Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2984-2987
CORRESPONDENCE
Questions Raised by the Benelux CML Study Group: Results From the
Randomized Study With Hydroxyurea Alone Versus Hydroxyurea Combined
With Low-Dose Interferon-
2b for Chronic Myeloid Leukemia
 |
LETTER |
To the Editor:
The recently reported Benelux study1 raised several issues,
some of them regarding current and future investigational studies in
chronic myeloid leukemia (CML).
Dose-intensity schedule of interferon-
(IFN-A)
therapy and outcome.
Our studies and several others,2-10 including a randomized
study by Alimena et al,4 have confirmed the association
between IFN-A dose schedule and response (Table
1). The Cancer and Leukemia Group B
(CALGB) study9 was also initiated at a lower dose schedule of IFN-A at 2 MU 5 times per week, which was abandoned after the first
16 patients on study because of low response rates in favor of a higher
dose schedule. There has also been an association between the IFN-A
dose delivered and response (Table
2).2,4,11-14 Our studies
using the maximally tolerated individual IFN-A dose have shown better
rates of cytogenetic response than studies delivering lower dose
schedules, even after accounting for the risk group distribution (Table
3).3
Despite these data, and relying on the results from a small study in 27 patients in early chronic phase,10 in which the investigators concluded that lower dose schedules were as effective as
higher dose schedules, many investigators adopted the lower dose
schedules of IFN-A, perhaps understandably, because they are less toxic
and less expensive. When the results with the lower dose schedules were
found to be less effective, as in the Benelux study, they concluded
that IFN-A, and not low-dose IFN-A (which was emphasized in the title,
but not in the Discussion), may not be effective. The Benelux study, in
our opinion, confirms what has already been well-known, ie, that
low-dose IFN-A schedules increase the cost and toxicity of therapy
without providing benefit. The benefit of IFN-A therapy is primarily
observed in patients who achieve a major cytogenetic response. If this
rate is reasonable, a survival benefit would be possibly reflected in
the total study group. Otherwise, it may not be, but would be observed
only among patients achieving a cytogenetic response. Predictably, with
a complete cytogenetic response of 9% and a partial cytogenetic response of 7% (major cytogenetic response, 16%) with IFN-A, a survival advantage was observed only among patients who obtained a
cytogenetic response (Fig 5 in the report by The Benelux CML Study
Group1).
Although it may be reasonable to conduct further randomized trials of
lower versus higher IFN-A dose schedules in CML, investigators reporting on lack of IFN-A efficacy, as in the Benelux study, should
emphasize that the study results apply only to low-dose IFN-A
schedules, not to IFN-A therapy in general. In studies combining IFN-A
with low-dose cytosine arabinoside (ara-C) or homoharringtonine (HHT),
in which myelosuppression may limit dose delivery, the outcome may be
less dependent on IFN-A dose intensity but more related to the
incidence and degree of the targeted endpoint, namely the rate of
significant and durable suppression of the Philadelphia chromosome
(Ph)-positive clones.
Intended study design versus treatment actually delivered.
The study intended to accrue 100 patients in each treatment group (200 total). However, 24 patients (25%) discontinued IFN-A for
side-effects, 8 (8%) for other reasons, and 16 (17%) to undergo transplant in chronic phase. The median treatment time on study was 25 months. Thus, the investigators were left with about only half of the
IFN-A study group (52 patients) whom they were treating with a low-dose
IFN-A schedule (3 MU 5 times per week; 2.2 MU daily) and still expected
to observe a benefit, a difficult proposition at best. To further
confound the results, 10 of 95 patients in the hydroxyurea arm were
switched to IFN-A therapy, 14 were taken off for other reasons, and 7 underwent transplant, leaving 64 patients to be evaluated for hydrea
therapy.
A similar problem of intended versus delivered therapy was also
discussed in the German trial,15 which concluded that a beneficial effect of IFN-A therapy would have been observed if patients
who actually received IFN-A therapy were analyzed. After all, it is
only logical to assume that, if there is any benefit to be expected
from a particular therapy, the treatment should actually be
administered to the patient.
Study design and statistical considerations.
