Hematopoietic Transplantation and Cellular Therapy 2014:

Challenges and Opportunities

Richard Champlin, MD

Current State of HSCT• HSCT is an effective treatment for a broad range of

hematologic, immune, metabolic and neoplastic diseases

• For nonmalignant diseases, HSCT replaces defective hematopoietic and immune cells; this offers definitive treatment for hereditary and acquired diseases.

• For malignancies, benefit related to high dose therapy and for allogeneic transplants, the immune graft-vs-malignancy effects

• HSCT offers a platform for cellular engineering with genetic modification of stem cells, lymphocytes and other hematopoietic cells

Cell Lineages after Hematopoietic Transplants

• Blood cells (granulocytes, erythrocytes, platelets)- donor

• Immune cells (T-cells, B-cells, NK cells)- donor

• Tissue macrophages, osteoclasts, antigen presenting cells- slowly become donor

• ---------------------------------------------• Connective Tissue- recipient• Epithelial cells- predominantly recipient*

– Possibly small population from the donor

Indications for Stem Cell Transplants

• Bone marrow/Immune failure states – Aplastic anemia, Severe combined immune deficiency– Thalassemia/Hemoglobinapathies

• Metabolic diseases – involving hematopoietic and immune cells

• Cancer- – Hematologic malignancies and selected solid tumors-

support for high dose therapy and induction of graft-vs-tumor immune effects

• Tolerance induction for organ transplantation*

Donors

• Best results with HLA= siblings• Matched unrelated donors comparable results,

– available for about half of patients (lower rate for in underrepresented racial ethnic groups); logistical issues coordinating rapid transplants to meet needs of recipients

• Recent advance- Cord Blood and Haploidentical transplants for patients who lack HLA identical donor

• Virtually all patients have a donor!

Mother Father

Siblings

Patient

HLA gene complex is on chromosome 6 and inherited as “haplotypes” and may be completely matched, half matched(haploidentical) or totally mismatched.

Effect of HLA Match for Unrelated HSCT

Permissible HLA Mismatches

Fleschhar et el Lancelt Oncol 2012

Unrelated Donors• Tremendous polymorphism of the HLA complex, chance of

matching an unrelated person is 1/100,000• Linkage disequillibrium- frequency of specific HLA alleles vary

among racial/ethnic groups• One is most likely to find a match within donors of similar ethnic

background. • In each ethnic group, there are common and uncommon HLA

haplotypes• It is important to create unrelated donor registries for all major

ethnicities• A large fraction of patients have rare alleles and haplotypes, so

effective approaches for HLA mismatched “alternative donors“ are needed

Need for Unrelated Donor Registries in Asia

• Work with existing registries, but Asians are underrepresented

• Registries needed in Asian countries– Recruitment of volunteer donors. Costs of typing falling

with next generation sequencing (<$50 per donor). – Cultural barriers

• Public education regarding safety of bone marrow and peripheral blood progenitor cell donation

• Infrastructure- System for collection, transport and transplantation

1 Consent Donors – Maternal and Family History

3 Collect umbilical cord blood

5 Overwrap 25 ml PCB unit & place in canister

7 Initiate automatic CRF & archival of PCB unit

6 Insert PCB unit into CRF module

Cord Blood Collection and Cryopreservation

4 Isolate Stem Cells into 20 ml and 5 ml cryoprotectant

2 Separate placenta

Cord Blood Transplantation• Rich source of stem cells• ~50,000 units banked, immediately available for

transplantation• Immunologically immature- less prone to produce

GVHD• Less risk of transmitting infection• Can successfully transplant across HLA mismatch• Major concern- low stem cell dose, longer time to

engraftment– Improved with ex vivo expansion– Still prolonged immune recovery in adults

• Results comparable to MUD BMTs

Haploidentical Transplants

• Ultimate challenge in HSCT• High risk of rejection and GVHD; historically high

rate of treatment related mortality• Most patients will have a haploidentical donor

– Parents– Half of siblings– Children

• Progress– T-cell depletion, particularly successful in children– Post transplant cyclophosphamide

Post Transplant Cyclophosphamide for Haploidentical Transplantation

Vose J M et al. JCO 2013;31:1662-1668

©2013 by American Society of Clinical Oncology

Autologous SCT for DLBCL

Tandem auto vs. auto-allo for Multiple Myeloma

Krishnan et al Lancet Oncol 2011

IV Bu-Flu Overall Survival andEvent Free Survival in AML

Outcomes of allogeneic HSCT stratified by overall disease/status risk group.

