Transplants for MPD and MDS

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1 Transplants for MPD and MDS The question is really who to transplant, with what and when. Focus on myelofibrosis Jeff Szer Royal Melbourne Hospital

2 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.

3 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

4 Probability of Survival after Allotransplants for MDS, Age ³20 Years, by Disease Status and Donor Type Probability of Survival, % Early, unrelated (N=418) Advanced, HLA-id sib (N=1,133) Early, HLA-id sib (N=523) Advanced, unrelated (N=1,019) P Years SUM08_21.ppt

5 Probability of Survival after Allotransplants for Early MDS, Age 50 Years, by Conditioning Regimen and Donor Type Probability of Survival, % Myeloablative, unrelated (N=71) Reduced Intensity Conditioning, unrelated (N=96) Myeloablative, HLA-id sib (N=109) Reduced Intensity Conditioning, HLA-id sib (N=122) P Years SUM08_22.ppt

6 ABMTRR

7 MDS BMT outcome

8 MYELOFIBROSIS

9 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:

10 Proposed nomenclature

11 Epidemiology per 100,000 Age-related 25% > 70 y 5% < 40 M/F 1.2: % in prior ET/PV by 20 years.

12 Structural Map of Janus Kinase 2 Janus Goldman J, N Engl J Med 2005;352:17

13 Involvement of Janus Kinases in Cytokine Signal Transduction Goldman J, N Engl J Med 2005;352;17

14 JAK2V617F STAT3: constitutive activation AKT: increased phosphorylation MPL: decreased expression BCL-xL: increased expression PI-3 kinase: increased expression

15 But now for something a lot simpler

16 Dupriez score Parameter Finding Points Haemoglobin >100 0 <100 1 WBC > <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:

17 Dupriez Score Score Risk Group Median survival 0 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:

18 Treatment Options Transfusions Androgens and prednisolone (<30% RR and transient) Erythropoietins Hydroxyurea for increased WBC or Plts Busulphan Melphalan 2-chlorodeoxyadenosine

19 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:

20 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:

21 Splenic Radiation Radiation in 23 pts cGy to spleen Transient benefit (6 months) from pain, spleen size 10% mortality from prolonged cytopenias Median survival 2 years

22 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 objective response.

23 Potential new agents Inhibitors Are not selective for mutated gene (ATPbinding site inhibitors) May preferentially inhibit cells with mutation because they depend on always active JAK2V617F Myelosuppression is expected side effect Elimination of the disease is unlikely.

24 Current studies CEP701 XL019 (exelixis) JAK2 and FLT3 JAK2 (stopped) MF ET/PV phase II MF TG01348 JAK2 MF phase I INCB SB1518 JAK1 and JAK2 JAK2 and FLT3 MF phase III, ET/PV phase II MF phase I AZD1480 JAK2 MF phase I

25 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:

26 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:

27 Donor & Transplant Characteristics

28 Causes of death

29 Overall Survival

30 Mortality: Univariate

31 Mortality: multivariate

32 Disease parameters

33 Survival No leukaemic transformation And myeloablative regimen Primary diagnosis

34 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

35 Conclusions Optimum conditioning regimen may depend on patient age and co-morbid conditions Role of JAK2 mutations in therapeutic decision making?

36 CIBMTR CK00-02: Outcome of allogeneic transplantation for myelofibrosis 289 pts allogeneic HCT for myelofibrosis between 1989 and HLA-identical sibling donor, 101 URD 26 alternative related donor Median age 45 Ballen BBMT 2010;16:

37 CIBMTR Ballen BBMT 2010;16:

38 MDAH: Leuk transformation N=14 OS EFS Ciurea BBMT 2010; 16:

39 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.

40 ABMTRR Study of 56 patients transplanted for primary MF

41 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

42 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

43 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

44 Overall survival Relapsed at 2 yr with del 13q Survival probability (%) AMI % n= Months after BMT

45 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

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