Transplants for MPD and MDS The question is really who to - - PowerPoint PPT Presentation

Transplants for MPD and MDS

The question is really who to transplant, with what and when. Focus on myelofibrosis

Jeff Szer Royal Melbourne Hospital

Myelodysplasia

• Little needs to be said
• Despite new therapies (such as azacitidine

and lenalidomide) MDS is incurable.

• Most MDS patients are too old to consider

allografting

• For those that are not, the trick is to time it

right and do it safely.

MDS Tools

• IPSS and WPSS

– Karyotype (type), transfusion dependency, MDS category (roughly blast-number related)

• Timing of transplant is best left to

immediately before progression to high risk disease

Cutler et al Blood 2004;104:579

Years

2 6 1 3 4 5

Probability of Survival after Allotransplants for MDS, Age ³ 2 0 Years, 1 9 9 8 -2 0 0 6

• by Disease Status and Donor Type -

Early, HLA-id sib (N= 523)

SUM08_21.ppt

Early, unrelated (N= 418) Advanced, HLA-id sib (N= 1,133) Advanced, unrelated (N= 1,019)

20 40 60 80 100 10 30 50 70 90 20 40 60 80 100 10 30 50 70 90

P  0.0001

Probability of Survival, %

Years

2 6 1 3 4 5

Probability of Survival after Allotransplants for Early MDS, Age 5 0 Years, 1 9 9 8 -2 0 0 6

• by Conditioning Regim en and Donor Type -

Myeloablative, HLA-id sib (N= 109)

SUM08_22.ppt

Myeloablative, unrelated (N= 71) Reduced Intensity Conditioning, HLA-id sib (N= 122) Reduced Intensity Conditioning, unrelated (N= 96)

20 40 60 80 100 10 30 50 70 90 20 40 60 80 100 10 30 50 70 90

P  0.6111

Probability of Survival, %

ABMTRR

MDS BMT outcome

MYELOFIBROSIS

Historical nomenclature

Mesa RA et al Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007; 31:737-740

Proposed nomenclature

Epidemiology

• 0.4-1.5 per 100,000
• Age-related

– 25% > 70 y – 5% < 40

• M/F 1.2:1.6
• 15-20% in prior ET/PV by 20 years.

Structural Map of Janus Kinase 2

Goldman J, N Engl J Med 2005;352:17

Janus Janus Janus

Involvement of Janus Kinases in Cytokine Signal Transduction

Goldman J, N Engl J Med 2005;352;17

JAK2V617F

• STAT3: constitutive activation
• AKT: increased phosphorylation
• MPL: decreased expression
• BCL-xL: increased expression
• PI-3 kinase: increased expression

But now for something a lot simpler…

Dupriez score

Parameter Finding Points Haemoglobin >100 <100 1 WBC >30 1 4-30 <4 1

Dupriez B, et al Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88:1013-1018.

Dupriez Score

Score Risk Group Median survival Low 93 months (7.75 yrs) 1 Intermediate 36 months (3 yrs) 2 High 13 months (1 yr)

Dupriez B, et al Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88:1013-1018.

Treatment Options

• Transfusions
• Androgens and prednisolone (<30% RR

and transient)

• Erythropoietins
• Hydroxyurea for increased WBC or Plts
• Busulphan
• Melphalan
• 2-chlorodeoxyadenosine

Splenectomy

• N=223
• Indications for surgery:

– Mechanical discomfort (39%) – Portal HTN (11%) – Severe hypercatabolic symptoms (5%) – Transfusions needed frequently (45%)

Tefferi et al.Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients Blood 2000;95:2226-2233

Splenectomy

Improvement in symptoms in majority

• 16% had increase in hepatomegaly
• 22% had increase in thrombocytosis
• 16% had blast transformation
• Median survival 2 years
• Low platelets and BM without

hypercellularity associated with poor prognosis

Tefferi et al.Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients Blood 2000;95:2226-2233

Splenic Radiation

• Radiation in 23 pts
• 100-500cGy to spleen
• Transient benefit (6 months) from pain,

spleen size

• 10% mortality from prolonged cytopenias
• Median survival 2 years

JAK2 inhibitors?

• Giles et al. MK-0457, a Novel Multikinase

Inhibitor, Is Active in Patients with Chronic Myeloid Leukemia (CML) and Acute Lymphocytic Leukemia (ALL) with the T315I BCR-ABL Resistance Mutation and Patients with Refractory JAK-2 Positive Myeloproliferative Diseases (MPD). Blood 2006; 108: abst 253

• “Six of 8 currently evaluable patients with JAK-2

positive refractory MPD have achieved an

• bjective response.”

