Curing Sickle Cell Disease: Bone Marrow Transplant, The Clinical - - PowerPoint PPT Presentation

▶
curing sickle cell disease
SMART_READER_LITE
LIVE PREVIEW

Curing Sickle Cell Disease: Bone Marrow Transplant, The Clinical - - PowerPoint PPT Presentation

Sep 30, 2022 240 likes •630 views

Curing Sickle Cell Disease: Bone Marrow Transplant, The Clinical Perspective Courtney D. Fitzhugh, M.D. Investigator Lasker Clinical Research Scholar Laboratory of Early Sickle Mortality Prevention Sickle Cell Disease Has an Immense Global

slide-1
SLIDE 1

Curing Sickle Cell Disease:

Bone Marrow Transplant, The Clinical Perspective

Courtney D. Fitzhugh, M.D. Investigator Lasker Clinical Research Scholar Laboratory of Early Sickle Mortality Prevention

slide-2
SLIDE 2
  • Globally, more than 300,000 babies are born with SCD each year1
  • SCD is caused by a point mutation which leads to red blood cell sickling, vaso-occlusion,
  • rgan damage, and early mortality
  • Because SCD affects the red blood cell, it is perfect for hematopoietic stem cell-based therapy
  • 1. Piel FB et al. NEJM, 2017. 376(16): 1561-1573.

Sickle Cell Disease Has an Immense Global Burden and can be Cured with HSCT

slide-3
SLIDE 3

Bone Marrow Transplants Replace the Seeds of the Blood

Sickling *Sickle mutation

Granulocytes Lymphocytes Red blood cells Platelets Bone marrow hematopoietic “stem cells” Progenitors Bone marrow stem cells produce all types of blood cells for the life of a patient.

John Tisdale, MD

slide-4
SLIDE 4

Stem Cell Transplantation Offers a Cure for Sickle Cell Disease

  • With a traditional transplant,

stem cells from a healthy donor are given to the patient

  • Donors are most commonly

HLA-matched siblings

  • Myeloablative (full)

conditioning completely replaces the patient’s bone marrow with that of their donor

Graft Rejection Graft versus Host Disease

PATIENT DONOR

slide-5
SLIDE 5

Myeloablative HLA-Matched Sibling Transplant has a High Success Rate

  • 1000 patients transplanted
  • At 5 years after the transplant
  • 93% alive
  • 91% free of sickle cell disease
  • 15% graft versus host disease
  • For children younger than 16 years
  • 95% alive
  • 93% free of sickle cell disease

Gluckman E et al. Blood, 2017. 129(11): 1548-1556.

slide-6
SLIDE 6

PATIENT DONOR

Mixed Chimerism is Sufficient to Reverse SCD

slide-7
SLIDE 7

Hsieh MM, Kang E, Fitzhugh CD, et al. NEJM, 2009. 361(24): 2309-2317. Sirolimus (target 10-15 ng/dL)

Non-myeloablative HLA-Matched Sibling Peripheral Blood Stem Cell Transplant for SCD

slide-8
SLIDE 8

Transplant Outcome

Matthew Hsieh John Tisdale

  • 55 patients transplanted
  • Median age 29 years, range 10-65 years
  • Median follow-up 6.4 years (range 0.5-14.4 years)
  • 93% alive
  • 87% free of sickle cell disease
  • No graft versus host disease
  • 8 patients have had 13 healthy babies post-transplant
slide-9
SLIDE 9

Our Results Were Duplicated at Other Institutions

1. Saraf SL et al. Biology of Blood and Marrow Transplantation, 2015. 22(3): 441-448. 2. Alzahrani M et al. American Society of Hematology Annual Meeting, 2018. 3. Guilcher G et al. Biol Blood Marrow Transplant, 2019.

