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1205
Long Term Treatment of Myeloproliferative Disease
with Interferon-a-2b
Feasibility and Efficacy
Harriet S. Gilbert,
M.D.
Albert Einstein College of Medicine, Bronx, New
York.
BACKGROUND. Recombinant interferon-a-2b (rIFN-a-2b) has shown therapeutic
potential in patients with chronic myelogenous leukemia and other myeloproliferative disorders (MPDs), including the ability to suppress the abnormal hematopoietic clone and to reverse myelofibrosis. This study was conducted to evaluate
further the efficacy and safety of rIFN-a-2b in a large group of patients with
polycythemia vera, essential thrombocythemia, or agnogenic myeloid metaplasia
and to determine maintenance of response after treatment discontinuation.
METHODS. Induction therapy began with subcutaneous rIFN-a-2b at 5.0 3 106
IU/day until a complete or partial response was achieved. Treatment continued at
2.5 3 106 IU/day until spleen size and hematologic parameters stabilized.
RESULTS. Fifty-four patients were studied (median follow-up, 7.3 years); at last
follow-up 27 patients still were participating (median follow-up, 3.8 years). Twenty-four of 24 patients with thrombocythemia (100%) and 14 of 14 patients with
hyperleukocytosis (100%) responded to induction therapy, whereas 26 of 39 patients (67%) experienced . 10% decrease in splenomegaly. Thirty-nine of 54
patients (72%) maintained response for a median of 39 weeks after withdrawal of
rIFN-a-2b; repeat courses in previously responding patients produced similar
results. The survival rate at 8 years was 60%. rIFN-a-2b generally was well tolerated,
but toxicity caused treatment withdrawal in 7 patients (13%).
CONCLUSIONS. rIFN-a-2b can produce regression of splenomegaly and control of
leukocyte and platelet counts in patients with MPD. These responses are sustained
for prolonged periods in some patients after therapy discontinuation. In patients
with recurrent disease, disease control can be attained again with reinitiation of
rIFN-a-2b. Therefore this therapy should be an important treatment consideration
for patients with MPD. Cancer 1998;83:1205–13.
© 1998 American Cancer Society.
KEYWORDS: interferon, myeloproliferative disease, long term efficacy, therapy.
Preliminary results presented at the Annual Meeting of The American Society of Hematology, Seattle, Washington, December 1–5, 1995.
Supported by a research grant from Schering Corporation, Kenilworth, New Jersey.
Address for reprints: Harriet S. Gilbert, M.D., Albert
Einstein College of Medicine, 115 E. 72nd Street,
New York, NY 10021.
Received August 22, 1997; revision received
March 2, 1998; accepted March 23, 1998.
© 1998 American Cancer Society
C
hronic myeloproliferative disorders (MPDs) result from monoclonal expansion of abnormal pluripotent stem cells and are characterized by abnormalities in hematopoietic cellular proliferation,
quantitative and qualitative alterations in bone marrow and peripheral blood cells, and fibrosis and extramedullary expansion of the
blood-forming organ.1–10 The latter sequela is manifested by hepatosplenomegaly, which may be debilitating even before cytopenias,
varices, gastrointestinal bleeding, or ascites occur. The chronic progressive myelofibrosis and extramedullary expansion may be mediated largely by a premalignant megakaryocyte population derived
from the neoplastic clone. Hematopoietic stem cells exhibit nonrandom chromosomal abnormalities in 33% of patients with MPD.4 – 6
1206
CANCER September 15, 1998 / Volume 83 / Number 6
Conventional treatment for MPD has been comprised either of mechanical removal of increased
hematopoietic populations by phlebotomy, apheresis,
and splenectomy or of myelosuppression by external
beam radiation, radioactive phosphorus, alkylating
agents, and/or hydroxyurea.1–3 However, these approaches are only palliative, and the disease progresses inexorably, with debilitating abdominal organomegaly, transfusion dependency, bleeding, infection, and transformation into acute leukemia. Bone
marrow transplantation has a curative but limited potential11-13 and may not be a suitable treatment option
for many patients with MPD because of their age or
