Antonio Di Stasi - Academia.edu (original) (raw)

Papers by Antonio Di Stasi

Blood, 2021

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) ca... more Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) can develop complications such as life-threatening infections, multi-system organ failure, ICU admission and ventilator support in the immediate post-transplant period. Whereas outcomes of these complications, particularly ICU admission and ventilator support, are known to be poor, little is known about the risk factors leading to them. Methods: We conducted a retrospective study to analyze the impact of pre-transplant risk factors on acute inpatient complications, focusing on ICU admission, ventilator support and multi-system organ failure, following allo-hsct at the University of Alabama at Birmingham (UAB) between 2008 and 2016. Mortality rates and survival outcomes of patients admitted to the ICU were also analyzed. Pre-transplant individual comorbidities were defined as per Sorror's HCT-CI. Results: There were 304 patients included with a median age of 52y (18-72y). There were 51%...

Cancer Drug Discovery and Development, 2022

Blood, 2020

Background: Chronic graft versus host disease (cGVHD) is a major cause of morbidity and late non-... more Background: Chronic graft versus host disease (cGVHD) is a major cause of morbidity and late non-relapse mortality after allogeneic hematopoietic cell transplantation and is commonly associated with prolonged immune suppression. Patients (pts) with inadequate response to steroids have few effective therapeutic options and represent an unmet medical need. Available therapies are associated with significant toxicity, immunosuppression, and increased risk of infections. Preclinical studies demonstrate that CSF-1/CSF-1R is a key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate cGVHD. Axatilimab (SNDX-6352, axa) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R. Axa affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34. It offers a novel therapeutic option for treatment of these pt...

Methods in Molecular Biology, 2018

Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of sever... more Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID). We performed a preclinical validation using a model of CD33+ AML, and generated iC9 CAR T-cells co-expressing a CAR targeting the AML-associated antigen CD33 and a selectable marker (ΔCD19). ΔCD19 selected (sel.) iC9-CAR.CD33 T-cells were effective in controlling leukemia growth in vitro, and could be partially eliminated (76%) using a chemical inducer of dimerization that activates iC9. Moreover, to completely eliminate residual cells, a second targeted agent was added. Future plans with these methods are to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant. Additional strategies that we are currently validating include (1) the modulation of the suicide gene activation, using different concentrations of the inducing agent(s), to be able to eliminate CAR T-cells modified by a regulatable gene, ideally aiming at preserving a proportion of the infused cells (and their antitumor activity) for mild to moderate toxicities, or (2) the co-expression of an inhibitory CAR aiming at sparing normal cells co-expressing an antigen not shared with the tumor.

Bone Marrow Transplantation, 2021

Mortality is highest in the first year following an allogeneic hematopoietic stem cell transplant... more Mortality is highest in the first year following an allogeneic hematopoietic stem cell transplant. With recent advancements, we have expanded the pool of patients to whom we are able to offer transplant as a treatment option. In this context, we analyzed socioeconomic, patient, disease and transplant-related variables that predicted for 1-year all-cause, relapse-related (RRM) and non-relapse related mortality (NRM) in 304 patients at the University of Alabama at Birmingham. The 1-year overall survival, RRM and NRM rates were 60.5%, 13.5% and 22.7% respectively. A KPS score < 80, pre-transplant infection and hypertension and non-complete remission disease status adversely effected all-cause mortality. For NRM, increasing age, pre-transplant infection and diabetes, and poor access to care were associated with higher mortality whereas haploidentical donor type was associated with improved survival. For RRM, a KPS score <80, high/very high disease risk index and the presence of comorbidities were risk factors for higher mortality. Poor access to care, in addition to individual comorbidities, performance status and high-risk disease characteristics, is associated with adverse outcomes following transplant. We propose the incorporation of socioeconomic variables with patient, disease, and transplant-related variables to predict 1-year NRM.

