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 (