debility, or because of the absence of appropriate donors. Furthermore, there is concern regarding complications relating to the procedure, particularly the risk
of transmission of infectious disease.14
Given the inexorable course of MPD and the lack
of effective treatments, a need exists for well tolerated
therapies that can be initiated relatively early, before
debilitating visceral organomegaly or end-organ damage occur. Recombinant human interferon-a(rIFN-a),
a glycoprotein produced by genetic engineering, has
shown significant activity in a variety of hematologic
and nonhematologic conditions, including hairy cell
leukemia,15,16 chronic myelogenous leukemia,17,18
high risk melanoma, and other variants of MPD.19 –25
In the latter patients, rIFN-a gradually decreased peripheral blood counts without unpredictable cytopenias, reduced visceral organomegaly, and produced
durable, unmaintained remissions without hematologic rebound on the cessation of therapy. Recombinant IFN-a also has shown activity in reversing
myelofibrosis and suppressing the abnormal hematopoietic clone. These clinical results support the findings of in vitro studies in which several classes of IFNs
reportedly suppressed cultured human fibroblast
growth and procollagen synthesis,26 –28 as well as cultured megakaryocyte proliferation and platelet production.29
Considering its reported therapeutic potential in
MPD and its favorable safety profile,30 –32 rIFN-a-2b
was studied to evaluate further its long term efficacy in
patients with MPD and to determine the effect of
treatment discontinuation on remission maintenance.
METHODS
Patients
Males and females ages 18 – 85 years with a diagnosis
of either polycythemia rubra vera, essential thrombocythemia, or agnogenic myeloid metaplasia, established through review of the case and relevant pathology specimens, were eligible for study enrollment. Any
previous treatment for MPD must have been com-
pleted at least 2 weeks before initiation of rIFN-a-2b,
or 2 months before in the case of radioactive phosphorus. The study was approved by the Institutional
Review Board, and informed written consent for study
participation was obtained from all patients.
Exclusion criteria included evidence for evolution
into a blastic phase; a Karnofsky performance status ,
60%; New York Heart Association status $ 3; pregnancy or lactation; severe intercurrent infection or
surgery within the previous 2 weeks (unless fully recovered); serum creatinine . 2 mg/dL; serum aspartate aminotransferase, bilirubin, or prothrombin
time . 23 the upper limit of normal; platelet count ,
40 000 cells/mL; and inability to comply with the treatment program or provide informed consent. Use of
effective contraception was required for all women of
childbearing potential.
Treatment
rIFN-a-2b (INTRONt A; Schering Corporation, Kenilworth, NJ) was obtained commercially. Each dose
was prepared by reconstituting the drug with the supplied diluent, and the total dose was administered
subcutaneously (s.c.).
An induction course comprised of 5.0 3 106 IU/
day of rIFN-a-2b was administered until patients
achieved a complete or partial response. Therapy continued in the absence of Grade 3 or 4 toxicity (World
Health Organization criteria), disease progression, infection with a leukocyte count , 1000 cells/mL, or
hemorrhagic complication with a platelet count ,
20,000 cells/mL. Maintenance treatment comprised of
2.5 3 106 IU/day s.c. of rIFN-a-2b then was administered until stabilization of spleen size and hematologic
parameters was achieved. (Titration was based on myelosuppression or toxicity.) Thereafter, rIFN-a-2b was
discontinued, and patients were observed for any
signs of increased disease activity. Such an increase
was an indication for readministration of rIFN-a-2b
therapy.
The daily dose of rIFN-a-2b was modified during
both the induction and maintenance phases in the
event of myelosuppression or other toxicity. The rIFNa-2b dose was withheld in the event of Grade 3 or 4
toxicity, disease progression, infection with a leukocyte count , 1000 cells/mL, or hemorrhagic complication with a platelet count , 20,000 cells/mL.
