About Leukemia Cancer

A type of cancer known as hematologic malignancy develops in the immune system cells or bone marrow of organs that produce blood (Zhang et al. 2017, p.02). One of the main causes of death worldwide and some of the frequent malignancies are hematologic illnesses (Tomblyn, Winkfield & Dabaja 2012, p.368; Do et al. 2017, p.02). In the United States in 2011, 9% of all previously treated malignancies were caused by a hematologic illness (Sammons 2012, p.04). More than ten hematologic malignancies have already been identified in patients; however, the most common are leukemia, lymphoma, and myeloma see figure 1.0. Even though hematologic cancers do not affect a high population, some risk factor facilitates its existence in a specific group of people. Some of the common risk factors of these hematologic cancers are age, exposure to benzene, radiation and particular therapies of malignancy, weakened immune system as well as exposure to some chemicals. In 2010 the federal government of the US reported that more than 50,000 people were diagnosed with Leukemia and nearly 21,840 deaths estimated. Leukemia malignancy befalls when the bone marrow produces a great number of irregular white blood cells (Harmon 2012, p.19). Myeloid and lymphocytic are the major types of leukemia affecting both adults and children. However, experts described them as either acute (immature) or chronic (mature). Acute Myeloid Leukemia occurs majorly in adults while acute lymphocytic leukemia in children (Taverna et al. 2017, p.03; Kumar et al. 2017, p.03). In adults, AML appears suddenly and attacks other body tissues rapidly. However, ALL causes death among children within weeks or months owing to infections or profuse bleeding. Consequently, the paper will analyze the development of Leukemia cancer therapy over the last few decades aimed at reducing deaths resulting from this malignancy.

Type of malignancy

Estimated new cases for 2012

Estimated deaths for 2012

Median age at diagnosis

Leukemia (all types)

47,150

26,830

66

Acute lymphocytic

6,050

1,440

14

Chronic lymphocytic

16,060

4,580

72

Acute myeloid

13,780

10,200

66

Chronic myeloid

5430

610

64

Myeloma

21,700

10,710

69

Lymphoma

79,190

43,120

64

Hodgkin’s

9,060

1,190

38

NonHodgkin’s

70,130

18,940

66

Fig. 1.0: Table showing demographic data for hematologic cancers in the United States.

Current treatment and diagnosis of leukemic cells and other hematologic malignancies follow the World Health Organization classification and standards first proposed in 2001; however, the agency revised it in 2008 (Popat 2011, p.190). The World Health Organization built the system based on the fused application and utilization of laboratory and clinical data generated from several methodologies, which entailed an assessment of immunophenotype, cell morphology, cytochemistry besides traditional and molecular genetics (Pont et al. 2016, p.05). The WHO integrated technique was built on the previous and widely accepted French American British Classification for leukemia cancer. The FAB classification depended primarily on morphological and cytochemistry characteristics to describe and outline the disease. The WHO classification reflects on various modality to provide a good outline for diagnosing hematologic neoplasms. The cytogenetic embraced by the WHO classification has played a considerable role in the treatment and detection of leukemia malignancies. The discovery that particular recurrent genetic disorders are part of the pathogenesis of several separate entities has backed the application of WHO diagnosis approach. According to the WHO classification system, the diagnostic process for victims with leukemia commences with an assessment of an automated complete blood count commonly abbreviated as CBC. The CBC is essential has it allows the doctors to get information concerning relative as well as absolute red blood cells, white blood cells counts and number of platelets. These measures of the content of blood permit the analysis of the best treatment strategy for that particular leukemia (Peccatori et al. 2015, p.396). Myeloid and lymphoid neoplasm are common types of leukemia cancer affecting both adults and children. Myeloproliferative neoplasms with clonal eosinophilia are infrequent, and they include two whole categories myeloid and lymphoid neoplasms with eosinophilia and platelet-derived growth factor receptor-α (PDGFRA), -β (PDGFRB) or fibroblast growth factor receptor 1 (FGFR1) abnormalities. Noteworthy these two types of hematologic malignancies besides eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFRI is a new class included in the 2008-revised standard of the WHO classification system. Below is a diagnostic method to myeloid and lymphoid neoplasms with eosinophilia according to the WHO classification system of 2008. The figure provides an understanding of how the various leukemic cell is identifiable.