With the small number of patients projected to be entered on study and
the expectation that a particular proportion (based on the
investigators' historical experience) may not be able to receive the
intended therapy, the study design must have assumed that a large
difference in outcome had been anticipated between the low-dose IFN-A
arm and the control arm. This may often not be the case. The recently
published study of Guilhot et al16 was able to detect a
small but significant difference in survival outcome with the addition
of low-dose ara-C to IFN-A (3-year survival rate of 86% with IFN-A
plus ara-C v 79% with IFN-A alone; P = .02) only
because of the large number of patients treated (~700 patients). Thus, future randomized studies should clearly delineate the
statistical design and the expectations (which should be reasonable)
and empower the study with enough patient numbers to answer the
questions posed.
The updated results of the Medical Research Council (MRC) Study.
The investigators quoted an earlier,17 but not a
subsequent18 update of the MRC study to support their
suggestion that low-dose IFN-A therapy is not superior to hydroxyurea
therapy. In fact, the subsequent update18 reports a
superior survival with IFN-A versus hydroxyurea therapy
(P = .05), whereas no difference in outcome was observed with
hydroxyurea versus busulfan therapy. Thus, the Italian and update MRC
trials show an advantage of IFN-A therapy over
hydroxyurea,11,18 as do the metaanalysis
results19 and even the German trial15 when
patients actually treated with IFN-A therapy were analyzed.
In summary, the present Benelux study, using a low-dose IFN-A schedule
in a small number of patients treated, can only conclude that the
benefit was not observed within the limitations of their particular
study. This has been observed in many studies of various treatments in
different cancers, in which contradictory studies are often explained
by different treatment schedules, suboptimal treatment deliveries, a
small number of patients, and unachievable statistical considerations.
The results of the Benelux study cannot be considered as representing
the relative benefit of IFN-A therapy in CML.
Hagop
M. Kantarjian
Moshe Talpaz
Departments of Leukemia and
Bioimmunotherapy
University of Texas M.D. Anderson Cancer
Center
Houston, TX
| |
REFERENCES |
1.
The Benelux CML Study Group:
Randomized study on hydroxyurea alone versus hydroxyurea combined with lose-dose interferon-2b for chronic myeloid leukemia.
Blood
91:2713,
1998[Abstract/Free Full Text]
2.
Kantarjian HM,
Smith TL,
O'Brien S,
Beran M,
Pierce S,
Talpaz M,
the Leukemia Service:
Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon- therapy.
Ann Intern Med
122:254,
1995[Abstract/Free Full Text]
3.
Kantarjian HM,
O'Brien S,
Anderlini P,
Talpaz M:
Treatment of chronic myelogenous leukemia: Current status and investigational options.
Blood
87:3069,
1996[Free Full Text]
4.
Alimena G,
Morra E,
Lazzarino M,
Liberati AM,
Montefusco E,
Inverardi D,
Bernasconi P,
Mancini M,
Donti E,
Grignani F,
Bernasconi C,
Dianzani F,
Mandelli F:
Interferon alpha-2b as therapy for Ph
-positive chronic myelogenous leukemia: A study of 82 patients treated with intermittent or daily administration.
Blood
72:642,
1988[Abstract/Free Full Text]
5.
Anger B,
Porzsolt F,
Leichtle R,
:
A phase I/II study of recombinant interferon alpha 2a and hydroxyurea for chronic myelocytic leukemia.
Blut
58:275,
1989[Medline]
[Order article via Infotrieve]
6.
Freund M,
von Wussow P,
Diedrich H,
:
Recombinant human interferon alpha-2b in chronic myelogenous leukaemia: Dose dependency of response and frequency of neutralizing anti-interferon antibodies.
Br J Haematol
72:350,
1989[Medline]
[Order article via Infotrieve]
7.
Gastl G,
Aulitzky Q,
Tilg H,
Huber H,
Hausmaninger H,
Seewann HL,
Coser C,
Prinoth P,
Huber C:
Dose related effectiveness of alpha interferon in chronic myelogenous leukemia.
Blut
54:251,
1987[Medline]
[Order article via Infotrieve]
8.