Armand P et al. Blood 2012;120:905-913

©2012 by American Society of Hematology

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Age and Reduced Intensity HSCT

• HSCT is primarily used for treatment of hematologic malignancies; median age of patients is > 65 years

• Myeloablative regimens excessively toxic in elderly patients, most centers limit to patients under age 60

• Reduced intensity and nonmyeloablative regimens allow HSCT to be performed in older and medically infirm patients. Results are generally similar to myeloablative transplants

• Age, per se, (at least up to 70 years) is not a barrier to HSCT

Nonablative AlloSCT vs Chemo for Elderly AML

Figure 3

CALGB and CIBMTR Farag et al Biology of Blood and Marrow Transplantation 2011; 17:1796-1803 (DOI:10.1016/j.bbmt.2011.06.005 )

GVHD Prevention• Post-transplant immunosuppression :

– Tacrolimus/Mtx – Cyclosporine-mycophenolate mofetil

(MMF) – Alemtuzumab (anti CD52, Campath) – Post transplant cyclophosphamide– Maribovir (alters homing)

• T-cell depletion of transplant– Removes effector cells causing GVHD

• Effectively prevents GVHD, but increased risk of rejection and relapse

Chronic GVHD

• Most frequent late complication of allogeneic BMT– Occurs in 1/3 to 1/2 of patients– Most frequent in patients with acute GVHD, but 1/3 of

cases develop de novo– More frequent with PBSC transplants, may be less

common with cord blood transplants, post transplant cyclophosphamide

• Treatment- steroids +/- other agents– Trade off immunosuppression improves

manifestations of GVHD, but increases risk of infection

Limitations of HSCT• Difficult, high risk treatment, patients and caregivers must

be totally dedicated to transplant for first 6-12 months. Many patients must leave home for ~4 months to be at transplant center

• Slow immune reconstitution• Toxicities and Treatment Related Mortality• GVHD occurs in large fraction of “successful” transplants;

chronic disability, steroid toxicities• High Cost; but uniquely effective for some diagnoses.

Lifetime cost compares favorably to many new targeted therapies

PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR LEUKEMIA

- Registered with the IBMTR, 1975-2002 -

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1975-1984 (N=2,334)

P = 0.0001

Professional Standards• Dynamic developing field

– Rapidly developing standards of care– Large variability in practice, outcomes– Need to develop standards, treatment guidelines, define evidence based

“best practices”• Need to define standards for different regions• Consider financial constraints

– Accreditation system to note centers that meet international standards, ensure delivery of high standard of care, objectively identify centers of excellence

– Identification of Centers of Excellence which meet professional standards is necessary for public confidence in HSCT.

– Public Demand for Center Specific Outcome Reporting• Reporting outcomes to US national SCT Outcomes Database

Cellular Therapy StandardsFACT-JACIE International Standards for Cellular

Therapy Product Collection, Processing, and Administration, • Developed by consensus by experts in the field

• FACT standards adopted for European accreditation process (JACIE)• International Committee for extension into Central and South America,

Asia

• Evidence Based-• Clinical program, Collection, Cell Processing Laboratory• Define minimal standards required for safe, efficacious

therapy• Require clinical outcome analysis

What Is Needed to Foster the Growth and Development of HSCT

• Growth: Worldwide need for transplant professionals, physicians, nurses, technical staff, transplant centers

• Professional training- (MD Anderson Cancer Center and other major centers), fellowships– Fundamental principles, “best practices”

• FACT Workshops– Standards for accreditation- train inspectors

• National/international program for accreditation of centers of excellence world wide, with monitoring of outcomes, and active quality management plans- FACT

• Expand unrelated donor registries and cord blood banks- including donors of all major ethnic groups

• Public education- safety of donation, importance to cure many blood cancers

Future of HSCT• Advances in transplant and tumor immunology are

being translated into the clinic– Immunoregulatory cells– Modulation of alloreactivity– Suicide genes

• Targeted cellular immune therapy– CARs, antigen specific T-cells– NK cells– May expand the field to include cellular therapies outside of

traditional transplant • Incorporation of targeted therapies

HSCT

Vaccine or ImmuneEffector cells

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Ideal Nonablative Hematopoietic Transplant

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No GVHD, Immune Reconstitution, GVL for malignancy

Conclusion

• HSCT is a unique effective treatment modality providing normal stem cells for regeneration of hematopoiesis and immunity – Definitive treatment for severe hematopoietic, metabolic and

immune diseases (hemoglobinapathies)– Highly effective treatment for hematologic malignancies

• Cellular immune therapy with CTL, is evolving into an independent effective treatment modality, given with HSCT or as a stand alone therapy

• Continuation and growth of use of HSCT and cellular therapy depends on continued advances in safety, efficacy and cost effectiveness