Persistent Eosinophilia



Underlying neoplasm, infection, atopy, drugs



Reactive eosinophilia

No

FIP1L1-PDGFRA fusion gene or PDGFRB or FGFR1 rearrangement



Myeloid/lymphoid neoplasm with eosinophilia and abnormality of PDGFRA, PDGFRB, or FGFR1

No

Other Clonal genetic or molecular abnormality or increased marrow blasts (5-19%)



Chronic Eosinophilic Leukemia, NOS

No

T- or B-cell clonality

Yes

Lymphoid neoplasm

No

End organ damage

Yes

Hypereosinoplasmic syndrome

No

Idiopathic hypereosinophilia

Fig. 1.1: Diagnostic approach to lymphoid and myeloid neoplasms with eosinophilia

The rearrangement of PDGFRA is associable with a CEL-like image; while cases related to PDGFRB reorganization resembles the CMML with eosinophilia. FGFRI 1 reorganization has a connection with a more heterogeneous cluster of cells and may be accompanied by a spectrum of phenotypes encompassing MPN, AML, B- or T- lymphoblastic leukemia.

The growing advancement in immunotherapy has improved leukemia cancer treatment over the last few decades (Ueda 2017, p.37; Rambaldi et al. 2015, p.02). In hematology, developments have shown success in the B-lymphoproliferative diseases, which include ALL. However, research has also exposed novel approaches that utilize the immune system in destroying cancer cells in the body to detect AML (Gale, Bennett & Hoffman 2017, p.02). Some antibody-based techniques have found sympathy; thus entering the standard treatment or almost getting approval as a practical treatment approach for ALL. Anti-CD22 called Rituximab has been beneficial as an additive to the traditional chemotherapeutic agents used in diagnosing most cancerous cells.

Antibody-drug Conjugates for Immunotherapy of AML

ADC is one of the newest developments towards a diagnosis of leukemic cells in the 21st century. The method consists of a group of monoclonal antibodies conjugated to several toxins that support therapy (Cornils et al. 2017, p.03). When compared to the orthodox antibody structure or format, ADC is the best tool to bridge the gap existing between chemotherapy and advanced immunotherapy. According to this technique, after internalization, ACD releases chemicals in the acidic surrounding of lysosomes, which reaches the nucleus. In the core, toxin induces death of leukemic cells through DNA double-strand break as well as cells cycle arrest. The approach majorly targets the CD33 in AML-affected cells. The protuberant ADC in a clinical setting was gemtuzumab ozogamicin a humanized CD33 igG4 antibody conjugated to calicheamicin. Excellent outcome in the clinical setting resulted in the fast endorsement of the antibody by the Food and Drug Administration in 2000.



Study Identifier

Study name

Antigen/target

Drug name

Combination therapy

Clinical phase

Indication (AML only)

NCT00766116

A phase I/II test of the combination 5-azacitidine and gemtuzumab ozogamicin therapy for management of relapsed AML

CD33

Gemtuzumab ozogamicin

Azacitidine

I/II

Relapsed AML

NCT01902329

A phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia

CD33

SGN-CD33A

Azacitidine or decitabine

I

Deteriorated AML or newly diagnosed AML

NCT02326584

A phase 1b dose-escalation study of SGN-CD33A in combination with standard-of-care for patients with newly diagnosed acute myeloid

CD33

SGN-CD33A

Standard of Care

I

Newly diagnosed AML

NCT02674763

A phase 1, multi-center, open-label study of IMGN779 administered intravenously in adult patients with relapsed/refractory CD33-positive

CD33

IMGN779

n.a.

I

r/r AML; CD33 expression

Fig. 1.2: Current Clinical trials, which applied antibody-drug conjugates for immunotherapy of AML





