1. Hematopoietic Stem Cell Current Status and Future Directions
Transplantation:
Current Status and Future Directions
RICHARD W. CHILDS M.D.
NIH, BETHESDA MD

2. Stem cell transplantation
Conditioning regimen
Autologous stem cell collection
Patient
Thaw + transplant
Autologous
Freeze
Stem Cells
First-Line Therapy:Multiple Myeloma
Prolongs PFS and survival (Attal et al-NEJM-1996)
Second-Line Therapy:Relapsed Hodgkin’s and NHL
Prolongs survival in NHL (Parma Trial-1995)
Prolongs DFS in HDz (but not survival)
PBSCT utilizing cyclosporine alone for GVHD prophylaxis is associated with significant incidence of aGVHD (~60% grade II-IV, ~40% grade III-IV)
Although well tolerated in younger patients, older patients (>50 years) have a TRM risk of ~ 30%, mostly related to GVHD.
We initiated a clinical study to assess the feasibility of our selective depletion approach in the setting of NST in older patients with hematologic malignancies. 2

3. Stem cell transplantation
Conditioning regimen
Autologous stem cell collection
Patient
Thaw + transplant
Autologous
Freeze
Stem Cells
Allogeneic stem cell collection
Patient
Conditioning regimen
Stem cell donor
transplant
Allogeneic
Tissue or HLA matched
PBSCT utilizing cyclosporine alone for GVHD prophylaxis is associated with significant incidence of aGVHD (~60% grade II-IV, ~40% grade III-IV)
Although well tolerated in younger patients, older patients (>50 years) have a TRM risk of ~ 30%, mostly related to GVHD.
We initiated a clinical study to assess the feasibility of our selective depletion approach in the setting of NST in older patients with hematologic malignancies. 3

4. Stem Cells Source Peripheral Blood Bone Marrow Umbilical Cord Blood
G-CSF subcutaneous injection for 5 days. Mononuclear cells collected by apheresis
Direct aspiration under general
Placental blood directly drained into bag

5. How Does Myeloablative Allogeneic BMT Cure?
Allograft
(PBSC + Lymphs)
Transplant
Day 0
T-Cells
Remission
GVL
Leukemia cells
Pre-transplant intensive
therapy
2) Graft-vs-Tumor
1) Conditioning Regimen 5

6. Types of Allogeneic Transplants
Conventional High Dose or Myeloablative Transplant
Conditioning fully eradicates the hosts bone marrow
Reduced Intensity Conditioning (RIC)
Low dose or non-myeloablative transplant
Immunologically eradicates host bone marrow
As most of you know, there are 2 conditioning approaches that can be utilized with allotransplants.
Conventional myeloablative conditioning which completely wipes out the bone marrow, and which is dose intensive vs RIC which uses lower intensity conditioning and which allows for the possibility of some autologous hematopoietic function, which is usually immunologically eradicates by the donor in weeks to months following the procedure.

7. Use of Reduced Intensity Conditioning on the Rise

8. Allogeneic Hematopoietic Stem Cell Transplantation:
Can Cure Patients With Chemotherapy Refractory
Hematological Malignancies

9. Graft-vs-TumorEffects After Reduced Intensity Allogeneic
Hematopoietic Cell Transplantation Can Cure
42 year female: Chemotherapy Refractory Mycosis Fungoides

10. T-cell Mediated Graft-Vs-Leukemia Effects Can Cure
Chemotherapy Resistant Malignancies
Her tumor grew early after the transplant, but shortly after being tapered off her CSA, the patient had a delayed GVT effect that resulted in complete eradication of her malignancy and probable cure of her disease.
Nov 2006
7 months post transplant
CSA Discontinued
May 2015
9 yrs post transplant
May 2006
1 month
After transplant
NHLBI Hematology Branch Transplant Protocol 02-H-0250

11. Hematological Malignancies Vary in Their Susceptibility
To Graft-Vs-Leukemia (GVL) Effects
Malignancy Susceptibility to GVL (response to DLI)
CML chronic phase High
CLL High
Low-grade NHL High
AML/ALL Intermediate
MDS Intermediate
Multiple myeloma Intermediate/low
Int/high grade NHL Intermediate
Hodgkin’s disease Intermediate
Refractory ALL/AML Low
CML blast crisis Low

12. Most Common Indications for an Hematopoietic Cell Transplant (HCT) in the U.S. 2014
Auto:
Myeloma
NHL
Allogeneic
AML
ALL
MDS/MPD
The majority of patients undergoing allogeneic transplants (shown in green) have a diagnosis of AML, with the next 3 most common indications being for ALL, MDS, and NHL.
The number of transplants performed for CML are now quite low, with the procedure being reserved for those pts failing TKI therapy.
Among nonmalignant diseases, the most common indication is for SAA.

