Transcript Levine-BMT

Congenital Neutropenia:
Making the Decision to
Transplant
John E. Levine, MD, MS
University of Michigan Blood
and Marrow Transplantation
Program
The BMT Process
Step 1: Do you need a transplant?
– (to be discussed later)
Step 2: Finding a donor
Finding a Donor
Tissue typing (HLA typing) patient, siblings (and
parents)
HLA typing: there are proteins are on the surface
of cells called HLA molecules
Everyone has their own pattern of these proteins
Typing is done to determine which pattern of
these proteins are present in the patient and
their potential donors
The pattern is inherited from your parents so
siblings are most likely to have the same pattern
Sibling Match
Father
Mother
A1
A3
A24
A27
B7
B44
B17
B18
C5
C7
C3
C11
DR4
DR15
DR3
DR5
Alan
Brian
Charles
Diane
A1
A27
A3
A27
A1
A27
A3
A24
B7
B18
B44
B18
B7
B18
B44
B17
C5
C11
C7
C11
C5
C11
C7
C3
DR4
DR5
DR15
DR5
DR4
DR5
DR15
DR3
What if no family match?
Alternative donors include:
– Adult unrelated donors
– Unrelated cord blood units
Unrelated donors/Cord blood units:
– www.bethematch.org
– 13 million donors
– ~200,000 cord blood units
Unrelated Donor BMT Numbers
Unrelated Donor BMT Numbers
Why are more BMT being performed?
Technological advances make BMT safer
– New chemotherapy regimens with less toxicity
– Better HLA matching techniques
– Improved management of infections
– Improved management of complications
(GVHD)
BMT PROCESS
Chemotherapy to:
– Eliminate diseased bone marrow
– Prevent rejection of the bone marrow
transplant
– 5-7 days (given in hospital)
Transplant
– Bone marrow is usually collected on day of
transplant
– Administered through intravenous catheter
BMT COMPLICATIONS
Infections
Relapse (if transplanted for MDS or
leukemia)
Graft-versus-host disease
– Donor immune system cells try to reject the
patient
BMT TIMELINE
D-7 to 0
Chemo
D0 to 14
Counts
decline
D14 on
Nadir counts
Infection, sores, etc
Recovery
GVHD risk
SCNIR est 1994
TREATMENT WITH G-CSF
>90% respond to G-CSF
– ANC 1000-1500/μl
– Both Ela2 and Hax1 pts equally likely to
respond
Long-term G-CSF effects:
– headache/bone pain
– splenomegaly
– osteopenia (28%)
G-CSF RESPONSE
Ziedler, BJH, 2008
G-CSF REFRACTORY
High risk of death from infection
11 patients with no or inadequate response to G-CSF
Myeloablative BMT
– Busulfan + cyclophosphamide 120-200 mg/kg
– ATG in 4
– Matched sibling donor: 8
– Alternative donor: 3
Median f/u 2y: 9/11 survived (all 8 sibs)
Additional unpublished data indicates continued good
results in G-CSF refractory setting
Ziedler, Blood, 2000
G-CSF RESPONSIVE:
OUTCOMES
1990s: increasingly clear that SCN pts were at
risk of MDS or AML
374 patients with SCN registered with SCNIR
11/1987 to 9/2000
Severe event defined as MDS/AML or
sepsis-related death
“Effective” GCSF dose was defined as the dose
at 6m
Average ANC from 6-18m was defined as the
effective response
Rosenberg, Blood, 2006
SEVERE EVENTS
10 y CI: 21%
12 y CI: 36%
10 y CI: 8%
HAZARD RATES
MDS/AML
p 6y: 2.9%/yr
p 12y: 8%/yr
Sepsis death:
0.9%/yr
MDS/AML OUTCOMES
Percent survival
100
HCT (n=31)
No HCT (n=11)
80
60
40
20
p=0.01
0
0
12
24
36
48
60
Months from MDS/AML dx
72
CAN WE PREDICT WHICH
PATIENTS ARE AT HIGHEST
RISK FOR SEVERE EVENTS?
G-CSF RECEPTOR MUTATIONS
G-CSFR point mutations are common
– Present in 30% of pts w/o leukemia
– Present in 80% of pts w/ leukemia
Can be present for prolonged periods
before leukemia develops (if ever)
Mechanisms leading to leukemia unknown
G-CSF DOSE AND
RESPONSE AS PREDICTORS
Reference Group:
MDS/AML
CI @ 10y: 11%
Sepsis death
CI @ 10y: 4%
Overall
CI @ 10y: 15%
G-CSF DOSE AND
RESPONSE AS PREDICTORS
Responders (≥8 µg/kg/d)
MDS/AML
CI @ 10y: 15%
Sepsis death
CI @ 10y: 3%
Overall
CI @ 10y: 18%
G-CSF DOSE AND
RESPONSE AS PREDICTORS
Weak responders (<8 µg/kg/d)
MDS/AML
CI @ 10y: 18%
Sepsis death
CI @ 10y: 7%
Overall
CI @ 10y: 25%
G-CSF DOSE AND
RESPONSE AS PREDICTORS
Weak responders (≥8 µg/kg/d)
MDS/AML
CI @ 10y: 40%
Sepsis death
CI @ 10y: 14%
Overall
CI @ 10y: 54%
RISK FACTORS
Group
MDS/
AML
P
value
Death
from
sepsis
P value
G-CSF < 8µg/kg/d,
ANC ≥2188/µl
1.0
NA
1.0
NA
G-CSF < 8µg/kg/d,
ANC <2188/µl
1.7
.42
0.6
.69
G-CSF ≥ 8µg/kg/d,
ANC ≥ 2188/µl
1.7
.40
0.5
.53
G-CSF ≥ 8µg/kg/d,
ANC <2188/µl
4.5
.008
3.8
.09
OPTIMIZING BMT REGIMEN
Univ Michigan pts (n=14) from 1996-2008
If AML: minimal or no chemo to treat cancer
Busulfan based conditioning + ATG
Target higher stem cell dose to avoid rejection
Augmented infection prophylaxis:
– Norfloxacin or levaquin from start of conditioning
– Aspergillus coverage (voriconazole)
High survival rate since 2001 (incl last 3 URD)
CONCLUSIONS
G-CSF responsive ~55%
Regular CBC and
BM exams (q6-12
mo)
G-CSF refractory
BMT with best
available donor
<10%
G-CSF ≥ 8µg/kg/d, ~33%
ANC <2188/µl
Consider BMT
MDS/AML
BMT with best
available donor
Increases
over time