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Phase II Study of PEND Chemotherapy in Patientswith Refractory/Relapsed Hodgkin Lymphoma
DINA IBRAHIMa, MITCHELL R. SMITHb, MARY VARTERASIANc, CHATCHADA KARANESd, MICHAELMILLENSONb, GWEN YESLOWb, PAMELA PEMBERTONa, PING LAIa, JUDITH ABRAMSa, and AYAD AL-KATIBa,*
aLymphoma and Myeloma Service, Division of Hematology/Oncology, Wayne State University, Detroit,Michigan, USA; bLymphoma Service, Fox Chase Cancer Center, and Fox Chase Cancer Center Network,
Philadelphia, Pennsylvania, USA; cPfizer Corporation, Ann Arbor, Michigan, USA; dNational Marrow DonorProgram, Minneapolis, Minnesota, USA
(Received 6 April 2004)
High-dose chemotherapy with autologous marrow or stem cell rescue (HDC/ASCT) is an effectivestrategy in patients with relapsed Hodgkin lymphoma. Various chemotherapy regimens have beenused for cytoreduction prior to HDC/ASCT. In this study, our objective was to determine theresponse rate to PEND in a group of patients with relapsed Hodgkin lymphoma. Nineteen patientswith relapsed or primary refractory Hodgkin lymphoma underwent treatment with the PENDregimen and received a median of 2 cycles (1 – 6 cycles). The PEND regimen builds on our prior resultswith ABDIC and consists of prednisone 40 mg/m2 orally (PO) daily6 5 days; etoposide 50 mg/m2 POdaily6 14 days; mitoxantrone 5 mg/m2/d IV, days 1 and 3; and DTIC 200 mg/m2/d intravenouscontinuous infusion (CIV) over 24 h, days 1 to 5, via central venous catheter. The treatment was givenevery 28 days. There were 3 complete responses (16%) and 10 partial responses (53%) yielding a totalresponse rate of 69% (95% C.I. 43%, 87%). Myelosuppression was the predominant toxicity; nodeaths were due to toxicity. After achieving maximum response to PEND, 10 eligible patients receiveda consolidative treatment with HDC/ASCT. All 6 patients who did not respond to PEND died fromdisease progression whereas 5 of 13 responders were alive after 10 years of follow-up (3 withoutdisease). There were 11 deaths due to disease progression; three from other causes. The initial responseto PEND before subsequent ASCT consolidation treatment appears to be associated with survival.All patients who failed to achieve a response have died. We conclude that PEND is an effectivetreatment strategy in Hodgkin lymphoma patients previously treated with both ABVD and MOPP.
Keywords: Relapsed Hodgkin Lymphoma; Treatment; Chemotherapy; PEND
INTRODUCTION
Treatment outcome of patients with Hodgkin lymphoma
has improved over the last few decades. The majority of
patients with Hodgkin lymphoma can be cured, however
approximately 30% of them may still suffer relapses, most
of those relapses take place within the first 5 years of
treatment [1]. Furthermore, a small percentage of patients
might be refractory to first line chemotherapy [1].
At relapse, the prognosis of patients depends largely
on the presence of specific risk factors like duration of
initial remission [2,3], B symptoms, number of prior
regimens and bulky disease [4]. Various chemotherapy
regimens have been designed to treat patients with
relapsed Hodgkin lymphoma. High dose chemotherapy
and hematopoietic rescue by autologous bone marrow
or peripheral blood stem cells have been incorporated
in the management of such patients [5 – 12]. Outcome of
such treatment strategy seems to depend largely on
prognostic factors at the time of relapse, the presence
of active disease at time of transplantation, chemosen-
sitivity of relapse, and first vs. subsequent relapse [13 –
15].
In this study we treated patients with relapsed
Hodgkin lymphoma, who were candidates for high-
dose chemotherapy, with a novel combination called
PEND (Prednisone, Etoposide, Novantrone, and
DTIC) prior to high-dose chemotherapy. This regimen
*Corresponding author. Address: Lymphoma Research Lab, 740 Hudson-Webber Cancer Research Center (HWCRC), 4100 John R, Detroit, MI48201, USA. Tel: 313-745-8853. Fax: 313-993-0307. E-mail: alkatiba@karmanos.org
Leukemia & Lymphoma, October 2004 Vol. 45 (10), pp. 2079–2084
ISSN 1042-8194 print/ISSN 1029-2403 online # 2004 Taylor & Francis LtdDOI: 10.1080/1042819042000223831
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is a modification of ABDIC [16] in which bleomycin is
omitted to reduce pulmonary toxicity and replaced by
etoposide and doxorubicin is replaced by mitoxantrone
to reduce cardiac toxicity and because virtually all
patients have already received doxorubicin. Our aims
were to determine the response rate of relapsed or
refractory Hodgkin lymphoma to this regimen before
high-dose chemotherapy with autologous marrow or
stem cell rescue. The results show that the PEND
regimen is an effective treatment regimen in patients
with Hodgkin lymphoma previously treated with
chemotherapy.
