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Long-term outcome after transplant in MF patients
can still occur late after transplant. Many studies have reported that relapse risk is related to the disease risk at the time of transplant; unfortunately, due to the retro- spective registry-based nature of this study, we did not have sufficient data to calculate a relevant International Prognostic Scoring System so this could not be analyzed. However, we observed that the relapse risk was higher in patients who received a RIC, which could be expected. We were, however, surprised that in long-term survivors, the intensity of the regimen still had some impact. In acute myeloid leukemia, the EBMT long-term study did not find that regimen intensity still influences late relapse.29 Occurrence of acute or chronic GvHD before the LM was the strongest factor preventing relapse in long-term survivors. While in many other studies GvHD increased the risk of late deaths, we failed to confirm this in our MF cohort.19,20 GvHD before LM (2 years) in long- term survivors was protective for both relapse risk as well as for mortality. Of course, from this analysis, we cannot extrapolate data confirming that GvHD is needed to improve long-term outcome, because patients with GvHD leading to death in the first two years of transplant had been excluded from the study.
The weakness for GvHD analysis within this cohort was that we could not delineate the risk of “active GvHD” because we had no data regarding GvHD resolu- tion, although it is probable that patients still alive at two years with chronic GvHD were those with the less severe GvHD. The vast majority of patients had onset of chronic GvHD before the LM, but some patients had also a late onset. Finally, the majority of survivors suffered (or had suffered) from chronic GvHD which may alter their qual- ity of life, and it is noteworthy that, even if they are in remission from their MF, patients could have a chronic GvHD which can be a cause of death particularly before five years.
Infectious complications remained a frequent cause of death between two and five years post transplant. It has previously been reported that splenectomy before trans- plant increased the risk of late severe infection which may in part contribute to these findings within the MF cohort.30 This high risk of lethal infection should be taken into account in long-term monitoring strategies and high- lights the importance of appropriate anti-infective pro- phylaxis.31,32
Second malignancies were also the cause of very late
Figure 3. Hazard rate for excess risk of mortality over time post transplant.
Curves show hazard rates for two reference patients, based on the Cox model for the excess hazard. They were both 50 years (y) of age at time of hematopoi- etic stem cell transplantation (Tx), had primary myelofibrosis, received standard conditioning, did not receive total body irradiation, had a matched sibling donor, marrow was source of stem cells, and had no previous graft-versus-host dis- ease. Solid line: male patient; dashed line: female patient.
References
1. Gangat N, Caramazza D, Vaidya R, et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. J Clin Oncol. 2011;29(4):392-397.
2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of rux- olitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
3. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013;98(12):1865-1871.
4. Verstovsek S, Mesa RA, Gotlib J, et al. Long- term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-con- trolled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.
5. Guardiola P, Anderson JE, Bandini G, et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood. 1999;93(9):2831-2838.
6. Kerbauy DMB, Gooley TA, Sale GE, et al. Hematopoietic cell transplantation as cura- tive therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential
thrombocythemia. Biol Blood Marrow
Transplant. 2007;13(3):355-365.
7. Patriarca F, Bacigalupo A, Sperotto A, et al.
Allogeneic hematopoietic stem cell trans- plantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514-1522.
8. Kröger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicen- ter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114 (26):5264-5270.
9. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibro- sis. Biol Blood Marrow Transplant J Am Soc
deaths, justifying long-term monitoring and cancer pre- vention in this population. After five years, 16% of deaths were due to second malignancies, and at ten years, cumulative incidence of secondary cancer was 14%. We could not analyze specific risk factors for second malig- nancies due to the small numbers involved. There are few long-term survivors for non-transplanted higher risk MF so there are no data for long-term secondary cancers within that population and risk factors are unknown. It is hard to determine how the transplantation process increases the risk of cancer, but chemotherapy, radiother- apy, immune deficiency, chronic GvHD, genetic suscepti- bility as well as age can cumulatively contribute towards an increased susceptibility.
In conclusion, patients with MF have good survival when alive and in remission two years after transplanta- tion, especially younger and female recipients. Severe late complications and late relapses should be monitored and prevention highlighted in order to reduce life-threatening complications. Lifelong follow up is required to optimize long-term outcomes.33
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