Concomitant therapy allowed during the study
included phlebotomy to maintain a hematocrit #
45%, allopurinol, acetaminophen, antihistaminics, antiplatelet aggregating therapy, nonmyelosuppressive
medications needed to treat coexisting disease, red
blood cell or platelet transfusions, and corticosteroids
(prednisone or equivalent, not to exceed 10 mg/day).
rIFN-a-2b in Myeloproliferative Disease/Gilbert
Response Evaluation and Criteria
Prior to the initiation of rIFN-a-2b therapy, all patients
were evaluated with medical history and physical examination. The laboratory tests performed included
hematology (complete blood count with differential,
platelets, and reticulocytes), bone marrow aspirate
and biopsy, prothrombin time/partial thromboplastin
time, routine biochemistry, urinalysis, electrocardiogram, chest X-ray analysis, and technetium sulfur colloid scans of the bone marrow and liver/spleen. Total
spleen size was measured by palpation as the sum of
the vertical and horizontal span using the left costal
margin and left midclavicular line as reference points.
Patients were evaluated weekly during the first 4
weeks of induction therapy and then every other week
if they had no Grade 3 or 4 toxicities. A complete blood
count with differential and platelets were determined
at each visit, and routine serum biochemistry and
urinalysis were performed monthly. Patients were
evaluated for response to rIFN-a-2b therapy after 40
and 52 weeks of treatment. All baseline studies were
repeated at the 40-week visit; hematology, bone marrow aspirate and biopsy, serum biochemistry, and urinalysis were repeated after 52 weeks.
A complete response was defined as normalization of the complete blood count (i.e., leukocyte
count . 4000 cells/mL; absolute granulocytes . 1500
cells/mL; hemoglobin, 12–18 g/dL and/or hematocrit,
35–52%; platelet count 125,000 –500,000 cells/mL); resolution of transfusion dependency; absence of hemorrhagic and/or thrombotic events during the preceding 3 months; nonpalpable spleen; and normalization
of bone marrow histology (cellularity, 30 –50%; myeloid:erythroid precursor ratio, 2:1 to 5:1; normal morphology and maturation of all cell lines; decrease in
bone marrow fibrosis). Patients who met any one of
the following criteria were judged to have a partial
response: hemoglobin . 9 mg/dL without transfusion
support and persisting for 4 weeks in patients entered
because of anemia; platelet count, 70,000 – 800,000
cells/mL for at least 4 weeks and absence of significant
hemorrhagic and/or thrombotic events for at least 3
months before assessment in patients enrolled because of thrombocytosis and/or a disorder of hemostasis; and $ 35% reduction in spleen size for patients
enrolled because of symptomatic splenomegaly.
Patients were divided into eight diagnostic
groups—agnogenic myeloid metaplasia (AMM), postpolycythemia vera myeloid metaplasia (PPV-MM),
postessential thrombocythemia myeloid metaplasia
(PET-MM), active polycythemia vera with myeloid
metaplasia (PV-MM), essential thrombocythemia
(ET), polycythemia rubra vera (PV), atypical myelo-
1207
TABLE 1
Diagnostic Criteria
Diagnosis
Clinical criteria
AMM
Leukoerythroblastic peripheral smear (immature
granulocytes, nucleated RBCs, dacryocytes)
Increased reticulin and/or collagen on bone marrow biopsy
Splenomegaly by physical or radiologic examination
Absence of TB, lymphoma, or other disease associated with
myelofibrosis
Elevated RBC mass by 51Cr (males, .36 mL/kg; females,
. 32 mL/kg)
Normal arterial O2 saturation .90%
Splenomegaly by physical or radiologic examination
If splenomegaly absent, patient must have 2 of following:
Leukocytosis . 12,000/mL in absence of fever or infection
Thombocytosis . 400,000/mL
Elevated leukocyte alkaline phosphatase . 100
Elevated B12 or B12 binding proteins
Platelet count . 1 3 106/mL for 3 mo
Hypercellular bone marrow with megakaryocyte hyperplasia
Hemoglobin , 16 g/dL (males), , 14 g/dL (females) with
normal RBC mass demonstrated by chromium study
Absence of iron deficiency, chronic inflammatory disease,
or second malignancy
Absence of Philadelphia chromosome
Myeloid metaplasia that evolved from PV
Increased splenomegaly
Increased bone marrow fibrosis
Stabilization of diminution of RBC mass
Leukoerythroblastosis featuring numerous teardrop
poikilocytes
Myeloid metaplasia that evolved from essential
thrombocythemia
Active PV with evidence of myeloid metaplasia
Increased proliferation and/or dysplasia of more than one
hematopoietic stem cell lineage; not classifiable under
the typical myeloproliferative diseases
Clinical and bone marrow findings indicative of acute
megakaryocytic leukemia (i.e., acute myelofibrosis) that
persists for .3 mo
PV
ET
PPV-MM
PET-MM
PV-MM
A-MPD
SM
AMM: agnogenic myeloid metaplasia; RBC: red blood cell; TB: tuberculosis; PV: polycythemia rubra
vera; ET: essential thrombocythemia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM:
postessential thrombocythemia myeloid metaplasia; A-MPD: atypical myeloproliferative disease; SM:
subacute myelofibrosis.