MATERIALS AND METHODS
Patient Population
To participate in this study, patients had to be more
than 15 years old, have a Karnofsky performance
status 4 60%, and meet the following criteria:
Histologically proven relapsed Hodgkin lymphoma
after prior chemotherapy with MOPP, ABVD, or
MOPP/ABV hybrid regimen; measurable tumor masses;
adequate hematopoiesis, renal and liver functions; and
cardiac left ventricular ejection fraction 4 40%.
Patients were required to have had no chemotherapy,
radiation therapy, or immunotherapy for 4 weeks
before the start of the treatment. All participants
signed an informed consent that was approved by
institutional review boards at Wayne State University
and Karmanos Cancer Institute or at Fox Chase
Cancer Center.
Evaluation
Before therapy, patients underwent a complete history
and physical examination. All prior anticancer treat-
ments were recorded. Laboratory studies included a
complete blood count (CBC), and SMA-18 (lytes,
glucose, blood urea nitrogen, calcium, phosphorus,
total protein, albumin, creatinine, total bilirubin, alka-
line phosphatase, serum glutamic pyruvic transaminase,
serum glutamic oxaloacetic transaminase and lactate
dehydrogenase). All patients had Computerized Axial
Tomography (CAT) scans for objective measurement of
disease within 4 weeks of starting treatment. Gallium
scans were not required. Further tests included bilateral
bone marrow aspiration and biopsy, and 2-D echo-
cardiogram or MUGA Scan and pulmonary functions
test.
During treatment, all patients were monitored every 2
weeks and before each cycle of therapy a CBC was
obtained, and toxicities were evaluated using the National
Cancer Institute toxicity criteria. After the first two
treatment cycles and at the end of therapy any radio-
graphic studies pertinent to measurable or evaluable
disease were repeated.
Response Criteria
Standard criteria for response were applied in determin-
ing response to PEND therapy. Complete response (CR)
is defined as complete disappearance of all clinical and
radiographic evidence of disease for a minimum of 4
weeks. Partial response (PR) is defined as 50% or more
decrease in bidimensional measurements of all tumor
masses for a minimum of 4 weeks. Stable disease (SD) is
designated when there has been no change or less than
50% reduction in bidimensional measurements of all
disease without appearance of new lesions. Progressive
disease (PD) indicates unequivocal increase in size of any
lesion or appearance of new ones.
Treatment Plan
Patients received PEND chemotherapy, consisting of
prednisone 40 mg/m2 orally (PO) rounded to the nearest
10 mg, daily6 5 days; etoposide 50 mg/m2 PO daily
rounded to nearest 25 mg and given as different doses on
alternate days as needed to achieve calculated average
daily dose6 14 days; mitoxantrone 5 mg/m2/d IV days 1
and 3; and DTIC 200 mg/m2/d continuous intravenous
infusion (CIV) over 24 h days 1 to 5 via central venous
catheter (CVC) delivered through portable pumps. The
treatment was generally administered as an outpatient.
The cycles were given every 28 days to maximum response
for ASCT candidates, and for additional 2 cycles after CR
or stable PR or until disease progression in other patients.
Experimental Design
This phase II study was designed using Fleming’s two-
stage design with type I error of 0.05 and statistical power
of 89% [17]. It was assumed that PEND would not be of
further interest if the true response rate was less than 15%
and would be of definite clinical interest if the response
rate were at least 45%. Eleven patients were enrolled in
the first stage and an interim analysis was performed. An
additional 8 patients were enrolled in the second stage for
a total of 19 patients.
Statistical Analysis
The primary endpoint clinical response is reported for
patients accrued during stage I of the study as well as for
all evaluable patients. Duration of response, duration of
best response and overall survival are estimated using
Kaplan-Meier methods. We report median time to event
and 95% confidence intervals (C.I.).
RESULTS
Nineteen patients were treated on the study protocol
between 1993 and 1998. Patients had a median age of 32
years (range 21 to 44); and were predominantly males
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(Table I). Most (84%) had nodular sclerosing Hodgkin
lymphoma; 76% had B symptoms. All had received at
least one previous treatment regimen in the form of
MOPP/ABV hybrid or MOPP alternating with ABVD;
38% had received more than one chemotherapy regimen
before PEND (including 3 patients who had prior high
dose chemotherapy and autologous stem cell transplant).
