Biology of Blood and Marrow Transplantation
Volume 16, Issue 8 , Pages 1145-1154, August 2010

Phase I/II Trial of GN-BVC, a Gemcitabine and Vinorelbine-Containing Conditioning Regimen for Autologous Hematopoietic Cell Transplantation in Recurrent and Refractory Hodgkin Lymphoma

  • Sally Arai

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • Corresponding Author InformationCorrespondence and reprint requests: Sally Arai, MD, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305.
    • ,
  • Renee Letsinger

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Ruby M. Wong

      Affiliations

    • Department of Health Research and Policy, Division of Biostatistics, Stanford University Medical Center, Stanford, California
    • ,
  • Laura J. Johnston

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Ginna G. Laport

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Robert Lowsky

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • David B. Miklos

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Judith A. Shizuru

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Wen-Kai Weng

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Philip W. Lavori

      Affiliations

    • Department of Health Research and Policy, Division of Biostatistics, Stanford University Medical Center, Stanford, California
    • ,
  • Karl G. Blume

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Robert S. Negrin

      Affiliations

    • Department of Medicine, Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
    • ,
  • Sandra J. Horning

      Affiliations

    • Division of Medical Oncology, Stanford University Medical Center, Stanford, California

Received 31 January 2010; accepted 22 February 2010. published online 02 March 2010.

Article Outline

Abstract 

Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m2, and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Key Words: Autologous, Transplantation, Hodgkin lymphoma

 

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Introduction 

High-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) is an effective treatment for patients with recurrent Hodgkin lymphoma (HL). Randomized controlled trials have shown improved freedom from progression (FFP) with high-dose BEAM (carmustine 300 mg/m2, etoposide, cytarabine, and melphalan) and AHCT over conventional salvage chemotherapy in chemosensitive patients 1, 2. The German Hodgkin Lymphoma Study Group/European Bone Marrow Transplant Registry (GHSG/EBMT) randomized trial of BEAM-AHCT versus Dexa-BEAM showed a 3-year FFP of 55% versus 34%, respectively [2]. Attempts to improve on FFP in AHCT have included further intensification of salvage therapy before transplant 2, 3, 4, 5, 6, 7, or intensification of the transplant conditioning regimen itself either with high-dose sequential therapy 8, 9 or with augmented carmustine (BCNU)-based regimens 10, 11, 12, 13, 14, 15, 16. With increasing doses of BCNU from 300 mg/m2 to 600 mg/m2, however, the incidence of pulmonary toxicity increases to 35% and higher 17, 18, 19, 20. When oral lomustine (CCNU) was substituted for BCNU in the conditioning, the interstitial pneumonitis incidence was as high as 63% [19]. Further, BCNU toxicity is likely underreported because symptoms of fever, fatigue, nausea, poor appetite, and weight loss are often not attributed [21]. Although it typically responds rapidly to corticosteroid therapy, the dose-related BCNU syndrome can be potentially life-threatening 22, 23, 24. The high-dose BCNU regimen most commonly reported in the literature is CBV (cyclophosphamide [Cy], carmustine 300 mg/m2, and etoposide) [25]. As previously reported by the Stanford group [12], our variation of the CBV regimen, which utilized high-dose BCNU at a maximum of 550 mg/m2, was associated with early (within 100 days posttransplant) and late (approximately 6 months posttransplant) treatment-related deaths, primarily respiratory (4% early respiratory deaths and 7% late respiratory deaths).

Gemcitabine and vinorelbine are active drugs in patients with HL with mechanisms of action distinct from alkylating agents 26, 27, 28, 29, 30, 31, 32. We hypothesized that these drugs would allow for reduction of the BCNU dose in conditioning, thereby reducing early and late adverse effects of this agent. The combination of gemcitabine and vinorelbine on days 1 and 8 was taken from solid tumor experience 33, 34, 35, 36, 37, 38. In this phase I/II study our goals were to reduce the BCNU dose from 550 mg/m2 to 350 mg/m2 in an effort to reduce the risk of pulmonary toxicity while simultaneously adding gemcitabine and vinorelbine in an effort to maintain or improve efficacy. We report the phase I/II experience of utilizing this 5-drug regimen for the treatment of 92 patients with relapsed or refractory HL.

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Patients and Methods 

Patient Selection 

Eligibility criteria included histologically proven, recurrent or refractory HL confirmed at Stanford University; aged ≤70 years; ECOG performance status 0-2. Adverse risk factors have been previously defined [12] as: (1) stage IV disease at relapse, (2) constitutional “B” symptoms at relapse, and (3) failure to achieve minimal disease (single lymph nodes ≤2 cm or >75% reduction in a bulky tumor mass or bone marrow [BM] involvement ≤10%) at transplant. High-risk HL patients were defined as those who had 1 or more of the above risk factors. All patients signed informed consent for the study approved by the institutional review board at Stanford University School of Medicine. Pretransplant testing included routine staging with medical history, physical examination, computed tomography (CT) with or without positron emission tomography (PET), BM aspiration, and biopsy with cytogenetics, baseline assessment of cardiac ejection fraction, and pulmonary function tests (PFTs). Patients with ejection fraction <40% and diffusion capacity corrected for hemoglobin <55% were not eligible for the study.

