1. health and fitness
2. therapy

RAPID COMMUNICATION
A New Treatment for Polycythemia Vera: Recombinant Interferon alfa
By Richard T. Silver
Recombinantinterferon alfa, a natural product with growth
inhibitory capabilities, has been demonstrated for the first
time to have significant therapeutic efficacy in controlling
the red cell mass in patients with the myeloproliferative
disease polycythemia vera. The starting dose was 3.0 x
lo6 U three times a week, subcutaneously (SC). In three
patients the dose required was 5.0 x lo6. U five times a
week, SC. Side effects were easily tolerated. The striking
advantage in the use of this drug is its presumed absence of
antileukemic effect. Further evaluation is necessary, but
the initial responsesare encouraging.
0 1990 by The American Society of Hematology.
P
by Lin et a1’ indicate that interferon alfa antagonizes the
action of PDGF by interfering with the activation of GO cells
for G1 traverse and S phase entry. The important clinical
implication of these observations is that interferon alfa may
control the proliferative aspects of polycythemia vera and
inhibit the development of myelofibrosis, a consequence of
the natural history of the disease. The fact that interferon
alfa is not leukemogenic adds significant attraction to its
proposed use.
The effectiveness of r I F N a was briefly noted after the
successful treatment of three patients with polycythemia
In this report, follow-up of the first three patients is
extended to approximately 3 years, and two additional
patients have been included.
OLYCYTHEMIA VERA is a disease of long duration
and varied complications in which several species of
hematopoietic cells are involved simultaneously or sequentially in the proliferative process. Although most hematologists believe that survival is increased and complications are
reduced in treated as compared with untreated patients,
conflicting opinions regarding optimum therapy are still held
by various investigators. Phlebotomy alone as the sole form
of therapy is advocated by those who believe that the major
causes of morbidity and mortality in polycythemia vera will
be prevented by correcting the increased red cell mass and
blood volume. However, phlebotomy has its risks in the
elderly patient and may produce thrombocytosis leading to
thrombosis. Others endorse myelosuppressive therapy, citing
the additional beneficial effects of these agents on thrombocytosis, leukocytosis, hyperuricemia, and hepatosplenomegaly.
Unfortunately and importantly, these drugs may be leukemogenic.
Because of the slow but, nevertheless, progressive nature of
polycythemia vera (even in patients treated with phlebotomy
only) and in an attempt to avoid the leukomegenic effects of
either P3*or chemotherapy (particularly in younger individuals), alternative treatment modalities have been constantly
sought. Recombinant interferon alfa (rIFNa) is a biologic
response modifier. It has had demonstrated myelosuppressive
activity that has been used in the treatment of chronic
myeloid leukemia by’.2 and others. It has had demonstrated
effectiveness in treating elevated platelet counts in patients
with chronic myeloid l e ~ k e m i a ,polycythemia
~
vera: and
essential thr~mbocythemia.’.~
Platelet-derived growth factor
(PDGF) initiates proliferation of fibroblasts. Recent studies
From the Division of Hematology/Oncology. The New York
Hospital-Cornell Medical Center, New York, NY.
Submitted April 2, 1990: accepted May 16,1990.
Supported by grants from the Cancer Research and Treatment
Fund, Inc, United Leukemia Fund, and the Audrey Lippman Cancer
Research Fund.
Presented in part at the 30th Annual Meeting of the American
Society of Hematology, December 5,1988, San Antonio, TX.
Address reprint requests to Richard T. Silver, MD, Division of
Hematology/Oncology, The New York Hospital-Cornell Medical
Center, 525 E 68th Si, New York, N Y 10021.
The publication costs ofthis arficle were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C.section 1734 solely to
indicate this fact.
0 I990 by The American Society of Hematology.
0006-4971/90/7604-002583.00/0
664
RESULTS
After receiving written informed consent, five patients
previously treated with phlebotomies only for control of their
disease were treated with rIFNa. The age, sex, year of
diagnosis, and average number of phlebotomies per year
before the institution of r I F N a for each patient are shown in
Table 1. There were three women and two men whose ages
ranged from 46 to 64 years. Although the duration of the
disease differed, the activity of the disease was essentially the
same for four patients, since the numbers of phlebotomies per
year were nearly the same (Table 1). The fifth patient
required 12 phlebotomies in the 5 months before the initiation of rIFNa.
Values of the red blood cell, white blood cell, and platelet
counts, hematocrit, and spleen size at diagnosis and median
counts during phlebotomy and 1 year after r I F N a are shown
in Table 2.
The starting dose was 3.0 x lo6 U three times per week,
SC. Since good control of disease occurred in two patients, it
was possible after 4 months to reduce gradually the dose of
r I F N a to 1.0 x lo6 U and then to 0.45 x lo6 U three times
per week, and, finally to discontinue it after 2 months. In both
patients, the hematocrit slowly rose, and rIFNa was restarted after 4 months and maintained at a dose of 0.5 x lo6
U twice a week. In the next three patients, the starting dose
of 3.0 x lo6 U three times per week was inadequate; it was
subsequently escalated to 5.0 x lo6 U five times per week,
and remission was induced within 4 months. After the
hematocrit fell to 45.0% or lower, the maintenance dose
ranged between 3.0 and 5.0 x lo6 U, three to five times per
week. Patient 3 required phlebotomies during the first 6
months after r I F N a was started (Table 1). His dose has
remained a t 3.0 x lo6 U, three times per week. Patient 4
B/ood, Vol 76, No 4 (August 15). 1990: pp 664-665
POLYCYTHEMIA VERA AND R I F N ~
665
Table 1. Results of Patients With Polycythemia Vera Treated With rlFNa-2b
Ptn. No.
