Annals of Oncology Advance Access published online on April 10, 2007
Annals of Oncology, doi:10.1093/annonc/mdm090
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© 2007 European Society for Medical Oncology
Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804
1 Siteman Cancer Center, Washington University School of Medicine, St Louis, MO
2 CALGB Statistical Center, Duke University Medical Center, Durham, NC
3 Dana Farber-Partners, Boston, MA
4 University of California at San Diego, San Diego, CA
5 University of Chicago, Chicago, IL
6 Memorial Sloan-Kettering Cancer Center, New York, NY
7 Georgetown University Medical Center, Washington, DC, USA
* Correspondence to: Dr Nancy L. Bartlett, Siteman Cancer Center, Washington University School of Medicine, 660 S Euclid, Box 8056, St Louis, MO 63110, USA. Tel: +314-362-5654; Fax: +314-747-5123; E-mail: nbartlet{at}im.wustl.edu
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Abstract |
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Background: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL).
Patients and methods: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m2, V 20 mg/m2, and D 15 mg/m2 for transplant-naive patients, and G 800 mg/m2, V 15 mg/m2, and D 10 mg/m2 for post-transplant patients.
Results: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively.
Conclusions: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.
gemcitabine, Hodgkin's lymphoma, liposomal doxorubicin, recurrent, salvage therapy, vinorelbine
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Approximately 15%–20% of patients with stage I–II Hodgkin's lymphoma (HL) and 35%–40% of patients with stage III–IV HL relapse after first-line therapy [1, 2]. The current standard of care for most patients with relapsed HL is cytoreductive chemotherapy followed by autologous stem-cell transplant (auto-SCT). This approach can benefit
50% of patients with chemosensitive relapse [3]. For patients with chemorefractory disease at relapse and those in whom auto-SCT failed, the long-term prognosis remains poor [4–6]. Multiple regimens have been used for pretransplant salvage for relapsed HL. No randomized trial exists comparing the effectiveness of these combinations. Historically, there have been two primary approaches. Many centers, especially in Europe, favor aggressive pretransplant regimens such as mini-BEAM (carmustine, etoposide, cytarabine, and melphalan) and Dexa-BEAM [3, 7, 8]. These intensive regimens are associated with significant hematologic toxicity and a 2%–5% treatment-related death rate, similar to rates seen with auto-SCT. Most other centers have utilized platinum-based regimens such as ICE (ifosfamide, carboplatin, and etoposide), DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, solumedrol, cytabarine, and cisplatin), or ASHAP (doxorubicin, solumedrol, cytarabine, and cisplatin) in an effort to introduce noncross-resistant drugs [9–12]. The choice of a pretransplant salvage regimen should be based on the potential to induce high response rates (RRs) with low toxic effects especially to bone marrow stem cells, allowing the majority of patients to proceed without delay to high-dose therapy [3, 7, 13].
Pretransplant cytoreduction represents an excellent opportunity to test new regimens in HL. Regimens with favorable RRs and low toxicity in the relapse setting may also be useful in the initial treatment of HL. Several newer agents, initially approved for use in solid tumors, have shown significant activity in HL. Devizzi et al. [14] reported a 50% RR to single-agent vinorelbine in heavily pretreated patients with relapsed HL. All patients had previous exposure to vincristine and vinblastine. Interestingly, pharmacologic studies show significantly higher pulmonary concentrations of vinorelbine than those achieved with other vinca alkaloids [15]. Lung is the most common extranodal site of HL, and lung involvement at the time of relapse portends a poor outcome with auto-SCT [16]. Phase II studies of single-agent gemcitabine showed RRs of 37% and 43% in relapsed HL [17, 18]. Gemcitabine is a purine analogue that resembles cytarabine in structure and metabolism, but exhibits multiple mechanisms of action and is exceptionally well tolerated when compared with cytarabine [19]. Single-agent pegylated liposomal doxorubicin has not been tested in HL, but would be expected to have significant activity given the effectiveness of doxorubicin. Recurrent HL often remains sensitive to previously administered agents. Potential cardiac toxicity limits the ability to re-treat with doxorubicin; however, the incidence of cardiac toxicity is significantly less with pegylated liposomal doxorubicin [20, 21].
