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Bone Marrow Transplantationand the Potential Role of Iomab-B
Hillard M. Lazarus, MD, FACPProfessor of Medicine, Director of Novel Cell Therapy
Case Western Reserve University
1
Hematopoietic Cell Transplantation (HCT) Background
• Life-saving art applied for:
– Hematologic malignancy (most common indication)
– Goal: eliminate malignancy
– Acquired and genetic disorders of hematopoiesis and the immune system
– Goal: restore normal blood production/immunity
• Premise(s):
– Cytotoxic agents required to turn off recipient’s immune system and allow engraftment (avoid rejection)
– Increasing doses of cytotoxic agents (chemotherapy, radiotherapy) markedly increase cancer cell kill
• BUT cytotoxics harm blood cell production (marrow injury)
• Leads potentially to fatal infection and bleeding
2
Hematopoietic Cell Transplantation (HCT) Background (cont’d)
• Infusion of hematopoietic progenitor cells “rescue” host
• Cells obtained from:
– patient himself/herself (autologous) or
– another person (allogeneic)
• Hematopoiesis restored over several weeks by infused cells
• Requires that recipient has been given vigorous supportive care with antibiotics, transfusions, other tools
3
Hematopoietic Cell Transplantation (HCT) Background (cont’d)
• HCT can be divided into many types; depends on:
• Intensity of chemo-radiation therapy given:
– myeloablative
– reduced-intensity conditioning
– non-myeloablative
4
Hematopoietic Cell Transplantation (HCT) Background (cont’d)
• Donor graft, related and unrelated:
– Autologous (self)
– Allogeneic (another person)
– Related: histo-compatible (HLA-identical) sibling
– Theoretically best donor
– Related: haplo-identical (“half-match” family member)
– At present, much less commonly used
– Alternative donor (not related)
– Unrelated (but histo-compatible, i.e. HLA-identical) adult
– Umbilical cord blood (obtained from the placenta after delivery)
5
Hematopoietic Cell Transplantation (HCT) Background (cont’d)
• Graft source
– Bone marrow (collected in OR from post-iliac crests)
– Blood (marrow progenitors mobilized into blood using agents, collected via large catheter (85% of all HCT)
– umbilical cord blood (from the placenta after delivery)
• Advantages/disadvantages for these various approaches
– Depends on disorder affecting recipient
– Donor availability
– Age and physical condition of the recipient
– Planned timing of transplant
– Many other factors
6
Autologous Hematopoietic Cell Transplant
Chronology of Approach
Stem Cell:
Collection
± Purging
Freezing
High-dose
Chemotherapy
Infusion
of Graft
Vigorous
Supportive
Care
Patient
Evaluation
7
Allogeneic Hematopoietic Cell Transplant
Chronology of Approach
Patient
Evaluation
High-dose
ChemotherapyInfusion
of Graft
Vigorous
Supportive
Care
Donor
Evaluation
Hematopoietic Cell
Collection
± T-cell depletion
± Freezing
Begin
GvHD
Prophylaxis
Therapy:
Immuno-
suppression
8
Hematopoietic Cell Transplant
Donor Availability and Transplant Type
Donor TypeMatch
Probability
% All
Transplants
HLA-compatible sibling 30% 54%
HLA-compatible unrelated 35-80% 38%
Umbilical cord blood (UCB) 10-90% 5%
Haploidentical 99% <5%
C Anasetti. BMT CTN State-of-the-Science, June 2007, Ann Arbor, MI9
Acute Myeloid Leukemia (AML) Survival by Age
Adapted from Juliusson G et al. Blood 2009;113:4179-4187
< 50
85+
10
Rationale for RIT in HCT Regimens
Relationship between Relapse and Dose♦ AML is highly radiosensitive.
♦ TBI effective in HCT at high doses.
♦ TBI cannot be safely dose-escalated
because normal organs cannot tolerate
more radiation.
♦ Tradeoff: more killing of leukemia
simultaneously destroys normal tissue.
TBI = total body irradiation RIT = radioimmunotherapy 11
Conditioning Regimens for Allogeneic HCT
12
Efficacy
Safe
ty
Myeloablative Conditioning
MA
Reduced-Intensity Conditioning
RIC
Non-myeloablativeConditioning
NMA
Iomab-B
= Tradeoff Zone; Safety versus Efficacy
Iomab-B Biodistribution
MARROW SPLEEN LIVER LUNG KIDNEY TOTAL BODY
Leukemia Leukemia Leukemia Normal Tissue
cells cells cellsBlood 2009 114:5444-5453
Iomab-B combines an anti-CD45 mAb
that targets lympho-hematopoietic cells
with a radio-toxin, the β-particle
emitting radionuclide 131I.