The first 7 patients all had high risk features and were enrolled in the phase I dose escalation study to determine the maximum tolerated dose (MTD) of gemcitabine. In phase II, all risk category patients were accepted.

Study Design 

In phase I, gemcitabine was dose-escalated at planned doses of 1250 mg/m2, 1500 mg/m2, and 1800 mg/m2, in combination with vinorelbine 30 mg/m2 on days −13 and −8, followed by a lowered dose of BCNU (10 mg/kg and capped at 350 mg/m2, compared to our standard dose of 15 mg/kg, capped at 550 mg/m2) on day −6, etoposide 60 mg/kg on day −4, and Cy 100 mg/kg on day −2. Cohorts of 3 high-risk patients proceeded at each gemcitabine dose level. Any grade III or IV nonhematologic toxicity constituted an adverse event.

The phase II portion of the study enrolled additional patients at the gemcitabine MTD.

Autologous Hematopoietic Cell Transplantation 

Patients' peripheral blood hematopoietic cells (PBHC) were mobilized from their salvage chemotherapy, or from cyclophosphamide 4 g/m2 with granulocyte-colony stimulating factor (G-CSF) (10 μg/kg per day), or from G-CSF alone per the treating physician's discretion. No specific recommendation was given for salvage chemotherapy prior to AHCT; however, 40 patients received DHAP (dexamethasone, cytarabine, cisplatin) [3], 35 patients received ICE (ifosfamide, carboplatin, etoposide) [5], and 17 patients received other chemotherapy combinations, including 2 with a gemcitabine combination. Leukaphereses were performed until ≥2 × 106 CD34 cells/kg were collected. The apheresis product was cryopreserved per institutional practice and infused on transplant day 0.

Supportive Care 

Patients received prophylactic antimicrobial treatment including ciprofloxacin, fluconazole, acyclovir, and trimethoprim-sulfamethoxazole. Low-dose intravenous heparin (100 U/kg/day) as a continuous infusion was used for prevention of sinusoidal obstruction syndrome (SOS), formerly referred to as hepatic veno-occlusive disease [39]. Patients received G-CSF beginning on day +6 after AHCT.

BCNU Toxicity 

Clinically significant BCNU-related toxicity was defined as a noninfectious syndrome of 1 or more of the following: low-grade fever, dyspnea, fatigue, nausea, poor appetite, weight loss, dry cough, pulmonary infiltrates, or a decrease in diffusing capacity of up to 20% from pretransplantation levels that, in the judgment of the treating physician, required corticosteroid therapy in the first 100 days posttransplant. The BCNU toxicity syndrome was assessed in all patients and categorized as either predominantly pulmonary or gastrointestinal (nausea, poor appetite, and weight loss) [21], based upon symptoms. Pulmonary function testing was repeated whenever possible for symptomatic patients suspected of having the BCNU toxicity syndrome.

Response Evaluation 

The disease status of all patients was evaluated prior to transplantation utilizing CT or PET-CT imaging and BM exam. Posttransplant restaging with CT or PET-CT imaging was performed routinely at 3 months, 6 months, 1 year, 18 months, 2 years, and annually thereafter until year 5 after transplantation. A BM biopsy was performed once at 3 months posttransplant and thereafter as clinically indicated. Response to therapy was assessed according to the revised response criteria for malignant lymphomas [40]. PET response followed the guidelines put forth by Hutchings et al. [41] and Gallamini et al. [42], which categorized patients as positive, negative, or minimal residual uptake (MRU, defined as standardized uptake value of 2.0 to 3.5). Patients with PET results showing MRU were considered PET negative for the purposes of analysis.

Posttransplantation Radiation Therapy 

Radiation therapy was administered to selected patients following transplantation based on previously published criteria [43]. Posttransplant radiation therapy was typically administered 2-3 months after transplantation.

Statistical Analysis 

The goal of the phase I portion of the study was to define the regimen-related toxicity and to determine the MTD for gemcitabine. The primary endpoint for the phase II portion of the study was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year FFP, event-free survival (EFS), and overall survival (OS) at the gemcitabine MTD. Probabilities of FFP, EFS, and OS over time were estimated with the product-limit method of Kaplan and Meier [44]. Progression of HL was the only event defined in FFP, with censoring at time of nonrelapse death. Disease progression and death from any cause defined events in the calculation of EFS. All calculations were made from the date of transplantation.

The Fisher's exact test or Pearson chi-square test was used to examine correlations across prognostic factors. Cox regression was used in both univariate and multivariate analyses for each of the outcome variables (FFP, EFS, and OS). The Wald test was used in testing hypotheses on covariates. Results from correlation and univariate analyses guided the selection of variables in the multivariate stepwise regression analyses. The log rank test was used to compare survival curves.