Year of
Diagnosis
AaeISex
Average No.
Phlebotomies/yr
Before rlFNa-Zb
1970
1983
1983
1986
1988
64lF
52lM
46lM
55/F
46/F
3.4
5.5
4.5
6.0
12.0t
No. Phlebotomies
While on
rlFNa-2b
Duration After
rlFNa-Pb
(mod*
34
34
39
23
20
*As of 311/90,
tAfter diagnosis (1/88), patient required 12 phlebotomies in 5 months.
Table 2. Median Hematologic Findings in Five Patients With Polycythemia Vera Before and During Phlebotomy,
and After r l F N a 9 b Therapy
RBC lx lo6/&)
PLT I x 1O'lpl)
WBC ( x 103/pl)
HCT (%)
SPL.
Ptn. No.
lmos duration)
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
l(34)
2(34)
3 (39)
4 (23)
5(20)
8.0
6.48
6.66
5.8
8.38
5.11
7.09
5.48
5.11
6.01
4.61
5.87
6.42
6.67
6.48
72.0
57.8
59.0
53.0
74.6
47.0
49.0
51.0
46.0
44.6
39.5
37.6
44.7
48.0
43.0
13.5
18.2
8.1
8.3
13.3
7.7
12.7
6.6
7.5
16.6
7.3
10.7
4.3
5.0
9.6
276
305
654
480
724
300
350
425
524
1,324
192
329
482
451
445
2.0
15.0
4.0
5.0
3.0
2.0
15.0
4.0
5.0
3.0
0
14.0
2.0
1.0
2.0
~
Abbreviations: RBC, red blood cell count; HCT, hematocrit level; WBC, white blood cell count; PLT, platelet count; SPL, spleen size; A, before
phlebotomy; 6, during phlebotomy; C, after rlFNa-2b therapy.
'Spleen size measured below the left costal margin in the third clavicular line.
required one phlebotomy during the first 3 months of r I F N a
therapy. Of considerable interest is the fact that the spleen
regressed in size in four patients after r I F N a whereas it had
remained the same or enlarged slightly during treatment
with phlebotomy. In the fifth patient (Patient 2) the spleen
remained unchanged in size. This was related to a previous
documented portal vein thrombosis.
The side effects of r I F N a were similar to those reported in
other studies and were dose-related. These included myalgia,
low grade fever, and muscle weakness in three of the five
patients. Virtually all symptoms were relieved with acetaminophen in the usual dose. One patient complained of dry skin.
Interval bone marrow determinations 1 year after the
institution of r I F N a indicate that the marrows have remained hypercellular with no significant change compared
with pretreatment marrows. There has been no change in
marrow reticulin or levels of serum erythropoietin.
COMMENTS
For the first time, these results clearly demonstrate the
effectiveness of r I F N a in controlling the excess red cell mass
in polycythemia vera. Red cell values were controlled within
6 months, eliminating the need for phlebotomy in all five
patients. Furthermore, as previously noted in other myeloproliferative diseases, elevated platelet counts were reduced'"
and spleen size diminished after rIFNa. In all patients, it was
possible to subsequently maintain the patient on relatively
small doses of drug.
Based on these studies, a reasonable starting dose is 3 to
5 x lo6 units SC, three to five times per week. It is possible
that subsequent patients may require more or less interferon,
depending upon response. Obviously, further follow-up is
required to determine the development, frequency, and type
of complications that may occur with long-term use of
rIFNa. The Occurrence of acute leukemia, myelofibrosis, and
cytogenetic abnormalities will be monitored carefully. In the
meantime, further evaluation of this drug in a larger number
of patients with this disease is certainly warranted.
ACKNOWLEDGMENT
The assistance of Audrey Gutfriend, BSN, and Helen Zurawinsky
in this study is gratefully acknowledged.
REFERENCES
1. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating
MJ, Gutterman JU: Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha in chronic
myelogenous leukemia. N Engl J Med 314:1065, 1986
2. Silver RT, Coleman M, Benn P, Verma R, Gutfriend A:
Interferon (rIFN-a) has activity in treating chronic myeloid leukeClin Oncol6:149, 1987
mia in rIFN-y failures. Proc Am SOC
3. Talpaz M, Maviglit G, Keating M, Walters RS,Gutterman J:
Human leukocytic interferon to control thrombocytosis in chronic
myelogenous leukemia. An Int Med 99789,1983
4. Ludwig H, Linkesch W, Gisslinger H, Fritz E, Sinzinger H,
Radaszklewicz T, Chott A, Roswitha F, Micksche M: Interferon
alfa corrects thrombocytosis in patients with myeloproliferative
disorders. Cancer Immunol Immunotherapy 25:266, 1987
5 . Giles FJ, Gray AG, Brozovic M, Singer CR, Davies SC, Yong
KL, Grant IR, Hoffbrand AU, Machin SJ, Mehta AB: Alphainterferon therapy for essential thrombocythemia. Lancet 2:70,1988
6. May D, Wandl UB, Niederle N: Treatment of essential
thrombocythemia with interferon alpha-2b. Lancet 1:96, 1989
7. Lin S, Kikuchi T, Pledger W, Tamm I: Interferon inhibits the
establishment of competence in GO/S phase transition. Science
233:356, 1986
8. Silver R T Recombinant interferon-alpha for treatment of
polycythemia vera. Lancet 2:403, 1988 (letter)
9. Silver RT: A new treatment for polycythemia vera: Recombinant interferon (rIFN) alfa-2b. Blood 72:817a, 1988 (abstr)