Tumori Journal, 2002

Aims and Background To determine the efficacy and safety of the FOLFOX 2 regimen in patients with... more Aims and Background To determine the efficacy and safety of the FOLFOX 2 regimen in patients with pretreated advanced colorectal cancer. Methods In this single-arm phase II study, 28 patients with heavily pretreated advanced colorectal cancer received the following drug combination: oxaliplatin (100 mg/m2 for 2 hrs on day 1), folinic acid (250 mg/m2 for 2 hrs on day 1) and 5-filuorouracil (1500 mg/m2 for 22 hrs continuous infusion on days 1 and 2) every 2 weeks (one cycle). The treatment was continued until unacceptable toxicity occurred or at most for 10 cycles. Results Nine patients (32%) had a partial response and 5 (18%) stable disease, with a median duration of tumor control of 24 weeks (range, 8-44). The median survival of patients with a partial response or stable disease was 32 weeks (range, 12-52), whereas the median overall survival was 32 weeks (range, 8-72). A clinical benefit was achieved in 32% (9/21) of the patients. Severe (grade 3-4) non-hematological toxicity inclu...

Biology of Blood and Marrow Transplantation, 2016

partners involves co-opting programmed cell death and cellremoval pathways during the development... more partners involves co-opting programmed cell death and cellremoval pathways during the developmental-regulated 'takeover' period of colony life. B. schlosseri colonies reproduce by a process of asexual budding in a highly coordinated weekly blastogenic cycle that ends in a massive apoptotic and phagocytic event of parental individuals. We identified 4266 genes from global RNA-seq expression profiling that changed at least four-fold (FDR < 0.05) shared by both blastogenic takeover and chimeric fusion-partner resorption. Among these, 275 genes increased by expression of at least 50 fold. These include an IL-17 family member (IL-17C), the phagocytic receptors (MerTK, AXL), a programmed cell removal factor (MFGE-8), vascular adhesion molecules (SELP, SELE, Tie1), complement factors (C3, MASP1, MASP2), coagulation factors (F2, F8, KLK3, KLKB1), TNF associated proteins (TRAF3, TRAF4), and matrix metalloproteinases (MMP9, MMP14, MMP16). Among the major pathways identified in chimeric partner elimination are key innate immune signaling processes under the GO terms for "blood coagulation", "cell death", "proteolysis," and "cellular adhesion." Major characteristics of the transcriptional and cellular programs that underlie chimeric fusion-partner resorption and their implications for development of new strategies to promote allogeneic graft survival in hematopoietic cell transplantation [HCT] will be presented.

American journal of blood research, 2013

Delayed recovery of platelet count post allogeneic hematopoietic stem cell transplantation (allo-... more Delayed recovery of platelet count post allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with worse transplant outcomes. Thrombopoietic agents have been successfully used in immune mediated thrombocytopenia or thrombocytopenia from bone marrow failure syndromes; however, the experience regarding their use after allo-HSCT is limited. Here we report on the safety and efficacy of romiplostim used in 3 consecutive patients with thrombocytopenia post allogeneic transplantation. Two patients had prolonged platelet recovery due to poor graft function while one had secondary failure of platelet recovery, likely immune mediated, post transplantation. Successful use of such agents post-transplant may improve platelet recovery, decrease rates of complications and potentially improve outcomes.

$Research paper thumbnail of Long-term results of high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin lymphoma: a single institution experience$

Leukemia & lymphoma, 2010

The introduction of high-dose (HD) chemotherapy (CT) and autologous stem cell (ASCT) or bone marr... more The introduction of high-dose (HD) chemotherapy (CT) and autologous stem cell (ASCT) or bone marrow transplant (ABMT) in the last two decades has improved the prognosis of patients with refractory or relapsed Hodgkin lymphoma (HL) over conventional-dose salvage CT. To evaluate the outcome of adult patients with HL treated with HD CT and ASCT or ABMT after failure or relapse from first-line treatment with CT +/- radiotherapy, we report the results of a retrospective analysis in 82 consecutive patients given HD CT and autologous transplant as second-line therapy between October 1984 and December 2006. Thirty-two patients were given sequential high-dose cytoreductive therapy while 50 received other conventional induction regimens. Seventy-three patients with chemoresponsive disease underwent the myeloablative phase, while eight patients had progressive disease during cytoreductive CT. After a median follow-up of 73 months, the 10-year progression-free survival (PFS) and overall surviva...

