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 A1 A3 B7B44 C5C7 DR4DR15 Mother A24 A27 B17B18 C3C11 DR3DR5 Alan A1 A27 B7B18 C5C11 DR4DR5 Brian A3 A27 B44B18 C7C11 DR15DR5 Charles A1 A27 B7B18 C5C11 DR4DR5 Diane A3 A24 B44B17 C7C3 DR15DR3

What if no family match? Alternative donors include: –Adult unrelated donors –Unrelated cord blood units Unrelated donors/Cord blood units: – – 13 million donors –~200,000 cord blood units

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 ChemoCounts decline Nadir counts Infection, sores, etc Recovery GVHD risk D-7 to 0D0 to 14D14 on

SCNIR est 1994

TREATMENT WITH G-CSF >90% respond to G-CSF –ANC /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 mg/kg –ATG in 4 –Matched sibling donor: 8 –Alternative donor: 3 Median f/u 2y: 9/11 survived (all 8 sibs) Additional unpublished data indicates continued good results in G-CSF refractory setting Ziedler, Blood, 2000

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 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 G-CSF RESPONSIVE: OUTCOMES

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

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 10y: 11% Sepsis death 10y: 4% Overall 10y: 15%

G-CSF DOSE AND RESPONSE AS PREDICTORS Responders (≥8 µg/kg/d) MDS/AML 10y: 15% Sepsis death 10y: 3% Overall 10y: 18%

G-CSF DOSE AND RESPONSE AS PREDICTORS Weak responders (<8 µg/kg/d) MDS/AML 10y: 18% Sepsis death 10y: 7% Overall 10y: 25%

G-CSF DOSE AND RESPONSE AS PREDICTORS Weak responders (≥8 µg/kg/d) MDS/AML 10y: 40% Sepsis death 10y: 14% Overall 10y: 54%

RISK FACTORS Group MDS/ AML P value Death from sepsis P value G-CSF < 8µg/kg/d, ANC ≥2188/µl 1.0NA1.0NA G-CSF < 8µg/kg/d, ANC <2188/µl G-CSF ≥ 8µg/kg/d, ANC ≥ 2188/µl G-CSF ≥ 8µg/kg/d, ANC <2188/µl

OPTIMIZING BMT REGIMEN Univ Michigan pts (n=14) from 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 <10% BMT with best available donor G-CSF ≥ 8µg/kg/d, ANC <2188/µl ~33% Consider BMT MDS/AML Increases over time BMT with best available donor