Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis

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Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We retrospectively analyzed the outcome of patients who underwent allogeneic HSCT, 1994–2008, and the potential risk factors affecting non-relapse mortality (NRM), OS and relapse-free survival (RFS). A total of 39 patients, 15–65 (median 49) years old, diagnosed with primary (n=27) or secondary (n=12) myelofibrosis underwent HSCT (25 related and 14 unrelated). In ten patients, disease had transformed into acute leukaemia. Lille prognosis score was low for 9, intermediate for 16 and high for 14 patients. The conditioning regimen was myeloablative (MAC) for 15 and reduced-intensity (RIC) fludarabine-based for 24, with successful engraftment in 38 patients. A total of 31 patients developed grade I–IV GvHD; 19 developed chronic GvHD. The 3-year OS, RFS and NRM rates (95% confidence interval) were 60% (42–74), 54% (37–59) and 30% (30–45), respectively.


Myelofibrosis is a stem cell-derived clonal myeloproliferative disorder characterized by ineffective haematopoiesis, BM fibrosis and extramedullary haematopoiesis. It is an uncommon disease, with an estimated incidence of 0.4–0.7/100 000 persons/year1 and predominantly a disease of the elderly patients with a median age of 65 years at onset, although up to 20% of patients are under 55 years of age at the time of diagnosis.2

The prognosis of myelofibrosis patients remains poor, with median survival ranging from 1.5 to 10 years,3 according to published risk factors.4, 5 After transformation into AML, mortality reaches 98% at 3 months.6 No survival advantage has been reported with conventional treatment, which is mainly supportive care. Curative therapy for myelofibrosis is currently possible only with allogeneic haematopoietic stem-cell transplant (HSCT), which obtains OS rates of 40–80%, depending on the origin of the cells transplanted and the conditioning regimen.7, 8

Here, we retrospectively analyzed the impact on relapse-free survival (RFS) of the characteristics of 39 patients and their allogeneic HSCT in four French centres.



The day of engraftment was defined as the first of three consecutive days with neutrophil counts >0.5 × 109/L. The day of plt engraftment was defined as the first of the seven consecutive days with plt counts >20 × 109/L without any transfusion. Primary graft failure was diagnosed when the granulocyte-engraftment end point was not reached by day 50. Anaemia was defined as Hb <120 g/L. Complete haematological remission was defined as the disappearance of all clinical signs, peripheral blood and cytogenetic abnormalities. Chimerism status was monitored by short tandem-repeat–based PCR in T- and non-T-cell subsets. Complete donor chimerism was defined as >95% donor cells. Mixed chimerism was defined as 6–95% donor cells.

JAK2-V617F mutation was screened with a single-nucleotide polymorphism genotyping assay using allele-specific Taqman probes and real-time PCR detection on an ABI 7500 fast apparatus (Applied Biosystems, Courtaboeuf, France).9

Transformation into AML was defined as more than 20% blasts in blood or BM.

Relapse was defined as the reappearance of host cells and morphological criteria of myelofibrosis after remission. Acute and chronic GvHD were graded according to standard criteria.10, 11, 12, 13 Determination of the comorbidity score was assigned using an HSCT-specific comorbidity index.14

Statistical analysis

Data were collected from the local database of each centre.

The end points were: engraftment, acute and/or chronic GvHD, relapse, OS, RFS and non-relapse mortality (NRM). All time-to-event data were calculated from the date of transplantation to the date of the event or last follow-up, whichever occurred first. NRM was defined as death without relapse, and was analyzed in a competing-risks setting, with relapse being treated as the competing event. Engraftment, acute and/or chronic GvHD were also analyzed in a competing-risks setting with death and relapse as competing events.

The cumulative incidences of engraftment, acute and/or chronic GvHD, relapse and NRM were estimated using usual methodology.15 OS and RFS curves were estimated using the Kaplan–Meier product-limit estimator. Distributions of time to engraftment were compared across groups using Wilcoxon's rank sum tests. RFS risk factors were analyzed using Cox proportional hazards models. The proportional hazards assumption was checked by examination of Schoenfeld residuals, and Grambsch and Therneau's lack-of-fit test. Because of the small number of patients, only univariable analyses were conducted.

