Activity of Esorubicin in Recurrent Malignant Lymphoma: A
`Southwest Oncology Group Study
`
`By Thomas P. Miller, Steve Dahlberg, Sydney E. Salmon, Steven K. Williamson, Robert J. Belt,
`Bruce W. Dana, and Richard I. Fisher
`
`A phase II trial of esorubicin (4' deoxydoxorubicin) was
`conducted by the Southwest Oncology Group in 88
`assessable patients with non-Hodgkin's lymphoma
`(NHL) and Hodgkin's disease (HD) at the time of first
`relapse. Esorubicin was administered at two dose
`levels: 25 mg/m 2 for patients at risk for excessive
`myelosuppression, and at 30 mg/m 2 for all others at
`21-day intervals. Overall, 33 of 88 patients (38%)
`responded to treatment including three complete re-
`missions (CRs; 3%) and 30 partial remissions (PRs;
`34%), with the median duration of response lasting 6.2
`months. Response rates did not differ significantly by
`histologic subtype: 31% of 26 patients with favorable
`
`T HE RESULTS of numerous pilot studies
`conducted over the past 10 years indicate
`that the proportion of patients cured of non-
`Hodgkin's lymphoma (NHL) and Hodgkin's dis-
`ease (HD) may have increased with the formula-
`tion of new doxorubicin-containing combination
`chemotherapy regimens. -3However, a high propor-
`tion of patients relapse following initial chemother-
`apy and eventually die of drug-resistant disease.47
`Even high-dose chemotherapy with autologous
`bone marrow rescue is ineffective for the majority
`
`From the Arizona Cancer Center, Tucson, AZ; Southwest
`Oncology Group Statistical Center, Seattle, WA; University of
`Kansas Medical Center, Kansas City, KS; Kansas City Clinical
`Oncology Program, Kansas City, MO; Oregon Health Sciences
`University, Portland, OR; and Loyola University Stritch School
`of Medicine, Maywood, IL.
`Submitted July 9, 1990; accepted January 30, 1991.
`Supported in part by the following Public Health Service
`Cooperative Agreement grant numbers awarded by the Na-
`tional Cancer Institute, Department of Health and Human Ser-
`vices: CA-13612, CA-37429, CA-46282, CA-12644, CA-35176,
`CA-46113, CA-22411, CA-35109, CA-35438, CA-35117,
`CA-37981, CA-03096, CA-32734, CA-04915, CA-35431,
`CA-45450, CA-42777, CA-36020, CA-35200, CA-35261, CA-
`35262, CA-45560, CA-35996, CA-28862, CA-03389, CA-
`13238, CA-14028, CA-04919, CA-46113, CA-27057, and CA-
`32102.
`Address reprint requests to Southwest Oncology Group
`(SWOG-8406), Operations Office, 5430 Fredericksburg Rd,
`Suite 618, San Antonio, TX 78229-6197
`C 1991 by American Society of Clinical Oncology.
`0732-183X/91/0907-000453. 00/0
`
`NHL, 33% of 43 patients with unfavorable NHL, and
`58% of 19 patients with HD. Twelve of 33 responding
`patients (36%) had relatively durable remissions last-
`ing from 1 to more than 4 years. Leukopenia (< 3,000
`cells per microliter) was seen in 65 of 88 patients (74%)
`and was severe (< 1,000 cells per microliter) in 20 of
`88 patients (23%). Clinical signs or symptoms of con-
`gestive heart failure were not seen and the ejection
`fraction (EF) fell 10% to 20% in three patients. Esorubi-
`cin is an active agent in patients with NHL or HD at the
`time of first relapse.
`J Clin Oncol 9:1204-1209. © 1991 by American Society
`of Clinical Oncology.
`
`of relapsing patients with either NHL or HD.8
`Currently, there is no predictably effective second-
`line (salvage) therapy for these patients.
`Esorubicin (4' deoxydoxorubicin) is an anthracy-
`cline analog synthesized by reduction of the 4'
`hydroxyl group on the aminosugar of doxorubicin.'
`Preclinical studies demonstrated esorubicin to be
`at least as active as doxorubicin against a wide
`range of tumors using both in vivo murine models
`and in vitro human clonogenic assays.1'" Further-
`more, esorubicin was shown to be more than twice
`as potent as doxorubicin, using an in vitro human
`tumor clonogenic assay system." In as. much as
`cardiac toxicity correlates with peak plasma anthra-
`cycline concentration, the increased potency of
`esorubicin at lower plasma concentrations appears
`to offer a cardiac-sparing advantage. Preclinical
`direct comparison studies using a cardiac toxicity
`model demonstrated that esorubicin caused few or
`no cardiac lesions histologically.'0
`Thus, esorubicin was tested in a phase II clinical
`trial in patients with recurrent NHL lymphoma
`and HD to establish its activity as second-line
`therapy.
