. To provide the clinician insight on outcomes of similar patients, we developed a descriptive tool to visually explore outcomes of cases with comparable features. We next generated 50 random survival forest models for the prediction of 1-year LFS. In contrast to single point-estimates, the ensemble of 50 models generates a prediction interval accounting for predictive uncertainty. There was heterogeneity of variable importance between models, with either disease status or KPS leading in all models (Figure A). The model was well calibrated (Figure B); the median c-statistic was 0.64 on the validation set. An online interface presents the individual outcomes of the fifteen patients most similar to the index case, the prediction interval, and a visualization of all 50 survival forest predictions. Predictions for a sample patient are shown in Figure (C). Conclusions: We present the first system for individualized prediction of leukemia-free survival following T-cell replete haplo transplantation. A key, novel component of the model, distinguishing it from standard risk scores, is that it provides a measure of predictive certainty. This is essential for judging the robustness of prediction. Our approach is applicable to other clinical settings and can be used for designing risk-guided interventions and for informing patients and clinicians. Figure Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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