Of the patients, 42% had prior remissions to first therapy
of less than 12 months duration (6 patients [31.5%] had
remission duration of less than 6 months), and 31% had
refractory disease to either first line therapy or to multiple
subsequent therapies (2 patients had progressive disease
on ABVD, and 4 patients had progressive disease on
salvage regimens).
Response to PEND
At the end of the study, 13 of 19 patients (69%) (95% C.I.
43%, 87%) had a best response of CR or PR (Table II).
The responding patients received a median of 2 PEND
cycles with a range of 1 to 6. There was a difference in
overall response rate (RR) to PEND based on response to
prior therapy. For this purpose, patients who had
achieved CR (11) or PR (1) to last regimen prior to
PEND are considered ‘‘chemo-sensitive,’’ whereas those
with progressive disease (PD, 6) are considered ‘‘chemo-
resistant.’’ The chemosensitivity status of 1 patient to last
regimen prior to PEND could not be determined. Of the
12 patients with sensitive disease, 9 responded to PEND [8
PR, 1 CR (75%)], whereas only 3 of 6 patients (50%) with
resistant disease responded (1 CR, 2 PR). This difference
was not statistically significant (using Fisher’s exact test).
Toxicity
None of the 19 evaluable patients required dose
reduction. More than half (58%) received 2 cycles of
treatment, and 2 patients each received 1, 3, 4 and 6
cycles. There were no deaths due to toxicity of PEND and
no grade-III or -IV non-hematologic toxicity. All patients
developed grade-III or -IV neutropenia, which was
reversible, and grade-II to -III thrombocytopenia, also
reversible; 21% of the patients required red blood cells
transfusions and 10% required platelet transfusions.
Treatment Post PEND
Post PEND therapy is summarized in Table III.
Eleven patients underwent stem cell transplantation
TABLE I Characteristics of patients and treatment
Characteristics
Median Range
Age 32 (21 – 44)
Number Percent
Gender
Male 13 (68)
Female 6 (32)
Ethnicity
Black 2 (11)
Hispanic 2 (11)
White 15 (79)
Stage at initial presentation
I 1 (5)
II 7 (37)
III 3 (16)
IV 8 (42)
Histology
LDHD 1 (5)
LPHD 1 (5)
MCHD 1 (5)
NSHD 16 (84)
No. of Previous regimens
1 12 (63)
2 2 (11)
3 3 (16)
4 2 (11)
Response to last regimen prior to PEND
CR 11 (58)
PR 1 (5)
PD 6 (32)
Unknown 1 (5)
Duration of CR prior to PEND (total= 11)
5 3 months 3 (27)
5 6 months 3 (27)
1 year 5 (46)
No. of PEND Cycles
1 2 (10.5)
2 11 (57.8)
3 2 (10.5)
4 2 (10.5)
6 2 (10.5)
TABLE II Best response to PEND
Stage I (n=11) Both Stages (n=19)
Best Response N Pct N Pct
CR 2 18.2 3 16
PR 5 45.4 10 53
SD 2 18.2 4 21
PD 2 18.2 2 10
TABLE III Post PEND therapy
Post PEND therapy
ResponseBMT
Other No further
to PEND Number Auto Allo Salvage therapy Surgery
CR 3 1 2
PR 10 7 1 1 1
SD 4 3 1
PD 2 2
TOTAL 19 10 1 4 3 1
2081PEND REGIMEN FOR HODGKIN LYMPHOMA
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following PEND therapy (10 autologous and one
allogeneic). Four patients received alternative salvage
therapy (including 2 that did not respond to PEND)
but died of progressive disease. Three patients
received no further therapy (2 that achieved CR
and one PR to PEND). One patient, who achieved
PR after PEND, underwent surgical resection of
residual lung mass.
Overall Survival Analysis
At the time of this analysis, 3 of the 13 responders
to PEND were alive without disease after 10 years (1
of these 3 patients had CR on PEND and needed no
further therapy; and 2 had partial remissions and
later received high dose chemotherapy and ASCT), 2
are alive with disease, 6 died of disease progression, 1
developed MDS and died, and 1 died of bone
marrow transplant complications. Follow-up times
for those still alive range from 8 to 88 months with
a median of 31 months. All the patients who did not
respond to PEND died from disease progression.
Median overall survival is 41 months (Fig. 1). Median
duration of best response (CR or PR) is 12.5 months
(Fig. 2).
