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Overview of Blood and Marrow Transplantation

Lenise Taylor, RN, MN, AOCNS, BMTCN

BMT/Immunotherapy Clinical Nurse Specialist

Seattle Cancer Care Alliance

University of Washington Medical Center

ltaylor@seattlecca.org

The Seattle Cancer Care Alliance is an NCI-designated comprehensive cancer center

FHCRC/SCCA has offered transplants to patients since 1969 with the highest

success rates in overall patient survival and one of only 13 transplant centers that

has better than predicted survival rates.

SCCA bone marrow transplant survival rates exceed expectations

• The Fred Hutch Bone Marrow Transplant Program at Seattle Cancer Care Alliance has been recognized by the Center for International Blood and Marrow Transplant Research® (CIBMTR) for outperforming its expected one-year survival rates for allogeneic transplant patients .

• SCCA’s program is one of only 13 centers around the country receiving this top evaluation and one of only six programs to exceed expectations for at least five years in a row.

• To arrive at its findings, CIBMTR® independently examined the survival rates of 23,846 transplant patients treated for blood cancers at U.S. centers in the National Marrow Donor Program® network. The reporting period for the 2017 report covered Jan. 1, 2013 to Dec. 31, 2015. During this three-year period, 795 allogeneic transplants were performed at the Fred Hutch Bone Marrow Program at SCCA and met the criteria for the study.

• SCCA’s program was one of 13 centers (7 percent nationally) identified as over-performing. Twenty-one centers’ (12 percent) survival rates were below the expected average, and 140 (80 percent) were average. Only six centers -- including SCCA’s -- had the distinction of being named a top performer for at least five years in a row.

Mission and Vision• SCCA

• Provide state-of-the-art, patient and family centered care.

• Support the conduct of cancer clinical research and education

• Enhance access to improved cancer interventions • Advance the standard of cancer care regionally and beyond

• UWMC• UW Medical Center improves health by providing exceptional patient- and family-centered care in an environment of education and innovation.

• SCH• We believe all children have unique needs and should grow up without illness or injury. With the support of the community and through our spirit of inquiry, we will prevent, treat and eliminate pediatric disease.

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Research

• The foundation of Mission for all parts of the Alliance

• SCH #15 in treating childhood cancer

• #4 in the West

• UWMC/SCCA #7 in treating adult cancer

• #1 in the West

Source: US News and World Reports Hospital Rankings 2018

Preclinical

Test in labs in/ex vivo

and in animals

Phase I

First in human

Optimal dose

Potential toxicities

5-10 patients

Phase II

Efficacy of Treatment

Adverse Events/Potential

toxicities

25-50 patients

Phase III

Efficacy compared to

standard therapy

50-100 patients

Phase IV

Post FDA Approval

Additional effectiveness

Real-world data

Phases of Clinical Trials

Staff Nurse Role in Research

• Participate in the informed consent process

• Education

• Assess patient

• Provide clinical care

• Comply with Protocol parameters

• Administer treatment

• Collect specimens

• Patient advocate

• Document patient response

• Coordinate with Study Coordinators and Nurses

Refer to Elements of Research handout for Protocol and Informed Consent elements

Elements of Informed Consent

• The Purpose

• Involves Research/ Experimental

• Randomization

• Procedures

• Subject’s responsibilities

• Risks/Benefits

• Alternatives

• Cost/Compensation

• Voluntary

• Access to PHI

• Confidentiality

• New information

• Contact information

• Duration

• # of Participants

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Staff RN role in Data Collection for Protocol

• Types of data collected• Specimens

• Vital signs

• ECG

• Administration of medications

• Data collected at specified timepoints

• What might go wrong?• Blood drawn at incorrect time or blood not drawn

• Vital signs done not within specified timepoint

• Medication administered over longer or shorter length of time

• Data collected outside of time points or incorrect data collected is protocol violation

Research at FHCRC/SCCA

• In 1969, E. Donnell Thomas performed first allogeneic

BMT.

• BMT considered experimental until late 1980’s

• BMT is considered Standard of Care for many diseases,

there are still many open treatment protocols

• Much like early BMT, expanding research with

Immunotherapy and seeing the first commercial

Immunotherapy use this year

Definitions*• Allogeneic BMT

• Autologous BMT

• Blood and Marrow Transplant (BMT)

• Conditioning Therapy

• Engraftment

• Graft vs. Host Disease (GVHD)

• Graft vs. Tumor Effect (GVT)

• Haploidentical

* Refer to definitions handout

• Hematopoietic Progenitor Cell (HPC)

• Hematopoietic (Stem) Cell Transplant (HCT)

• Human Leukocyte Antigen (HLA)

• Mobilization Therapy

• Mixed Chimerism BMT (NonMyeloablative, Reduced Intensity, Mini)

• Sinusoidal Obstructive Syndrome (SOS or VOD)

• Syngeneic

Pluripotent Stem Cell

• Progenitor of all blood cells, “uncommitted”

• Asynchronous division

• Self renewing

• Location• Marrow

• Peripheral Blood

• Umbilical Cord Blood

• Migratory/homing properties• Cord Blood takes longer to “home”

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Identifying Pluripotent (Hematopoietic)Stem Cells

•Cluster of differentiation antigen (CD)▪Cell surface marker

•CD 34+ Cell▪ Identifies early progenitor

cells

▪Non-specific• Expressed on leukemic cells

• 30% of CD34+ cells are not progenitors

Theory behind Therapy:Autologous

• Autologous/Syngeneic:

