ࡱ> q`\bjbjqPqP .::T&&&&&&&:))))|^*:C.N+N+N+N+N+N+N+N+'C)C)C)C)C)C)C$Dh>GhMC&,N+N+,,MC&&N+N+bC>>>,&N+&N+'C>,'C>>&&>N+B+ ):V>#@xC0C>G-=G>>"G&?N+>+,>+$+N+N+N+MCMC> N+N+N+C,,,,:::$$:::$:::&&&&&&  GEMCITABINE IN THE TREATMENT OF RELAPSED AND REFRACTORY HODGKINS DISEASE Short title: Gemcitabine for Hodgkins disease GEMCITABIN FR DIE BEHANDLUNG VON RELAPSIERTEN UND REFRAKTOREN HODGKIN LYMPHOM Kurztitel: Gemcitabin fr Hodgkin Lymphom SUMMARY Introduction: Patients with refractory Hodgkins disease or relapsing after high-dose therapy and autografting have a bad prognosis. We present our experience with gemcitabine in this setting. Patients and methods: We treated 14 patients with relapsed or refractory Hodgkins disease with gemcitabine. The treatment was given on a compassionate case basis, off-label and not according to a study protocol. Patients were 17-46 years old. One was in stage IA, 2 in IIIB and 11 in IVB. Nine were irradiated, 8 autografted, and one autografted and allografted. Gemcitabine was administered at a starting dose of 1g/m2 on days 1 and 8 every 3 weeks in combination with steroids. Results: Median follow-up was 10 months. Hematological toxicity grade 3-4 occurred in 12 patients leading to dose reductions. One patient died of neutropenic sepsis. No other non-hematological toxicity was seen. The response rate was 64% with 6 patients achieving CR and 3 PR. Median time to treatment failure was 9 months and survival 11 months. Responses were seen in previously transplanted patients and in patients refractory to previous treatment. The longest responder is still in CR for over 68 months. Conclusion: Gemcitabine is an effective treatment for Hodgkins disease. Dose reductions are often necessary in heavily pretreated patients. Key words: Hodgkins disease, relapse, therapy; gemcitabine ZUSAMMENFASSUNG Hintergrund: Patienten mit Hodgkin Lymphom, das auf Standardtherapie refraktr ist oder nach Hochdosistherapie und Autotransplantation rezidiviert, haben eine schlechte Prognose. Wir berichten hier ber unsere Erfahrungen mit Gemcitabin in diesen Konstellationen. Patienten und Methoden: Wir behandelten 14 Patienten im Alter von 17-46 Jahren mit refraktrem oder rezidivierendem Hodgkin Lymphom mit Gemcitabin. Die Behandlung erfolgte auf Grund von Einzelfallbeobachtungen, "off-label" und auerhalb von klinischen Studien. Ein Patient befand sich im Stadium IA, 2 im Stadium IIIB und 11 im Stadium IVB. 9 Patienten erhielten Bestrahlungen, 8 wurden autolog und ein Patient sowohl autolog als auch allogen transplantiert. Gemcitabin wurde alle 3 Wochen in einer Anfangsdosis von 1g/m2 an den Tagen 1 und 8 in Kombination mit Steroiden verabreicht.Ergebnisse: Die mittlere Follow-up-Zeit betrug 10 Monate. Hmatologische Toxizitt vom Grad 3-4 fhrte in 12 Patienten zur Dosisreduktion. Ein Patient verstarb an einer neutropenen Sepsis. Es wurde keine nicht-hmatologische Toxizitt beobachtet. Die Ansprechrate betrug 64%, wobei 6 Patienten eine komplette und 3 Patienten eine partielle Remission erreichten. Die mediane Zeitdauer bis zum Therapieversagen betrug 9 Monate und das mediane Patientenberleben 11 Monate. Sowohl zuvor transplantierte als auch auf die bisherige Therapie refraktre Patienten sprachen auf die Behandlung an. Die lngste komplette Remission dauert bereits ber 68 Monate an. Schlussfolgerung: Gemcitabin ist eine effektive Behandlungsoption fr das Hodgkin Lymphom. Dosisreduktionen sind bei intensiv vorbehandelten Patienten oft erforderlich. Schlsselwrter: Hodgkin Lymphoma, Relaps, Behandlung; Gemcitabin INTRODUCTION Most patients with Hodgkin's disease (HD) are cured with modern front-line chemotherapy and radiotherapy. The cure rates range from 95% for early-stage disease to 75% for those with advanced high-risk disease [1-4]. Patients relapsing after front-line treatment are generally treated with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Approximately 50% of relapsing patients can be cured with this approach. For the remaining half, failing ASCT, there is no standard treatment and they generally succumb to their disease. The same is true for patients refractory to treatment who, even after ASCT, have a relapse rate of over 75% [5,6]. Gemcitabine is a relatively novel pyrimidine antimetabolite, commonly used for treatment of pancreatic, non-small cell lung, bladder and breast cancer [7]. Gemcitabine is relatively well tolerated, the dose-limiting toxicity is hematological and non-hematological toxicity is generally mild. Preclinical data indicate that it is very active against hematological neoplasia [8] but this indication has not been extensively studied. A few reports have been published indicating that it is active in patients with HD failing standard treatment options. Almost six years ago we gave gemcitabine to a 17 year old patient relapsing after ASCT. His excellent response and lack of non-hematological toxicity prompted us to offer this treatment to all further patients with HD needing compassionate treatment. The treatment was given off-label and not according to a study protocol. Here we present our experience with this approach. PATIENTS AND METHODS Patients We treated 14 patients with refractory or relapsed HD with gemcitabine. Their characteristics are presented in Table 1. All had received ABVD, COPP/ABVD or COPP/ABV as first or second (in case of patients