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Results 

Patient Characteristics 

From September 2001 to March 2008, 114 patients were prospectively screened for enrollment on the trial at Stanford University Medical Center. Eighteen patients were deemed ineligible because of diffusion capacity for carbon monoxide (DLCO) corrected for hemoglobin <55% (2 patients), history of recent pulmonary embolus or radiation pneumonitis (2 patients), active uncontrolled infection (2 patients), known allergy to etoposide (1 patient), a history of grade 3 hemorrhagic cystitis with Cy (1 patient), equal to or greater than grade 2 sensory or motor peripheral neuropathy from prior vinca alkaloid (2 patients), prior malignancy (3 patients), and inadequate PBHC collection (5 patients).

In phase I, 3 patients received gemcitabine at 1250 mg/m2 without dose-limiting toxicity. Four patients proceeded to gemcitabine 1500 mg/m2, where the dose-limiting toxicity was reached in 3 of the patients based on grade 3-4 elevated liver transaminases and a symptom complex of fever, headache, and skin toxicity. These 4 patients treated at gemcitabine 1500 mg/m2 were excluded from phase II analysis. A total of 92 patients were treated at the gemcitabine MTD of 1250 mg/m2, including the first 3 patients in phase I and an additional 89 patients in phase II, to determine the safety and efficacy for the phase II analysis.

The pretransplant characteristics for the 92 patients are shown in Table 1.

Table 1. Patient Characteristics
CharacteristicTotal n = 92
Median age at transplant in years33 (range 18-64)
Sex
Male48
Female44
Initial remission duration
Induction failure36
≤1 year34
>1 year22
Prior RT history
None46
Single course of RT alone2
Combined modality44
No. prior chemotherapy regimens∗
One2
Two74
Three or more16
Primary chemotherapy
ABVD60
Stanford V32
Status at transplant
Complete remission/minimal disease53
Partial remission32
Stable disease1
Progressive disease6
PET status at transplant†
Positive29
Minimal residual uptake (SUV 2.0-3.5)6
Negative42
Not done15
Risk factors
Stage IV at relapse29
B symptoms at relapse39
>Minimal disease at transplant39
No. of risk factors at transplant‡
024
137
223
38

PET indicates positron emission tomography.

∗Includes cytoreduction prior to transplant.

†Based on 77 patients who had PET-CT scans.

‡Risk factors defined as stage IV at relapse, B symptoms at relapse, more than minimal disease at transplant.

Thirty-six patients (39%) were characterized as primary induction failures. Primary induction failure was defined as progression of disease during induction treatment, or initiation of second-line treatment, or response of <60 days duration [35]. Fifty-six patients (61%) had previously achieved a CR (duration >1 year in 22 patients and ≤1 year in 34 patients). Before transplantation, most patients received cytoreductive chemotherapy with the goal of achieving a minimal disease state. Typical cytoreduction consisted of 2 to 3 cycles of combination chemotherapy.

Status at transplant referred to the response to cytoreductive chemotherapy just prior to transplantation. Eighty-five patients (92%) responded to treatment before transplant conditioning. Complete remission or a minimal disease state was achieved in 53 patients (58%). Only 7 patients had stable or progressive disease. With regard to the previously defined 3 adverse risk factors for prognosis [12], 24 patients (26%) had no risk factors, and 68 (74%) had 1 or more risk factors.

PET status at the time of transplantation was recorded in 77 patients. Thirty-eight percent (29/77) of patients were PET positive at time of transplant, 55% (42/77) were PET negative, and 8% (6/77) had MRU.

Hematopoietic Recovery 

The median time to absolute neutrophil count (ANC) >500/μL was 10 days (range: 8-17). The median time to untransfused platelet count of 20,000/μL was 15 days (range: 8-34).

Posttransplantation Involved Field Radiation Therapy 

Twenty-two patients received posttransplantation involved field radiation. The posttransplant radiation dose ranged from 1200-3600 cGy, depending on previous radiation treatment and normal tissue tolerance. Fourteen patients received posttransplant regional irradiation (modified mantle or inverted Y) to a total dose of 3600 cGy, whereas the remaining 8 patients had variable doses to a single radiation field.

Toxicity 

Three patients (3%) suffered early treatment-related mortality. The causes of early death were fungal infection in 2 patients (day +12 and day +15) and severe SOS in 1 patient (day +34). Fever and mucositis were the most common grade 3 toxicities, followed by transaminase elevations, skin rash, headache, and culture positive infections. Grade 4 toxicities occurred in only 2 patients and in both cases were related to elevated transaminases. Table 2 lists grade 3-4 toxicities.

Table 2. Regimen-Related Toxicities
N (%)
ToxicityGrade 3Grade 4Grade 5
Fever58 (63)
Mucositis63 (68)
Skin rash22 (24)
Headache6 (7)
Elevated transaminases37 (40)2 (2)
SOS 1 (1)
Cardiac (tamponade) 1 (1)
Infection
Bacterial8 (9)
Fungal2 (2) 2 (2)

SOS indicates sinusoidal obstruction syndrome.

