The World Health Organization (WHO) classification system recognizes four variants
of myelofibrosis (MF): primary (PMF), prefibrotic (pre-PMF), post-essential thrombocythemia
(post-ET MF) and post-polycythemia vera (post-PV MF).
1
Current prognostic models in PMF include the International Prognostic Scoring System
(IPSS),
2
the dynamic IPSS (DIPSS),
3
and DIPSS-plus.
4
These prognostic systems utilize up to 8 risk factors: age >65 years, hemoglobin <10 g/dl,
leukocyte count >25 × 109/l, circulating blasts ⩾1%, presence of constitutional symptoms,
unfavorable karyotype, red cell transfusion need and platelet count <100 × 109/l).
When these prognostic systems were applied to 1000 consecutive PMF patients from the
Mayo Clinic,
5
the application of DIPSS-plus resulted in median survivals of 1.7, 4.7, 8.1 and 19.2
years for high, intermediate-2, intermediate-1 and low-risk patients, respectively;
the corresponding median survivals using DIPSS were 1.5, 2.7, 6.3 and 17.5 years and
using IPSS 2, 4.6, 6.8 and 17.5 years.
The objectives of the current study were as follows: (i) to determine if the aforementioned
eight variables used in IPSS/DIPSS/DIPSS-plus are independently predictive of shortened
survival in post-PV/ET MF and (ii) to assess the performance of the IPSS, DIPSS and
DIPSS-plus risk stratification in post-PV/ET MF. Study patients were selected from
the Mayo Clinic institutional database of myeloproliferative neoplasms (MPN). Diagnoses
of ET, PV and post-ET/PV MF were according to WHO and International Working Group
for MPN research, and treatment criteria.
1, 6
Statistical analyses considered the clinical and laboratory data collected at the
time of documented disease transformation from PV to post-PV MF or from ET to post-ET
MF. Survival was calculated from the date of disease transformation to the date of
death or last contact.
A total of 125 patients with post-PV (n=79) or post-ET (n=46) MF were studied (median
age 62 years; 50% females); percentages of patients were 46% for age >65 years, 44%
for hemoglobin <10 g/dl, 19% for red cell transfusion need, 19% for leukocyte count
>25 × 10(9)/l, 14% for platelet count <100 × 10(9)/l, 45% for circulating blasts ⩾1%,
38% for constitutional symptoms and 17% for unfavorable karyotype. Risk distribution
of the 125 patients with post-PV/ET MF, according to IPSS, was high in 39 (31%) patients,
intermediate-2 in 40 (32%), intermediate-1 in 30 (24%) and low in 16 (13%); the corresponding
percentages for DIPSS were 10, 38, 38 and 13%, and for DIPSS-plus 26, 41, 21 and 12%.
Comparison of patients with post-PV and post-ET MF disclosed higher hemoglobin level
(P=0.002), higher leukocyte count (P=0.0007) and larger palpable spleen size (P=0.002)
in post-PV MF.
After a median follow-up of 3 years, from the date of fibrotic progression, 86 (69%)
deaths and 10 (8%) leukemic transformations were documented. Multivariable analysis,
which included the 5 aforementioned risk variables used in IPSS or DIPSS, disclosed
independent predictive value for shortened survival, for all but constitutional symptoms:
HR (95% CI; P-value) were 2.6 (1.6–4.2; P<0.0001) for age >65 years, 2.2 (1.4–3.5;
P=0.001) for circulating blasts ⩾1%, 1.8 (1.1–2.8; P=0.01) for hemoglobin <10 g/dl,
1.8 (1.1–3.1; P=0.02) for leukocyte count >25 × 10(9)/l and 1.2 (0.7–1.9; P=0.5) for
constitutional symptoms. Similarly, multivariable analysis that included all eight
risk variables used in DIPSS-plus disclosed significant predictive value for all except
constitutional symptoms (P=0.9) and leukocyte count >25 × 10(9)/l with borderline
significance (P=0.06).
Application of IPSS, DIPSS and DIPSS-plus, to the 125 study patients with post-ET/PV
MF is outlined in Figure 1. HR (95% CI) using IPSS were 2.3 (1.4–3.7) for high vs
intermediate-2, 4.3 (2.2–8.5) for high vs intermediate-1, 6.6 (2.9–15.3) for high
vs low, 2.9 (1.3–6.7) for intermediate-2 vs low, 1.9 (1.0–3.8) for intermediate-2
vs intermediate-1 and 1.5 (0.6–3.9) for intermediate-1 vs low; accordingly, IPSS in
this group of patients was effective in delienating high- and intermediate-2-risk
patients but was less effective in distinguishing low from intermediate-1-risk patients.
Similar analyses using DIPSS and DIPSS-plus produced similar results (Figure 1).
With the exception of constitutional symptoms, the current study confirms the prognostic
value of the eight risk variables used in IPSS, DIPSS and DIPSS-plus, in the setting
of post-PV/ET MF. The study also validates the adequate performance of the three prognostic
models in delineating high- vs intermediate-2- vs low/intermediate-1-risk patients;
the lack of significant distinction between intermediate-1- and low-risk patients,
as well as the appearance of similar survival data between intermediate-2- and intermediate-1-risk
disease (Figure 1; although significantly different), might be related to either the
small number of informative cases or the demonstrated loss of significant contribution
from constitutional symptoms.
The spirit of our observations is somewhat different than that echoed by our respected
colleagues from Italy regarding their recently published new prognostic system for
post-ET/PV MF.
7
In the particular study, the authors found constitutional symptoms to retain its significance,
along with anemia, thrombocytopenia, advanced age, circulating blasts and absence
of CALR mutations, and used these variables to devise a newly-proposed prognostic
model. Although the effort to include molecular markers is laudable, it might have
been truncated in this instance because of the absence of information on other mutations
known to affect outcome in PMF, such as ASXL1 and SRSF2.
8
On the other hand, considering the fact that virtually all patients with post-PV MF
are JAK2-mutated, one can argue the appropriateness of using driver mutational status,
as a variable for a risk model, in post-PV MF. Consistent with these reservations,
another recent study of 359 patients with post-ET/PV MF did not find a survival impact
from either the type of driver mutation or its allele burden;
9
instead, the study reported a detrimental effect of triple-negative driver mutational
status and SRSF2 mutations in post-ET MF only. From a practical standpoint, our observations
provide the evidence to support the use of IPSS/DIPSS/DIPSS-plus in post-PV/ET MF,
thus maintaining familiarity and uniformity, until a molecularly more robust system
is developed.