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1821
Recombinant Interferon-a Therapy in Patients with
Follicular Lymphoma
Howard Ozer, M.D., Ph.D.1
Peter H. Wiernik, M.D.2
Francis Giles, M.D.3
Craig Tendler, M.D.4
BACKGROUND. Advanced stage, follicular, non-Hodgkin’s lymphoma (NHL) has no
cure and no single standard of care. Remissions induced by standard chemotherapy regimens generally are not durable and, with the exception of selected patients
with limited early stage disease, most patients with follicular NHL eventually die of
their disease. Recombinant interferon-a (rIFN-a) has demonstrated activity against
1
Allegheny University Cancer Center, Allegheny
University of the Health Sciences, Philadelphia,
Pennsylvania.
2
Albert Einstein Cancer Center, Albert Einstein
College of Medicine, Bronx, New York.
3
Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California.
4
Schering-Plough Research Institute, Kenilworth, New Jersey.
follicular NHL in clinical trials.
METHODS. A comprehensive survey of current therapeutic options for follicular
NHL patients was conducted with emphasis on the role of rIFN-a used in conjunction with chemotherapy regimens.
RESULTS. Phase III studies have demonstrated that rIFN-a delays disease progression and may improve overall survival when administered either with chemotherapy or as maintenance therapy after induction treatment for follicular lymphoma.
Adverse effects from combination or maintenance regimens are not significantly
different from those from chemotherapy alone.
CONCLUSIONS. Recombinant IFN-a is safe and effective when given in conjunction
with standard chemotherapeutic regimens in selected patients with follicular NHL,
and may especially benefit patients with minimal residual disease after induction
chemotherapy. Cancer 1998;82:1821–30. q 1998 American Cancer Society.
KEYWORDS: non-Hodgkin’s lymphoma, interferon-a, combination chemotherapy,
hematology.
T
Address for reprints: Howard Ozer, M.D., Ph.D.,
Allegheny University Cancer Center, Allegheny
University of the Health Sciences, Broad and
Vine, Mailstop 487, Philadelphia, PA 19102.
Received August 21, 1997; accepted December
15, 1997.
he incidence of non-Hodgkin’s lymphoma (NHL) has increased
by ú 65% since the early 1970s and now ranks fifth in frequency
of new cancer cases.1 Although the 5-year survival rate for NHL has
improved from 31% to 52% over the past 30 years, the mortality rate
has more than doubled during the same period. Follicular lymphomas
constitute the vast majority of low to intermediate grade NHL. They
comprise the most common NHL subgroup, representing approximately 35% of all cases.2,3 The disease is characterized by a follicular
growth pattern, a B-cell immunophenotype, and the presence of a
t(14; 18) chromosomal translocation with rearrangement of the bcl-2
protooncogene in virtually all subtypes.4,5 This rearrangement results
in overexpression of the bcl-2 gene product, which blocks programmed cell death and apoptosis in lymphoid cells, thereby prolonging lymphoid cell survival that may lead to the development of
follicular lymphoma.6
Greater than 80% of patients with follicular lymphoma present
with advanced disease at diagnosis, including Stage III or Stage IV.
In the majority of patients with disseminated but nonaggressive disease, the lymphoma follows an indolent course (i.e., slow progression
with a median survival of 7 – 10 years).7 – 9 A ‘‘watch and wait’’ policy
of delaying treatment typically is adopted for these patients because
q 1998 American Cancer Society
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1822
CANCER May 15, 1998 / Volume 82 / Number 10
no difference in overall survival has been demonstrated between patients treated at diagnosis and patients for whom therapy is deferred.10 – 12
A subset (approximately 50%) of follicular lymphoma patients presents with a large tumor burden,
and their disease follows a more aggressive course.13
Criteria that have been utilized for confirming a diagnosis of large tumor burden include the presence of
at least one of the following: bulky tumor mass (ú 7
cm), involvement of ¢ 3 lymph node sites (ú 3 cm
each), systemic ‘‘B’’ symptoms, significant splenomegaly, major organ obstruction or compression
syndromes, malignant effusion, or leukemia with
bone marrow failure.8,9,13 – 15 Symptomatic follicular
lymphoma patients with large tumor burden are in
clinical need of treatment and usually cannot be managed with a ‘‘watch and wait’’ policy. Despite objective
response rates (i.e., complete response [CR] plus partial response [PR]) of 70 – 90% from initial treatment,
the majority of these patients eventually recur and die
of their disease after a median survival of approximately 5 – 6 years.8,13 – 15
The utilization of more intensive combination
chemotherapeutic regimens has not resulted in improved overall survival for this patient population.
