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
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 - 100 100 90 90 Probability of Survival, % 80 80 70 70 60 60 50 50 Early, HLA-id sib (N= 523) 40 40 30 30 Early, unrelated (N= 418) Advanced, unrelated (N= 1,019) 20 20 Advanced, HLA-id sib (N= 1,133) 10 10 P 0.0001 0 0 0 1 2 3 4 5 6 Years SUM08_21.ppt
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 - 100 100 90 90 Probability of Survival, % 80 80 70 70 Reduced Intensity Conditioning, unrelated (N= 96) 60 60 50 50 Myeloablative, HLA-id sib (N= 109) 40 40 Myeloablative, unrelated (N= 71) 30 30 20 20 Reduced Intensity Conditioning, HLA-id sib (N= 122) 10 10 P 0.6111 0 0 0 1 2 3 4 5 6 Years SUM08_22.ppt
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 Janus Janus Janus Goldman J, N Engl J Med 2005;352:17
Involvement of Janus Kinases in Cytokine Signal Transduction Goldman J, N Engl J Med 2005;352;17
JAK2 V617F • 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 0 <100 1 WBC >30 1 4-30 0 <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 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;88:1013-1018.
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 objective 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 MF ET/PV FLT3 phase II XL01 9 J AK2 MF (exelixis) (stopped) TG01 348 J AK2 MF phase I INCB01 8424 J AK1 and MF phase III, J AK2 ET/PV phase II SB1 51 8 J AK2 and MF phase I FLT3 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 N=14 OS EFS Ciurea BBMT 2010; 16: 555-559
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 Relapsed at 2 yr with del 13q Relapsed at 2 yr with del 13q Relapsed at 2 yr with del 13q 100 Survival probability (%) 72 18% 80 60 AMI AMI n=13 40 20 0 0 24 48 72 96 120 144 168 Months after BMT
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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