Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1837-1838
CORRESPONDENCE
Leukemic Transformation in Polycythemia Vera
 |
LETTER |
To the Editor:
The recent report by Najean and Rain for the French Polycythemia Study
Group1 comparing hydroxyurea with pipobroman in the
treatment of polycythemia vera (PV) makes an important contribution to
the debate about the treatment of this condition. We would like to make
some observations about the presentation of their results. This
particularly relates to their statements about the observed actuarial
risk of leukemia. The investigators chose, both in the text and the
summary, to state that for both drugs "the risk of leukemia is
approximately 10% at the 13th year." This statement may be
misleading if it is compared to other studies without presenting
confidence intervals for their observation and also appreciating that
other studies often quote an overall percentage incidence of leukemia
rather than actuarial risk. In their study approximately 27% and 15%
of the total number of patients involved remained under observation at
the 10th and 13th year, respectively. Thus, by the 13th year the number
of patients remaining was relatively small and the accuracy of the
actuarial risk of leukemia at this timepoint is likely to be suspect.
We suggest that since the number remaining at 10 years was considerably
larger, the investigators should have focused in the text and in their abstract on the actuarial risk of leukemia at that time. From their
data, this is approximately 5% and 3% for hydroxyurea and pipobroman,
respectively. This compares with the actuarial risk of leukemia at 10 years in the PVSG-01 study2 of approximately 16% and 18%
in the 32P and chlorambucil limbs, respectively. Also in
this study the estimates of risk of leukemia beyond 10 years are
unstable because of the small number of patients still at risk.
With respect to leukemia, the figure of 1.5% is often quoted as the
background incidence in those patients with PV not treated by
cytoreductive therapy. This 1.5% incidence relates to those patients
entered into the phlebotomy-only limb of the PVSG-01 study. However,
this figure of 1.5% is misleading for two reasons. First, it was not
based on an "intention to treat" basis; instead, patients
requiring cytoreductive therapy were censored from analysis. Therefore, the figure relates to a highly selected group of patients. Secondly, as Najean and Rain3 point out, the number of
patients managed by phlebotomy alone diminished rapidly over time
to
less than 50% by the 5th year and 10% by the 10th year. Thus, the
median follow-up time is significantly shorter than the other limbs of the PVSG-01 trial.
We believe that the evidence provided in these unique studies must be
precisely evaluated to permit informed discussions in the possible
leukemogenic risk of agents used in the treatment of PV.
T.C. Pearson
Department of Haematology
St Thomas'
Hospital
London, UK
A.R. Green
Department of
Haematology
MRC Centre
Cambridge, UK
J.T.
Reilly
Department of Haematology
Royal Hallamshire
Hospital
Sheffield, UK
Georgina Harrisoni on behalf of the MPD(UK) Study Group
CTSU
Radcliffe
Infirmary
Oxford, UK
| |
REFERENCES |
1.
Najean Y,
Rain J-D:
Treatment of polycythemia vera: The use of hydroxyurea and pipobroman in 292 patients under the age or 65 years.
Blood
90:3370,
1997[Abstract/Free Full Text]
2.
Goldberg JD:
Treatment of polycythemia vera: A summary of clinical trials conducted by the Polycythemia Vera Study Group
, in Wasserman LR,
Berk PD,
Berlin NI
(eds):
Polycythemia Vera and the Myeloproliferative Disorders.
Philadelphia, PA, Saunders
, 1995
, p 166
3.
Najean Y,
Rain J-D:
A very long-term evolution of polycythemia vera: An analysis of 318 patients initially treated by phlebotomy or 32P between 1969 and 1981.
Semin Hematol
34:6,
1997[Medline]
[Order article via Infotrieve]
| |
RESPONSE |
I have read with interest the letter of my friend Prof Pearson. I am
not a biostatistician and I am not sure to have well understood his
argument. Why so sharp a criticism of the actuarial method for
calculating the risks of complications and of death in a therapy
protocol?
If we consider, for instance, the arm hydroxy-urea of our protocol of
treatment of polycythemia, we observed six cases of leukemia,
occurring at 4, 6, 7, 10, 10.5, and 11 years. It would be illogical to
calculate the risk of leukemia from the number of events reported to
the number of patients who did enter the protocol (136), since some of
them have been treated for only a few months or years. Such a
calculation would show a risk of leukemia of only 4.4%. I know that
some investigators have published results with this type of
calculation, but in my opinion, they are wrong. The actuarial method
assigns each event to the number of living cases, treated and followed
at the time of each event (95 cases at the 4th year, but only 39 at the
11th year). From the present data, we find a 10.8% risk, not the
previous 4.4%.
I agree with Prof Pearson that there is an uncertainty when the number
of cases is low. For instance, in the pipobroman arm, we did observe
two cases of myelodysplasia at 3.5 and 4.5 years (respectively, 69 and
54 patients at risk), but the following cases of leukemia did occur at
the 12th and 13th years (only 12 and 8 patients are then at risk). In
this case, we clearly need a longer follow-up to give precise data
beyond the 10th year. However, our results show that, at least for the
first 10 years, the risk of leukemia in the pipobroman branch is not
higher, and perhaps even lower, than that observed in the hydroxyurea
branch.
The same method has been used for analyzing the risk of other
complications, vascular events, carcinomas, myelofibrosis, and death.
It has been also used for the 32P branch of our protocol.
Why does Prof Pearson not criticize these data?
On the contrary, I agree with Prof Pearson's other criticism. If, in
fact, some patients with a particular risk are precociously excluded
from a therapy protocol, the calculation of this risk for the whole
population will be wrong. That was the case in the phlebotomy branch of
the P.V.S.G. protocol, where the oldest and those with vascular risk
factors or thrombocytosis have been excluded and treated otherwise. So,
the true risk of leukemia could be under-estimated. But this is
not a criticism of the method of calculation; this a criticism of the
design, or of the fulfilment, of the protocol.
Yves Najean
Hôpital Saint-Louis
Paris,
France