  • 12 of 13 adults at University of Illinois, Chicago free of SCD

(=92% free of SCD)1

  • No graft versus host disease
  • 31 of 34 patients >14 years in Saudi Arabia free of SCD (=91%

free of SCD)2

  • No graft versus host disease
  • 16 of 16 children down to 3 years of age in Alberta, Canada

free of SCD (=100% free of SCD)3

  • No graft versus host disease
  • Multi-center study is being initiated in children at Children’s

National Medical Center

slide-10
SLIDE 10

Why aren’t More Patients with Sickle Cell Disease Transplanted?

slide-11
SLIDE 11

36% with an HLA matched sibling donor

Vast Majority of Patients do not have an HLA-Matched Sibling

287 patients had HLA typing 102 patients had 6/6 HLA-match siblings 12 patients did not meet disease severity 2 patients died prior to transplantation 36 patients underwent transplant 18 patients had insufficient information to determine eligibility 19 patients excluded for major ABO mismatch or other antibodies to donor red cells In 2 patients, their donors declined to donate 13 patients receiving

  • ptimizing medical

therapy patients

slide-12
SLIDE 12

Pediatric Related Umbilical Cord Transplants for SCD

Reference

HLA match Number of patients (age range) Alive without SCD Acute GvHD (Gr 2-4) Chronic GvHD (extensive) Death (cause) Brichard, 1996

6/6 1 (5) 1

Miniero, 1998

6/6 3 (3-11) 2

Gore, 2000

6/6 1 (9) 1

Walters, 2005

6/6 42 pts, 4/6 4 pts* 8 (NR) 6 NR NR 1 (intractable seizures)

Matthes- Martin, 2013

6/6 1 (11.1) 1

Locatelli, 2013

6/6 30 (2-20)* 27 11% (Gr 2-3)* 3 (2 hemorrhage, 1 organ failure)*

Total

Mostly 6/6 44 38 (86%) 11% 9% (of total)

*Includes patients with sickle cell disease and thalassemia

slide-13
SLIDE 13

Pediatric Unrelated Umbilical Cord Transplants for SCD

Reference HLA match Number of patients (age range) Alive without SCD Acute GvHD (Gr 2-4) Chronic GvHD (extensive) Death (cause) Adamkie- wicz, 2007

5/6 2 pts, 4/6 5 pts 7 (3.4-16.8) 3 4 1 1 (multi-organ failure)

Ruggeri, 2011

6/6 (2) 5/6 (4) 4/6 (10) 16 (6) 8 23% 16% 1 acute GvHD

Kamani, 2012

6/6 (1) 5/6 (7) 8 (7.4-16.2) 3 2 (Gr 2) 1 (extensive) 1 (respiratory failure)

Radhak- rishnan, 2013

NR 8 (1-10) 4 4 3 (infection)

Khar- banda 2014

4/6 2 (8)

Total

Mostly mismatched

41 18 (44%) 33% (of total) 11% (of total) 15% (of total)

  • More recent study more encouraging: 9 children transplanted, 100% alive, 78% free of SCD, 10-20% GVHD1

Abraham A el al. Biol Blood Marrow Transplant, 2017. 23: 1580-1596.

slide-14
SLIDE 14

Reference Number of patients (age) Alive without SCD Acute GvHD (Gr 2-4) Chronic GvHD (extensive) Death (cause) Strocchio, 2015

6 (27-48) 5

Shenoy, 2016

29 (6-19) 20 8 11

6 (GVHD) 1 (following 2nd transplant) Marzollo, 2017

2 (6.5-10.5) 2 2 Gr 2

Gillman, 2017

2 (5-13) 2

Krishna- murti, 2019

5 3 1 Gr 3 1 1 (GVHD)

Total

44 29 (73%) 25% (of total) 27% (of total) 18% (of total)

Matched Unrelated Donor Transplants for SCD

slide-15
SLIDE 15

Matched Unrelated Donor Transplant for Adolescents and Young Adults with SCD

  • 22 patients median age 22 years
  • 17 HLA-matched sibling
  • 5 MUD
  • MUD results
  • 4 of 5 alive
  • 3 of 5 free of SCD
  • 4th SCD-free after 2nd transplant
  • 1 patient developed grade 3 acute

GVHD and 1 severe chronic GVHD

Krishnamurti L et al. American J Hematology, 2019.