proliferative disorder (A-MPD), and subacute myelofibrosis (SM)— based on the diagnostic criteria established by the Polycythemia Vera Study Group.3,33
These criteria are described in Table 1.
The median durations of the induction course of
rIFN-a-2b, the second course of rIFN-a-2b therapy,
and the periods of unmaintained response were calculated for each diagnostic group. The median time
on the study protocol was calculated both for each
diagnostic group and for the entire study population.
Mean changes in leukocyte counts, platelet counts,
hematocrit levels, and spleen size also were determined by diagnostic group. In addition, response to
1208
CANCER September 15, 1998 / Volume 83 / Number 6
TABLE 2
Baseline Profile of Study Population
TABLE 3
Patient Outcomes Summary
Variable
No.
Males
Females
Median age (yrs) (range)
Diagnosis by Polycythemia Vera Study Group
AMM
PPV-MM
PET-MM
PV-MM
ET
PV
A-MPD
SM
Time from diagnosis to start of rIFN-a-2b therapy (yrs)
,1
.1 (range, 2–33)
Therapeutic indications for rIFN-a-2ba
Symptomatic splenomegaly
Thrombocythemia
Hyperleukocytosis
Portal hypertension
Previous therapy
No treatment
Chemotherapy
33
21
Percentage
60%
40%
61 (22–77)
14
6
2
17
3
8
3
1
30%
11%
4%
31%
5%
15%
5%
2%
9
45
17%
83%
39
24
14
4
72%
44%
26%
7%
25
29
46%
54%
Median time on study (yrs) (range)
All patients (n 5 54)
Active (i.e., ongoing) patients (n 5 27)
Study termination (total)
Adverse events
Intercurrent illness
Splenectomy
Progressive hematologic disease
Deaths (total)
Lost to follow-up
a
2.5 (0.12–8.1)
3.8 (0.8–7.8)
25 (46%)
7 (13%)
7 (13%)
5 (9%)
6 (11%)
22 (41%) (7.5 yearsa)
2 (4%)
Median follow-up.
rIFN-a-2b therapy was analyzed according to the indication for treatment (i.e., thrombocythemia, hyperleukocytosis, and splenomegaly).
portal hypertension (4 patients). Some patients had
more than one indication for treatment.
Patient outcomes are summarized in Table 3. The
median time on study for the entire group of 54 patients was 2.5 years (range, 0.12– 8.1 years). At last
follow-up 27 patients still were participating in the
study, with a median follow-up of 3.8 years (range,
0.8 –7.8 years). Twenty-five patients went off the study
at the patient’s request or on the advice of the treating
physician because of either adverse events (7 patients), intercurrent illness (7 patients), election to
undergo splenectomy (5 patients), or progressive hematologic disease (6 patients). Sixteen of the patients
removed from the study died (intercurrent illness: 6
patients; splenectomy: 4 patients; and progressive hematologic disease: 6 patients). The median time to
death after the completion of rIFN-a-2b therapy was
0.92 years (range, 1 week-2.9 years). Two patients were
lost to follow-up.
RESULTS
Hematologic and Spleen Outcomes
Patients
Table 4 summarizes the changes in spleen size and
laboratory values that occurred after the induction
course of rIFN-a-2b therapy, with patients categorized
according to Polycythemia Vera Study Group diagnosis. Mean total spleen size was reduced by 17% in the
AMM patients, 19% in the PPV-MM patients, 0.1% in
the PET-MM patients, 33% in the PV-MM patients,
and 73% in the PV patients. Increases in mean total
spleen size of 56% and 7% occurred in the ET patients
and A-MPD patients, respectively.