Cancer, 2002

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HS... more Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n ¼ 8; combined bone marrow and CNS relapse, n ¼ 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P ¼ .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P ¼ .10) and without previous CNS involvement (P ¼ .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.

Blood, 2014

Key Points Allodepleted-T-cells containing the iC9 safety gene persist long-term in vivo, promote... more Key Points Allodepleted-T-cells containing the iC9 safety gene persist long-term in vivo, promote immune recovery, and protect against infections. GvHD caused by iC9-T cells can be permanently controlled by a single administration of AP1903 without abrogating immune reconstitution.

Blood, 2009

For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably... more For the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment. By contrast, effector CD8+ T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic functi...

Biology of Blood and Marrow Transplantation, 2014

in univariate analysis, adjusting for standard HCT variables (age, HCT-CI, conditioning regimen i... more in univariate analysis, adjusting for standard HCT variables (age, HCT-CI, conditioning regimen intensity, disease risk). Results: 203 adults >¼50 years completed GA and underwent HCT. Mean age was 59 years (range 50-73); 45% had high disease risk, 76% received reduced intensity conditioning, and 14% underwent cord blood HCT. With median follow-up of 36 months, IADL limitations (P < 0.0001), slow walk speed (P ¼ 0.01), low SF36-MCS (P ¼ 0.01), and high CRP (P <0.001) were significantly associated with inferior OS, independent of standard HCT variables. The prognostic effect of these GA variables was greater in older recipients (Table 1). We then created a simple risk score with 1 point for the most prognostic functional measure (IADL impairment) and 1 point for comorbidity (HCT-CI >¼3). This significantly stratified outcomes, particularly in those 60 years, such that 2-year OS was 63%, 29%, and 0% for 0, 1, and 2 points, respectively. Conclusion: GA measures confer independent prognostic utility in older HCT recipients, especially in those >¼60 years. Implementation of GA prior to HCT may aid in appropriate selection of older adults for HCT.

Biology of Blood and Marrow Transplantation, 2013

fertility. If such a strategy is used, novel measures to induce immune tolerance may also be requ... more fertility. If such a strategy is used, novel measures to induce immune tolerance may also be required to minimize rejection.

Blood, 2007

Adoptive transfer of Epstein Barr virus (EBV)–specific cytotoxic T-lymphocytes (EBV-CTLs) has sho... more Adoptive transfer of Epstein Barr virus (EBV)–specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (± 11%) and 22% (± 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR+ CTLs killed both autologous EBV+ cells through their native receptor and EBV−/CD30+ targets through their major histocompatibility complex (MHC)–unrestricted CAR. A subpopulation of activated T cells also ...

Transplantation and Cellular Therapy

Journal of the National Comprehensive Cancer Network

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells ... more Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient’s own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results ...

Journal of Clinical Oncology

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be cura... more TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regim...

Blood

Background: The use of post-transplant cyclophosphamide (PT-Cy) in combination with other immunos... more Background: The use of post-transplant cyclophosphamide (PT-Cy) in combination with other immunosuppressive agents for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. PT-Cy mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. Extrapolating from the success of PT-Cy in haplo transplants, we investigated the benefit of PT-Cy (at a lower dose than that used in haplo HSCT) in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial between September 2013 and June 2018 of PT-Cy for GVHD prophylaxis following myeloablative MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 till day +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidenc...

$Research paper thumbnail of Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML$

New England Journal of Medicine