Nevertheless, prolongation of disease free and/or
overall survival has been achieved by long term use
of recombinant interferon-a (rIFN-a) in conjunction
with chemotherapy or as maintenance treatment after
successful cytoreductive therapy.
This review will focus on four different treatment
strategies used for patients with follicular lymphoma:
1) combination chemotherapy, 2) rIFN-a as a single
agent treatment, 3) rIFN-a plus chemotherapy, and 4)
rIFN-a as maintenance therapy after chemotherapy.
Each treatment strategy will be discussed.
COMBINATION CHEMOTHERAPY
inItial therapy for follicular lymphoma patienTs with
large tumor burden usually is composed of a combination chemotherapy regimen with or without doxorubicin. Table 114,16 – 23 summarizes several combination
chemotherapy regimens that have been utilized in the
treatment of follicular lymphoma with large tumor
burden. One frequently used doxorubicin-containing
combination chemotherapy regimen is known as
CHOP (cyclophosphamide, doxorubicin, vincristine,
and prednisone).21,24 Other doxorubicin-containing
combinations (e.g., cyclophosphamide, doxorubicin,
teniposide, and prednisone [CHVP]; or cyclophosphamide, vincristine, prednisone, and doxorubicin
[COPA]) also have been used and are commonly referred to as ‘‘CHOP-like’’ regimens.9,23,25 Similar to
CHOP, the CHOP-like regimens all contain an alkylat-
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ing agent (cyclophosphamide), an anthracycline (doxorubicin), a vinca alkaloid (vincristine or teniposide),
and a steroid (prednisone or dexamethasone) at varying doses. In addition to doxorubicin-containing
CHOP-like regimens, combination chemotherapy without doxorubicin (e.g., cyclophosphamide, vincristine,
and prednisone; cyclophosphamide, vincristine, procarbazine, and prednisone; or cyclophosphamide and
prednisone) also has been used successfully in the
therapy of follicular lymphoma.16,18 – 20,26
Although chemotherapeutic approaches produce
an objective response in the majority of follicular
lymphoma patients with large tumor burden, these
treatments have not demonstrated significant improvements in overall survival. Regardless of the chemotherapy regimen, the pattern of repeated recurrence and limited median survival of approximately 5
years is not altered.9,16,18 – 21,23,24,27
CLINICAL STUDIES WITH rIFN-a
Phase I and II Studies
In an effort to improve survival, rIFN-a was first introduced in the early 1980s as a single agent in Phase
I/II clinical studies to determine its activity in low
grade lymphoma (Table 2)28 – 31 In Phase I studies, approximately 50% of low grade lymphoma patients
treated with recombinant interferon-a-2b (rIFN-a-2b)
achieved an objective clinical response, including patients who previously had been treated with combination chemotherapy.30,31 These early studies demonstrated that single agent rIFN-a had substantial clinical activity with minimal toxicity and was an effective
treatment for patients with follicular lymphoma.
Because of its well established efficacy as a single
agent, its diverse mechanisms of action, and its largely
nonoverlapping toxicity profile, rIFN-a was studied as
an adjuvant to established chemotherapy regimens for
follicular NHL in a number of Phase II studies. This
combination approach was supported by extensive in
vitro data that indicated synergistic effects between
rIFN-a and cytotoxic drugs (e.g., cyclophosphamide
and doxorubicin) in tumor cell lines,32 as well as in
murine xenograft models33,34 resulting in prolonged
survival with administration of rIFN-a after cytotoxic
agent-induced remission.
Data from these Phase II studies suggested that
rIFN-a in combination with single or multiple agent
chemotherapy increased and prolonged clinical response without synergistic toxicities (Table 2).35 – 37
Moreover, the results revealed that clinical benefit
could be achieved even in patients with previously
treated low grade NHL, especially those with follicular
lymphoma. Although the objective response rates observed in these combination trials were similar to
W: Cancer
Recombinant Interferon-a in Follicular NHL/Ozer et al.
1823
TABLE 1
Clinical Trials Evaluating Combination Chemotherapy for the Treatment of Lymphoma
Results
Reference
No.