Total N= 92 patients.

BCNU-Related Toxicity 

The incidence of BCNU-related toxicity in this study was 15% (14 of 92 patients, 95% confidence interval (CI) 9% to 24%). Table 3 shows the BCNU toxicity characteristics. Only 2 patients had a documented decrease in DLCO of ≥20%, although 8 others had 1 or more respiratory symptoms, of whom 3 did not have formal pulmonary function testing. All patients recovered from the BCNU-toxicity symptoms with corticosteroid therapy, which was administered at an initial dose of 1 mg/kg/day with a taper of 10 mg per week as tolerated. BCNU-related toxicity was not more prevalent in patients with a history of chest irradiation. There was 1 late pulmonary death (day +532) from adult respiratory distress syndrome (ARDS).

Table 3. BCNU-Related Syndrome Characteristics
Respiratory Signs/SymptomsNonrespiratory Signs/Symptoms
SPN% DLCO declineCDXFMGIDay Onset
399231● ● 42
383727●● 46
372916● ●● 60
30798●● ● 71
38806● ●● 37
3075ND●● ● 44
343519 ● ● 33
368616 ● ● 51
3482ND ●● 97
3756ND ● ●●56
361518 ● 52
402311 ●●68
37899 ●●50
3350ND ● ●44

C indicatres cough; D, dyspnea; X, abnormal CXR; F, fever; M, malaise; GI, nausea; SPN, Stanford patient number; DLCO, diffusing capacity for carbon monoxide.

Survival Data 

The median follow-up of the entire group of 92 patients is 29 months (range: 8-86 months). Figure 1 illustrates the Kaplan-Meier survival curves for the entire population. FFP at 2 years was 71% (CI 61%-81%) and EFS at 2 years was 67% (CI 57%-77%). The actuarial 2-year OS was 83% (CI 75% to 91%). The 2-year nonrelapse mortality (NRM) for the entire study was 6%. Causes of NRM included candidemia, pulmonary fusariosis, severe SOS, pulmonary embolus, and ARDS. There were 16 deaths, 11 from relapse and 5 from NRM. Twelve patients with relapse are still alive. Of the 7 patients with advanced disease status at transplant (1 with stable disease and 6 with progressive disease) (Table 1), 3 patients relapsed within 4 months of transplant and subsequently died; 1 patient died from complications of SOS at 1 month posttransplant and was too early for disease follow-up, and 3 patients are alive and in CR at last follow-up.

  • View full-size image.
  • Figure 1 

    Survival curves for the entire group of 92 patients. Freedom from progression (FFP) at 2 years, 71% (CI 61%-81%). Event-free survival (EFS) at 2 years, 67% (CI 57%-77%). Overall survival (OS) at 2 years, 83% (CI 75%-91%). Event-free survival (EFS) at 2 years was 67% (CI 57%-77%), and freedom from progression (FFP) at 2 years was 71% (CI 61%-81%).

Figure 2a illustrates the Kaplan-Meier plot of FFP according to the number of risk factors present. The 2-year FFP was 96%, 72%, 67%, and 14% for 0, 1, 2, and 3 risk factors, respectively, P < .0001.

  • View full-size image.
  • Figure 2 

    (A) FFP in 92 patients according to number of risk factors. 0 (n = 24), 1 (n = 37), 2 (n = 23), 3 (n = 8). (B) FFP according to induction failure (IF) versus induction response (non-IF). Induction failure (n = 36), induction response (n = 56). (C) FFP according to presence of B symptoms at relapse (n = 39) versus absence of B symptoms at relapse (n = 53).

Because response to induction therapy had been reported to be significantly correlated with the success of autologous transplantation in recurrent and refractory HL by Stanford and other groups 9, 12, 45, we examined the 2-year FFP according to duration of initial chemotherapy remission (duration > or <1 year or induction failure). Primary induction failure (IF) was associated with a significantly worse 2-year FFP of 48% (CI 30%-66%) compared to initial remission duration ≤1 year (90%, CI 79%-100%; P < .0001), or >1 year (80%, CI 62%-98%, P = .05); however, there was no significant difference in FFP outcomes between remission duration ≤1 year or >1 year (P = .25). Figure 2b shows FFP significantly inferior for IF patients versus non-IF patients (P = .0003). The presence of B symptoms at relapse also significantly reduced 2-year FFP (56%, CI 38%-74%) versus without B symptoms (83%, CI 72%-94%), P = .008 (Figure 2c). Pretransplant PET status was available in 77 of the 92 patients and allowed for further analysis. As shown in Figure 3a, FFP at 2 years was significantly lower for PET-positive (47%, CI 24%-70%) versus MRU or PET-negative (87%, CI 76%-98%) patients, P < .0001. A summary of survival statistics is provided in Table 4.