Thaler J,
Gastl G,
Fluckinger T,
Niederwieser D,
Huber H,
Seewann H,
Sill H,
Lang A,
Falk M,
Duba C,
Utermann G,
Kuhr T,
Aulitzky W,
Huber D,
Austrian Biological Response Modifier (BRM) Study Group:
Interferon alpha-2c therapy of patients with chronic myelogenous leukemia: Long-term results of a multicenter phase-II study.
Ann Hematol
72:349,
1996[Medline]
[Order article via Infotrieve]
9.
Ozer H,
George SL,
Schiffer CA,
Rao K,
Rao PN,
Wurster-Hill DH,
Arthur DD,
Powell B,
Gottlieb A,
Peterson BA,
Rai K,
Testa JR,
LeBeau M,
Tantravahi R,
Bloomfield CD:
Prolonged subcutaneous administration of recombinant 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival: Cancer and Leukemia Group B Study 8583.
Blood
82:2975,
1993[Abstract/Free Full Text]
10.
Schofield J,
Robinson WA,
Murphy JR,
Rovira DK:
Low doses of interferon- are as effective as higher doses in inducing remissions and prolonging survival in chronic myeloid leukemia.
Ann Intern Med
121:736,
1994[Abstract/Free Full Text]
11.
The Italian Cooperative Study Group on Chronic Myeloid Leukemia:
Inteferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia.
N Engl J Med
330:820,
1994[Abstract/Free Full Text]
12.
Allan NC,
Richards SM,
Shepherd PCA:
UK Medical Research Council randomised, multicentre trial of interferon-nl for chronic myeloid leukaemia: Improved survival irrespective of cytogenetic response.
Lancet
345:1392,
1995[Medline]
[Order article via Infotrieve]
13.
Hehlmann R,
Heimpel H,
Hasford J,
Kolb HJ,
Pralle H,
Hossfeld DK,
Queisser W,
Loffler H,
Hochhaus A,
Heinze B,
Georgii A,
Bartram CR,
Griesshammer M,
Bergmann L,
Essers U,
Falge C,
Queisser U,
Meyer P,
Schmitz N,
Eimermacher H,
Walther F,
Fett W,
Kleeberg UR,
Kabisch A:
Randomized comparison of interferon- with busulfan and hydroxyurea in chronic myelogenous leukemia.
Blood
84:4064,
1994[Abstract/Free Full Text]
14.
Mahon F,
Montastruc M,
Faberes C,
Reiffers J:
Predicting complete cytogenetic response in chronic myelogenous leukemia patients treated in chronic myelogenous leukemia patients treated with recombinant interferon-.
Blood
84:3592,
1994[Free Full Text]
15.
Ansari H,
Hasford J,
Hehlmann R,
the German CML Study Group:
Fallacies of the intention-to-treat analysis.
J Mol Med
75:B243,
1997(abstr 297)
16.
Guilhot F,
Chastang C,
Michallet M,
Guerci A,
Harousseau JL,
Maloisel F,
Bouabdallah R,
Guyotat D,
Cheron N,
Nicolini F,
Abgrall JF,
Tanzer J:
Interferon alpha2b (IFN) and cytarabine (Ara-C) increase survival and cytogenetic response in chronic myeloid leukemia (CML). Results of a randomized trial.
N Engl J Med
337:223,
1997[Abstract/Free Full Text]
17.
Shepherd PCA,
Richards SM,
Allan NC:
Progress with interferon in CML
Results of the MRC UK CML III study.
Bone Marrow Transplant
17:S15,
1996(suppl 3)
18.
Allan NC,
Richards SM,
Shepherd PCA:
Interferon- therapy with busulphan or hydroxyurea compared with either BU or HU alone in treatment of chronic phase CML. Results from MRC CML III trial.
Int J Hematol
64:S68,
1996(abstr 258, suppl 1)
19.
CML Trialists' Collaborative Group:
Inteferon alfa versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials.
J Nat Cancer Inst
89:1616,
1997[Abstract/Free Full Text]
| |
RESPONSE |
We thank Drs Kantarjian and Talpaz for their extensive comments on our
report.1 Above all, we would like to underline that we did
not compare low-dose IFN- with hydroxyurea. Instead, as outlined in
the title of the manuscript, our study compared low-dose IFN plus
hydroxyurea with hydroxyurea alone. From the remarks made by the MD
Anderson Cancer Center, it again becomes clear that only randomized
trials analyzed on an intention to treat basis provide the best way to
evaluate the benefit of a therapy.2,3
Dose intensity of IFN- and risk profile.