Based on good single-agent RRs and limited toxicity, the Cancer and Leukemia Group B (CALGB) initiated a phase I/II trial to evaluate the combination of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) for relapsed HL. Objectives were to determine the maximum tolerated dose (MTD), toxicity, and efficacy of this combination in patients before transplant and in patients with relapsed HL following an auto-SCT.
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patients and methods |
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From July 2000 to July 2003, 20 CALGB-affiliated institutions accrued patients to this phase I/II trial. The Institutional Review Board of each participating institution approved the protocol and all patients gave written informed consent. Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and study chairperson. As part of the quality assurance program of the CALGB, in order to verify compliance with federal regulations and protocol requirements, members of the Data Audit Committee reviewed on-site medical records for 34% (32/94) of patients registered to this protocol. Statistical analyses were performed by CALGB statisticians. The progress of the phase I portion of the study was monitored via biweekly telephone conference calls involving the study chair, statistician, data coordinator, and treating physicians. Weekly submission of toxicity forms to the study chair from treating institutions was mandatory.
patient selection
Eligibility criteria included relapsed or refractory HL; no prior therapy with gemcitabine, vinorelbine, or pegylated liposomal doxorubicin; measurable disease; absolute neutrophil count (ANC) 
1500/µl; platelets 100 000/µl; bilirubin level 
2.0 mg/dl, creatinine level 2.0 mg/dl, and aspartate aminotransferase (AST) 2 x the upper limit of normal. Left ventricular ejection fraction 45% was required in patients with a lifetime cumulative dose of doxorubicin >400 mg/m2. There was no limit to the number of prior therapies, and patients who relapsed after SCT were eligible. This therapy was not to be considered for patients in lieu of SCT. Transplant candidates could receive two or more cycles of GVD as salvage therapy before the procedure.
treatment plan
Gemcitabine (provided by Eli Lilly and Co., Indianapolis, IN), vinorelbine, and pegylated liposomal doxorubicin (provided by Ortho Biotech, Bridgewater, NJ) were administered on days 1 and 8 of a 21-day schedule. Vinorelbine was administered first for a period of 6–10 min, followed by gemcitabine for 30 min, and then pegylated liposomal doxorubicin for a period of 30–60 min. Phase I dose levels were developed empirically based on the MTD of the single agents and preliminary data on the doublets of vinorelbine/gemcitabine and gemcitabine/pegylated liposomal doxorubicin in solid tumors [22, 23]. Table 1 lists the three dose levels that accrued patients. No dose escalation beyond dose level 1 was planned for patients in whom a prior SCT failed.
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Dose-limiting toxic effects (DLT) were defined as (i) any grade 3 or 4 non-hematologic toxicity except nausea or vomiting, (ii) grade 4 neutropenia for
7 days, (iii) febrile neutropenia, (iv) grade 4 thrombocytopenia associated with life-threatening bleeding or requiring more than one transfusion, or (v) a treatment delay >14 days due to hematologic toxicity. Toxicity grading was according to Common Toxicity Criteria version 2.x. The MTD was defined as the dose at which no more than one of six patients in a single cohort experienced DLT in the first cycle.
GVD doses were decreased one dose level for febrile neutropenia. For patients experiencing febrile neutropenia on dose level –1, the protocol allowed for the institution of granulocyte colony-stimulating factor or granulocyte–macrophage colony-stimulating factor or a 25% dose reduction of gemcitabine and vinorelbine in all subsequent cycles, at the discretion of the treating physician. Recurrence of febrile neutropenia despite a dose reduction warranted discontinuation of protocol treatment. A platelet nadir <20 000/µl required a 25% dose reduction of gemcitabine and vinorelbine in all subsequent cycles. GVD was interrupted until the neutrophil count was 1200/µl and platelet count 100 000/µl on day 1 of each cycle. Day 8 dose modifications included a 25% dose reduction in gemcitabine and vinorelbine for ANC 500–1199/µl or platelets 75–99 000/µl, and a delay until ANC >500 and platelets 75 000/µl. Antiemetics were at the discretion of the treating physician. Patients who experienced an acute infusion-related reaction to pegylated liposomal doxorubicin, defined as flushing, shortness of breath, facial swelling, chills, back pain, or tightness in chest or throat, were premedicated with diphenhydramine 50 mg intravenously (i.v.), an H2 blocker, and hydrocortisone 100 mg i.v. for all subsequent doses.