Regimen
Patient population
132
ChP
Ezdinli et al., 198517
Glick et al., 198118
Steward et al., 198819
Kalter et al., 198720
Ezdinli et al., 198517
Glick et al., 198118
Kimby et al., 199416
48
20
162
15
27
18
127
CP
CP
CVP
CVP
COPP
COPP
CHOP
Dana et al., 199321
Dana et al., 199321
Sullivan et al., 198322
Romaguera et al., 199114
260
72
16
21
CHOP
CHOP
CHOP
CHOP-Bleo
Romaguera et al., 199114
Romaguera et al., 199114
Anderson et al., 198423
80
16
18
CHOP-Bleo
CHOP-Bleo
M-BACOD
Symptomatic, low
grade
FSCL
FML
Low grade NHL
FSCL
FSCL
FML
Symptomatic, low
grade
FSCL
FML
Low grade NHL
Follicular with high
tumor burden
FSCL
FML
Follicular with
bulky disease
Kimby et al., 1994
16
Overall response
rate (CR / PR)
5-year survival
rate
Median survival
36%
49%
—
64%
95%
56%
53% (CR)
78%
94%
60%
62%
—
54%
46%
70%
—
54%
—
ú60 mos
64 mos
4 yrs
—
41 mos
—
64% (CR)
64% (CR)
69% (CR)
52% (CR)
70%
45%
—
—
8.1 yrs
4.3 yrs
54 mos
44 mos
78%
75%
94%
64%
54%
46%
—
—
—
CR: complete response; PR: partial response; ChP: chlorambucil and prednisone; CP: cyclophosphamide and prednisone; FSCL: follicular, small cleaved cell lymphoma (International Working Formulation [IWF]
class B); FML: follicular mixed lymphoma (IWF class C); NHL: non-Hodgkin’s lymphoma; CVP: cyclophosphamide, vincristine, and prednisone; COPP: cyclophosphamide, vincristine, procarbazine, and prednisone;
CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP-Bleo: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus bleomycin; M-BACOD: methotrexate, bleomycin,
doxorubicin, cyclophosphamide, vincristine, and dexamethasone.
those achieved with single alkylating agents, these
studies were not designed to determine the effect of
rIFN-a on recurrence free and overall survival. However, these studies provided the rationale for developing prospective, randomized Phase III studies to investigate the potential benefit of adding rIFN-a to
standard chemotherapy regimens for the treatment of
follicular lymphoma.
Phase III Studies of rIFN-a Plus Single Agent
Chemotherapy
Two randomized, controlled Phase III trials have investigated the combination of rIFN-a with a single
alkylating agent (Table 2).
The Medical Research Council study38,39 examined
124 previously untreated patients with low grade Stage
III or IV follicular NHL who required therapeutic intervention due to large tumor burden and/or symptoms.
Patients were randomized to receive induction treatment for 18 weeks with chlorambucil with or without
rIFN-a-2b (2 MIU/m2 subcutaneously [sc], three times
a week [TIW]). Responding patients then were randomized to a maintenance regimen of the same dosage of rIFN-a-2b for 12 months or no further treatment. Although no significant difference in response
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rates was observed between the induction treatment
groups, patients who received rIFN-a-2b maintenance
therapy had a significantly longer remission duration
(P õ 0.013). Of these patients, 20% recurred during
maintenance therapy, whereas 40% of the untreated
group recurred during the same period. At 1-year follow-up,39 patients receiving rIFN-a-2b had a significantly lower recurrence rate (P Å 0.04), but there was
no difference in overall survival for those patients receiving rIFN-a-2b either as induction or maintenance
treatment.
A study by Peterson et al.40,41 examined 581 previously untreated patients with Stage III or IV follicular
NHL randomized to induction treatment for 3 months
with cyclophosphamide with or without rIFN-a-2b (2
MIU/m2 sc, TIW). Responding patients (n Å 204) subsequently were randomized to 2 years of maintenance
treatment with the same dose of rIFN-a-2b or no further treatment. The results revealed no significant difference in overall response rate or duration of response between the induction treatments. Moreover,
the addition of rIFN-a-2b to oral cyclophosphamide
consistently was more toxic to granulocytes and platelets than was cyclophosphamide alone. Results from
the maintenance segment of the study demonstrated
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CANCER May 15, 1998 / Volume 82 / Number 10
TABLE 2
Recombinant Interferon-a as Single Agent or plus Chemotherapy for the Treatment of Low Grade NHL
Reference
No.