Drs Kantarjian and Talpaz say that the interferon dose in the Benelux
study was ineffective. They appear to ignore the data presented in
Table 4 of our report. Thus, the major/complete cytogenetic response
rate to IFN therapy was 16% in the low-dose Benelux randomized trial
and 19% in the high-dose Italian trial,4 the difference being predictable on the basis of the lower percentage high-risk Sokal
patients in the Italian trial. We do not accept that the lower dose
schedules increase cost and toxicity without benefit; rather, they
diminish cost and toxicity while achieving benefit equivalent to that
seen in high-dose randomized, multicenter trials.
As was extensively discussed by us, it is still not known which dose of
IFN is required to obtain the best results in CML. Of note, all studies
cited in Table 1 of the MDACC letter are either nonrandomized or very
small. Although Drs Kantarjian and Talpaz always stated that "more
is better," their Table 2 illustrates quite the opposite: the
cytogenetic responses and survival duration do not differ between the
multicenter studies that used high doses and those that applied much
lower doses. Moreover, tables such as this should be accompanied by
risk profiles, because these correlate very well with survival:
patients with a low Sokal risk score having a median survival of 96 months5 and with the new IFN-based prognostic
score5 also 96 months. The percentage of patients with a
low Sokal risk score in the MDACC was 52%, versus 23% to 29% in the
studies from Germany, Great Britain, and the Benelux. Therefore, the
superior results obtained by both single-center institutions (the MDACC
and the Bordeaux group represented by the letter by Mahon et
al6) illustrate that a careful selection of patients with
a low Sokal risk profile, who tolerate high doses of IFN for a long
time, in a treatment setting offered by experienced hematologists, can
produce apparently excellent results for CML patients. There is only
one approach that will give a definitive answer to the vexed question
of the best dose. To this end, two multicenter randomized
dose-comparing studies are underway (Dutch HOVON 20 and British MRC
CML-V). The results from these trials will finally show whether the
maximally tolerated dose approach or the low-dose approach provides the
best results for the patient when costs, quality of life, and survival
are all taken into account.
Statistical considerations.
Drs Kantarjian and Talpaz recalculated the Benelux results by leaving
out all patients who went off study because of side effects or bone
marrow transplantation, which in our opinion evidently will bias the
outcome of any study.2,3 Randomized clinical trials should
always be analyzed using an intention-to-treat approach, because
discontinuation of therapy is not a random event. The percentages of
patients going off protocol in the Benelux study seem high, but are in
line with other important studies. In the Italian study,4
42% of the patients assigned to IFN therapy discontinued therapy for
reasons similar to our patients. In the recently published French
study,7 these percentages were even higher: 50%
discontinued therapy in the interferon-cytarabine arm; 28% did so
already during the first 6 months.
The Benelux Study was designed in 1986, assuming to detect a 20%
improvement from 50% to 70% for a 3-year median freedom from progression. We agree this assumption would nowadays be considered as
too optimistic and that future randomized studies using IFN in CML
generally will require many more patients than in the past, because the
expected difference between experimental arms generally will not exceed
a 10% improvement in survival.
MRC III results.
In an abstract published in 1996,8 a borderline
significance was seen in favor of IFN versus hydroxyurea. However, a
full report published in the same year showed a loss of
significance.9 A more recent update shown at the 6th
Meeting of the European Investigators on CML and IFN (Uppsala, Sweden,
June 1998) confirmed that there still is a clear trend in favor of IFN,
but that this was again not significant
(P = .08; Dr N.C. Allan and Dr S.M. Richards,
personal communication).
Concluding remarks.