13. Outcomes superior for older pts with allogeneic HCT
Allogeneic Transplant For AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients
Results:
Outcomes superior for older pts with allogeneic HCT
Survival
Relapse
> 45 allo
>45 conv
>45 conv.
Stelljes et al JCO 2014:32(4

14. Major Improvements in Transplant Outcomes Over the Past 2 Decades
Historical Problem Solution
Conditioning regimens too toxic
Older patients ineligible due to prohibitive risk of mortality
Death from invasive fungal process and CMV frequent
Lack of donors precludes the use of the procedure
Development of reduced intensity conditioning regimens
Advent of better antifungal medications/voriconazole, PCR to detect early viral reactivation
Growth of unrelated registry, increasing use MUDS, cord transplants and haploidentical donors
There have been a number of modifications and advances that have occurred in the transplant procedure over the past 20 years that have overcome major historical problems associated with the procedure.
For instance, historical conditioning regimens were only fully myeloablative and were very toxic, too toxic for older patients, limiting the procedure to pts who were 55 or younger. This limitation has been overcome by the use of safer conditioning regimens that reduce the risk of complications like pneumonitis, by shielding the lungs during TBI, or the use of IV busulfan, which is associated with a much lower risk of VOD compared to oral busulfan. Further, the advent of RIC regimens have dramatically reduced toxicity associated with conditioning making allotransplant an option for pts up to the age of 70, or older. reduced intensity transplants read
The risks of death from invasive fungus and CMV pneumonitis has dropped off dramatically with the use of new drugs such as voriconazole and the use of molecular screening for CMV reactivation for the use of early empiric gancyclovir therapy.
Finally, and perhaps most importantly, the lack of a sutiable stem cell donor for up to 60% of pts precluding them from undergoing a transplant, is no longer a problem in the 21st century, given the dramatic increase in the number of volunteer MUD in the world wide registry and the increasing use of mismatched cord blood transplant and more recently haplo-identical transplants, which we will talk about more later.

15. REQUIRMENTS FOR ALLOGENEIC TRANSPLANTATION
An HLA compatible donor to donate stem cells
25% each sibling will be HLA identical
In the U.S., there is approximately a 25% that a patients will have an HLA identical sibling

16. Finding An Unrelated HLA Identical Donor….. A 1/10,000 chance
15 million donors in the World-Wide Registry=60% chance
NMDP=National Marrow Donor Program

17. Likelihood of Finding an 8/8 HLA Matched Unrelated Donor
Unrelated donors now more than 20 million volunteers world-wide registered
Age cut-off 60 years
This figure shows the Likelihood of Finding a perfectly matched 8/8 HLA Donor based on current Availability and with Recruitment Trends Extended to These data are based on a Projected recruitment growth of 9% cumulatively each year.
So the majority of Caucasians in the US would be expected to have a perfectly matched donor, while minorities such as African American asians have less than a 50% chance of finding a perfectly matched donor. This discrepancy is largely the consequence of much greater HLA diversity amongst these populations rather than them not being equally represented percentage wise in these registries.
Based on Current Donor Availability and with Recruitment Trends Extended to 2017.
Gragert L et al. N Engl J Med 2014;371:

18. Availability of a Stem Cell Sources for Allogeneic Transplantation
0% % % % % % % % % % %
Chances of Finding a Stem Cell Donor
HLA Matched
Sibling
HLA Matched
Unrelated Donor
No HLA Matched
Donor
Potential Candidates
For a Cord Blood Transplant or
A Haploidentical Transplant
But the good news is there are transplant options for pts who lack a MUD or sib matched donor. These pts may be candidates for UCB or haplo-matched transplants. 18

19. Unrelated Cord Blood Transplantation (UCBT)
Unrelated Cord Blood (UCB) transplants are a transplant option for patients lacking an HLA identical donor:
- Cord blood is a rich source of Hematopoietic progenitor cells- more than human BM
60-80% of patients will have a cord unit in the public registry that could be used for a transplant
Volume 25 mls
Placenta
Umbilical Cord
Cord Blood Unit 19

20. Haploidentical BM Transplants
Transplants that utilize stem cells collected from a relative who
only matches for half of the HLA tissue antigens
Advantages;
Virtually every patient will have a haplo-identical relative to serve as a
stem cell donor
Disadvantages:
- Higher incidence of graft versus host disease
- Obligates use of T-cell depletion
But the news keeps getting better in terms of donor availability. One of the big game changers to come along in the last 5 years is the increasing use of and excellent results of haplotransplants using a relative who is only matched for half of the HLA antigens.
Virtually every patient will have a haplo donor who could serve as a stem cell donor.
Historically, these types of transplants were very dangerous, and were associated with a very high risk of TRM due to a high risk of infection, rejection, and GVHD.