Regimen
Patient population
Results
Foon et al., 198429
37
rIFN-a-2a: 50 MIU/m2,
im, TIW for ¢3 mos
13/24 (54%)
2/6 (33%)
1/7 (14%)
O’Connell et al., 198628
20
Wagstaff et al., 198630
34
23 follicular NHL, 11 CLL
13/23 CR / PR (57%)
4/11 CR / PR (36%)
Leavitt et al., 198731
21
rIFN-a-2a: 12 MIU/m2
im, TIW for 8 wks,
then same dose weekly
for 16 wks
rIFN-a-2b: MIU/m2 sc,
TIW for 1 yr or until
progression
rIFN-a-2b: 10 MIU/m2 sc,
TIW for 1 yr
24 low grade NHL 6 intermediate
grade NHL, 7 high grade NHL;
pTx and refractory to
chemotherapy
16 follicular NHL, 4 CLL
Low grade NHL; pTx
Rohatiner et al., 198735
23
Chisei et al., 198837
22
10 follicular NHL, 5 diffuse mixed
NHL, 7 diffuse poorly
differentiated NHL
3/21 CR (14%)
7/21 PR (33%)
10/21 overall
response rate
(48%)
14/23 objective
response (61%)
1 CR / 13 PR,
including 8/11
with follicular NHL
(73%)
Response rate: 80%
Response rate: 60%
Response rate: 43%
Ozer et al., 198736
43
Stage III/IV follicular NHL
Overall response: 84%
Price et al., 199138
124
Stage III/IV clinically aggressive
follicular NHL; No pTx
Prolonged remission
duration (P õ
0.013)40
Lower recurrence rate
(P Å 0.40)43
Stage III/IV follicular lymphoma:
70% indolent with no history
of symptoms: no pTx
Overall response 84%;
no impact on
survival, trend
toward improved
time to treatment
failure
Rohatiner et al., 199639 (MRC)
Petersen et al., 199340
(CALGB)
581
rIFN-a-2b: 2MU/m2 sc,
TIW for 18 wks plus
chlorambucil (10 mg/
day for 6 wks, then 3
cycles of 2 wks on, 2
wks off)
rIFN-a-2b: 3MU/m2 sc,
TIW 1 6 mos plus
chlorambucil (10 mg/
day)
rIFN-a-2b: 2MU/m2 sc,
TIW plus
cyclophosphamide
(100 mg/m2/day) for 2
years
Chlorambucil { rIFN-a2b: 2 MIU/m2 sc, TIW
for 18 wks;
Maintenance rIFN-a-2b
for 12 months for
responders
Cyclophosphamide {
rIFN-a-2b: 2 MIU/m2
sc, TIW, for 3 mos
after response;
Maintenance rIFN-a-2b
for 2 yrs or
observation for
responders
Recurrent low grade NHL
7/16 CR / PR (44%)
1/4 CR / PR (25%)
NHL: non-Hodgkin’s lymphoma; IFN: interferon; MIU: million international units; im: intramuscular; TIW: three times weekly; pTx: previous treatment; CR: complete response; PR: partial response; CLL: chronic
lymphocytic leukemia; sc: subcutaneous; CALGB: Cancer and Leukemia Group B.
a trend toward improved time to treatment failure at
4 years for patients treated with rIFN-a-2b (53% vs.
41%; P Å 0.06). However, it should be noted that there
was no effect on overall survival and approximately
70% of this study population had indolent follicular
lymphoma with small cell histology (International
Working Formulation [IWF] Grade B). By today’s standards, this patient population usually is managed with
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a ‘‘watch and wait’’ treatment approach, and may not
benefit from rINF-a therapy.10,11
Phase III Studies of rIFN-a plus Combination
Chemotherapy
Two randomized, controlled Phase III trials have investigated the potential benefit of administering a doxorubicin-containing combination chemotherapy regi-
W: Cancer
Recombinant Interferon-a in Follicular NHL/Ozer et al.
1825
TABLE 3
Phase III Studies of Recombinant Interferon-a plus Combination Chemotherapy for the Treatment of Low Grade NHL
Reference
No.
27
Regimen
2
Patient population
Results
Median duration of CR3.2 yr prolonged with
rIFN-a-2a (P Å 0.03)
Median TTF3.2 yr prolonged with rIFN-a-2a
(P õ 0.001)
TTF5 yr prolonged with rIFN-a-2b (P Å
0.0013)
Median progression free survival: 2.9
years vs. 1.5 years (P Å 0.0002)
Median overall survival: not reached vs.