Patients received a minimum of two cycles and a maximum of six cycles of therapy, unless rapid disease progression or unacceptable toxic effects occurred. Patients were reevaluated for response after every two cycles of GVD. Patients with stable disease (SD) (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) could either continue to a maximum of six cycles or stop treatment at the discretion of the treating physician.
response criteria
Response was evaluated after every two cycles of therapy using published International Workshop Response Criteria for non-Hodgkin's lymphoma (NHL) [24]. All responses were based on computed tomography criteria only. Results of positron emission tomography (PET) scans and gallium scans were not incorporated into response assessment.
statistical considerations
phase I
A traditional phase I design was used. DLT and MTD were determined separately for transplant-naive and post-transplant patients. Three patients were entered at a given dose level. If no DLT was observed in the first cycle for these three patients, the dose was escalated one level for the next three patients entered. If, however, one of the first three patients at the given dose level experienced DLT in the first cycle, three additional patients were entered at the given dose level. If no DLT occurred in these additional patients, the dose was escalated one level for the next three patients entered. If, however, any DLT occurred among the additional patients at the given dose level, the next three patients entered were treated at the next lowest dose level. Because accrual was not suspended pending review of the patients on a given dose level, during the phase I portion of the trial, one additional patient was treated on dose level 1 and two additional patients on dose level 2 than was originally planned.
phase II
The primary objectives were to determine RR and toxic effects. RRs were assessed independently for transplant-naive and post-transplant patients. Within each subgroup, a two-stage design had a 0.83 power and 0.07 significance level to test the null hypothesis that the RR was <0.3 versus the alternative that the RR was at least 0.5. Patients treated in phase I at the MTD were included in the phase II analysis. Overall survival (OS) was measured from trial entry until death from any cause and event-free survival (EFS) was measured from trial entry until documented progression or death from any cause. Survival curves were estimated using the method of Kaplan and Meier [25]. Patients with a partial remission (PR), complete remission (CR) or SD to GVD who went on to receive a SCT were not censored from the EFS curve at the time of transplant and were considered failures only at relapse or death from any cause.
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results |
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Ninety-four patients were registered to the trial. Three patients did not begin protocol treatment (two insurance denials and one incorrect diagnosis) and were excluded from all analyses.
patient characteristics
The median age, upon entry, was 33 years (range 19–83 years). Histology was lymphocyte predominant in two patients and classic HL in the remainder. Of the 91 patients treated, 40 had previously undergone and relapsed from auto-SCT. For the transplant-naive patients (n = 51), 79% had received one prior regimen, 17% two prior regimens, and 4% three or more regimens. Seventy percentage of the prior-transplant patients received three or more prior regimens. Most patients had chemosensitive disease with 84% (61/73 with available data) responding to the most recent treatment, including 89% of patients in whom prior transplant failed. Eighty-seven percentage (67/77 with available data) of patients had received prior ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).
dose levels and DLT/MTD
transplant naive
One of the first three patients treated on dose level 1 had an ANC <500/µl for >7 days and grade 3 elevation of AST during cycle 1. Four additional patients were accrued to dose level 1 with no DLT. The dose was escalated to dose level 2 and one of the first three patients had DLT with an ANC <500 for 14 days, febrile neutropenia, and grade 3 dysphagia and esophagitis. Five additional patients were recruited to dose level 2. One of these five patients spiked a temperature to 106°F immediately following the gemcitabine infusion and required intubation for metabolic acidosis. He was extubated the following day and had no permanent sequelae. This complication was believed to be an idiosyncratic reaction to gemcitabine and unlikely dose related. The last two of the eight patients accrued to dose level 2 had grade 3 mucositis and one had grade 3 rash and desquamation. Dose level 1 was determined to be the MTD. Thirty-six additional patients were treated at dose level 1 in the phase II portion of the study, for a total of 43 patients treated at the MTD.