As shown in the meta-analysis,10 IFN- therapy for newly
diagnosed CML patients offers a 13% survival advantage at 5 years when
compared with chemotherapy alone. The low dose IFN- + hydroxyurea results of the Benelux study are in line with the results from three
other randomized trials as far as hematologic responses, cytogenetic
responses, and median survival are concerned.6,8,11 What is
remarkable about the Benelux data is that the group treated with
hydroxyurea did so well. In addition, the Benelux study suggests that
hydroxyurea alone, administered at a dose aiming at strict control of
the white blood cell counts, can result comparatively in a very good
median survival of 68 months. A joint analysis of all
hydroxyurea-treated patients in the Benelux study, Italian study,4 and German trial11 will be undertaken
to see whether the Benelux results obtained by hydroxyurea are indeed
better, and if so, to find explanations. Because the median age of CML patients is around 60 years, insight may be obtained from that analysis
and may help those (frequently elderly) patients who do not tolerate
IFN.
J.C. Kluin-Nelemans
Department of
Hematology
Leiden University Medical Center
Leiden, The
Netherlands
A. Delannoy
Department of Hematology
Jolimont
Hospital
Haine-Saint-Paul, Belgium
A. Louwagie
Department
of Hematology
University Hospital St. Jan
Brugge, Belgium
On
Behalf of the Benelux CML Study Group
| |
REFERENCES |
1.
CML Benelux study group:
Randomized study on hydroxyurea alone versus hydroxyurea combined with low dose interferon-alpha 2b for chronic myeloid leukemia.
Blood
91:2713,
1998
2.
Peto R,
Pike MC,
Armitage P,
Breslow NE,
Cox DR,
Howard SV,
Mantel N,
McPherson K,
Peto J,
Smith PG:
Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design.
Br J Cancer
34:585,
1976[Medline]
[Order article via Infotrieve]
3.
Peto R,
Pike MC,
Armitage P,
Breslow NE,
Cox DR,
Howard SV,
Mantel N,
McPherson K,
Peto J,
Smith PG:
Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples.
Br J Cancer
35:1,
1977[Medline]
[Order article via Infotrieve]
4.
The Italian Cooperative Study Group on Chronic Myeloid Leukemia:
Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia.
N Engl J Med
330:820,
1994
5.
Hasford J,
Pfirrmann M,
Hehlmann R,
Allan NC,
Kluin-Nelemans JC,
Alimena G,
Steegmann JL,
Ansari H:
A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa.
J Nat Cancer Inst
90:850,
1998[Abstract/Free Full Text]
6.
Mahon F,
Montastruc M,
Faberes C,
Reiffers J:
Predicting complete cytogenetic response in chronic myelogenous leukemia patients treated in chronic myelogenous leukemia patients treated with recombinant interferon-.
Blood
84:3592,
1994
7.
Guilhot F,
Chastang C,
Michallet M,
Guerci A,
Harousseau JL,
Maloisel F,
Bouabdallah R,
Guyotat D,
Cheron N,
Nicolini F,
Abgrall JF,
Tanzer J:
Interferon alpha2b (IFN) and cytarabine (Ara-C) increase survival and cytogenetic response in chronic myeloid leukemia (CML). Results of a randomized trial.
N Engl J Med
337:223,
1997
8.
Allan NC,
Richards SM,
Shepherd PCA:
Interferon- therapy with busulphan or hydroxyurea compared with either BU or HU alone in treatment of chronic phase CML. Results from the MRC III trial.
Int J Hematol
64:S68,
1996(abstr 258, suppl 1)
9.
Shepherd PCA,
Richards SM,
Allan NC:
Progress with interferon in CMLResults of the MRC UK CML III study.
Bone Marrow Transplant
17:S15,
1996(suppl 3)
10.
CML Trialists' Collaborative Group:
Interferon alfa versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials.
J Natl Cancer Inst
89:1616,
1997
11.
Hehlmann R,
Heimpel H,
Hasford J,
Kolb HJ,
Pralle H,
Hossfeld DK,
Queisser W,
Löffler H,
Hochhaus A,
Heinze B,
Georgii A,
Bartram CR,
Griesshammer M,
Bergmann L,
Essers U,
Falge C,
Queisser U,
Meyer P,
Schmitz N,
Eimermacher H,
Walther F,
Fett W,
Kleeberg UR,
Käbisch A:
Randomized comparison of interferon- with busulfan and hydroxyurea in chronic myelogenous leukemia.
Blood
84:4064,
1994