Results of all 22 patients

slide-16
SLIDE 16

BMT CTN #1503

  • Phase 2 multi-center study comparing 2-year
  • verall survival in young adults with severe SCD

who receive transplant compared to standard of care

  • Age 15-40 years
  • Donors:
  • HLA-matched sibling
  • Matched unrelated donor
slide-17
SLIDE 17
  • Haploidentical donors

– Most accessible – Large cell doses feasible – Repeat collections feasible

  • Immunologic barrier greater

– Higher degree of immunosuppression

Haploidentical PBSC Transplantation for Adults with Severe Sickle Cell Disease

slide-18
SLIDE 18

Post-Transplant Cyclophosphamide in the Haploidentical Setting for Patients with Severe Hemoglobinopathies

  • 17 patients received BMT, 14 haploidentical

donors, 3 HLA-matched sib donors

  • Median age 30 (15-46 years)

Balanos-Meade J et al. Blood, 2012. 120(22): 4285-4291.

  • 100% alive
  • 50% free of SCD
  • No graft versus host disease
  • 75% engrafted patients off of

immunosuppressive therapy

slide-19
SLIDE 19

Fitzhugh CD et al. Blood Advances, 2017. 1(11): 652-661.

Nonmyeloablative Haploidentical PBSC Transplantation for Adults with Severe Congenital Anemias

slide-20
SLIDE 20

1 2 3 4 5 6 7 18-20 21-25 26-30 31-35 36-40 41-45 >45 Number of individuals Age range

  • N = 23
  • Age range: Median 36, range 20-56 years old
  • Follow-up: 5.9 years (range 3.4-8.6 years)
  • Except where indicated, the remainder have HbSS

1 b-thal 1 Hb Sb0 1 b-thal 1 HbSC

Nonmyeloablative Haploidentical PBSC Transplantation for Adults with Severe Congenital Anemias

slide-21
SLIDE 21

Haplo Patients with Severe Organ Damage Tolerate Conditioning

N (%) Hepatic Iron overload Cirrhosis 20 (87) 18 (78) 2 (9) Recurrent ACS and/or VOC 19 (83) Neurologic Stroke Moyamoya syndrome TIA 8 (35) 6 (26) 4 (17) 1 (4) Cardiac Systolic dysfunction Diastolic dysfunction 7 (30) 5 (22) 3 (13) Renal ESRD on PD ESRD on HD CRI with baseline Cr 2.5-5.0 mg/dL 6 (26) 3 (13) 1 (4) 2 (9) Pulmonary hypertension 5 (22) Autoimmune Multiple sclerosis Rheumatoid arthritis 2 (9) 1 (4) 1 (4)

slide-22
SLIDE 22
  • No mortality before day 100
  • 5 patients who rejected their grafts died 6 months and 3, 5, 7 and 8 years post-

transplant, mostly from SCD-related complications (78% free of SCD)

Cohort

Cumulative Cytoxan Dose (mg/kg) Engraftment Rate (Before Day +100) Free of SCD Graft Versus Host Disease 1 1/3 (33%) 0/3 (0%) 2 50 5/8 (63%) 2/8 (25%) 1 Grade I Acute 3 100 10/12 (83%) 6/12 (50%) 1 Grade I Acute 1 Mild Chronic

Fitzhugh CD et al. Blood Advances, 2017. 1(11): 652-661.