CAR T cells for immunotherapy of AML

CAR T cells consider a similar technology has that of T cell-engaging antibody which builds one more step (Bonini et al. 2015, p.67; Lichtenegger 2017, p.07; Brenner 2012, p.818). CARs are cell membrane-bound receptors that are genetically constructed. These structures amalgamate the extracellular antibody binding and intracellular effector cell signaling (Fowler, 2014, p.211). Therefore allowing both MHC-independent antigen binding and highly potent cytotoxic effector cell functioning (Bund 2013, p.39; Mortensen et al. 2012, p.142; Vonderheide & June 2014 p.07; O'Reilly et al. 2015, p.43). Most of the hematologic malignancy result from exposure to radiation either during cancer therapy or from other sources from the environment. The development of this treatment has dramatically motivated a friendly diagnosis that does not upsurge the spread of cancerous cells. Until now, the most antigen target for CAR T cell therapy is CD19 owing to its expression pattern and proper safety outline (Lendvai, Cohen & Cho 2015, p.770; Brehm et al. 2013, p.349). However, despite the promising early outcomes and increasingly expanding figure of anti-CD19, CAR T cells tests; this innovative drug design is still not fully understood and can never be considered safe. For instance, March this year, Juno shut down the advancement of anti-CD19 CD28-constimulatory JCAR015 CAR T cells and their phase II ROCKET test in r/r adult ALL after the occurrence of five deaths associated with CAR T cell-motivated neurotoxicity (Lichtenegger 2017, p.07). Additionally, deciphering CAR T cell treatment to AML is multifaceted again by the non-constrained expression of AML-linked antigens. To date, only one small trial of analyzing anti-LeY CAR T cells (CTX08-0002) has completed successfully. The table below shows the present clinical tests by CAR T cells for immunotherapy of AML.

Identifier

Study name

Antigen/target

Drug name

Combination therapy

Clinical phase

Indication (AML only)

NCT01864902

Treatment of Relapsed and/or Chemotherapy Refractory CD33 Positive Acute Myeloid Leukemia by CART-33 (CART33)

CD33

CART-33

2nd

4-1BB

Lentiviral

NCT02159495

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

CD123

CD123R(EQ) 28Z/EGFRt

2nd

CD28

Lentiviral

NCT02203825

Safety Study of Chimeric Antigen Receptor Modified T-cells Targeting NKG2D-Ligands

NKG2D-ligands

CM-CS1 T-cells

2nd

DAP10

Retroviral

NCT03190278

Study Evaluating Safety and Efficacy of UCART123 in Patients With Acute Myeloid Leukemia (AML123)



CD123

UCART123

n.a.

n.a.

n.a.

Fig. 1.4: Table showing current clinical trials by utilizing CAR T cells for immunotherapy of AML.



References

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Bonini, C, Peccatori, J, Stanghellini, M, Vago, L, Bondanza, A, Cieri, N, Greco, R, Bernardi, M, Corti, C, Oliveira, G, Zappone, E, Traversari, C, Bordignon, C, & Ciceri, F 2015, 'Haploidentical HSCT: a 15-year experience at San Raffaele', Bone Marrow Transplantation, 50, pp. S67-S71, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Brehm, C, Huenecke, S, Pfirrmann, V, Rossig, C, Mackall, C, Bollard, C, Gottschalk, S, Schlegel, P, Klingebiel, T, & Bader, P 2013, 'Highlights of the Third International Conference on Immunotherapy in Pediatric Oncology', Pediatric Hematology & Oncology, 30, 5, pp. 349-366, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Brenner, M, K 2012, 'Will T-cell therapy for cancer ever be a standard of care?’ Cancer Gene Therapy, 19, 12, pp. 818-821, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Bund, D, Buhmann, R, Gökmen, F, Zorn, J, Kolb, H, & Schmetzer, H 2013, 'Minor Histocompatibility Antigen UTY as Target for Graft-versus-Leukemia and Graft-versus-Haematopoiesis in the Canine Model', Scandinavian Journal Of Immunology, 77, 1, pp. 39-53, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

Cornils, K, Thielecke, L, Winkelmann, D, Aranyossy, T, Lesche, M, Dahl, A, Roeder, I, Fehse, B, & Glauche, I 2017, 'Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion', Molecular Cancer, 16, pp. 1-12, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Do, H, Oh, T, Yang, J, Park, K, & Ma, J 2017, 'Davallia mariesii Moore Improves FcεRI-Mediated Allergic Responses in the Rat Basophilic Leukemia Mast Cell Line RBL-2H3 and Passive Cutaneous Anaphylaxis in Mice', Mediators Of Inflammation, pp. 1-9, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Fowler, D, H 2014, 'Rapamycin-resistant effector T-cell therapy', Immunological Reviews, 257, 1, pp. 210-225, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

Gale, R, Bennett, J, & Hoffman, F 2017, 'Who Has Therapy-Related AML?', Mediterranean Journal Of Hematology & Infectious Diseases (2035-3006), 9, 1, pp. 1-3, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

Harmon, D, E 2012, ‘Leukemia: current and emerging trends in detection and treatment’, New York, Rosen Pub. 19

Kumar, A, Kankainen, M, Parsons, A, Kallioniemi, O, Mattila, P, & Heckman, C 2017, 'The impact of RNA sequence library construction protocols on transcriptomic profiling of leukemia', BMC Genomics, 18, 1, pp. 1-13, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Lendvai, N, Cohen, A, & Cho, H 2015, 'Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma', Bone Marrow Transplantation, 6, p. 770, Academic OneFile, EBSCOhost, viewed 10 November 2017.