prior transplant
Three patients were treated on dose level 1. Two patients had febrile neutropenia following cycle 1 and the third patient had an ANC <500/µl for >7 days. The dose level was decreased to dose level –1. None of the first three patients at level –1 experienced DLT. Therefore, level –1 was determined to be the MTD. Thirty-two additional patients were treated at dose level –1 in the phase II portion of the study, for a total of 37 patients treated at the MTD.
toxicity at MTD
Table 2 summarizes the grade 3 and 4 toxic effects for patients treated at the MTD: dose level 1 for the 43 patients with no prior transplant and dose level –1 for the 37 patients who had received a prior transplant. There was one treatment-related death in a 20-year-old woman treated previously with ABVD, mediastinal radiotherapy, and an auto-SCT. The patient was admitted 3 weeks after cycle 5 with new pleural and pericardial effusions. Following pericardiocentesis, she had increasing respiratory distress requiring intubation. She was given a clinical diagnosis of acute respiratory distress syndrome (ARDS) and died 2 weeks later despite aggressive resuscitation efforts. Autopsy revealed extensive alveolar hemorrhage and no evidence of HL. Platelets were normal throughout her hospital course. Febrile neutropenia occurred in 9% (7/80) of patients and documented clinical infection in 5% (4/80). Toxic effects at the MTD were similar in the transplant-naive and post-transplant patients with the following exceptions. Grade 3 or 4 thrombocytopenia occurred in 43% (16/37) of patients with a prior transplant and only in 14% (6/43) of transplant-naive patients. Only two patients required platelet transfusions and there were no clinically significant bleeding episodes except the alveolar hemorrhage described above. Grade 3 or 4 leukopenia (33% versus 16%), neutropenia (63% versus 51%), and mucositis (23% versus 0%) were more common in transplant-naive patients. Significant fatigue, nausea, vomiting, or alopecia was uncommon. There have been three cases of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) reported, all following an auto-SCT. Patient characteristics and cytogenetics for these three patients are described in Table 3. Two of the patients received GVD before transplant and one as salvage after transplant.
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treatment delivery at MTD
Transplant naive
Forty patients received more than one cycle of therapy at the MTD. Of the 248 scheduled doses (124 cycles), 14% were reduced and 13% delayed. The majority of delays and dose reductions were due to a low neutrophil count, with a minority due to delayed platelet recovery. Only 32% of patients received all doses on schedule at full dose.
prior transplant
Of the 32 patients who received more than one cycle of therapy at the MTD, complete data are available on dose delivery for 31. Of the 298 scheduled doses (149 cycles), 5% were missed, 14% were reduced, and 11% were delayed. The most common reasons for dose reduction or delay were thrombocytopenia followed by neutropenia. Only 26% of patients received all doses on schedule at full dose.
response
Of the 91 patients treated, eight received fewer than two cycles of chemotherapy and had no follow-up scans before going off protocol treatment (Figure 1). Five of these eight patients were removed from protocol treatment due to toxicity; their response is labelled indeterminate in Table 4, in which RRs are shown for each dose level, and they are considered as failures in the response analysis. Four of these five patients had prior transplants and were treated at dose level –1; they had persistent cytopenias after cycle 1 and were removed from protocol therapy per protocol guidelines after treatment was delayed >2 weeks. One of the five patients was transplant naive, was treated at dose level 2, and went off protocol treatment immediately after his first dose secondary to fever and metabolic acidosis requiring intubation immediately following gemcitabine infusion. Three of the eight inassessable patients went off protocol therapy due to nontreatment-related reasons; they are not assessable for response, are not included in Table 4, and are not included in the efficacy analysis. One of these three patients was transplant naive and was treated at dose level 1, and transferred care to a more convenient hospital after one cycle. Two of the three patients, one with prior transplant and treated at dose level –1 and the other transplant naive and treated at dose level 1, went on to allogeneic transplant after one cycle without restaging scans before transplant.