Survival and cumulative incidence rates are presented as estimates and 95% confidence intervals (95% CIs), and factors associated with RFS are presented as hazard ratios (95% CI).

All tests were two-sided and P<0.05 was considered significant. Analyses were performed using R 2.6.2 statistical software (The R Foundation for Statistical Computing, Vienna, Austria).

Patient and disease characteristics

A total of 39 patients diagnosed with primary myelofibrosis, post-polycythemia vera or essential thrombocytemia fibrosis underwent allogeneic HSCT in four French centers between January 1994 and June 2008. Patient and disease characteristics are summarized in Table 1. Median age was 49 years (range 15–65). At time of transplantation, 30 (77%) patients had intermediate or high Lille prognosis score. Cytogenetic analyses of 25 patients revealed clonal abnormalities in 14. JAK2-V617F mutation was tested in 23 patients and was mutated in 30% of them. Around 20 and 13 patients received red blood cell or plt transfusions, respectively, before transplantation. A total of 23 patients were splenectomized and 3 underwent spleen radiotherapy before transplantation. Median total nucleated cell dose was 2.7 × 108 per kg for patients receiving BM and 7.6 × 106 per kg cell for patients receiving peripheral blood stem cells.

Table 1 Characteristics of the 39 patients and their transplants

Transplantation characteristics

Donor and transplant characteristics are summarized in Table 1. On the basis of high HLA resolution (HLA-A, -B, -C, -DRB1 and -DQB1), all but one patient received an HLA-matched donor transplant. Eight recipients were CMV (CMV)-positive (R-CMV+) and received HSCT from a CMV-negative donor (D-CMV).

The conditioning regimens were chosen according to age, comorbidities and time of transplantation and policy of each centre (Table 1). A total of 12 patients received rabbit antithymoglobulin as part of their reduced-intensity (RIC).



The only primary engraftment failure occurred in a patient who had received myeloablative conditioning with BU and CY; he died of relapse 5 months after transplantation. One patient's engraftment was delayed by hypersplenism and she underwent splenectomy after transplantation, followed by successful engraftment. Two patients experienced no aplasia at all. The median time to neutrophil engraftment was 15 (range 0–40) days. The cumulative incidence of neutrophil engraftment is shown in Figure 1a. Factors associated with neutrophil engraftment were PBSC vs BM origin (14.5 vs 21 days, P=0.011), splenectomy before transplantation (13 vs 18 days, P=0.017) and RIC regimen (13.5 vs 19.5 days, P=0.017). High numbers of nucleated cells infused was not significantly associated with neutrophil engraftment (P=0.06). Median time to plt engraftment was 19 (range 0–136) days. Four patients died or relapsed before plt engraftment on days +23, +59, +62 and +161.

Figure 1

Cumulative incidence of engraftment (a), grade II–IV acute GvHD (b), chronic GvHD (c). Dashed lines represent point-wise 95% confidence intervals.

Chimerism was assessed on blood leucocytes from 27 patients and showed complete donor chimerism within 3 months in 22 patients. One patient remained completely recipient because his graft never engrafted. Two patients had mixed chimerism and died before the third month post transplant from related complications. One patient had mixed chimerism at 3 months and relapsed at 4 months. Another patient with mixed chimerism at 3 months achieved complete donor chimerism within 1 year.


A total of 31 patients suffered from acute GvHD with maximum grades I, II, III or IV, respectively, for 4 (10%), 22 (56%), 2 (5%) or 3 (8%). The cumulative grade II–IV acute GvHD incidence is shown in Figure 1b.

A total of 19 patients developed chronic GvHD, which was limited in 6 and extensive in 13. The cumulative incidence of chronic GvHD is shown in Figure 1c.

Survival, relapse and NRM

With median follow-up of 40 (range 8–140) months, 3-year OS was 60% (95% CI, 42–74) (Figure 2a). A total of 18 patients died and causes of death were: graft failure (n=1), infection (n=3), haemorrhage (n=2), GvHD (n=3), relapse (n=6), multi-organ failure (n=1), acute cardiac arrest at home (n=1) and second cancer (n=1). Six patients relapsed within a median of 6 (range 41–13) months post transplantation. No patient received donor lymphocyte infusions.

