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1.
bioRxiv ; 2024 May 14.
Article En | MEDLINE | ID: mdl-38798470

Recent developments in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy, have encountered challenges such as immune-related adverse events and resistance, especially in solid tumors. To advance the field, a deeper understanding of the molecular mechanisms behind treatment responses and resistance is essential. However, the lack of functionally characterized immune-related gene sets has limited data-driven immunological research. To address this gap, we adopted non-negative matrix factorization on 83 human bulk RNA-seq datasets and constructed 28 immune-specific gene sets. After rigorous immunologist-led manual annotations and orthogonal validations across immunological contexts and functional omics data, we demonstrated that these gene sets can be applied to refine pan-cancer immune subtypes, improve ICB response prediction and functionally annotate spatial transcriptomic data. These functional gene sets, informing diverse immune states, will advance our understanding of immunology and cancer research.

2.
Am J Hematol ; 99(5): 836-843, 2024 May.
Article En | MEDLINE | ID: mdl-38400519

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.


Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Inotuzumab Ozogamicin , Prospective Studies , Recurrence , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Alkylating Agents , Transplantation Conditioning/methods
3.
Nat Med ; 30(3): 772-784, 2024 Mar.
Article En | MEDLINE | ID: mdl-38238616

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .


Hematopoietic Stem Cell Transplantation , Neoplasms , Receptors, Chimeric Antigen , Animals , Mice , Humans , Receptors, Chimeric Antigen/genetics , Interleukin-15 , Killer Cells, Natural , Immunotherapy, Adoptive/adverse effects , Antigens, CD19 , Adaptor Proteins, Signal Transducing
5.
Immunol Rev ; 320(1): 217-235, 2023 Nov.
Article En | MEDLINE | ID: mdl-37548050

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on-target off-tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.


Neoplasms , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , T-Lymphocytes , Receptors, Antigen, T-Cell/metabolism , Immunotherapy, Adoptive/adverse effects , Killer Cells, Natural , Antigens, Neoplasm
6.
Sci Adv ; 9(30): eadd6997, 2023 07 28.
Article En | MEDLINE | ID: mdl-37494448

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct.


Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Interleukin-15/genetics , Interleukin-15/metabolism , Cytokines/metabolism , Cell Line, Tumor , Killer Cells, Natural , Cell- and Tissue-Based Therapy
7.
Stem Cells Transl Med ; 12(2): 55-71, 2023 03 03.
Article En | MEDLINE | ID: mdl-36779789

Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as well as the associated delayed engraftment and immune reconstitution, pose limitations to the wide application of UCBT. Research into several aspects of UCBT has been evaluated, including the ex vivo expansion of cord blood HSCs and the process of fucosylation to enhance engraftment. Additionally, UCB has also been used in the treatment of several neurodegenerative and cardiovascular disorders with varying degrees of success. In this article, we will discuss the biology, clinical indications, and benefits of UCBT in pediatric and adult populations. We will also discuss future directions for the use of cord blood.


Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adult , Humans , Child , Bone Marrow Transplantation , Fetal Blood/transplantation
8.
Front Immunol ; 13: 1018047, 2022.
Article En | MEDLINE | ID: mdl-36203567

The current global platelet supply is often insufficient to meet all the transfusion needs of patients, in particular for those with alloimmune thrombocytopenia. To address this issue, we have developed a strategy employing a combination of approaches to achieve more efficient production of functional megakaryocytes (MKs) and platelets collected from cord blood (CB)-derived CD34+ hematopoietic cells. This strategy is based on ex-vivo expansion and differentiation of MKs in the presence of bone marrow niche-mimicking mesenchymal stem cells (MSCs), together with two other key components: (1) To enhance MK polyploidization, we used the potent pharmacological Rho-associated coiled-coil kinase (ROCK) inhibitor, KD045, resulting in liberation of increased numbers of functional platelets both in-vitro and in-vivo; (2) To evade HLA class I T-cell-driven killing of these expanded MKs, we employed CRISPR-Cas9-mediated ß-2 microglobulin (ß2M) gene knockout (KO). We found that coculturing with MSCs and MK-lineage-specific cytokines significantly increased MK expansion. This was further increased by ROCK inhibition, which induced MK polyploidization and platelet production. Additionally, ex-vivo treatment of MKs with KD045 resulted in significantly higher levels of engraftment and donor chimerism in a mouse model of thrombocytopenia. Finally, ß2M KO allowed MKs to evade killing by allogeneic T-cells. Overall, our approaches offer a novel, readily translatable roadmap for producing adult donor-independent platelet products for a variety of clinical indications.