Mean leukocyte counts were decreased by 0.2% in
the AMM patients, 25% in the PPV-MM patients, 35%
in the PET-MM patients, 59% in the PV-MM patients,
50% in the ET patients, 48% in the PV patients, and
22% in the A-MPD patients, and by 66% in the SM
patient.
Mean platelet counts were reduced in all but one
of the diagnostic categories. The mean percent
AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM:
postessential thrombcythemia myeloid metaplasia; PV-MM: active polycythemia vera with meyloid
metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute myelofibrosis; rIFN-a-2b: recombinant interferon-a-2b.
a
May have had more than one indication.
Fifty-four patients participated in the study over a
period of 7.8 years between November 6, 1986 and
September 1, 1995. A summary of their baseline and
demographic characteristics appears in Table 2. The
study population included 33 males and 21 females
with a median age of 61 years (range, 22–77 years). The
MPD variants represented were: AMM: 14 patients;
PPV-MM: 6 patients; PET-MM: 2 patients; PV-MM: 17
patients; ET: 3 patients; PV: 8 patients; A-MPD: 3 patients; and SM: 1 patient. The duration of MPD before
study entry was # 1 year in 9 patients and . 1 year in
the remaining 45 patients. Conventional chemotherapy had failed in 29 patients, and 25 were previously
untreated.
The indications for rIFN-a-2b therapy were symptomatic splenomegaly (39 patients), thrombocythemia
(24 patients), hyperleukocytosis (14 patients), and
rIFN-a-2b in Myeloproliferative Disease/Gilbert
1209
TABLE 4
Summary of Mean Changes in Spleen Size and Laboratory Variables after the Induction Course of rIFN-a-2ba
Spleenb
Leukocytes
Platelets
Hematocrit
PVSG
diagnosis
No.
(%) Change
(%) Range
(%) Change
(%) Range
(%) Change
(%) Range
(%) Change
(%) Range
AMM
PPV-MM
PET-MM
PV-MM
ET
PV
A-MPD
SM
14
6
2
17
3
8
3
1
217.42
219.4
20.1
233
56
273
7
0
275 to 18.8
241 to 0
28 to 18
288 to 118
0 to 1167
2400 to 0
271 to 114
—
20.19
225
235
259
250
248
222
266
218 to 1425.8
280 to 180
258 to 212
291 to 187
257 to 244
278 to 26
283 to 131
—
229
240
264
243
263
227
213
44
240.5 to 1157.7
282 to 14
265 to 262
268 to 22.6
282 to 236
276 to 1165
226 to 26
—
29.6
28
228
26
221
2
3.7
220
233 to 120
238 to 16
238 to 218
234 to 135
240 to 25
29 to 124
210 to 118
—
rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polcythemia Vera Study Group;. AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia: PET-MM: postessential thrombocythemia
myeloid metaplasia; PV-MM: active polycythemia vera with meyloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute
myelofibrosis.
a
Values for variables after treatment with recombinant interferon-a-2b are at completion of induction course.
b
Total spleen was measured as the sum of the vertical and horizontal span.
changes were 29% in the AMM patients, 40% in the
PPV-MM patients, 64% in the PET-MM patients, 43%
in the PV-MM patients, 63% in the ET patients, 27% in
the PV patients, and 13% in the A-MPD patients. The
SM patient experienced a 44% increase in mean platelet count.
Mean hematocrit was reduced by 10%, 8%, 28%,
6%, 21%, and 20% in patients with AMM, PPV-MM,
PET-MM, PV-MM, ET, and SM, respectively. The
mean hematocrit increased by 2% and 4% in patients
with PV and A-MPD, respectively.
Response to rIFN-a-2b therapy also was analyzed
according to the indication for treatment. Twenty-two
patients with thrombocythemia at study entry responded, and platelet counts returned to normal in 18
of these 22 patients (82%). Of the 13 patients with
leukocytosis, 12 (92%) responded, with the leukocytosis becoming normal in 3 patients and decreasing by a
mean of 76% (range, 43–91%) in the other 9 patients.