`
`PATIENTS AND METHODS
`
`Patient Selection
`
`Patients with a histologic diagnosis of malignant lym-
`phoma, including HD and NHL, were eligible for this study.
`All patients had received previous treatment, but prior
`chemotherapy exposure was limited to the following defini-
`tions. Eligible patients with HD had received prior treat-
`
`1204
`
`Journal of Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1204-1209
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1040-0001
`
`

`
`ESORUBICIN AND LYMPHOMA
`
`ment with mechlorethamine, vincristine, procarbazine, and
`prednisone (MOPP) and doxorubicin, bleomycin, vinblas-
`tine, and dacarbazine (ABVD) or a MOPP-ABV hybrid
`combination. Patients with unfavorable histologies of NHL
`(intermediate- and high-grade histologies according to the
`Working Party Formulation) were limited to treatment with
`one prior drug regimen. Patients with favorable histologies
`of NHL (low-grade histologies in the Working Party Formu-
`lation) had received prior treatment with single-agent
`alkalators and/or one drug combination. Thus, esorubicin
`was given as second-line treatment to patients with HD and
`unfavorable histologies of NHL, and as second- or third-line
`treatment to patients with favorable histologies of NHL. All
`patients had measurable disease and a life expectancy of at
`least 8 weeks. Peripheral blood counts were normal (leuko-
`cytes > 3,000 cells per microliter and platelets > 100,000
`cells per microliter) unless there was evidence of bone
`marrow involvement by lymphoma. The serum creatinine
`was less than 2.0 mg/dL and the serum bilirubin was less
`than 2.0 mg/dL. Patients with a previous history of conges-
`tive heart failure or cardiac arrhythmia were ineligible.
`Patients were ineligible if the cumulative dose of prior
`doxorubicin exceeded 350 mg/im. Patients with a prior
`doxorubicin cumulative dose of less than 350 mg/im2 were
`eligible for the protocol provided a radionuclide ejection
`fraction (EF) was greater than 50%. Patients were informed
`of the investigational nature of the study and written
`informed consent was obtained in accordance with institu-
`tional and Food and Drug Administration guidelines.
`
`Treatment Plan
`Based on a phase I study by Garewal et al,' 8 patients
`received esorubicin, 30 mg/im2 as a rapid intravenous (IV)
`infusion over 5 minutes through a side arm of a freely
`running IV infusion unless (1) the patients were older than
`the age of 65 years, (2) had received extensive previous
`pelvic or mediastinal irradiation, or (3) had bone marrow
`involvement with lymphoma resulting in low peripheral
`leukocytes or platelets. These patients received an initial
`dose of esorubicin of 25 mg/m2. Esorubicin was adminis-
`tered every 21 days for a minimum of two cycles of therapy.
`Dose modifications were based on peripheral blood counts
`obtained on the day treatment was due. Forpatients having
`total leukocytes greater than 3,000 cells per microliter,
`granulocytes greater than 1,500 cells per microliter, and
`platelets greater than 100,000 cells per microliter, no
`changes in dose were made. For patients with total leuko-
`cytes of 2,000 to 3,000 cells per microliter, granulocytes of
`1,000 to 1,500 cells per microliter, or platelets of 50,000 to
`100,000 cells per microliter, esorubicin administration was
`delayed until there was peripheral blood count recovery,
`and the dose was reduced by 25%. For patients with total
`leukocytes less than 2,000 cells per microliter, absolute
`granulocytes less than 1,000 cells per microliter, or platelets
`less than 50,000 cells per microliter, esorubicin administra-
`tion was delayed until there was peripheral blood count
`recovery, and the dose was reduced by 50%. Patients
`responding to esorubicin continued to receive the drug until
`there was evidence of disease progression or unacceptable
`toxicity. Cardiac toxicity was monitored with serial radionu-
`clide EFs repeated at intervals of 150 mg/m 2 of esorubicin
`
`1205
`
`administered. The esorubicin was discontinued if there was
`a fall in the EF greater than 10%.