  • View full-size image.
  • Figure 3 

    (A) FFP in 77 patients according to pretransplant PET status. PET negative (n = 48), PET positive (n = 29). (B) FFP in patients who are PET positive, symptomatic (n = 15), PET positive, asymptomatic (n = 14), PET negative, symptomatic (n = 19), and PET negative, asymptomatic (n = 29). Three degrees of freedom log rank test for equality over 4 groups, P < .0001. Pairwise significant differences: between PET+ Bsx+ and PET+Bsx−, P = .004; between PET+Bsx+ and PET−Bsx+, P < .0001; between PET+Bsx+ and PET−Bsx−, P < .0001.

Table 4. Summary of Survival Statistics
VariableN2-Year FFP (%) (95% CI)P∗2-year EFS (%) (95% CI)P∗2-Year OS (%) (95% CI)P∗
Overall9271 (61-81) 67 (57-77) 83 (75-91)
Risk factors <.0001 .0004 .07
02496 (88-100) 83 (64-100) 80 (58-100)
13772 (56-88) 68 (52-84) 86 (74-98)
22367 (46-88) 67 (46-88) 91 (79-100)
3814 (0-40) 13 (0-36) 42 (1-83)
PET status† <.0001 .003 .07
Negative4887 (76-98) 79 (67-91) 91 (82-100)
Positive2947 (24-70) 45 (22-68) 77 (58-96)
Initial remission duration .0003 .0002 .025
Non-IF5686 (76-96) 82 (71-93) 89 (79-99)
IF3648 (30-66) 44 (26-62) 74 (59-89)
B symptoms .008 .005 .18
Absent5383 (72-94) 79 (67-91) 85 (73-97)
Present3956 (38-74) 52 (36-68) 79 (65-93)

FFP indicates freedom from progression; CI, confidence interval; EFS, event-free survival; OS, overall survival.

∗All P values are from the log rank test; 1 degree of freedom for variables with 2 groups; 3 degrees of freedom for number of risk factors.

†N = 77, as only 77 of the 92 patients had pretransplant PET exams.

We next explored the significant factors of PET status, induction response, induction regimen and constitutional symptoms in multivariate analysis of 77 study participants. Pretransplant PET-positive status and constitutional symptoms were significantly predictive of FFP (hazard ratios [HRs] of 5.9 and 4.8) and EFS (HRs of 3.3 and 4.3). ABVD primary therapy was of borderline significance (HR of 2.8). Table 5 summarizes these data.

Table 5. Factors Significantly Affecting FFP and EFS on Multivariate Analysis
FFPEFS
Prognostic FactorN∗Hazard Ratio(95% CI)PHazard Ratio(95% CI)P
PET status .001 .01
Negative1.0 1.0
Positive5.9(2.0-17.1) 3.3(1.3-8.0)
Constitutional B symptoms .007 .003
Absent1.0 1.0
Present4.8(1.5-14.6) 4.3(1.7-11.2)
Primary therapy .046
Stanford V— —1.0
ABVD 2.8(1.0-7.8)

FFP indicates freedom from progression; PET, positron emission tomography; CI, confidence interval; EFS, event-free survival.

∗N = 77.

As shown in Figure 3b, patients with both risk factors (PET-positive and symptomatic) had a 14% (CI 0%-38%) 2-year FFP compared to 86% (CI 67%-100%), 82% (CI 63%-100%), and 91% (CI 79%-00%) 2-year FFP in those who were PET-positive and asymptomatic, PET-negative and symptomatic, or PET-negative and asymptomatic, respectively.

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Discussion 

Although high-dose chemotherapy and AHCT is the most effective treatment for patients with recurrent or refractory HL, disease recurrence in nearly half of patients requires new approaches 1, 2, 9, 46, 47. We sought to reduce the toxicity of the conditioning regimen while maintaining efficacy to create an optimal platform for posttransplant therapeutics. In our previous experience, the pulmonary toxicity associated with augmented BCNU regimens (550 mg/m2) prohibited the introduction of posttransplant therapy in the first 100 days 12, 19.

The present study was designed to evaluate the feasibility of a transplant regimen in which the combination of gemcitabine and vinorelbine allowed for a lowered dose of BCNU along with standard doses of etoposide and Cy (GN-BVC). It was recognized that pretransplant GN-containing salvage regimens were being developed during this trial period with similar GN-dosing [7]. Our toxicities and responses as a transplant regimen, compared to a pretransplant salvage approach with GN, however, might be expected to be different because of the administration close to BVC and thus, was a new experience.