5.6 years (P Å 0.0084)
Smalley 1992, Andersen
199325 (ECOG)
249
COPA { rIFN-a-2a: 6 MIU/m sc,
TIW for 10 mos
Stage III/IV clinically aggressive
low or intermediate grade
NHL; not previously treated;
mixture of IWF groups
(A–E)
Solal-Celigny 1993, and 19969,42
(GELF)
242
CHVP { rIFN-a-2b: 5 MIU sc,
TIW for 18 mos
Advanced stage follicular
lymphoma: not previously
treated
NHL: non-Hodgkin’s lymphoma; COPA: cyclophosphamide, vincristine, prednisone, and doxorubicin; IFN: interferon; CR3.2 yr : Complete response at 3.2 years; sc: subcutaneous; TIW: three times weekly; TTF3.2 yr
time to treatment failure with 3.2 years of follow-up; IWF: International Working Formulation; TTF5 yr time to treatment failure with 5 years of follow-up; CHVP: cyclophosphamide, doxorubicin, teniposide, and
prednisone; ECOG: Eastern Cooperative Oncology Group; GELF: Group d’Etude des Lymphomes Folliculaires.
men plus rIFN-a for patients with clinically aggressive
(i.e., large tumor burden), follicular lymphoma (Table 3).9,25,27,42
The Eastern Cooperative Oncology Group randomized 249 patients with newly diagnosed Stage III/
IV NHL (IWF Grades A-E) to receive 8 – 10 cycles of
COPA or COPA / rIFN-a-2a (I-COPA) (6 MIU/m2 daily
on Days 22 – 26 of each 28-day chemotherapy cycle).27
Although the addition of rIFN-a-2a did not affect the
objective response rate (86% in each treatment group),
the median duration of CRs was significantly longer
for patients receiving I-COPA (not yet reached at last
follow-up vs. 1.7 years for the COPA group; P Å 0.03).
Moreover, median time to treatment failure, defined
as disease progression, recurrence, or death, was 2.5
years for the I-COPA group, which was significantly
longer than the 1.6 years for the COPA group (P õ
0.001). A 5-year follow-up indicated that time to treatment failure was longer for patients receiving I-COPA,
with only 66% of these patients experiencing disease
progression versus 81% of patients treated with COPA
(P Å 0.0013), but no significant difference in overall
survival was noted between the two treatment
groups.25
This study has been criticized primarily because
the analyses did not include the subgroup of patients
with follicular lymphoma only.13 The interpretation of
the benefit of an rIFN-a regimen for follicular
lymphoma was complicated by the inclusion of other
lymphoma subtypes in the study population. In addition, intermittent dosing with rIFN-a-2a for õ 1 year
in the I-COPA regimen may have been inadequate to
yield a survival benefit. Despite these criticisms, this
study was the first to demonstrate that rIFN-a-2a
could be effectively and safely administered with
CHOP-like doses of cyclophosphamide (600 mg/m2/
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cycle) and doxorubicin (50 mg/m2/cycle), and that this
approach delayed disease progression.
A study evaluating rIFN-a-2b plus a doxorubicincontaining combination chemotherapy regimen was
conducted by the Groupe d’Etude des Lymphomes
Folliculaires (GELF ).9,42 Two hundred and seventythree patients with advanced follicular lymphoma and
large tumor burden prospectively were randomized to
receive CHVP or CHVP / rIFN-a-2b (5 MIU/m2 sc,
TIW) for 18 months. Patients were selected with large
tumor burden as defined by having at least one of
the following criteria: bulky tumor mass (ú 7 cm),
involvement of ¢ 3 lymph node sites (ú 3 cm each),
significant splenomegaly, systemic ‘‘B’’ symptoms
(e.g., fever, chills, significant weight loss), major organ
obstruction or compression syndromes, malignant effusion, or leukemia with bone marrow failure.9,15
Twelve cycles of CHVP were administered to both
treatment groups, with the first 6 cycles administered
monthly and the second 6 cycles administered every
other month. After the first 6 cycles of chemotherapy,
76% of the group administered CHVP / rIFN-a-2b had
responded to therapy, compared with 58% of those
treated with CHVP alone (P Å 0.004). For the entire
induction-plus-maintenance sequence, 85% of the
CHVP / rIFN-a-2b group responded versus 69% of
the CHVP-alone group (P Å 0.006).