`
`Definitions of Outcome
`
`to treatment was classified as a complete
`Response
`remission (CR) if all clinical evidence of active disease
`resolved for a minimum of 4 weeks. A partial remission
`(PR) was defined as a 50% or greater decrease in the sum of
`the products of the maximum perpendicular diameters of all
`measured lesions lasting at least 4 weeks. Contingency x2
`tests of statistical significance were used to compare remis-
`sion rates. Exact 95% confidence intervals (CIs) for re-
`sponse rates were also calculated. Response duration was
`measured as relapse-free survival (RFS) from the date of
`CR or PR to the first sign of relapse, last follow-up, or
`death. Survival duration was measured from the date of
`registration to the date of death or last follow-up. All causes
`of death are included for survival and RFS estimates.
`Graphic representation of survival and RFS were per-
`formed using the method of Kaplan and Meier." Statistical
`significance between patient groups was performed using
`the log-rank test of statistical significance. 20 All tests are
`two-sided.
`
`RESULTS
`Between August 1984 and March 1988, 97
`patients from 33 institutions were registered onto
`the study. Nine patients were ineligible for the
`following reasons. Three patients had exceeded
`the eligibility criteria for prior treatment, having
`received too many drug regimens before registra-
`tion; two patients began treatment with esorubicin
`before registration; one patient had a serum creat-
`inine exceeding 2.0 mg/dL; and one patient had no
`baseline radionuclide EF. In addition, two pa-
`tients were deemed ineligible after expert histo-
`logic review. Of the 88 eligible patients, 55 had
`received prior doxorubicin (62%) including all
`patients with unfavorable histologies of NHL. For
`patients who had received prior doxorubicin, the
`median cumulative dose was 217 mg/m2 (range, 25
`to 350 mg/m 2).
`Some of the pretreatment patient characteris-
`tics and responses to treatment with esorubicin
`are summarized in Table 1. There were 59 men
`and 29 women with a median age of 61 years
`(range, 20 to 80 years). Overall, 33 of 88 patients
`(38%; 95% CI, 27% to 48%) responded to treat-
`ment. There were three CRs (3%) and 30 PRs
`(34%). All three CR patients previously received
`doxorubicin-containing combination chemother-
`apy and subsequently relapsed within 1 year of
`completing initial treatment. Overall response by
`histologic subtype included eight of 26 patients
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1040-0002
`
`

`
`1206
`
`MILLER ET AL
`
`Table 1. Patient Characteristics and Response to Treatment
`With Esorubicin
`
`Characteristic
`
`All patients
`Histology
`Favorable NHL
`Unfavorable NHL
`Hodgkin's disease
`Initial dose level
`30 mg/m'
`25 mg/m'
`
`No.
`Patients
`
`CR
`
`No.
`
`88
`
`26
`43
`19
`
`39
`49
`
`3
`
`1
`2
`0
`
`2
`1
`
`PR
`
`No.
`
`30
`
`7
`12
`11
`
`14
`16
`
`%
`
`34
`
`27
`28
`58
`
`36
`33
`
`%
`
`3
`
`4
`5
`0
`
`5
`2
`
`with favorable NHL (31%; 95% CI, 14% to 52%),
`14 of 43 patients with unfavorable NHL (33%;
`95% CI, 19% to 49%), and 11 of 19 patients with
`HD (58%; 95% CI, 34% to 80%). Response did
`not vary by the initial dose of esorubicin adminis-
`tered, with responses seen in 16 of 39 patients
`(41%) receiving an initial dose of 30 mg/m2 and in
`17 of 49 patients (35%) receiving 25 mg/m 2 as the
`initial dose (P = .66). Prior treatment with doxoru-
`bicin did not correlate with response to esorubicin,
`with 32 of 55 nonresponding patients (58%) receiv-
`ing prior doxorubicin compared with 22 of 33
`responding patients (67%).
`Twenty-six eligible patients are currently alive,
`and median follow-up for these patients is 26.0
`months (range, 11.0 to 45.5 months). Overall
`survival did not differ significantly by histologic
`subtype (Fig 1, P = .10), but did vary by initial
`dose of esorubicin (P = .02). Those patients older
`than 65 years, those who had previously received
`extensive radiotherapy, and those who had low
`peripheral leukocytes or platelets due to bone
`marrow involvement and received 25 mg/m 2 esoru-
`bicin had a median survival of 8.9 months. The
`median survival was 27.3 months for patients who
`
`1
`
`0
`
`12
`24
`Months After Registration
`
`36
`
`48
`
`Fig 1. Overall survival by histologic subtype for 88 patients
`treated with esorubicin. (-) Favorable NHL, (-) unfavorable
`NHL, (-) HD.