Figure 2

OS (a) and relapse-free survival (b) with dashed lines representing point-wise 95% confidence intervals, and cumulative incidence of non-relapse deaths (treatment-related mortality) and relapses (c).

The 3-year RFS and NRM rates were 54% (95% CI 37–59) and 30% (95% CI, 30–45), respectively, and are shown in Figures 2b and c.

According to statistical analysis, risk factors for RFS and NRM were pretransplant thrombocytopenia, previous transfusion and R-CMV+/D-CMV CMV status (Table 2).

Table 2 Univariable analysis of relapse-free survival and non-relapse mortality rates at 3 years


Here, we describe the outcomes of 39 myelofibrosis patients who underwent allogeneic HSCT in four French centres. Our 60% OS is encouraging in this disease that has no other known curative treatment. Risk factors for OS identified in this cohort were thrombocytopenia and CMV-positive recipient receiving CMV-negative transplant. Most deaths were attributed to transplantation.

This study is limited by its small size, decreasing potential power of statistical analysis and the retrospective collection of data leading to: (1) some missing data, that is, blast cell numbers at the time of transplantation, spleen size, Karnofsky score and ferritinemia (2) heterogeneity of patients and conditioning regimen because of different local policy through periods and centres (3) heterogeneity of follow-up, including BM and chimerism analysis, which were not systematically and regularly performed underestimating relapse incidence and late mixed chimerims.

In our population, primary engraftment despite myelofibrosis occurred in all but 1 patient. All but 2 patients alive at 3 months and tested for blood chimerism were 100% donor. Neutrophil engraftment was better with RIC, PBSC source uses and pretransplant splenectomy. Patients who underwent pretransplant splenectomy had shorter periods of aplasia but no significant survival improvement. The risk of AML transformation in splenectomized patients, reported by others16, 17 was not observed in these patients who underwent transplantation a few months after splenectomy. OS was in accordance with recently published findings and better than that reported by the GITMO.17, 18

RIC regimens have engendered much enthusiasm, achieving lower NRM rates and advantages for older patients or those with more comorbidities, but our patients given RIC did not benefit from lower NRM or OS rates. Moreover, Kerbauy8 showed that some myeloablative conditioning regimens, including targeted BU and CY, were well tolerated and seemed to give better results than other kinds of regimens (reduced or not). Patients receiving RIC or myeloablative conditioning were not comparable, but their similar OS rates regularly observed despite their different ages and morbidities are encouraging. To date, no data have been published comparing RIC and myeloablative conditioning in myelofibrosis or in other myeloid diseases.

CMV status and thrombocytopenia were significantly and independently associated with RFS. In contrast to others,17 the Lille prognosis score did not predict outcome for our patients, but a lack of statistical power can be evoked in this small cohort. The new international prognosis scoring system is very relevant to classify patients at diagnosis5 or during disease evolution19 but no data exist after HSCT. In Passamonti study, only 8 patients among 525 received a HSCT during their evolution.19 Our study was initially not designed to calculate this score and some data, including blastosis or general symptoms are missing.

Pretransplantation thrombocytopenia increased the risk of death. This observation was previously reported by other teams.8, 16, 20 CMV couple status was also prognostic, D-CMV/R-CMV+ which has been already reported at higher risk of mortality, attributed not only to CMV reactivation but also to bacterial or fungal infections, reflecting an immune defect associated with CMV or its treatment.21

RFS was poorer in patients with pretransplantation AML transformation but remains acceptable around 40%. Even though these patients were probably selected among those who were younger and without severe comorbidities, this finding should be highlighted and AML transformation should not be systematically considered as a contraindication for transplantation. Indeed, no efficient alternative treatment exists for these patients and life expectancy is less than a few months without HSCT.6

The results of this multicentric retrospective study confirmed the curative ability of HSCT for 50% of myelofibrosis patients. Encouraging results were obtained, even for patients with advanced disease, some comorbidities or those whose transplants came from unrelated donors.


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Correspondence to M Robin.

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Lissandre, S., Bay, J., Cahn, J. et al. Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis. Bone Marrow Transplant 46, 557–561 (2011) doi:10.1038/bmt.2010.276

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  • myelofibrosis
  • allogeneic haematopoietic stem-cell transplantation
  • JAK2-V617F mutation
  • CMV
  • GvHD

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