Median progression free survival was significantly
longer in patients receiving CHVP / rIFN-a-2b compared with those receiving CHVP alone (2.9 years vs.
1.5 years; P õ 0.002). In patients receiving CHVP alone,
the median overall survival was 5.6 years, but a median
had not yet been reached in patients with CHVP /
rIFN-a-2b as of the database cutoff date (mean followup duration was 72 months). However, 5 years after
therapy, 70% of the patients receiving CHVP / rIFN-
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CANCER May 15, 1998 / Volume 82 / Number 10
a-2b were alive, compared with only 56% of those in
the CHVP group (P Å 0.016), indicating a significant
survival benefit for the combined regimen. The survival in the CHVP-treated patients was comparable to
that of similar patient populations treated with other
doxorubicin-containing combination chemotherapy
regimens such as CHOP,16,21 COPA,25 M-BACOD
(methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone),23 or CHOPBleo (CHOP plus bleomycin).14
Asthenia, fever, neutropenia, increased hepatic enzymes, alopecia, headache, anorexia, flu-like symptoms,
myalgia, and thrombocytopenia occurred more frequently (¢ 10% difference in incidence) in the patients
treated with CHVP / rIFN-a-2b compared with patients
treated with CHVP alone. Fifty-one of the 138 patients
(37%) randomized to receive CHVP / rIFN-a-2b had
temporary modification/interruption or discontinuation
of their rIFN-a-2b therapy, but only 13 patients (10%)
permanently stopped rIFN-a-2b because of toxicity.
There were no treatment-related deaths.
To evaluate the balance between clinical benefit and
toxicity of rIFN-a-2b / CHVP treatment, a retrospective
analysis of prospectively collected adverse event data was
performed. This analysis utilized the quality-adjusted
time without symptoms and toxicity (Q-TWiST) methodology.43 This method integrates Kaplan-Meier estimates
for disease free survival, overall survival, and time spent
experiencing toxicity. The analysis showed that the time
without either symptoms of disease or treatment-related
toxicity (TWiST time) was significantly prolonged for patients treated with rIFN-a-2b / CHVP compared with
those treated with CHVP alone (P õ 0.05).44
The GELF study demonstrates that the addition of
rIFN-a-2b to a doxorubicin-containing combination
chemotherapy regimen for patients requiring treatment
for advanced follicular NHL significantly improves the
percentage of patients achieving a clinical response, progression free survival, and overall survival. The doxorubicin-containing combination chemotherapy utilized in
the GELF study was CHVP, a variation of CHOP designed
to deliver similar cumulative doses of doxorubicin and
cyclophosphamide with treatment spread over 18
months rather than 8–10 months. Although dose intensity for doxorubicin and cyclophosphamide was lower
in CHVP compared with a standard CHOP regimen, survival was not compromised, and therapy was well tolerated with minimal incremental toxicity beyond that of
the chemotherapy alone.
rIFN-a MAINTENANCE THERAPY AFTER
CHEMOTHERAPY
Recombinant IFN-a appears to play a significant therapeutic role when used as maintenance therapy in
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patients with low grade NHL who achieved tumor bulk
reduction after cytoreductive therapy (Table 4),45 – 50 including patients with high tumor burden.48 Despite
the heterogeneity of patient populations and dosing
regimens, studies indicate that rIFN-a maintenance
treatment prolongs the duration of remission in patients with low grade NHL. This clinical benefit is observed in the advanced stage, clinically aggressive, follicular lymphoma patient population.45,46,48 In an updated report on the study by McLaughlin et al.,45
patients treated with CHOP-Bleo for 1 year followed
by recombinant IFN-a-n1 (rIFN-a-n1) (3 MIU/m2 sc,
TIW) had increased failure free survival after 10 years
compared with historic controls who received the
same chemotherapy regimen without rIFN-a-n1
maintenance (24% vs. 15%; P Å 0.01).14 The improved
10-year overall survival rate (50% vs. 38%) was somewhat better for rIFN-a – treated patients, but did not
achieve statistical significance (P Å 0.07). It must be
noted that not all low grade NHL patients in this study
had follicular lymphoma, and many did not have adverse factors that would have required treatment at
the time of enrollment.