Splenomegaly decreased by a mean of 35% (range,
15– 88%) in 21 of 36 patients (58%). Of the remaining
15 patients, spleen size remained stable in 10 patients
and increased in 5 patients.
The clinical benefits of rIFN-a therapy are illustrated in the following example. A 38-year-old female
patient who developed PV at age 32 years required
phlebotomy for 2 years until experiencing a transformation to myeloid metaplasia with progressive
splenomegaly and loss of her phlebotomy requirement. By the time the patient was age 35 years her
spleen had enlarged into the right side of the abdomen
and she was experiencing fatigue, early satiety, bilateral pedal edema, and abdominal fullness and discomfort. A course of hydroxyurea had no beneficial
effect on spleen size and resulted in progressive anemia. Therapy with rIFN-a-2b was administered for 44
weeks, during which time there was a gradual reduction in splenomegaly. This was accompanied by correction of anemia, reduction of leukocyte and platelet
counts to normal, and relief of all symptoms. The
patient remained in remission for 1.5 years after the
course of rIFN-a-2b therapy.
Therapy and Unmaintained Response Durations
Table 5 summarizes the durations of induction therapy and of response off therapy for two courses of the
rIFN-a-2b regimen. Overall, the median duration of
induction therapy was 34 weeks (range, 6 –129 weeks).
Considering patients by diagnostic categories, median
durations of induction therapy were as follows: AMM:
32 weeks; PPV-MM: 51 weeks; PET-MM: 20 weeks;
PV-MM: 34 weeks; ET: 34 weeks; PV: 43 weeks; A-MPD:
12 weeks; and SM: 36 weeks.
After discontinuation of induction therapy, 40 responding patients were monitored for unmaintained
response. The median duration of unmaintained response among these patients was 60 weeks (range,
4 –249 weeks). By diagnostic group, median durations
for unmaintained response were as follows: AMM: 46
weeks; PPV-MM: 35 weeks; PET-MM: 92 weeks; PVMM: 34 weeks; ET: 86 weeks; PV: 71 weeks; A-MPD:
173 weeks; and SM: 48 weeks.
After the first off-therapy period, 24 patients exhibited increasing disease activity and were administered a second course of rIFN-a-2b. The median duration of the second course of treatment was 31 weeks
(range, 4 –287 weeks). Considering patients by diagnostic categories, the median durations of the second
1210
CANCER September 15, 1998 / Volume 83 / Number 6
TABLE 5A
Patient Outcomes and Duration of rIFN-a-2b Therapy: Induction Course
Induction therapy
Off therapy (unmaintained response)
PVSG diagnosis
No. of patients
Weeksa
Range
No. of patients
Weeksa
Range
AMM
PPV-MM
PET-MM
PV-MM
ET
PV
A-MPD
SM
Median duration
14
6
2
17
3
8
3
1
32
51
19.5
34
34
42.5
12
36
34
6–129
13–86
15–24
6–95
20–97
6–86
7–31
—
11
5
1
12
2
6
1
1
45.5
35
92
34
85.5
71
173
48
59.5
11–168
25–60
—
4–87
12–159
24–249
—
—
rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polycythemia Vera Study Group; AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycthemia vera myeloid metaplasia; PET-MM: postessential thrombocythemia
myeloid metaplasia; PV-MM: active polycythemia vera with myeloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute
myelofibrosis.
a
Values expressed represent median calculations.
TABLE 5B
Patient Outcomes and Duration of rIFN-a-2b Therapy: Second Course
Second course
Off therapy (unmaintained response)
PVSG diagnosis
No. of patients
Weeksa
Range
No. of patients
Weeksa
Range
AMM
PPV-MM
PET-MM
PV-MM
ET
PV
A-MPD
SM
Median duration
5
3
1
10
1
4
—
—
69
14
21
29.5
134
33
—
—
31.25
7–34
8–56
—
10–287
—
4–44
—
—
5
3
1
9
—
2
—
—
26
22
64
48
—
17.5
—
—
26
6–81
16–35
—
15–149
—
15–20
—
—
rIFN-a-2b: recombinant interferon-a-2b; PVSG: Polycythemia Vera Study Group; AMM: agnogenic myeloid metaplasia; PPV-MM: postpolycythemia vera myeloid metaplasia; PET-MM: postessential thrombocythemia myeloid metaplasia; PV-MM: active polycythemia vera with myeloid metaplasia; ET: essential thrombocythemia; PV: polycythemia rubra vera; A-MPD: atypical myeloproliferative disorder; SM: subacute
myelofibrosis.