Engraftment and Success Rates Improve with PT-Cy

slide-23
SLIDE 23

Additional Up Front Conditioning and T cell Depletion has Improved the Outcome for Haploidentical HSCT

slide-24
SLIDE 24

Modified Hopkins Regimen for Patients with SCD Undergoing Haploidentical Transplant

  • 8 patients
  • Age 20-38 years

Saraf SL et al. Biol Blood Marrow Transplant, 2018. 24: 1754-1770. TBI 300 cGy

PBSCT infusion

slide-25
SLIDE 25

Improved Results with 300cGy TBI and Peripheral Blood Stem Cells

  • With a median follow-up
  • f 17 months:
  • 7 patients are alive

(88%)

  • 6 patients are free of

SCD (75%)

  • 2 patients developed >2

acute GVHD, 1 chronic GVHD

Saraf SL et al. Biol Blood Marrow Transplant, 2018. 24: 1754-1770.

slide-26
SLIDE 26

Another Modified Hopkins Regimen for Patients with SCD Undergoing Haploidentical Transplant

  • 17 (12 patients with SCD, 5 patients with b-Thal)
  • Age 6-31 years

Bolanos-Meade J et al. Lancet Haematology, 2019.

rabbit ATG MMF 15mg/kg po tid Sirolimus TBI 400 cGy

slide-27
SLIDE 27

Improved Results with 300cGy TBI and Peripheral Blood Stem Cells

  • 100% Alive
  • 83% Free of SCD
  • 29% grade 2-4 acute GVHD (6% grade 3)
  • 18% chronic GVHD (2 mild, 1 moderate)
  • All GVHD resolved as of last follow-up with no

systemic GVHD therapy

  • 91% engrafted patients off of immunosuppressive

therapy

Bolanos-Meade J et al. Lancet Haematology, 2019.

slide-28
SLIDE 28
  • 15 patients
  • Age 12 to 26

de la Fuente J et al. Biology of Blood and Marrow Transplant, 2018.

thiotepa 10mg/kg

One More Modified Hopkins Regimen for Patients with SCD Undergoing Haploidentical Transplant

slide-29
SLIDE 29

Improved Results with Thiotepa

  • With a median follow-up of

13 months

  • 15 patients alive
  • 14 free of SCD (93%)
  • 13% grade 3-4 acute GVHD
  • 7% moderate chronic GVHD

de la Fuente J et al. Biology of Blood and Marrow Transplant, 2018.

slide-30
SLIDE 30

BMT CTN #1507

  • Phase II, single arm, multi-center trial to estimate the efficacy

and toxicity of haplo BMT in patients with sickle cell disease

  • Two strata

– Children (aged 5 – 14 years)

  • Stroke is the only indication

– Adults (aged 15 – 45 years)

  • Stroke or neurologic event lasting >24 hours
  • ≥ 2 episodes of ACS in the 2 year period preceding enrollment
  • ≥ 3 episodes of VOC per year in the 2 year period preceding enrollment
  • Regular RBC transfusions (≥ 8 transfusions per year for ≥1 year) to prevent vaso-occlusive

clinical complications (stroke, pain or ACS)

  • ECHO finding of TRJ velocity ≥2.7 m/sec (steady state)
  • Sample Size

– 40 participants per strata

Robert Brodsky, Michael DeBaun, Adetola Kassim, Mark Walters

slide-31
SLIDE 31

Lymphocyte Depletion associated with High Engraftment and Low Toxicity

  • 9 patients median age 16 years (range 3-31 years) underwent myeloablative

haploidentical PBSCT

  • 8 of 9 patients are free of SCD (89%)
  • 1 patient died from infection
  • 56% grade 1-2 acute GVHD, 1 moderate chronic GVHD

Foell J et al. Bone Marrow Transplant, 2017. 52(6): 938-940.

  • 10 -9 -8
  • 7 -6 -5 -4 -3

+120

ATG 15 mg/kg/d Fludarabine 40 mg/m2/d Treosulfan 14 g/m2/d MMF and Cyclosporine through day +120 Thiotepa 5mg/kg/d