The primary endpoint of the study was met in terms of demonstrating a reduced incidence of BCNU-related toxicity of 15% (CI 9%-24%). A nominal rate of 35% was used as the historic control rate in the study design, which was a best estimate based on our own data and those of other studies using augmented BCNU dosing 10, 11, 12, 13, and served to establish the study size for high probability to detect a toxicity reduction. It should be noted that a more stringent pulmonary definition of BCNU-related toxicity (DLCO decrease ≥20%) was applied in prior Stanford studies [19]. In fact, only 2 patients had a documented DLCO decrease of at least 20% in the current study, suggesting an even more favorable result. Reducing the dose of BCNU from 15 mg/kg to 10 mg/kg in this regimen likely contributed to the reduced toxicity. Better supportive care in the current era of autografting 23, 48, 49, as well as earlier recognition and initiation of corticosteroid treatment for BCNU pneumonitis, has undoubtedly played a role in reducing BCNU-related toxicity and deaths. Our institution does not use prophylactic corticosteroids in the high dose BCNU regimens; however, this practice has allowed certain groups to decrease their incidence of interstitial pneumonitis while maintaining BCNU doses of 600 mg/m2 23, 49. A specific pretransplant pulmonary function threshold that predicts for posttransplant pulmonary complications and mortality is not yet established [50], and this remains the case for BCNU toxicity. A corrected DLCO of 55% was used for entry onto the current study, which is the lowest threshold for our institution's AHCT regimens, and thus allowed more compromised patients to move forward to AHCT with less toxicity result.

The antitumor efficacy of the conditioning regimen did not appear to be compromised in our cohort. With a median follow-up of 29 months, the 2-year FFP was 96%, 72%, 67%, and 14% for 0, 1, 2, and 3 risk factors, respectively. As a comparison, in our previous report [12], the 3-year FFP were 85%, 57%, 41%, and <20% for 0, 1, 2, and 3 risk factors, respectively. Patients with 1 or 2 risk factors appear to benefit with this new regimen over our historic experience. The distribution of risk factors was similar in the earlier and current studies [12]. When looking at more universal risk factor groups, such as duration of first remission, our study results showed 2-year FFP of 48% for primary IF, 90% for remission duration ≤1 year, and 80% for remission duration >1 year. As a comparison, the conditioning approach utilizing high-dose sequential therapy followed by BEAM-AHCT, reported in the phase 2 Cologne trial by the GHSG [8], shows a freedom from second failure for risk groups having progressive disease versus early relapse (≤1 year) versus late relapse (>1 year) of 41%, 62%, and 65%, respectively, at a median follow-up of 30 months. The ongoing GHSG/EBMT randomized trial [9] is investigating the efficacy of high-dose sequential therapy and BEAM-AHCT with standard DHAP followed by BEAM-AHCT, and results are awaited; however, this is limited to chemosensitive patients and questions remain on outcomes for chemorefractory patients prior to AHCT.

Subsequently, FDG-PET imaging has become incorporated in HL response assessment 40, 41, 42. In the current study, pretransplant PET status significantly correlated with FFP (P < .0001) and EFS (P = .003), and was of borderline significance with regard to OS (P = .07). Constitutional symptoms at relapse (P = .008) and induction failure (P = .0003) were also identified as significant adverse risk features. In multivariate analysis, PET-positive status and constitutional symptoms were independent risk factors for treatment failure. Further, we observed that the combination of constitutional symptoms and PET-positive status, representing 19% of patients with pre-transplant scans, conferred a very poor prognosis, with just 14% FFP at 2 years. In contrast, FFP at 2 years was >80% for patients with only 1 or neither risk factor. This observation should be viewed as hypothesis-generating and interpreted with caution given the small sample size.

In general, the literature is concordant regarding adverse risk factors prior to transplant for HL. Constitutional symptoms at relapse, extranodal disease, chemoresponsiveness before transplantation, and remission duration <1 year 5, 46, 51, 52, 53 have been reported as independent predictors of long-term disease-free survival (DFS) in primary refractory and relapsed HL patients. More recently, there are several reports indicating the prognostic significance of PET pretransplant. The retrospective study by Jabbour et al. [54] identified pretransplant PET status to be independently predictive for progression-free survival (PFS) and OS. In that study, 3-year PFS rates for PET positive and negative patients was 23% and 69%, respectively. Castagna et al. [55] further showed that early PET after 2 cycles was predictive of survival after AHCT with 2-year PFS of 10% for PET-positive versus 93% for PET-negative patients (P < .001). Of note, patients who achieve normalization of PET prior to AHCT with additional noncross-resistant second-line therapy had improved EFS in single institution study [56], but it is unclear if this strategy results in selection bias, meaningful tumor reduction for cure, or a combination of both.

In conclusion, the regimen of GN-BVC is associated with less pulmonary toxicity than the prior augmented BCNU-containing regimen with equal or greater efficacy. A prospective comparison of this new combination with other conditioning regimens using risk stratification is warranted. Whether using the previously established risk model or incorporating PET, about two-thirds of patients are alive and event-free at 2 years after transplant. A small group with multiple risk factors [12] in our former model or both symptomatic and PET-positive, had a dismal outcome. Targeting these higher risk patients for novel therapies should be the objective for future studies. Tandem AHCT [57] has been explored in a risk-adapted transplant strategy, but requires further study. Other approaches could include antibody-drug conjugates, histone deacetylase inhibitors, immunomodulating agents, and cell-based therapies, which hold promise as peritransplant therapeutics 58, 59, 60, 61.