a
Values expressed represent median calculations.
course of therapy were as follows: AMM: 69 weeks;
PPV-MM: 14 weeks; PET-MM: 21 weeks; PV-MM: 30
weeks; ET: 134 weeks; and PV: 33 weeks.
Twenty patients were followed after discontinuation of the second course of treatment. Overall, these
patients exhibited a median duration of unmaintained
response of 26 weeks (range, 6 –149 weeks). Among
individual treatment groups, the median durations of
these second unmaintained responses were as follows:
AMM: 26 weeks; PPV-MM: 22 weeks; PET-MM: 64
weeks; PV-MM: 48 weeks; and PV: 18 weeks.
Fourteen patients received . 2 courses of rIFNa-2b therapy (overall range, 3– 41 weeks). These subsequent courses produced results similar to those
demonstrated by the initial two courses of therapy.
Overall, a total of 54 induction courses were administered, 24 second courses, 14 third courses, 11 fourth
courses, 5 fifth courses, and 2 sixth courses.
Survival
At a median follow-up of 7.3 years, the median survival in this patient population had not been reached
(Fig. 1). The survival rate at 8 years was 60%.
Adverse Events
Recombinant IFN-a-2b therapy generally was well tolerated. Adverse events reported by . 5% of patients
included fever, chills, arthralgia, myalgia, fatigue, loss
of appetite, alopecia, erythema and induration at the
injection site, diarrhea, and neurologic symptoms.
rIFN-a-2b in Myeloproliferative Disease/Gilbert
FIGURE 1.
Overall survival of 52 evaluable patients as of last follow-up
(January 1998).
The majority of side effects tended to be mild to moderate in severity, transient in nature, and rapidly reversible on dose modification. Initially, nearly all
study participants experienced a flu-like syndrome
characterized by pyrexia, chills, malaise, arthralgia,
and myalgia. Tachyphylaxis to this adverse event generally occurred after 7–14 days of treatment. Adverse
events, primarily a persistent flu-like syndrome and
chronic fatigue, were responsible for five patients discontinuing study participation.
DISCUSSION
IFN-a is considered the standard of care in patients
with chronic myelogenous leukemia (CML) who are
ineligible for bone marrow transplantation.34 Complete hematologic remissions have been attained with
rIFN-a therapy in 70 – 80% of patients with CML, and
major cytogenetic responses have occurred in up to
40% of patients.35 Within the past 7 years, an increasing number of reports have been published suggesting
a potential therapeutic role for rIFN-a therapy in the
management of other variants of MPD. Several investigators have reported that rIFN-a treatment resulted
in hematologic control accompanied by a reduced
need for phlebotomy in a relatively large proportion of
patients with PV.36 – 40 Other benefits of rIFN-a therapy
noted in studies of PV patients include decreased
splenomegaly,40 – 43 reduced risk of thrombosis, and
remittance of intractable pruritus.36,39,44,45 Reduced
platelet counts with relief of clinical symptoms also
have been reported in series of patients with ET receiving rIFN-a therapy.38,46 – 49 Among patients with
myeloid metaplasia, responses to rIFN-a therapy have
been more variable.21,22,50 –52 Hematologic responses
with primary rIFN-a induction therapy occur in approximately 75% of PV patients and 86% of ET pa-
1211
tients.53 These response rates compare favorably with
those achievable with hydroxyurea. However, unlike
conventional therapeutic approaches, including phlebotomy and chemotherapy, rIFN-a substantially controls splenomegaly, reduces the incidence of thrombohemorrhagic events, and may potentially alter the
natural history of these diseases. Moreover, in a subset
of patients, rIFN-a therapy produces long term responses of . 5 years.41
The results of the study presented in this article
provide further evidence that rIFN-a-2b may be a
useful agent in the management of PV, ET, and myeloid metaplasia. Evaluation of response according to
the indication for treatment in the heterogeneous patient population that comprised this study clearly
demonstrated that rIFN-a-2b can produce regression
of splenomegaly, control of leukocyte and platelet
counts, an increase in hematocrit among anemic patients, and a decreased need for phlebotomy in polycythemic patients (data not shown).