`
`did not have these poor prognostic features, and
`who received an initial dose of 30 mg/m 2 esorubi-
`cin (comparison is not provided as the two patient
`groups are not comparable). RFS for 33 respond-
`ing patients did not differ significantly by histo-
`logic subtype (Fig 2, P = .80) or initial dose of
`esorubicin (P = .24). The median time to relapse
`or death was 2.9 months for eight patients with
`favorable NHL, 24.9 months for 14 patients with
`unfavorable NHL, and 6.2 months for 11 patients
`with HD. Notably, there have been only three
`relapses in 12 responding patients followed from 1
`to 4 years.
`Toxicity of treatment with esorubicin is summa-
`rized in Table 2 for 87 assessable patients (one
`patient did not receive enough esorubicin to allow
`valid toxicity assessments). Table 2 tabulates the
`most severe toxicity during treatment with esorubi-
`cin, including a median of three treatment courses
`(range, one to 33) while administering a median of
`60 mg/m2 (range, 19 to 822 mg/m2). Myelosuppres-
`sion, especially neutropenia, was the most com-
`mon and dose-limiting toxicity. Thirty-two of 39
`patients (82%). treated with 30 mg/m 2 esorubicin
`and 33 of 48 patients (69%) treated with 25 mg/m2
`esorubicin developed leukopenia. The leukopenia
`was life-threatening (< 1,000 cells per microliter)
`in 13 of 39 patients (33%) treated at the higher
`initial dose and in seven of 48 patients (15%)
`treated at the lower initial dose. One patient died
`as a complication of treatment with esorubicin (30
`mg/m2 initial dose) secondary to sepsis associated
`with leukopenia. Three patients were shown to
`have a decrease in the radionuclide EF (2 10%
`change from baseline), but no patient developed
`symptoms or findings to suggest CHF. Phlebitis
`
`100
`
`80
`
`60
`
`40
`
`20
`
`n
`
`0
`
`1 _.
`
`12
`
`·
`24
`Months After Response
`
`36
`
`I.
`I I
`
`48
`
`Fig 2. RFS by histologic subtype for 33 responding patients
`treated with esorubicin including 30 partial responders and 3
`complete responders. (--) Favorable NHL, (-) unfavorable
`NHL, (-) HD.
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1040-0003
`
`

`
`ESORUBICIN AND LYMPHOMA
`
`Table 2. Toxicity of Treatment With Esorubicin for Patients
`Having Severe or Worse Complications Classified According
`to Initial Dose
`
`Esorubicin Dose
`2
`
`30 mg/m
`(N
`39)
`
`2
`
`25 mg/m
`(N
`48)
`
`Toxicity
`
`Alopecia (complete)
`Anemia (hemoglobin < 7 g/dL)
`Cardiac (> 10% decrease in EF)
`Leukopenia
`1,000-2,000 cells/pL
`<1,000 cells/LL
`Vomiting (>6 times)
`Thrombocytopenia
`25,000-50,000 cells/.L
`<25,000 cells/pL
`Phlebitis (severe)
`
`No.
`
`2
`3
`
`7
`13
`3
`
`2
`1
`1
`
`%
`
`5
`8
`
`18
`33
`8
`
`5
`3
`3
`
`No.
`
`%
`
`1
`3
`
`18
`7
`1
`
`2
`3
`2
`
`2
`6
`
`37
`15
`2
`
`4
`6
`4
`
`was relatively common (17 of 87 patients, 20%)
`but gradually resolved without sequelae in most
`instances.
`
`DISCUSSION
`This phase II study indicates that esorubicin is
`an active single agent against NHL and HD as
`gauged by a 38% response rate in, 88 assessable
`patients and a median RFS time of 6.2 months for
`all histologies combined. The duration of re-
`sponses was remarkable for a proportion of pa-
`tients as indicated by the relative flattening of the
`RFS curves at approximately 30% for patients
`with intermediate- and high-grade histologies of
`NHL, slightly higher for patients with low-grade
`histologies of NHL, and at approximately 15% for
`patients with HD. These findings are unusual for
`single-agent therapy of relapsing lymphoma and
`provide some justification for the use of single-
`agent experimental therapy (including drug ana-
`logs) at the time of first relapse in patients with
`malignant lymphomas. These results compare fa-
`vorably with previous Southwest Oncology Group
`phase II trials of single-agent chemotherapy in
`relapsing lymphoma. For example, our previous
`trial of mitoxantrone resulted in a 24% response
`rate in 37 previously treated lymphoma patients
`with a median response duration of 7.7 months.21
`A phase II trial of bisantrene resulted in a 10%
`response rate in 40 patients, with a median re-
`sponse duration of only 4 months.22 However,
`these previous studies included heavily pretreated
`patients, whereas the current study tested esorubi-
`cin at the time of first relapse.