One randomized study of rIFN-a-2b maintenance
resulted in a survival advantage.50 Avilés et al.50 treated
patients in complete remission after induction chemotherapy with rIFN-a-2b (5 MIU/m2 sc, TIW) for 1 year.
Patients were selected from a ‘‘low grade lymphoma’’
population, but nearly 90% had follicular NHL. Many
did not have adverse prognostic factors such as large
tumor burden or systemic ‘‘B’’ symptoms at the time
of enrollment and therefore did not require immediate
treatment. Thus the extent of tumor burden for these
patients is not comparable to those treated in the
GELF study. After 9 years of follow-up, 62% of the
patients in the rIFN-a-2b group remained in first complete remission compared with 25% in the control
group (P õ 0.001).
Similarly, in the European Organization for the
Research and Treatment of Cancer Lymphoma Cooperative Group trial,46 the patient population was composed of follicular lymphoma patients but was not
restricted to those requiring therapeutic intervention.
Progression free survival was significantly prolonged
in patients receiving rIFN-a-2a maintenance therapy
versus those treated with observation alone (P Å 0.02).
The use of lower rIFN-a-2a doses for a shorter time
may have contributed to the study’s failure to demonstrate a survival benefit for follicular lymphoma patients compared with the GELF study.
The follicular lymphoma patients evaluated by the
German Low-Grade Lymphoma Study Group47 – 49 all
had large tumor burden, like those in the GELF study.
In the German Low-Grade Study Group, responding
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Recombinant Interferon-a in Follicular NHL/Ozer et al.
1827
TABLE 4
Phase III Studies of Recombinant Interferon-a as Maintenance Therapy after Chemotherapy for Lymphoma
Reference
McLaughlin et al., 1993
45
No.
Regimen
Patient population
Results
127
After CHOP-Bleo induction,
rIFN-a-n1 3 MIU/m2 im,
TIW for 24 mos
After CVP induction, rIFNa-2a: 3 MIU/m2 sc, TIW
for 1 yr or observation
After CVP or prednimustine
induction, rIFN-a-2b 5
MIU/m2 sc, TIW until
progression or
observation
After MTX, CEOP-Bleo, and
CVP, rIFN-a-2b 5 MIU
sc, TIW for 1 yr or
observation
Stage IV low grade NHL
Five-year failure free survival rate
significantly better than
historical controls (P Å 0.01).
Significant prolongation of PFS
for rIFN-a-2a (P Å 0.03). No
difference in overall survival.
Median DFS prolonged on rIFNa-2b compared with
observation (31 mos vs. 12
mos; P Å 0.0048)
Hagenbeek et al., 199546
(EORTC)
253
Hiddemann et al.,
199447; Unterhalt et
al., 199548; Unterhalt
et al., 199649 (German
Group)
Avilés et al., 199650
247
98
Stage III/IV follicular
NHL; no previous
treatment
Stage III/IV follicular or
mantle cell
lymphoma after
treatment failure or
recurrence
Low grade NHL in CR
Nine-year remission rate of 62%
for rIFN-a-2b vs. 25% for
observation (P õ 0.001).
Median survival prolonged in
rIFN-a-2b group
CHOP-Bleo: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus bleomycin; NHL: non-Hodgkin’s lymphoma; IFN: interferon; MIU: million international units; im: intramuscular; TIW: three
times weekly; CVP: cyclophosphamide, vincristine, and prednisone; PFS: progression free survival; DFS: disease free survival; MTX: methotrexate; CR: complete response; sc: subcutaneous; EORTC: European
Organization for Research and Treatment of Cancer.
patients were treated with combination chemotherapy
and then were randomized to receive rIFN-a-2b or
no further therapy. Recombinant IFN-a-2b was given
without a fixed time limitation until recurrence or intolerable toxicity at a dose of 5 MIU/m2 sc, TIW. The
improvement in progression free survival from 20
months in the control group to 37 months in the rIFNa-2b arm (P Å 0.0033) is comparable to the benefit
achieved with prolonged rIFN-a-2b therapy in the
GELF study (range, 18 – 35 months; P õ 0.002). Both
studies demonstrated clinical benefit with ú 12
months of rIFN-a-2b therapy. In the German study,
randomization was terminated due to the significant
improvement in the disease free survival of patients
treated with rIFN-a-2b compared with the patients in
the observation group.
DISCUSSION
Although the randomized Phase III studies enrolled
patients with advanced stage follicular NHL to study
the efficacy of induction or maintenance rIFN-a therapy, significant differences among the clinical and
therapeutic parameters preclude strict comparisons.