Lichtenegger, F, S, Krupka, C, Haubner, S, Kohnke, T, & Subklewe, M 2017, ‘Recent developments in immunotherapy of acute myeloid leukemia’, Journal of Hematology & Oncology. Retrieved on November 11, 2017 from: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0505-0.

Mortensen, B, Rasmussen, A, Larsen, M, Larsen, M, Lund, O, Braendstrup, P, Harndahl, M, Rasmussen, M, Buus, S, Stryhn, A, & Vindeløv, L 2012, 'Identification of a Novel UTY-Encoded Minor Histocompatibility Antigen', Scandinavian Journal Of Immunology, 76, 2, pp. 141-150, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

O'Reilly, R, Koehne, G, Hasan, A, Doubrovina, E, & Prockop, S 2015, 'T-cell depleted allogeneic hematopoietic cell transplants as a platform for adoptive therapy with leukemia selective or virus-specific T-cells', Bone Marrow Transplantation, 2 SI, p. 43, Academic OneFile, EBSCOhost, viewed 10 November 2017.

Peccatori, J, Forcina, A, Clerici, D, Crocchiolo, R, Vago, L, Stanghellini, M, Noviello, M, Messina, C, Crotta, A, Assanelli, A, Marktel, S, Olek, S, Mastaglio, S, Giglio, F, Crucitti, L, Lorusso, A, Guggiari, E, Lunghi, F, Carrabba, M, Tassara, M, Battaglia, M, Ferraro, A, Carbone, M, Oliveira, G, Roncarolo, M, Rossini, S, Bernardi, M, Corti, C, Marcatti, M, Patriarca, F, Zecca, M, Locatelli, F, Bordignon, C, Fleischhauer, K, Bondanza, A, Bonini, C, & Ciceri, F 2015, 'Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors', Leukemia, 2, p. 396, Academic OneFile, EBSCOhost, viewed 10 November 2017.

Pont, M, Honders, M, Kremer, A, van Kooten, C, Out, C, Hiemstra, P, de Boer, H, Jager, M, Schmelzer, E, Vries, R, Al Hinai, A, Kroes, W, Monajemi, R, Goeman, J, Böhringer, S, Marijt, W, Falkenburg, J, & Griffioen, M 2016, 'Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies', Plos ONE, 11, 5, pp. 1-20, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

Popat, U, R 2011, ’Leukemia’, New York, NY, Demos Medical Pub.

Rambaldi, A, Biagi, E, Bonini, C, Biondi, A, & Introna, M 2015, 'Cell-based strategies to manage leukemia relapse: efficacy and feasibility of immunotherapy approaches', Leukemia (08876924), 29, 1, pp. 1-10, Academic Search Premier, EBSCOhost, viewed 10 November 2017.

Taverna, L, Tremolada, M, Bonichini, S, Tosetto, B, Basso, G, Messina, C, & Pillon, M 2017, 'Motor skill delays in pre-school children with leukemia one year after treatment: Hematopoietic stem cell transplantation therapy as an important risk factor', Plos ONE, 12, 10, pp. 1-14, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Tomblyn, M, B, Winkfield, K, M, & Dabaja, B, S 2012, ‘Hematologic malignancies’, New York, Demos Medical Pub. http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&AN=529436.

Ueda, T 2017. Chemotherapy for Leukemia: Novel Drugs and Treatment. http://public.eblib.com/choice/publicfullrecord.aspx?p=4843675.Bottom of Form

Vonderheide, R, & June, C 2014, 'Engineering T cells for cancer: our synthetic future', Immunological Reviews, 257, 1, pp. 7-13, Academic Search Premier, EBSCOhost, viewed 11 November 2017.

Zhang, P, Zhao, X, Zhang, W, He, A, Lei, B, Zhang, W, & Chen, Y 2017, 'Leukemia-associated gene MLAA-34 reduces arsenic trioxide-induced apoptosis in HeLa cells via activation of the Wnt/β-catenin signaling pathway', Plos ONE, 12, 10, pp. 1-16, Academic Search Premier, EBSCOhost, viewed 11 November 2017

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