`
`1207
`
`The toxicity of treatment with esorubicin was
`generally acceptable with leukopenia being the
`dose-limiting toxicity in the majority of patients
`(Table 2). The dose chosen for initial treatment
`(25 mgim2 to 30 mg/m2 depending on age and
`previous radiotherapy) appears to be an adequate
`dose of esorubicin, as 52% of patients at each
`dose level achieved significant myelosuppression
`(<2,000 leukocytes per microliter). The higher
`dose of esorubicin used in younger patients with-
`out prior radiotherapy (30 mg/m2) resulted in
`leukopenia below 1,000 cells per microliter in 44%
`of patients. This would appear to be the maximally
`tolerated dose-rate for esorubicin as used in an
`outpatient setting.
`Because preclinical studies suggested that esoru-
`bicin might be less cardiotoxic, evidence of conges-
`tive heart failure was monitored closely. No pa-
`tient developed overt symptoms or physical findings
`of congestive heart failure. Three patients (3%)
`who were all treated at the lower dose-rate of
`esorubicin were shown to have a decline in the EF
`based on serial radionuclide EFs of greater than
`10% and less than 20%. This small frequency of a
`marginal decline in EF may not signal significant
`cardiotoxicity and may more accurately reflect the
`difficulty of reproducing radionuclide EF. Al-
`though we found no conclusive evidence of signifi-
`cant cardiac toxicity, our data may significantly
`underestimate the incidence of cardiac injury, as
`patients received a relatively low total dose of
`esorubicin (median cumulative dose, 217 mg/m2 in
`patients receiving prior doxorubicin). The other
`toxicities as indicated in Table 2 were generally
`infrequent and reversible. Severe episodes of vom-
`iting, thrombocytopenia, and phlebitis were infre-
`quent. A relatively common, but mild or moderate
`side effect, was a syndrome of weakness and
`fatigue associated with esorubicin. The symptoms
`were reversible but could last up to 2 weeks
`following an injection with esorubicin.
`The design of the current trial does not permit
`evaluation of esorubicin non-crossresistance with
`doxorubicin. All patients with intermediate- and
`high-grade NHL and all patients with HD had
`previously received doxorubicin as a component of
`combination chemotherapy as initial treatment. In
`these patients, the doxorubicin was not adminis-
`tered at maximally tolerated dose rates, and clini-
`cal resistance to doxorubicin cannot be deter-
`mined. There was no significant difference
`in
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1040-0004
`
`

`
`1208
`
`response rates between patients with low-grade
`non-Hodgkin's lymphomas who had not received
`any previous doxorubicin and those patients with
`unfavorable histologies of NHL and patients with
`HD who had all received previous doxorubicin.
`However, Hill et a123 have previously shown a
`complete absence of cross-resistance using esoru-
`bicin in a doxorubicin murine lymphoma cell line.23
`More recently, Coley et a124 demonstrated esorubi-
`cin to be moderately effective against a doxorubi-
`cin-resistant human small-cell lung cancer cell
`line, but esorubicin was fully cross-resistant with
`doxorubicin in a murine mammary tumor cell line.
`Thus, there is conflicting in vitro data suggesting
`that esorubicin may be non-crossresistant with
`doxorubicin. A future clinical trial of esorubicin in
`patients carefully selected for doxorubicin-resis-
`tance is justified. Because such patients likely will
`not have received doxorubicin in maximally toler-
`
`REFEREN
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`
`MILLER ET AL
`
`ated single or cumulative doses, other markers of
`doxorubicin resistance, such as p-glycoprotein ex-
`pression, would be of particular interest. 25,26
`The results of the current trial suggest that
`esorubicin is an active single agent in patients with
`malignant lymphoma at the time of first relapse
`based on a 38% response rate and prolonged
`remissions in 36% of responsive patients. Analysis
`of the toxicity of treatment with esorubicin sug-
`gests that 30 mg/m2 is an appropriate dose-rate for
`treatment in an outpatient setting using a 21-day
`schedule and is in accord with the findings of the
`phase I study.18 The activity of esorubicin in
`previously treated patients, together with preclini-
`cal studies suggesting possible non-cross-resis-
`tance with doxorubicin, suggests that esorubicin
`should be pursued as a possibly effective treatment
`option in patients with clinical evidence of drug
`resistance.
`
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