21. Post Transplant Cyclophosphamide Following T-cell Replete Haploidentical Transplantation of BM or PBSC
But that has all changed now with the advent of post transplant cytoxan to prevent GVHD in this setting. This type of transplant approach, pioneered by investigators at JHU, utilizes a strategy where …………………………………..
Fuchs E. et al JHU

22. Myeloablative Reduced Intensity
Haploidentical Transplant With Post-Transplant Cyclophosphamide has similar outcome to matched unrelated transplants
Survival
Myeloablative Reduced Intensity
Ciurea S. et al Blood :8:

23. In the year 2016
Virtually every patient should have a donor stem cell source available to allow an allogeneic transplant, if indicated.

24. Complications of an Allogeneic Stem Cell Transplant
Toxicities related to the conditioning regimen
- Mucosal inflammation (Mucositis)
- Liver toxicity (Veno-occlusive disease)
- Lung inflammation (pneumonitis)
Graft Rejection
- occurs rarely with conventional transplants
Infection
- bacterial/fungal: during neutropenic phase of transplant
- Viral: first 100 days of the transplant
Graft vs host disease- decreases relapse risk
- acute: from engraftment until day +100
- Chronic: from day 100 until 2 years post transplant
Drug toxicities
- many drugs given to prevent infection/GVHD have toxicities
Morbidity and
mortality

25. Mortality is Decreasing with Allogeneic Stem Cell Transplants
60% reduction in TRM
N=1418
N=1148
Historically, Allogeneic transplantation has been associated with a very high risk of TRM , in the range of 30%.
Numerous recent studies have now shown that allogeneic transplantation has become substantially safer over the past 2 decades. In this study conducted by investigators at the FHCRC, the risk of dying from complications of a transplant dropped by 60% in cohorts transplanted from (where mortality rates were 16% by day 200) compatred to cohorts transplanted . IN When mortality rates were about 30%).
This reduction in TRM resulted in a 40% overall reduction in mortality associated with an AHSCT. While transplants are getting safer, and outcome is improving, we clearly still have work to do.
Bacterial, viral and fungal infections reduced
Reduction in severe Grade III-IV GVHD
Dramatic reduction in day 200 transplant-related mortality (TRM) and overall TRM
Gooley et al; NEJM 2010: 363;22

26. Improving transplant outcome Better supportive care
100
HLA-matched sibling
URD 80 60
One-Year Survival, percent
Better supportive care 40
Gentler conditioning 20
Improved mgmt of GVHD
1988-
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
1990
Pasquini MC, Wang Z. CIBMTR

27. Eligibility Status of Candidates for An
Allogeneic Transplant Is In Continuous Flux
Expanding:
Donor availability not limiting ( MUDS, Cords, Haplos)
Older patient age (up to 75 years with RIC)
Pts with medical co-morbidity eligible
Contracting:
Some disease categories shrinking as breakthrough drugs developed
CML effectively treated with TKI
High-risk CLL effectively treated with BTK/PI3K inhibitors
Eculizumab for PNH
Immunotherapy breakthrough's (CAR CD19 T-cells)

28. Am I A Candidate for an Allogeneic Stem Cell Transplant?

29. Questions To Be Answered
Does the potential benefit of a transplant justify the risk?
(i.e. do I have a disease that chemotherapy can cure or make me live a long time)
Is my disease controlled sufficiently to where a transplant would help?
i.e. Acute leukemias should be in remission before transplant
Do I Have a stem cell donor?
HLA tissue matched sibling
Matched Unrelated donor
Cord blood or haplo-identical donor
What are the chances I could be harmed by a transplant?
Am I Healthy enough to go through the procedure?
Am I young enough?
Have prior treatments put me at increased risk for complications 29

30. Non-relapse mortality
Long-term Survival after HCT
CIBMTR study of 10,632 allogeneic HCT recipients surviving ≥ 2 years in remission (median follow-up 9 years)
Overall survival
Non-relapse mortality
Patients surviving greater than 2 years after a transplant do quit well. In this long term follow up study of CIBMTR patients, those who survived in remission > 2 years post transplant had excellent 10 year survival and a very low risk of disease relapse.
J Wingard et al, J Clin Oncol Jun 1;29(16):2230-9

31. 20 years of Transplant at NIH

32. NIH Clinical Center 2015
I’d like to acknowledge all the members of my research team and NHLBI staff and staff of the NIH Clinical Center, in particular members of our DTM who have supported these efforts and are responsible for generating most of the data I have presented to you today. 32