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.

2082 D. IBRAHIM et al.

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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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