•Lethal doses of chemotherapy/radiation therapy •Patient’s own stem cells “rescue” the ablated marrow

•Cure is chemotherapy/radiation, stem cells are supportive care

•Patient does not require immunosuppression as Graft vs Host disease should not occur

Theory behind Therapy: Allogeneic

• Myeloablative:

•Lethal doses of chemotherapy/radiation •Donor stem cells “rescue” the ablated marrow and provide a new immune system for a graft versus tumor effect

•Cure is both chemotherapy/radiation and stem cells and graft vs tumor effect

• Nonmyeloablative:

•Lower doses of chemotherapy/radiation

•Cure is the stem cells and graft vs tumor effect, chemotherapy eliminates microscopic disease

Theory behind Therapy: Allogeneic

• Immunosuppression

•Cyclosporine, tacrolimus, Mycophenolate mofeteil

•Required to prevent Graft vs. Host Disease

•NonMyeloablative and Haploidentical BMT will receive dual immunosuppression

•NonMyeloablative: Cyclosporine/Tacrolimus and MMF

•Haplo: add Cyclophosphamide post transplant

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Indications for BMT

▪ Malignant diseases:▪ Acute and Chronic Leukemia ▪ Hodgkin's Lymphoma and Non-

Hodgkin's lymphoma ▪ Myelodysplastic Syndromes ▪ Multiple Myeloma ▪ Amyloidosis▪ Selected solid tumors

▪ Breast (rare)▪ Renal cell▪ Germ cell▪ Primary CNS▪ Neuroblastoma

▪ Non-malignant diseases:▪ Hematologic Disorders

▪ Aplastic Anemia▪ Fanconi’s Anemia▪ Sickle Cell▪ Thalassemia

▪ Congenital Immunodeficiencies• SCID▪ Wiskott Aldrich Syndrome)

▪ Inborn Errors of Metabolism▪ Hurler’s Syndrome▪ Guacher Disease

▪ Autoimmune Diseases▪ Systemic Sclerosis▪ Multiple Sclerosis

Transplants at SCCA

Adults Peds

Allogeneic

Related

Unrelated

Non-myeloablative

Cord Blood

Haploidentical

192

67

125

44

14

11

64

24

40

12

11

9

Autologous 152 11

Total Auto Allo

2018 440 176 264

2017 482 204 278

2016 485 209 276

Stem Cell SourcesAdvantages Disadvantages

Bone Marrow

►Abundance of stem cells in BM

►Lower rate of infections days +100 to + 365

►Anesthesia risk for donor

►Post-operative pain for donor

Peripheral Blood

►Faster neutrophil and platelet recovery

►Faster immune reconstitution

►Reduced treatment-related

mortality

►Lower rate of infections to

day +100

►More GVL effect than BM or UCB

►Easier collection

►Bone pain for donor

►Slightly higher risk of GVHD

Umbilical Cord Blood

►More quickly available

►Lack of donor risks

►Less risk of GVHD

►More “matches”

►Slowest engraftment

►Smaller “dose” of stem cells

► Slightly higher rate of early mortality

►Cannot obtain more cells from donor

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Prognostic Factors

•Disease

•Previous treatment

•Stage

•Relapse vs. remission

•Type of Previous therapy

•Age

•Type of transplant

•Degree of HLA typing

Preparative regimen

•Comorbidities

BMT Outcomes

▪Full recovery from BMT

• Complete remission

▪No long-term complications

• life returns to normal

▪Few long-term complications• “new normal”

▪Multiple long-term complications

• Poor QOL

• Death

• Relapse of Disease

▪Death

▪Partial recovery from BMT, death

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New Frontiers in Research: Immune Effector Cells (IEC)

• BMT is the predecessor of current explorations in IEC• T-cells are non-specific in stem cell products

• Current Investigations: Tumor specific T-cells are collected, manipulated, and infused to “seek and destroy” cancer cells

Adoptive cell therapy.

Cassian Yee Clin Cancer Res 2013;19:4550-4552

©2013 by American Association for Cancer Research

Immunotherapy?

• Immunotherapy: Enhancing the immune response• Augment immune response externally: IL-2, interferon• Modify T cell response

• TIL: Tumor Infiltrating Lymphocytes• Lymphocytes harvested from a tumor and expanded ex vivo• Not subject to normal immune response such as T regulation• May ”see” cells that have mutated

• TCR/CAR: T cell receptor• Specific to CD antigens• Modified using lente or retro viruses

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Key Principles of IEC

• Re-infused T-cells are a “living” therapy that can expand and act on cancer cells over time

• Targeted therapy usually derived from the patient’s own immune system

• Lymphodepletion prior to infusion improves persistence of T-cells

Rosenberg, S.A, & Restifo, N. P., Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348 (6230); 62-68.

Key Areas of Research Interest

• Durability of responses- Long-term f/u data is currently limited to small groups of patients• Phase I and 2 trials only

• Looking for dose and toxicities

• Molecular targets for T-cells that are specific to cancer cells.

• Understanding toxicities that can develop with expansion of the T-cells and best cell dose to achieve responses

• Identifying reasons why responses occur for some patients and some cancers but not others

Resources

• American Cancer Society www.cancer.org, select “Learn About Cancer

• National Cancer Institute www.cancer.gov, select “Cancer Topics”

• National Comprehensive Cancer Network www.nccn.org, select “NCCN Clinical Practice Guidelines in Oncology”

• National Marrow Donor Program www.marrow.org, select Physicians

• Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2010. Available at: http://www.cibmtr.org