The heterogeneity of NHL types, tumor burden, rIFNa dosages, chemotherapeutic regimens, and follow-up
periods varied considerably among studies.
Differing proportions of IWF Grade B and C NHL
cases, or the rare presence of patients with IWF Grade
D (classified as intermediate grade NHL), in these clinical studies should not prevent broad conclusions re-
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garding the therapeutic value of rIFN-a from being
drawn, because the overwhelming majority of NHLs
in these studies were small cell and mixed small cell/
large cell follicular lymphomas (IWF Grades B and C,
respectively). Only a few studies27,48 included a number of nonfollicular NHL cases large enough to preclude specific conclusions regarding the follicular NHL
cases. Furthermore, the importance of histologic and
therapeutic distinctions among the follicular lymphomas has been questioned due to frequent lack of diagnostic concordance among pathologists.51 – 53 The Revised European-American Classification of Lymphoid
Neoplasms classification of NHLs reflects this by relegating IWF Grades B, C, and D to the status of provisional grades within a single category.
As laboratory diagnostic techniques have become
more refined and sensitive, defining CR has become
more difficult.54 For example, the increased use of
polymerase chain reaction (PCR)-based molecular
techniques, which are able to identify 1 in 100,000
malignant cells, is leading to a reexamination of the
frequency and significance of bone marrow infiltration
by lymphoma cells. The PCR technology also may
make it easier to determine whether masses observed
after induction therapy are composed of viable tumor
cells or residual fibrosis. Thus, PCR may necessitate a
reevaluation of disease free survival because the latter
will depend on how diligently the search for microscopic foci of residual primary or metastatic disease
is conducted. This might be particularly problematic
W: Cancer
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CANCER May 15, 1998 / Volume 82 / Number 10
in comparing clinical outcomes from separate trials or
institutions. For these reasons, progression free survival and overall survival may be the most meaningful
clinical end points.
Tumor burden has emerged as a particularly important therapeutic consideration for follicular NHL
patients.9,12,42,55 Defined in terms of the prospectively
defined criteria, these studies support the value of high
tumor burden over that of the Ann Arbor stage alone in
defining a follicular lymphoma population with poor
prognosis. Indeed, in the GELF study, survival of patients with low tumor burden was markedly greater
than those with high tumor burden (78% vs. 57%, respectively, at 5 years).12
Phase III studies show that rIFN-a is well tolerated
and effective for treating clinically aggressive follicular
NHL when administered at dosages ranging from 10 –
20 MIU/m2 sc, weekly. In particular, the GELF concomitant rIFN-a-2b study of follicular lymphoma patients with high tumor burden9,42 as well as the study
by Avilés et al.50 and the German lymphoma study49
of prolonged rIFN-a-2b maintenance demonstrated
good patient tolerance for the 5 MIU/m2 sc, TIW regimen. Because many rIFN-a – associated side effects
generally are dose-related, this dosage minimizes the
acute ‘‘flu-like syndrome’’ as well as the chronic symptoms.56,57
Studies of prolonged rIFN-a maintenance therapy
for minimal residual disease or after response during
initial chemotherapy demonstrate that rIFN-a maintenance significantly prolongs remission. This ability to
prolong time to disease progression in nearly all the
reported Phase III trials validates a therapeutic benefit
for rIFN-a-2b in the treatment of patients with follicular lymphoma.
CONCLUSIONS
Randomized Phase III studies of patients with previously untreated clinically aggressive follicular NHL
requiring therapeutic intervention indicate that rIFNa is associated with prolonged time to treatment failure, and in two studies,42,50 an overall survival benefit.
Recombinant IFN-a also prolongs time to treatment
failure during maintenance therapy in follicular NHL
patients with a high tumor burden with minimal residual disease after dose-intensive cytoreductive chemotherapy. Recombinant IFN-a is an effective choice for
the treatment of follicular lymphoma patients with a
high tumor burden. Phase III studies demonstrate that
rIFN-a is safe and well tolerated in this setting. However, careful case management is important for the
success of rIFN-a therapy.
Phase III studies support the validity of high tumor
burden as a basis for IFN-a treatment decisions re-
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cana
garding follicular NHL. Follicular lymphoma patients
with poor prognostic risk factors achieve clinically
meaningful benefit from the addition of rIFN-a to their
treatment regimens.
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