Potential new agents

• Inhibitors

– Are not selective for mutated gene (ATP- binding site inhibitors) – May preferentially inhibit cells with mutation because they depend on always active J AK2V61 7F – Myelosuppression is expected side effect – Elimination of the disease is unlikely.

Current studies

CEP701 J AK2 and FLT3 MF ET/PV phase II XL01 9 (exelixis) J AK2 (stopped) MF TG01 348 J AK2 MF phase I INCB01 8424 J AK1 and J AK2 MF phase III, ET/PV phase II SB1 51 8 J AK2 and FLT3 MF phase I AZD1 480 J AK2 MF phase I

Allogeneic BMT for MF

Kerbauy et al Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplat 2007; 13:355-365

Patient characteristics

One patient had CIMF that evolved to CML. One patient had a concurrent diagnosis of non-Hodgkin lymphoma, and 2 patients showed myelodysplastic changes in addition to the typical morphology of CIMF. One patient had ITP in addition to marrow fibrosis

Kerbauy et al BBMT 2007; 13:355-365

Donor & Transplant Characteristics

Causes of death

Overall Survival

Mortality: Univariate

Mortality: multivariate

Disease parameters

Survival

No leukaemic transformation And myeloablative regimen Primary diagnosis

Conclusions

• HCT offers potentially curative therapy for

patients with myelofibrosis of various aetiologies.

• Optimum timing for transplantation

remains to be determined, although the data suggest that higher success rates can be expected at earlier disease stages

Conclusions

• Optimum conditioning regimen may

depend on patient age and co-morbid conditions

• Role of JAK2 mutations in therapeutic

decision making?

CIBMTR

• CK00-02: Outcome of allogeneic

transplantation for myelofibrosis

• 289 pts allogeneic HCT for myelofibrosis

between 1989 and 2002

– 162 HLA-identical sibling donor, – 101 URD – 26 alternative related donor

• Median age 45

Ballen BBMT 2010;16: 358-367

CIBMTR

Ballen BBMT 2010;16: 358-367

MDAH: Leuk transformation

Ciurea BBMT 2010; 16: 555-559 N=14 OS EFS

CIBMTR

• Conclusions

– allogeneic HCT cures approximately 1/3 of patients with myelofibrosis – young patients with HLA-matched sibling donors have superior survival – results have improved over the last decade.

ABMTRR

• Study of 56 patients transplanted for

primary MF 1992-2005

RMH Data

• 13 pts with myelofibrosis undergoing BMT

from 9/03-3/07

• Age: 45 (34-56)
• Donors: 9 matched sibs, 4 VUD
• Conditioning: 12 Cy/TBI, 1 Flu/Mel
• 2 deaths: 1 from progressive disease, 1

from AMI.

• 1 alive with low grade active MDS

Drivers for transplant

• Interval from diagnosis to transplant

– 21 months (5-132).

• 3 pts transplanted >10 yr after diagnosis of MPD but 8, 9 and

17 months after diagnosis MF

• Prior splenectomy:

4

• Reasons

– Transfusion dependency 3 – Falling counts/osteosclerosis 4 – Transformation from ET/PV 2 – MDS/AML 3 – Time 1

Sequential bone marrows

• Data on 10 > 1yr

– 6 completely normalised BM

• 3 months-2yr

– 3 with osteosclerosis have normalised – 4 persistent mild increase reticulin at 2 years

• 1 with recurrent MPD (JAK2+)
• 3 pts < 1yr

– All 3 have residual fibrosis at day 100 – All show “improved” fibrosis

Overall survival

24 48 72 96 120 144 168 20 40 60 80 100

7218% n=13

Months after BMT Survival probability (%)

Relapsed at 2 yr with del 13q AMI Relapsed at 2 yr with del 13q AMI Relapsed at 2 yr with del 13q

Conclusions

• HCT offers potentially curative therapy for

patients with myelofibrosis of various aetiologies.

• Optimum timing for transplantation remains to be

determined, although the data suggest that higher success rates can be expected at earlier disease stages

• Optimum conditioning regimen may depend on

patient age and co-morbid conditions

• The role of JAK2 inhibitors or other biological

therapies with BMT remains to be determined