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Acknowledgments 

Financial disclosure: This work was supported in part by P01 CA49605; presented previously at ASCO 2005, abstract 6651 and ASH 2008, abstract 2194.

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Authorship Statement 

S.A. was responsible for conduct of study, data collection, data analysis, and manuscript writing. S.J.H. was responsible for study design, data analysis, and manuscript writing. R.L. was responsible for data collection. R.M.W. and P.W.L. conducted statistical analysis and edited manuscript. R.S.N. and K.G.B. were involved in critical editing of manuscript. L.J.J, G.G.L., R.L., D.B.M., J.A.S., and W-K.W. were involved in final approval of manuscript.

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References 

  1. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomized trial. Lancet. 1993;341:1051–1054
  2. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomized trial. Lancet. 2002;359:2065–2071
  3. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988;71:117–122
  4. Josting A, Rudolph C, Reiser M, et al. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol. 2002;13:1628–1635
  5. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97:616–623
  6. Baetz T, Belch A, Couban S, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2003;14:1762–1767
  7. Bartlett NL, Niedzwiecki D, Johnson JL, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007;18:1071–1079
  8. Josting A, Rudolph C, Mapara M, et al. Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann Oncol. 2005;16:116–123
  9. Glossmann J-P, Josting A, Pfistner B, Paulus U, Engert A. A randomized trial of chemotherapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) plus peripheral stem cell transplantation (PBSCT) vs single-agent high-dose chemotherapy followed by BEAM plus PBSCT in patients with relapsed Hodgkin's disease (HD-R2). Ann Hematol. 2002;81:424–429
  10. Reece DE, Barnett MJ, Connors JM, et al. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol. 1991;9:1871–1879
  11. Nademanee A, O'Donnell MR, Snyder DS, et al. High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors. Blood. 1995;85:1381–1390
  12. Horning SJ, Chao NJ, Negrin RS, et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood. 1997;89:801–813
  13. Wheeler C, Eickhoff C, Elias A, et al. High-dose cyclophosphamide, carmustine, and etoposide with autologous transplantation in Hodgkin's disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant. 1997;3:98–106
  14. Frankovich J, Donaldson SS, Lee Y, et al. High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease: atopy predicts idiopathic lung injury syndromes. Biol Blood Marrow Transplant. 2001;7:49–57
  15. Stiff PJ, Unger JM, Forman SJ, et al. The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: a Southwest Oncology Group phase II trial. Biol Blood Marrow Transplant. 2003;9:529–539
  16. Yuen AR, Rosenberg SA, Hoppe RT, Halpern JD, Horning SJ. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood. 1997;89:814–822
  17. Cao TM, Negrin RS, Stockerl-Goldstein KE, et al. Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2000;6:387–394
  18. Reece DE, Nevell TJ, Sayegh A, et al. Regimen-related toxicity and non-relapse mortality with high-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV) and CBV plus cisplatin (CBVP) followed by autologous stem cell transplantation in patients with Hodgkin's disease. Bone Marrow Transplant. 1999;23:1131–1138
  19. Stuart MJ, Chao NS, Horning SJ, et al. Efficacy and toxicity of a CCNU-containing high-dose chemotherapy regimen followed by autologous hematopoietic cell transplantation in relapsed or refractory Hodgkin's disease. Biol Blood Marrow Transplant. 2001;7:552–560
  20. Benekli M, Smiley SL, Younis T, et al. Intensive conditioning regimen of etoposide (VP-16), cyclophosphamide and carmustine (VCB) followed by autologous hemtopoietic stem cell transplantation for relapsed and refractory Hodgkin's lymphoma. Bone Marrow Transplant. 2008;41:613–619
  21. Takvorian T, Parker LM, Hochberg FH, Canellos GP. Autologous bone-marrow transplantation: host effects of high-dose BCNU. J Clin Oncol. 1983;1:610–620
  22. Wheeler C, Antin JH, Churchill WH, et al. Cyclophosphamide, carmustine, etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose-finding study. J Clin Oncol. 1990;8:648–656
  23. Kalaycioglu M, Kavuru M, Tauson L, Bolwell B. Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carumustine (BCNU). Chest. 1995;107:482–487
  24. Horwitz SM, Negrin RS, Blume KG, et al. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood. 2004;103:777–783
  25. Jagannath S, Dicke KA, Armitage JO, et al. High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin's disease. Ann Intern Med. 1986;104:163–168
  26. Borchmann P, Schnell R, Diehl V, Engert A. New drugs in the treatment of Hodgkin's disease. Ann Oncol. 1998;9(Suppl 5):S103–S108
  27. Santoro A, Bredenfeld H, Devizzi L, et al. Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol. 2000;18:2615–2619
  28. Zinzani PL, Bendandi M, Stefoni V, et al. Value of gemcitabine treatment in heavily pretreated Hodgkin's disease patients. Haematologica. 2000;85:926–929