DISCUSSION
In this study we treated relapsed Hodgkin lymphoma
patients with the PEND regimen. This regimen was
designed building on our previous experience with
ABDIC regimen [16]. The main goals of this study were
to maintain activity and minimize toxicity since it was
anticipated that patients will receive high dose
chemotherapy and stem cell transplantation subsequent
to PEND. First, bleomycin was deleted from the
original ABDIC to minimize pulmonary toxicity.
Second, doxorubicin (Adriamycin) was substituted by
mitoxantrone (Novantrone). At the time of designing
this study (1992), it was believed that mitoxantrone is
less cardiotoxic than doxorubucin (which was not
substantiated by subsequent clinical studies). Finally,
etoposide was added based on a number of studies of
active regimens that have incorporated this agent [26 –
28]. In this patient population with generally poor
prognostic factors, PEND induced a total response rate
of 69% (compared with 63% in ABDIC), with a median
overall survival of 41 months. Eleven of the 19 patients
(58%) underwent subsequent stem cell transplantation
successfully compared with 37% (7 of 19) in the ABDIC
study.
The prognosis of patients with relapsed Hodgkin
lymphoma depends on a variety of factors that have
been previously identified [18 – 21] and include time to
relapse (5 12 months vs. 4 12 months), presence of B
symptoms and clinical stage. Time to relapse appears to
be the most significant risk factor. Bonfante [22] treated
patients with relapsed Hodgkin lymphoma after MOPP-
ABVD and reported that at 8 years the overall survival
rate was 27%. Patients whose initial complete remission
was longer than 12 months had a survival rate of 54%
whereas those with initial remission of 5 1 year had a
28% survival rate.
A variety of salvage regimens have been used in the
treatment of relapsed Hodgkin lymphoma with variable
results, and response rates range from 45% to 80%
[5,6,9,11,23]. Most of these reports, however, are in Phase
II studies or single institutions series, with heterogeneous
groups of patients, which makes comparing the efficacy of
these different regimens impossible.
The Cancer and Leukemia Group B study had
demonstrated that it was possible to successfully treat
patients with the MOPP regimen after their disease failed
to respond to ABVD [24]. Viviani [25] showed that CR
with salvage MOPP can be achieved in 25% of the
patients but the toxicities associated with MOPP as
salvage therapy, especially in patients who are being
considered for high dose chemotherapy, make the design
of alternative salvage regimens a priority.
Etoposide containing regimens like CAV [26] (CCNU/
melphalan/etoposide), EVA [27] (etoposide, vinscritine,
doxorubicin), MIME [28] (methyl-GAG/ifosfamide/
methotrexate/etoposide) have resulted in 48%, 58%
and 60% total response rates respectively. Patients
FIGURE 1 Overall survival.
FIGURE 2 Best response.
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treated with platinum based regimens have also had high
response rates for instance with ASHAP [29] the total
response rate was 70%, with ICE a response rate of
88% was reported [30], and with DHAP the response
rate was 89% [31]. Mini BEAM regimen [32] (BCNU,
Etoposide, Ara-C, and melphalan) was given as a
cytoreductive treatment for 55 patients with a response
rate of 84% however, this regimen required inpatient
hospitalization and induced significant toxicity so that
61% of patients required admission to the hospital for
febrile neutropenia, and a considerable number of
patients required blood products support/transfusion.
The PEND regimen was administered in an outpatient
setting only 1 patient required admission to the hospital
for febrile neutropenia.
Our patient population had poor prognostic factors
upon relapse, with extensive disease and B symptoms.
Fourteen patients had either refractory disease or disease
which relapsed within 1 year after achieving CR.
Furthermore, 5/19 patients received 3 or 4 prior
chemotherapy regimens, yet they tolerated the PEND
treatment well.
Although this regimen induced a response rate of 69%,
with a median survival of 41 months and compares
favorably with other regimens, further research to
improve these results is still needed, perhaps by using
newer chemotherapy agents like gemcitabine [33] which
has shown encouraging results in the treatment of
relapsed Hodgkin lymphoma, possibly followed by non-
myeloablative allogeneic stem cell transplant to minimize
the toxicity associated with full allogeneic transplant.
In conclusion, our study shows that PEND is an
effective cytoreductive treatment in patients with refrac-
tory or relapsing Hodgkin lymphoma before high-dose
chemotherapy. It can be administered in an outpatient
setting, is well tolerated, and should be considered in
patients with relapsed Hodgkin lymphoma prior to high
dose chemotherapy and autologous bone marrow/
peripheral blood stem cell transplant.
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2083PEND REGIMEN FOR HODGKIN LYMPHOMA
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