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

Alan
A1 A27
B7
C5
B18
C11
DR4 DR5
Sibling Match
Father
A1 A3
B7
C5
B44
C7
DR4 DR15
Mother
A24 A27
B17
C3
B18
C11
DR3 DR5
A3
B44
C7
Brian
A27
B18
C11
DR15 DR5
Charles
A1 A27
B7
C5
B18
C11
DR4 DR5
A3
B44
C7
Diane
A24
B17
C3
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

D-7 to 0 D0 to 14
BMT TIMELINE
D14 on
Chemo Counts decline
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Additional unpublished data indicates continued good results in G-CSF refractory setting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
100
80
60
40
20 p=0.01
0
0 12 24 36 48 60 72
Months from MDS/AML dx
HCT (n=31)
No HCT (n=11)

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%

Group
GCSF < 8µg/kg/d,
ANC ≥2188/µl
GCSF < 8µg/kg/d,
ANC <2188/µl
GCSF ≥ 8µg/kg/d,
ANC ≥ 2188/µl
GCSF ≥ 8µg/kg/d,
ANC <2188/µl
RISK FACTORS
MDS/
AML
1.0
P value
NA
Death from sepsis
1.0
1.7
1.7
4.5
.42
.40
0.6
0.5
.008
3.8
P value
NA
.69
.53
.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%
G-CSF refractory <10%
Regular CBC and
BM exams (q6-12 mo)
BMT with best available donor
GCSF ≥ 8µg/kg/d,
ANC <2188/µl
~33%
MDS/AML Increases over time
Consider BMT
BMT with best available donor