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The overall RR for all patients was 70%, with CR in 19% and PR in 51%. RRs are shown in Table 4 for each dose level. For the transplant-naive group, overall RR at the MTD was 61% [25/41; 95% confidence interval (CI) 44.5, 75.8]. Fifteen (37%) transplant-naive patients had SD at dose level 1. Twelve of the 15 patients had minor responses with decreases of 13%–47% (median 38%) in the sum of the product of two-dimensional measurements; three of the 12 had negative PET scans. All 15 patients with SD went on to transplant without additional salvage therapy, and 10 of 15 remained in remission. The only transplant-naive patient with progressive disease on therapy had lymphocyte-predominant HL. The RR at the MTD for the prior-transplant patients was 75% (27/36; 95% CI 57.8, 87.9) with 17% CR (6/36; 95% CI 6.4% to 32.8%). There was no difference in RRs to GVD for patients with 1, 2, or
3 prior regimens (data not shown).
survival
Figures 2 and 3 show the EFS and OS rates for all patients registered to the study according to whether they had a prior transplant or not. Patients in the transplant-naive group were not censored at the time of transplant. Therefore, the EFS and OS curves for this group represent the outcome with GVD plus autologous SCT in the majority of patients. Median follow-up time among the patients still alive is 3.6 years (range 1.9–4.8 years). For the transplant-naive patients, the median duration for EFS has not been reached with 52% (95% CI 0.34, 0.68) progression free at 4 years. The median duration of EFS was 8.5 months (95% CI 0.57, 0.82) in the patients with prior transplant. Of the 49 assessable patients in the transplant-naive group, 39 went on to transplant following GVD therapy, including 34 of 41 treated at MTD (82.9%). Seven of the 10 patients who did not go on to transplant were 62 years old and were not referred for transplant, presumably because of age or comorbidities. Of the three younger patients who did not go on to transplant, one refused and two were not referred for transplant because of long first remissions. Of the 10 patients who did not go on to transplant, five were treatment failures including two deaths. The other 5 patients are alive and in remission at 3+ years (range 3.3–4.8 years) following GVD alone. The 4-year EFS for the group who did go on to transplant is 0.53 (95% CI 0.32, 0.71) compared with 0.5 for the 10 patients who did not have a transplant. We did not gather formal data on peripheral stem-cell harvests following GVD, but all patients where transplant was part of the planned therapy were able to undergo the procedure implying adequate collections.
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The median OS has not been reached for the transplant naive with 70% (95% CI 0.49, 0.84) alive at 4 years. Median OS for the prior-transplant group was 3.5 years. Cause of death was known in 34 of 36 patients including alveolar hemorrhage/acute respiratory distress syndrome related to protocol therapy as described above (n = 1), progressive HL (n = 27), chronic obstructive pulmonary disease (n = 1), secondary AML (n = 1), and transplant-related complications (n = 4). All four of the transplant-related deaths were following second transplants in patients who received GVD after failing a first transplant.
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discussion |
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GVD is an effective and well-tolerated pretransplant salvage regimen. Outpatient administration and modest toxicity make it an attractive alternative to more intensive regimens such as ICE, ESHAP, or Dexa-BEAM. There were no toxic deaths in the transplant-naive group and the incidence of febrile neutropenia was only 7%. Growth factors were not routinely administered. As is often the case in HL, the RR by International Workshop Response Criteria may underestimate the benefit of the therapy because of residual radiographic abnormalities. The maximal response to GVD may not have been appreciated in patients who proceeded to transplant after two or more cycles of GVD. The EFS or progression-free survival rates continue to be the most accurate determination of outcome in HL.
