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Radionuclide Therapy of Leukemias and Multiple Myeloma

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Nuclear Oncology

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Abstract

Monoclonal antibodies (MAbs) raised against cancer antigens may mediate antibody-dependent cell-mediated cytotoxicity. This form of cancer control arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or natural killer cells. However, most of these antibodies have low/moderate efficacy in the tumor control. Antibodies targeting hormone receptors expressed by cancer have shown greater tumor control compared with other cell membrane targets. Moreover, the labeling of these antibodies with a toxin can potentiate their efficacy in the tumor control. In this way, the antibody becomes an invaluable targeting vector for delivery of the toxin to the cancer cells. The toxin/antibody complex is called the immunoconjugate. Different molecules, chemicals, or radioisotopes can serve themselves as toxins; toxins may have long half-lives in the body (e.g., ricin), thus increasing the toxicity to both the cancer and normal tissues.

However, the different radioisotopes (e.g., iodine-131, lutetium-177) have a wide range of half-lives and radiation decay that make them useful for different applications.

Beta-emitting radioisotopes, predominantly I-131, have had only modest success in radioimmunotherapy. More recently, high linear energy transfer (LET) radiation in the form of alpha particles has been studied: alpha radiation is ideal for killing isolated cancer cells in transit in the vascular and lymphatic systems and regressing tumors by disruption of tumor capillary networks by targeting and killing tumor capillary endothelial cells.

Over the past 20 years the development of alpha-immunoconjugates has enabled targeted alpha therapy (TAT) to progress from in vitro studies, through in vivo experiments, to clinical trials. The dose to normal tissues always provides a limitation to the injected dose and that received by the tumor. However, TAT can achieve cancer regression within the maximum tolerance dose for normal tissue. TAT was originally thought to be an ideal therapy for “liquid” cancers, e.g., leukemia and micro-metastases, as the short half-lives of the radioisotopes were sufficient to target these cancer cells and the short range ensured that the targeted cancer cells received the highest radiation dose. Different antibodies have been developed and tested in clinical trials as conditioning treatment, but none of them have yet been approved for radioimmunotherapy (RIT) in multiple myeloma (MM). Addiotinally, bone-seeking radiopharmaceuticals are being evaluated in MM patients in the transplant setting.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALL:

Acute lymphocytic leukemia

alloHSCT:

Allogeneic hematopoietic stem cell transplantation

AML:

Acute myeloid leukemia

APL:

Acute promyelocytic leukemia

ASCO:

American Society of Clinical Oncology

ASCT:

Autologous stem cell transplantation

ATO:

Arsenic trioxide

ATP:

Adenosine 5′-triphosphate

ATRA:

All-trans retinoic acid

BCP-ALL:

B-cell precursor acute lymphoblastic leukemia

BCR:

B-cell receptor

BMT:

Bone marrow transplantation

BR:

Bendamustine plus rituximab

BTK:

Bruton’s tyrosine kinase

CBF:

Core binding factor

cDNAs:

Complementary deoxyribonucleic acid

Clb:

Chlorambucil

CLL:

Chronic lymphocytic leukemia

CML:

Chronic myeloid leukemia

CNS:

Central nervous system

CR:

Complete response

CRAB:

Syndrome including hypercalcemia, renal failure, anemia, bone lesions

CT:

X-ray computed tomography

CTD:

Cyclophosphamide/thalidomide/dexamethasone

CVAD:

Cyclophosphamide, vincristine, doxorubicin, dexamethasone

DCF:

Deoxycoformycin

DIC:

Disseminated intravasal coagulation

DNA:

Deoxyribonucleic acid

DOTA:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

DOTMP:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid

DSF:

Disease-free survival

DTPA:

Diethylenetriaminepentaacetic acid

DVD:

Doxorubicin liposomal-vincristine-dexamethasone

EBRT:

External beam radiotherapy

EDTMP:

Ethylenediamine tetra(methylene phosphonic acid)

EMA:

European Medicines Agency

ESMO:

European Society of Clinical Oncology

FCR:

Chemotherapy regimen based on fludarabine cyclophosphamide, and rituximab

[18F]FDG:

2-Deoxy-2-[18F]fluoro-d-glucose

GMMG:

German Multicenter Myeloma Group

GVHD:

Graft versus host disease

Gy:

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HAMA:

Human anti-mouse antibody

HCL:

Hairy cell leukemia

HCL-V:

Hairy cell leukemia variant

HD:

High-dose

HLA:

Human leucocyte antigen

HLA-DR:

Human Leukocyte Antigen-antigen D related

HOVON:

Dutch-Belgian Hemato-Oncology Cooperative Group

HR:

High risk

IFN-α:

Interferon-α

IMiDs:

Immunomodulatory drugs

ITD:

Internal tandem duplications

KIR:

Killer immunoglobulin-like Receptor

LAIP:

Leukemia-associated immunophenotype

LET:

Linear energy transfer

MAbs:

Monoclonal antibodies

MDACC:

MD Anderson Cancer Center

MDR:

Multidrug resistance

MDS:

Myelodysplastic syndrome

MM:

Multiple myeloma

MP:

Melphalan and prednisone

MPR:

Melphalan/prednisone/lenalidomide

MPT:

Melphalan/prednisone/thalidomide

MRD:

Minimal residual disease

mRNAs:

Messenger ribonucleic acid

MTD:

Maximum tolerable dose

NHL:

Non-Hodgkin lymphomas

NLS:

Nuclear localization signal peptide

NMRI:

Naval Medical Research Institute

NOD:

Nonobese diabetic

NPM:

Nucleophosmin

NSG:

Mouse model of immunodeficiency

OR:

Odd ratio

OS:

Overall survival

PAD:

Bortezomib, doxorubicin, and dexamethasone

PCR:

Polymerase chain reaction

PET:

Positron emission tomography

PFS:

Progression-free survival

Ph+:

Philadelphia positive

PRIT:

Pretargeted radioimmunotherapy

R:

Rituximab

RANKL:

Receptor activator of nuclear factor kappa-B ligand

RIC:

Dose-reduced chemotherapy intensity

RIT:

Radioimmunotherapy

RT:

Reverse transcriptase

RVD:

Lenalidomide-bortezomib-dexamethasone

SCID:

Severe combined immunodeficiency

SCT:

Stem cell transplantation

SLL:

Small lymphocytic leukemia

SPECT:

Single-photon emission computed tomography

SR:

Standard risk

TAT:

Targeted alpha therapy

TBI:

Total body irradiation

TD:

Thalidomide-dexamethasone

TKI:

Tyrosine kinase inhibitor

TRM:

Treatment-related mortality

VAD:

Chemotherapy regime based on vincristine, adriamycin, doxorubicin

VCD:

Bortezomib-cyclophosphamide-dexamethasone

VMP:

Bortezomib/melphalan/prednisone

VP:

Bortezomib-prednisone

VTD:

Velcade-thalidomide-dexamethasone

VTP:

Bortezomib-thalidomide-prednisone

WBC:

White blood cells

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Authors and Affiliations

  1. Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Martina Sollini

  2. Regional Center of Nuclear Medicine, Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Francesco Bartoli & Paola A. Erba

  3. Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Sara Galimberti

  4. Nuclear Medicine Unit, “Papa Giovanni XXIII” Hospital, Bergamo, Italy

    Roberto Boni

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  1. Martina Sollini
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  2. Francesco Bartoli
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  4. Roberto Boni
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  5. Paola A. Erba
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  1. Associate Professor and Director of Nuclear Medicine, University of Pisa, Pisa, Italy

    Duccio Volterrani

  2. Translational Research, Pisa University, PISA, Pisa, Italy

    Paola A. Erba

  3. Attending Emeritus, Memorial Sloan-Kettering Cancer Center Dept. Radiology, New York, NY, USA

    H. William Strauss

  4. Professor Emeritus, University of Pisa, Pisa, Italy

    Giuliano Mariani

  5. Attending Physician, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Steven M. Larson

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Sollini, M., Bartoli, F., Galimberti, S., Boni, R., Erba, P.A. (2022). Radionuclide Therapy of Leukemias and Multiple Myeloma. In: Volterrani, D., Erba, P.A., Strauss, H.W., Mariani, G., Larson, S.M. (eds) Nuclear Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-26067-9_48-2

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  1. Latest

    Radionuclide Therapy of Leukemias and Multiple Myeloma
    Published:
    09 April 2022

    DOI: https://doi.org/10.1007/978-3-319-26067-9_48-2

  2. Original

    Radionuclide Therapy of Leukemias and Multiple Myeloma
    Published:
    30 September 2016

    DOI: https://doi.org/10.1007/978-3-319-26067-9_48-1

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