The mAb does not bind to other normal
tissues and directs radiation to only
leukemic and immune cells.
RA
DIA
TIO
N D
OS
E (
cG
y/m
Ci
131I)
13
Iomab-B: Targeted Radiation Enabling HCT
♦ Iomab-B is a “guided missile” which
selectively ablates bone marrow,
killing leukemia cells as well as host
immune system cells (the latter
prevents rejection of hematopoietic
cells from another person)
♦ This therapy is part of the transplant
regimen; must be followed
immediately by infusion of a
hematopoietic graft from another
person to restore marrow function
♦ New marrow grows back over
several weeks and blood production
resumes
IV infusion Antibody targeting
Targeted ablation Bone marrow transplant
LEUKEMIA CELLSCD45
14
Iomab-B Phase I/II Results
• Prior data from the Fred Hutchinson Cancer Research Center
• Patients > 50 years old with advanced AML and high risk MDS
• Patients received Iomab-B followed by hematopoietic cell transplant
• N= 21; patients treated at MTD
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 0.5 1 1.5 2 2.5 3 3.5 4
Pro
bab
ility
Years after Transplant
Overall Survival
Disease - Free Survival
Non - Relapse Mortality
Relapse
Censor
Adapted from Blood 2009 114:5444-5453 15
Iomab-B Phase I/II Results
Definitions:
♦ Primary Refractory AML:
– Leukemia is uncontrolled and resistant to treatment
– No response seen after two cycles of induction attempts
♦ Myeloablation
– Depletion of bone marrow; carries standard risks of infection and bleeding;
– Patients are isolated and given vigorous supportive care, i.e. transfusions and
antibiotics
♦ Complete Remission (CR):
– No obvious evidence of leukemia
– Recovery of white blood cells and platelets
16
Iomab-B Phase I/II Results
All relapsed/refractory AML patients over 50
N = Number of patients treated. Iomab-B results from FHCRC clinical trials;
Current BMT and Chemotherapy results from MD Anderson outcomes analysis
Sources: Blood 2009 114:5444-5453; unpublished FHCRC data
30%
19%
10%
0%
10%
0%0%
5%
10%
15%
20%
25%
30%
35%
1 year 2 years
Perc
en
tag
e S
urv
ival
Iomab-B BMT (N=27)
Current BMT (N=10)
Chemotherapy (N=61)
♦ Complete response rate: 100%
♦ Engraftment by day 28: 100%
♦ Non-relapse mortality (NRM): Day 100<10%, Overall ~20%
(NRM = 46% in comparable patients with conventional
myeloablative conditioning transplants*)
*
17
Rel/ref AML patients over 50 w/ poor cytogenetics
Iomab-B Phase I/II with Poor Cytogenetics
N = Number of patients treated Iomab-B results from FHCRC clinical trials;
Current BMT and Chemotherapy results from MD Anderson outcomes analysis
Sources: Blood 2009 114:5444-5453; unpublished FHCRC data
33%
16%
3%
0%
3%
0%0%
5%
10%
15%
20%
25%
30%
35%
1 year 2 years
Per
cen
tag
e S
urv
ival
Iomab-B BMT (N=18)
Current BMT (N=19)
Chemotherapy (N=95)
18
– Single pivotal study, pending trial results
– Patient population: refractory AML patients over the age of 55 years
– Trial arms: study arm and control arm with physician’s choice of conventional care with curative intent
– Trial size: 150 patients total, 75 patients per arm
– Study timeline: enrollment approximately 12 months; primary endpoint additional 8 months; secondary
endpoint additional 4 months; follow-up 5 years
Iomab-B Pivotal Phase III Trial Design
*Control arm subjects with no CR are offered crossover to Iomab-B for ethical reasons.
**NMA/RIC = Nonmyeloablative Conditioning/Reduced Intensity Conditioning transplant
1. Based on the End of Phase II meeting and subsequent communications with the FDA.
2. Refractory is defined as either primary failure to achieve a complete remission after 2 cycles of induction therapy; relapsed after <6 months
in complete remission; second or higher relapse; or relapsed disease not responding to intensive salvage therapy
Control Arm
(Chemotherapy)
CR
No CR
NMA/RIC**
and
HSCT
Initial
Screening
Not
enrolledFail
R
A
N
D
O
M
I
Z
E
PassCrossover*
CR
No CRStudy Arm
Iomab-B
and
NMA/RIC
transplant
Enrolled
Observation
Off Study
Negative Response
ATNM Drug Candidate
Positive Response
Current Treatments
19
Appendix: Likelihood of Finding an 8/8 HLA Match
In 2015, nearly every patient can have a donor.
20
Gragert L et al. N Engl J Med 2014;371:339-348.