Comparison of response, OS, and EFS rates of pretransplant salvage regimens is difficult [3, 8, 9, 11, 12, 26]. Some series such as the large randomized trial of Dexa-BEAM ± auto-SCT report follow-up only for patients who responded to Dexa-BEAM [3]. Other reports include follow-up on all patients participating in the conventional salvage protocol, regardless of additional therapy. Three-year EFS rates range from 27% for ESHAP, where only nine of 22 patients went on to transplant, to 58% for ICE, where 56 of 65 patients went on to transplant [9, 11]. The 3-year EFS rate of 62% for all 49 transplant-naive patients who received GVD, with 39 going on to auto-SCT, compares very favorably with all other reported series.
Other recently described gemcitabine-based salvage regimens have also reported low rates of grade 3–4 toxicity and RRs in the range of those seen with more toxic regimens [26, 27]. Investigators for the National Cancer Institute of Canada reported on 23 patients with relapsed HL treated with gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, and dexamethasone 40 mg/day on days 1–4 every 21 days [27]. Overall RR was 70% with no grade 4 neutropenia or thrombocytopenia, 8% grade 3 neutropenia, and 13% grade 3 thrombocytopenia. All patients had successful stem-cell collection and underwent auto-SCT. Chau et al. [26] reported an 80% RR in 21 patients with refractory or recurrent lymphoma (10 HL and 11 NHL) treated with gemcitabine 1000 mg/m2 on days 1, 8, and 15; cisplatin 100 mg/m2 on day 1; and methylprednisolone 1000 mg/day on days 1–5 every 28 days. The only grade 3–4 toxicity was myelosuppression. There were no reported cases of febrile neutropenia.
For patients relapsing after auto-SCT, GVD resulted in high RRs; however, the median EFS was only 8.5 months. The short remission duration suggests prolonged therapy until relapse may be more useful. Seventy-four percentage (29/39) of patients completed four or more cycles and 49% (19/39) received all six cycles. Given the lack of known cumulative toxicity with any of the agents in GVD, additional cycles may be feasible. Interestingly, the 3-year OS for the 39 patients in whom prior transplant failed was 55%, compared with 35% recently reported by Grupo Español de Linfomas /Trasplante Antólogo de Médula Ósea for 175 patients with relapsed HL after auto-SCT [6]. This excellent OS despite high relapse rates may reflect the excellent tolerability and low septic death rate of GVD in this vulnerable population. Because the majority of patients with HL remain chemosensitive to a nonalkylating agent regimen after failing auto-transplant, this setting is reasonable to test activity of new agents for HL.
The schedule of GVD was based on regimens designed for use in solid tumors [28]. Subsequent studies in patients with solid tumors show that higher doses of gemcitabine can probably be administered on a day 1 and 15 schedule every 28 days, compared to a day 1 and 8 schedule every 21 days. In a phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with refractory solid tumors, Fracasso et al. [23] recommended pegylated liposomal doxorubicin 20 mg/m2 and gemcitabine 2000 mg/m2 days 1 and 15 every 28 days as the phase II dose. A phase I trial of a day 1 and day 15 schedule every 28 days of gemcitabine and vinorelbine showed that the MTD was not reached at vinorelbine 30 mg/m2 and gemcitabine 3000 mg/m2 [22]. A phase II study in lung cancer patients administered vinorelbine 35 mg/m2 and gemcitabine 1200 mg/m2 on days 1 and 15, every 28 days with only one of 27 patients experiencing grade 3 neutropenia [29]. There was no thrombocytopenia or other grade 3–4 toxic effects. A day 1 and day 15 schedule would also make the administration of growth factors between doses more feasible. We made no attempt to increase the dose of gemcitabine or vinorelbine after unacceptable toxicity was seen when the dose of pegylated liposomal doxorubicin was increased. A more comprehensive phase I study would be needed to test escalation of all drugs in the regimen sequentially and should probably be undertaken if this regimen is to be considered as first-line therapy.