CD3+-/CD19+- depleted PBSCs

slide-32
SLIDE 32

Reference # of patients (age) Alive without SCD Acute GvHD (Gr 2-4) Chronic GvHD (extensive) Death (cause) Foell, 2017 9 (3-31) 8 56% (Gr 1-2) 1 (moderate) 1 (CMV) Marzollo, 2017 2 (13-16) 2 1 Wiebking, 2017 3 (5-20) 3 Gilman, 2017 8 (8-23) 7 2 1 1 (aspergillus) Frangoul, 2018 4 (12-23) 4 4 (Gr 2) Saraf, 2018 8 (20-38) 6 2 1 1 (unknown) Pawlowska, 2018 4 (12-23) 4 Gaziev J, 2018 3 (<17) 3 28% (Gr 2-3) 21% ? (thal pts included in study) de la Fuente, 2018 15 (12-26) 14 3 1 Total 56 91% 32% (of total) 8% (of total) 6% of total

slide-33
SLIDE 33

Pento Pento Pento Pento 4mg/m2

  • Target ALC of <100 cells/uL prior to starting alemtuzumab
  • Sirolimus starting day +4 post-transplant

Oral cyclophosphamide 200mg/day until day -8 Alemtuzumab (1 mg/kg total) TBI 200 cGy

Unmanipulated G-CSF mobilized PBSC infusion

  • 19
  • 18
  • 17
  • 16
  • 15
  • 14
  • 13
  • 12
  • 20
  • 11
  • 10
  • 9
  • 21

Cy

  • 6
  • 5
  • 4
  • 2
  • 1
  • 7
  • 8
  • 3

+1 +2 +3 PT-Cy 50mg/kg TBI 200 cGy

  • 1
  • 2

Protocol 17-H-0069: Haploidentical PBSC Transplantation for Patients with Severe Sickle Cell Disease

slide-34
SLIDE 34

Pt # Date % Donor chimerism GVHD 1 6/16/17 48% myeloid 74% CD3 None 2 9/8/17 100% myeloid 100% CD3 Grade II Acute, resolved with steroids 3 10/6/17 99% myeloid 44% CD3 None 4 2/23/18 100% myeloid 39% CD3 None 5 3/2/18 89% myeloid 16% CD3 None 6 3/9/18 N/A None 7 10/19/18 100% myeloid 73% CD3 None 8 2/8/19 93% myeloid 6% CD3 None 9 3/29/19 100% myeloid None 10 4/12/19 100% myeloid 20% CD3 None

slide-35
SLIDE 35
  • HLA-matched sibling
  • Myeloablative conditioning has high efficacy in children
  • Nonmyeloablative conditioning aimed at tolerance induction has

lower rate of GVHD

  • Matched unrelated donor
  • Largest study in children associated with high rate of GVHD
  • Study ongoing to further evaluate efficacy and toxicity in adults
  • Unrelated umbilical cord
  • More intensive conditioning has decreased the graft rejection rate
  • Haploidentical
  • Low rate of graft rejection and GVHD in studies performed over

the past 2 years

  • Longer follow-up is necessary to evaluate efficacy and to

monitor for late effects

  • Patients should be enrolled on clinical trials

Conclusions

slide-36
SLIDE 36

Life Without Sickle Cell Anemia

  • “After being out of work since November

2004, the transplant has taken me to new heights…today I work every day as a computer technician…I was able to return to what I love…my frail 6 foot 8 inch frame has done things it never could do like gain weight and exercise. People who knew me then are blown away by the person I am now…This transplant has given me life….”

slide-37
SLIDE 37

Life Without Sickle Cell Anemia

  • “Well, my son knows

I’m his mother now because I’m not usually in the hospital…I can actually play with him, go to the playground, do normal things…Now, I can keep my promises- when I say I’m going to be somewhere, I can actually be there.”

slide-38
SLIDE 38
  • Protocol Support

− Nona Coles − Beth Link − Sasha Morehouse − Stephanie Helwing − Stephanie Housel − Adriana Byrnes − Terri Wakefield

  • The Patients and Families
  • Tisdale Lab

− John Tisdale − Matt Hsieh − OJ Phang − Pat Weitzel − Tiffani Taylor

  • Jonathan Powell
  • Leo Luznik

Acknowledgements

  • Swee Lay Thein
  • Jasmine Abdi
  • Jessica Peterson
  • Roger Kurlander
  • Thomas Hughes
  • Sharon Adams
  • Transfusion Medicine
  • Clinical Staff of the CRC