Other standard-of-care modalities for MPD are
associated with serious complications. Both radioactive phosphorus and cytotoxic drugs can induce leukemia or myelofibrotic transformation,33,53,54 whereas
reduction of peripheral blood counts by phlebotomy
may increase the risk of thrombotic accidents.33 In
contrast to hydroxyurea, busulfan, and radioactive
phosphorus, rIFN-a does not have any known leukemogenic or teratogenic effects. Nevertheless, rIFN-a
therapy is not without toxicity. All patients receiving
rIFN-a-2b in this study experienced a flu-like syndrome. Although this syndrome and other minor side
effects associated with rIFN-a therapy may not be
treatment-limiting, there is a potential for more serious adverse events to occur, particularly with long
term therapy.
The 39 patients who responded to therapy and
who subsequently were withdrawn from rIFN-a-2b
therapy add to previously reported evidence that
rIFN-a produces durable treatment responses in patients with MPD after cessation of therapy.40,46,47 In
the current study, the median duration of unmaintained response after the first course of rIFN-a-2b
therapy was 60 weeks, but some patients were maintained successfully off treatment for $ 2 years. Moreover, no evidence was noted of patients becoming
refractory to rIFN-a-2b therapy. Early reinstitution of
rIFN-a-2b treatment in patients manifesting increased
disease activity resulted in a return of hematologic
control, whereas repeated courses of therapy cumulatively decreased splenomegaly. The ability to reinstitute treatment successfully with rIFN-a-2b in patients
with recurrent disease also has been reported previously elsewhere40,47; however, to our knowledge this
1212
CANCER September 15, 1998 / Volume 83 / Number 6
report represents the longest follow-up reported to
date (median, 7.3 years). The long term survival analysis presented in the current study demonstrates a
median survival in excess of 8 years, although median
survival has not been reached. This compares favorably with conventional modalities, but it is too early to
draw definitive conclusions from this analysis.
Studies conducted in patients with CML demonstrate that rIFN-a, unlike other drugs, suppresses the
growth of cells bearing the abnormal karyotype and
permits the reestablishment of a normal polyclonal
bone marrow population in a significant number of
patients.15,16 Cytogenetic studies on bone marrow
specimens from patients with other variants of MPD
treated with rIFN-a also show that this agent may
inhibit the neoplastic clone selectively and allow reemergence of normal hematopoietic progenitor
cells.42,43,51 Unfortunately, no cytogenetic data are
available for any patients on this study.
The fact that rIFN-a has produced unmaintained,
long-standing disease remissions in patients with
MPD suggests that rIFN-a has immunomodulatory
activity in patients with MPD. Recombinant IFN-a has
potent inhibitory effects on a variety of hematopoietic
progenitor cells, including megakaryocyte progenitors, and this most likely is the primary mechanism by
which rIFN-a therapy controls thrombocytosis and
erythrocytosis.
rIFN-a-2b appears to be a valuable agent in the
management of MPD. It produces regression of
splenomegaly, improvement in peripheral blood
counts, and a reduction in the need for phlebotomy.
Recombinant IFN-a-2b also is well tolerated and is
capable of producing durable unmaintained responses.
Based on this experience and other published reports, future studies with rIFN-a-2b are warranted.
Therapy with rIFN-a-2b may be appropriate for early
intervention in younger patients to halt disease progression before end-organ damage occurs. In addition, it may be a desirable treatment for elderly patients because of its minimal hematologic toxicity.
Multicenter trials enrolling larger patient populations
should be conducted to determine the optimal dosing
regimen for this drug, the pattern of response to treatment, and whether any MPD phenotypes or patientrelated factors are predictive of success and sustained
unmaintained response.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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