  29. Lucas JB, Horwitz SM, Horning SJ, Sayegh A. Gemcitabine is active in relapsed Hodgkin's disease. J Clin Oncol. 1999;17:2627–2628
  30. Devizzi L, Santoro A, Bonfanti V, Viviani S, Bonadonna G. Vinorelbine: a new promising drug in Hodgkin's disease. Leukemia Lymphoma. 1996;22:409–414
  31. Bonfante V, Viviani S, Santoro A, et al. Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol. 1998;103:533–535
  32. Rule S, Tighe M, Davies S, Johnson S. Vinorelbine in the treatment of lymphoma. Hematol Oncol. 1998;16:101–105
  33. Grunewald R, Kantarjian H, Du M, et al. Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol. 1992;10:406–413
  34. Mani S, Kugler JW, Knost JA, et al. Phase II trial of 150-minute weekly infusion of gemcitabine in advanced colorectal cancer: minimal activity in colorectal cancer. Invest New Drugs. 1998;16:275–278
  35. Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs. 1997;15:331–341
  36. Hainsworth JD, Burris HA, Litchy S, et al. Gemcitabine and vinorelbine in the second-line treatment of non-small cell lung carcinoma patients: a Minnie Pearl Cancer Research Network phase II trial. Cancer. 2000;88:1353–1358
  37. Lorusso V, Carpagnano F, Frasci G, et al. Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non-small cell lung cancer. J Clin Oncol. 2000;18:405–411
  38. Delord JP, Raymond E, Chaouche M, et al. A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies. Ann Oncol. 2000;11:73–79
  39. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22:27–42
  40. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586
  41. Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR. Prognostic value of interim FDG-PET after two or 3 cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol. 2005;16:1160–1168
  42. Gallamini A, Hutchings M, Rigacci L, et al. Early interim2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from the Joint Italian-Danish Study. J Clin Oncol. 2007;25:3746–3752
  43. Poen JC, Hoppe RT, Horning SJ. High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin's disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys. 1996;36:3–12
  44. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stati Assoc. 1958;53:457–481
  45. Horning SJ. Primary refractory Hodgkin's disease. Ann Oncol. 1998;9(Suppl 5):S97–S101
  46. Lavoie JC, Connors JM, Phillips GL, et al. High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood. 2005;106:1473–1478
  47. Moskowitz AJ, Perales MA, Kewalramani T, et al. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol. 2009;146:158–163
  48. Cheng YC, Rondon G, Yang Y, et al. The use of high-dose cyclophosphamide, carmustine, and thiotepa plus autologous hematopoietic stem cell transplantation as consolidation therapy for high-risk primary breast cancer after primary surgery or neoadjuvant chemotherapy. Biol Blood Marrow Transplant. 2004;10:794–804
  49. Wadhwa PD, Fu P, Koc ON, et al. High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality. Biol Blood Marrow Transplant. 2005;11:13–22
  50. Chien JW, Madtes DK, Clark JG. Pulmonary function testing prior to hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35:429–435
  51. Josting A, Franklin J, May M, et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 2002;20:221–230
  52. Majhail NS, Weisdorf DJ, Defor TE, et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin's lymphoma. Biol Blood Marrow Transplant. 2006;12:1065–1072
  53. Nademanee A, Molina A, Fung H, et al. High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced-stage Hodgkin's disease during first partial or complete remission. Biol Blood Marrow Transplant. 1999;5:292–298
  54. Jabbour E, Hosing C, Ayers G, et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer. 2007;109:2481–2489
  55. Castagna L, Bramanti S, Balzarotti M, et al. Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy. Br J Haematol. 2009;145:369–372
  56. Moskowitz CH, Nimer SD, Zelenetz AD, et al. Normalization of FDG-PET Pre-ASCT with additional non-cross resistant chemotherapy improves EFS in patients with relapsed and primary refractory Hodgkin lymphoma-Memorial Sloan Kettering Protocol 04-047. Blood. 2008;112:(abstr 775)
  57. Morschhauser F, Brice P, Ferme C, et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM Study Group. J Clin Oncol. 2008;26:5980–5987
  58. Bartlett N, Forero-Torres A, Rosenblatt J, et al. Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL). J Clin Oncol. 2009;27:15s(Suppl) (abstr 8500)
  59. Younes A, Fanale M, Pro B, et al. A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma. J Clin Oncol. 2007;25:18s(Suppl) (abstr 8000)
  60. Fehniger TA, Larson S, Trinkaus K, et al. A phase II multicenter study of lenalidomide in patients with relapsed or refractory classical Hodgkin lymphoma: preliminary results. Blood. 2008;112:(abstr 2595)
  61. Mendler JH, Friedberg JW. Salvage therapy in Hodgkin's lymphoma. Oncologist. 2009;14:425–432

 Financial disclosure: See Acknowledgments on page 1152.

PII: S1083-8791(10)00095-9

doi:10.1016/j.bbmt.2010.02.022

Biology of Blood and Marrow Transplantation
Volume 16, Issue 8 , Pages 1145-1154, August 2010

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