November 2020 Clinical case of the month
Title: Post PV Myelofibrosis
Submitted by Syed Ali Abutalib and Nicolaus Kröger
Physicians expert perspective: Nicolaus Kröger
54-year-old female with known diagnosis of polycythemia vera (PV) comes for a second opinion with concerns of disease progression. She was diagnosed with JAK2 V617F positive PV, approximately 7 years ago, which has been treated with periodic phlebotomy (goal to keep HCT <45%) and interferon. She complains of 6 kg weight loss with increasing night sweat and abdominal pain. The Karnofsky score is 90%. In the last 6 months no phlebotomy has been done due to worsening anemia plus interferon is stopped because of new depressive mood. The examination is remarkable for enlarged spleen, 4 cm below the costal margin. The routine laboratory parameters are abnormal for hemoglobin of 10.5 g/dl, platelets of 130 x 10e9/L and leukocytes 18 x 10e9/L. The review of peripheral blood smear shows leukoerythroblastic picture with 2% blasts; the serum LDH levels are also elevated at 690U/L. Repeat bone marrow examination shows new fibrosis of grade 3 with normal cytogenetics and persistence of JAK2 V617F mutation with variant allele fraction of 65%. In addition, new SRSF2 and EZH2 molecular aberrations are detected by next generation sequencing (NGS). She has two HLA-identical sibling donors (younger brother and older sister) and 3 HLA-haplo-identical donors (younger sister and parents).
Which of the following statement about this case is INCORRECT?
A. Treatment with JAK2-inhibitor would be reasonable
B. According MY-SEC risk score for post ET/PV myelofibrosis the median survival is less than 5 years
C. DIPSS/ DIPSS plus and MIPSS70 are not the proper risk score models for this patient’s condition
D. According the myelofibrosis transplant scoring system (MTSS) the estimated overall survival at 6-years after immediate allogeneic hematopoietic cell transplantation would be about 70%
E. Anemia is as strong negative risk factor for survival in the transplant and in the non- transplant setting
Expert Perspective by Professor Dr. Nicolaus Kröger
Patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis have a median survival of approximately 6 years but survival varies between more than 15 years and less than 2 years.1 Several risk scores such as IPSS, dynamic IPSS (DIPSS), or DIPSS plus are currently used in clinical practice to determine prognosis of patients with primary myelofibrosis (PMF).1 More recently also molecular markers have been introduced into the PMF prognostic risk score model (MIPSS70)2. This, and other score models however are only validated for PMF (not in post ET/PV myelofibrosis) and a specific score for post ET/PV myelofibrosis (MYSEC) have been proposed recently³. Ruxolitinib, a JAK-2 inhibitor is approved in Europe for patients with myelofibrosis and symptomatic splenomegaly (with and without JAK2 mutation) to reduce spleen size and improve constitutional symptoms or disease burden.1
Since ruxolitinib is approved for symptomatic myelofibrosis several investigations used ruxolitinib prior to transplantation to improve constitutional symptoms and to reduce spleen size in an anticipation that such intervention might improve transplant outcomes. The European LeukemiaNet and the European Society for Blood and Marrow Transplantation recommend the use of ruxolitinib at least 2 months prior to transplantation and a careful weaning prior to conditioning to avoid rebound disease phenomenon. More recent data suggest better outcome after transplantation if patients received transplant after responding to ruxolitinib rather postponing the transplant until ruxolitinib failure4,5.
Due to the lack of prospective randomized studies allogeneic hematopoietic cell transplantation (allo-HCT) is currently recommended for patients less than 70 years with an estimated median survival of less than 5 years, based on a comparison between transplanted and non-transplanted patients in the pre-ruxolitinib era5. The intensity of the conditioning regimen has not been tested prospectively but retrospective comparisons resulted in similar outcome6. Because of the reduced toxicity and advance patient age in this disease, reduced-intensity conditioning regimens are currently used more frequently and are accounted for about 2/3 of allotransplants for myelofibrosis (both primary and secondary) in the EBMT registry.
Regarding the donor selection, several studies reported worse outcome for HLA-matched or mismatched unrelated donors in comparison to HLA-identical sibling transplantation. Cord blood resulted in a high risk of graft failure and haplo-identical donor with post-transplantation cyclophosphamide as GVHD prophylaxis is currently under investigation and more recent EBMT data reported a 5-year survival of only 38%7,8.
Beside HLA-mismatched donor other risk factors included in the Myelofibrosis Transplant Risk score (MTSS), which predicts outcome after allo-HCT are low platelet count (<150 x10e9/L), leukocytes (>25 x10e9/L), Karnofsky score (< 90%) age (<57 years), non CALR/MPL mutation and ASXL-1 mutation9. Beside survival these factors also predict non-relapse mortality (NRM) after allo-HCT. Interestingly, anemia which is a strong negative risk factor in the IPSS, DIPSS, MIPSS and MYSEC scoring systems did not influence outcome after allo-HCT in this study significantly9,10.
Correct Answer: E
- Harrison C, Kiladjian JJ, Kathrin Al-Ali H, et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. N Engl J Med 2012; 366(9): 787-98.
- Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36:310-318.
- Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31:2726-2731.
- Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29:2126-2133.
- Shanavas M, Popat U, Michaelis LC, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. Biol Blood Marrow Transplant. 2016;22:432-440
- McLornan D, Szydlo R, Koster L, Chalandon Y, Robin M, Wolschke C, et al. Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019 Nov;25(11):2167-2171.
- Robin M, Giannotti F, Deconinck E, et al. Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis. Biol Blood Marrow Transplant. 2014;20:1841-1846.
- Raj K, Olavarria E, Eikema D-J, et al. Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party. Blood. 2016;128:4655-4655.
- Gagelmann N, Ditschkowski M, Bogdanov R, Bredin S, Robin M, Cassinat B, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood 2019; 133(20): 2233-2242.
- Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125:3347-3350;
Syed Ali Abutalib, MD
Associate Director, Hematology and Cellular Therapy Program
Director, Clinical Apheresis Program
Cancer Treatment Centers of America, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science
Nicolaus Kröger, MD
Professor and Medical Director of the Department of Stem Cell
Transplantation at the University Hospital Hamburg-Eppendorf, Germany
University Hospital Hamburg, Hamburg, Germany
Correspondence: Nicolaus Kröger, MD
Future Clinical Case of the Month
If you have a suggestion for future clinical case to feature, please contact Nicolaus Kröger.