While ABVD has excellent activity as first-line therapy HL, there are certain settings where the toxicity profile of this regimen is of greater concern. Older patients, especially those with underlying cardiopulmonary disease, have significantly more toxicity with ABVD. In patients with HL over the age of 60 years treated on CALGB 8251 or 8952, protocols comparing ABVD with combination chemotherapy with mechlorethamine, vincristine, procarbazine and prednisone (MOPP), MOPP/ABV hybrid or MOPP/ABVD, there was a 19% and 15% toxic death rate, respectively, with nearly equal numbers of deaths in all arms (J. L. Johnson, personal communication). GVD might provide an excellent alternative for front-line therapy in treating older patients or those in whom bleomycin should be avoided. Other settings where a regimen for HL with less potential cardiopulmonary toxicity may be particularly advantageous include patients with bulky mediastinal HL and pediatric HL. The incidence of anthracycline cardiac toxicity is significantly higher in young children, even at doses <240 mg/m2 of doxorubicin [30]. Overlapping toxic effects are also a potential problem with the use of ABVD and mantle radiotherapy in bulky mediastinal HL.
GVD is a well-tolerated, active regimen for relapsed HL which can be used as pretransplant salvage for patients in whom transplant failed. Potential future studies suggested by our results include evaluating a day 1 and day 15 schedule in an effort to escalate vinorelbine and gemcitabine without additional toxicity, and comparing GVD with other pretransplant salvage regimens such as ICE or DHAP in a randomized trial to evaluate RR, toxicity, and quality of life. CALGB is currently studying GVD in relapsed HL with the anti-CD30 mAb SGN-30 based on preclinical data showing synergy between SGN-30 and these agents.
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Acknowledgements |
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The research for CALGB 59804 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky). NLB was supported by grant CA77440, DN by CA33601, JLJ by CA32291, KBJ by CA11789, KvB by CA41287, ADZ by CA77651, BDC by CA77597, and GPC by CA32291. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.
The following institutions participated in this study: CALGB Statistical Center, Durham, NC—Stephen George; Dana Farber-Partners, Boston, MA—George P Canellos; Dartmouth Medical School–Norris Cotton Cancer Center, Lebanon, NH—Marc S. Ernstoff, supported by CA04326; Georgetown University Medical Center, Washington, DC—Edward Gelmann, supported by CA77597; Grand Rapids Clinical Oncology Program, Grand Rapids, MI—Kathleen J. Yost; Illinois Oncology Research Assoc, Peoria, IL—John W. Kugler, supported by CA35113; Massachusetts General Hospital, Boston, MA—Michael L. Grossbard, supported by CA12449; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC—James N. Atkins, supported by CA45808; Syracuse Hematology–Oncology Assoc. CCOP, Syracuse, NY—Jeffrey Kirshner, supported by CA45389; The Ohio State University Medical Center, Columbus, OH–Clara D Bloomfield, M.D., supported by CA77658; University of California at San Diego, San Diego, CA—Joanne Mortimer, supported by CA11789; University of California at San Francisco, San Francisco, CA—Alan P. Venook, supported by CA60138; University of Chicago Medical Center, Chicago, IL—Gini Fleming, supported by CA41287; University of Iowa, Iowa City, IA—Gerald Clamon, supported by CA47642; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO—Michael C Perry, supported by CA12046; Wake Forest University School of Medicine, Winston-Salem, NC—David D. Hurd, supported by CA03927; Walter Reed Army Medical Center, Washington, DC—Thomas Reid, supported by CA26806; Washington University School of Medicine, St Louis, MO—Nancy Bartlett; Weill Medical College of Cornell University, New York, NY—Scott Wadler, supported by CA07968.
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Footnotes |
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N. L. Bartlett designed research, performed research, analyzed data, and wrote the paper; D. Niedzwiecki designed research and analyzed data; J. L. Johnson designed research, collected data, and analyzed data; J. W. Friedberg treated significant proportion of patients on trial and edited the paper; K. B. Johnson treated significant proportion of patients on trial and edited the paper; K. van Besien treated significant proportion of patients on trial and edited the paper; A. D. Zelenetz designed research; B. D. Cheson edited the paper; and G. P. Canellos designed research and edited the paper.
Received for publication September 11, 2006. Revision received February 12, 2007. Accepted for publication February 13, 2007.
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References |
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