Hematopoietic Stem Cell Transplantation , Thrombocytopenia , Animals , Cytokines/pharmacology , Fetal Blood , Megakaryocytes , Mice , T-Lymphocytes , rho-Associated Kinases
9.
Nat Med ; 28(10): 2133-2144, 2022 Oct.
Article En | MEDLINE | ID: mdl-36175679

Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROG+ siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.


Receptors, Chimeric Antigen , Antigens, Neoplasm , Cell Line, Tumor , Immunotherapy, Adoptive/methods , Killer Cells, Natural , Receptors, Chimeric Antigen/metabolism , Trogocytosis , Tumor Escape
10.
J Clin Oncol ; 39(24): 2710-2719, 2021 08 20.
Article En | MEDLINE | ID: mdl-33929874

PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.


Cystitis/drug therapy , Hemorrhagic Disorders/drug therapy , T-Lymphocytes, Cytotoxic/metabolism , Vascularized Composite Allotransplantation/adverse effects , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Young Adult
11.
J Immunother Cancer ; 9(2)2021 02.
Article En | MEDLINE | ID: mdl-33637601

BACKGROUND: Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT. METHODS: A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed. RESULTS: Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01). CONCLUSIONS: ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.


Cyclophosphamide/administration & dosage , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Immune Checkpoint Inhibitors/administration & dosage , Immunosuppressive Agents/administration & dosage , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Adult , Aged , Cyclophosphamide/adverse effects , Databases, Factual , Drug Administration Schedule , Female , Graft vs Host Disease/epidemiology , Graft vs Host Disease/immunology , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunosuppressive Agents/adverse effects , Incidence , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/immunology , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/immunology , Retrospective Studies , Risk Assessment , Risk Factors , Texas/epidemiology , Transplantation, Homologous/adverse effects , Treatment Outcome
12.
Adv Exp Med Biol ; 1342: 143-192, 2021.
Article En | MEDLINE | ID: mdl-34972965

The past decade has witnessed a revolution in the development of immune checkpoint inhibitors for the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors have notably improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established except for microsatellite instability high (MSI-H) tumors. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This book chapter is a comprehensive review of immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.


Carcinoma, Renal Cell , Carcinoma, Transitional Cell , Kidney Neoplasms , Urinary Bladder Neoplasms , Carcinoma, Renal Cell/therapy , Humans , Immunotherapy , Kidney Neoplasms/therapy , Male
13.
Br J Haematol ; 193(2): 216-230, 2021 04.
Article En | MEDLINE | ID: mdl-33216984

Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time-to-treatment for autologous CAR-T cells, and the risk of graft-versus-host disease (GvHD) associated with allogeneic CAR-T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR-based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK-cell therapy, and the strategies to overcome the challenges encountered.


Immunity, Innate/drug effects , Immunotherapy, Adoptive/adverse effects , Killer Cells, Natural/immunology , Neoplasms/therapy , Receptors, Chimeric Antigen/therapeutic use , Allografts , Clinical Trials as Topic , Cytokine Release Syndrome/chemically induced , Genetic Engineering/methods , Graft vs Host Disease/chemically induced , Humans , Immunotherapy/methods , Immunotherapy, Adoptive/economics , Immunotherapy, Adoptive/methods , Induced Pluripotent Stem Cells/immunology , Induced Pluripotent Stem Cells/transplantation , Neurotoxicity Syndromes/etiology , Receptors, Chimeric Antigen/administration & dosage , Safety , Time-to-Treatment/statistics & numerical data
14.
Blood Adv ; 4(24): 6117-6126, 2020 12 22.
Article En | MEDLINE | ID: mdl-33351107

In relapsed/refractory acute myeloid leukemia (AML), the prognostic impact of complete remission (CR) and measurable residual disease (MRD) negativity is not well established. We retrospectively analyzed 141 patients with relapsed/refractory AML who received first salvage therapy and had MRD assessed by multiparameter flow cytometry at the time of response. Patients who achieved CR with full hematologic recovery as best response vs those with incomplete hematology recovery had lower cumulative incidence of relapse (P = .01) and better relapse-free survival (P = .004) but not overall survival (P = .15); a similar trend was observed in patients who achieved MRD negativity vs those who were MRD positive (P = .01, P = .05, and P = .21, respectively). By multivariate analysis, CR and MRD negativity were each independently associated with lower cumulative incidence of relapse (P = .001 and P = .003, respectively) and better relapse-free survival (P < .001 and P = .02) but not overall survival. Patients who achieved CR with MRD negativity had the lowest rates of relapse and best survival (2-year overall survival rate, 37%), which was driven largely by lower rates of early relapse and an increased ability in this group to undergo hematopoietic stem cell transplantation (HSCT); however, post-HSCT outcomes were similar regardless of response to salvage chemotherapy. Overall, in patients with relapsed/refractory AML, CR with MRD negativity was associated with the best outcomes, supporting it as the optimal response in this setting.


Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Neoplasm, Residual , Prognosis , Remission Induction , Retrospective Studies
15.
Blood ; 136(4): 401-409, 2020 07 23.
Article En | MEDLINE | ID: mdl-32526029

Allogeneic hematopoietic stem cell transplantation (allo-SCT) offers cure for a variety of conditions, in particular, but not limited to, hematologic malignancies. However, it can be associated with life-threatening complications, including graft-versus-host disease (GVHD) and infections, which are factors limiting its widespread use. Technical advances in the field of microbiome research have allowed for a better understanding of the microbial flora of the human intestine, as well as dissection of their interactions with the host immune system in allo-SCT and posttransplant complications. There is growing evidence that the commensal microbiome is frequently dysregulated following allo-SCT and that this dysbiosis can predispose to adverse clinical outcomes, especially including acute intestinal GVHD and reduced overall survival. In this review, we discuss the interactions between the microbiome and the components of the immune system that play a major role in the pathways leading to the inflammatory state of acute intestinal GVHD. We also discuss the microbiome-centered strategies that have been devised or are actively being investigated to improve the outcomes of allo-SCT patients in regard to acute intestinal GVHD.


Gastrointestinal Microbiome , Graft vs Host Disease/microbiology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Acute Disease , Dysbiosis , Graft vs Host Disease/etiology , Humans , Transplantation, Homologous
16.
Adv Exp Med Biol ; 1244: 107-147, 2020.
Article En | MEDLINE | ID: mdl-32301013

The past decade has witnessed a revolution of immune checkpoint inhibitors in the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established, but clinical trials investigating their use are ongoing. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is a great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This chapter is a comprehensive review of the immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.


Immunotherapy , Urogenital Neoplasms/therapy , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/therapy , Humans , Kidney Neoplasms/immunology , Kidney Neoplasms/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Urogenital Neoplasms/immunology
17.
Br J Haematol ; 188(2): 207-223, 2020 01.
Article En | MEDLINE | ID: mdl-31566728

The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies, including tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20 and CD22), bispecific antibodies and chimeric antigen receptor T- cell therapy. A number of new therapies have been approved by the US Food and Drug Administration in the past 5 years, including blinatumomab in 2014, inotuzumab ozagamicin in 2017 and tisagenlecleucel in 2017 for relapsed/refractory ALL. This has led to tremendous improvement in long-term survival, of more than 50% in patients with precursor B-ALL [50-70% in patients with Philadelphia chromosome (Ph)-positive ALL)], 50-60% in T-ALL and 80% in mature B-ALL. Research is ongoing to optimize the benefit of targeted therapeutics with the goal of decreasing the use of cytotoxic therapies.


Antineoplastic Agents, Immunological/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents, Immunological/pharmacology , Humans , Middle Aged , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
19.
Best Pract Res Clin Haematol ; 32(2): 163-176, 2019 06.
Article En | MEDLINE | ID: mdl-31203998

Myelodysplastic syndromes and acute myeloid leukemia are sporadic for the majority of cases affecting the elderly population. Inherited cases, however, do occur. Genetic predispositions to myeloid malignancies can be classified into three categories: familial cancer syndromes associated with increased risk of various malignancies including myelodysplasia and acute myeloid leukemia such as Li-Fraumeni syndrome and constitutional mismatch repair deficiency (CMMRD); germline mutations conferring a specific increased risk of myelodysplastic syndrome and acute myeloid leukemia such as mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes; and finally primarily pediatric inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, severe congenital neutropenia, Shwachman-Diamond syndrome and Diamond Blackfan anemia. The recognition of these germline syndromes is essential in the management and follow-up of patients. Herein, we review the conditions associated with hereditary myeloid leukemia with a special clinical focus on management and monitoring.


Germ-Line Mutation , Hematologic Neoplasms , Myeloproliferative Disorders , Neoplasm Proteins , Neoplastic Syndromes, Hereditary , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/therapy , Humans , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/therapy , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Neoplastic Syndromes, Hereditary/therapy
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