previously receiving OPPA at pediatric centers) line treatment. Various salvage chemotherapy regimens had been used prior to gemcitabine including DHAP, IEP, BEACOPP escalated, CVP, EVAP and CCEP, each in 1-3 patients only. Nine patients had received radiotherapy. Eight were in relapse after ASCT, one after ASCT and allotransplantation; five were refractory to the last treatment. Two were in stage IIIB, eleven in IVB and one in IA. The latter was already auto- and allografted and had active disease in a previously radically irradiated region. Six had a low and 8 high Hasenclever index [9]; 13 had Jostings prognostic score for relapsed Hodgkins disease >1 [10]. Staging procedures Routine staging procedures were performed prior to treatment start. These included careful palpation of peripheral lymph node areas, CT scans of the thorax, abdomen and pelvis and bone marrow biopsy. Positive imaging studies and bone marrow biopsies were repeated after three cycles of treatment. In responding patients imaging studies were thereafter repeated only if clinically indicated, i.e. if patients had signs or symptoms of disease recurrence. Treatment Gemcitabine was infused over 30 minutes on days 1 and 8 every three weeks at a dose of 1 g/m2. All patients received steroids, 60 mg/m2 daily of prednisone or equivalent, on days 1-8 of each cycle. Due to hematologic toxicity the dose had to be reduced in most patients. The median actually delivered dose was 800 mg/m2 once every three weeks. In case of granulocytopenia or thrombocytopenia grade 3 or higher, treatment was delayed until recovery and the dose of gemcitabine subsequently reduced. G-CSF support was not used. The number of cycles was determined individually, based on response, toxicity and the possibility of further treatment, i.e. ASCT. Responding patients received between 2 and 8 treatment cycles. Patients received standard outpatient supportive care: ciprofloxacin and fluconasole were given prophylactically during severe neutropenia, Toxicity Blood counts were performed on day 1 and 8 of each cycle. Biochemical tests were performed before treatment start and at reevaluation. Laboratory testing was otherwise performed only if clinically indicated. Therefore, hematological toxicity described in this paper refers to blood counts on day 22 of each cycle, not to nadirs during cycles. Toxicity was graded according to the National Cancer Institutes Common Toxicity Criteria [11]. Response Response was analyzed according to the standard international Cheson criteria [12]. Complete remissions and complete remissions-unconfirmed were considered complete responses. Data Analysis Actuarial survival and time-to-treatment failure (TTF) were analyzed using the Kaplan-Meier method [13]. Treatment failure was defined as death, start of a new treatment for HD except for ASCT or disease progression. In the TTF analysis, patients transplanted in CR after treatment with gemcitabine were censored at time of ASCT. Ethics Treatment was given on a compassionate basis. Patients were informed of the unlicensed and experimental nature of treatment and gave oral informed consent. RESULTS Toxicity Twelve patients experienced hematological toxicity grade 3 or 4 leading to gemcitabine dose reductions and omissions of treatment on day 8 (Table 2). One patient died of neutropenic sepsis. No other cases of severe non-hematological toxicity were seen. Patients who were previously irradiated tolerated the treatment as well as those who were not. Response and survival Median follow-up of the whole cohort was 10 months. The overall response rate was 64%. Six patients achieved CR, and 3 PR (Fig. 1). All responses were achieved after 2-3 cycles. Responses were seen in all patient categories, irrespective of previous treatment (transplanted vs. non-transplanted), disease status (relapsed vs. refractory) or risk (low vs. high Hasenclever index). Actuarial survival is 10 months (Fig. 2). After a median follow-up of survivors of 9 months, 5 are still alive. Time to treatment failure was 9 months (Fig. 2). Three patients are off treatment without signs of disease. One of them was autografted after achieving CR. The patient with longest CR is our first patient, treated in relapse after ASCT who remains in remission after a follow-up of 68 months. DISCUSSION Most HD patients are cured with modern front-line therapy. The cure rates range from 95 to 75% depending on disease extent and other factors [1-4,9]. While approximately one half of relapsing patients can be salvaged with high-dose chemotherapy and ASCT, refractory HD responds badly to all standard treatment options and has a dismal outcome [5,6]. Indeed, the concept of intensification of front-line treatment, as developed by Diehl and coworkers in the escalated BEACOPP regimen, is based on the attempt to prevent the development of refractory disease [4,14]. A treatment that could change the outlook of this small cohort of patients would therefore be of great value. The same is true for patients failing ASCT. Unlike non-Hodgkins lymphoma, allotransplant for HD have a high mortality and only borderline graft-versus-lymphoma effect [15]. Therefore, patients failing ASCT are candidates for experimental treatment approaches. We are aware of five other fully published reports on the use of single-agent gemcitabine with or without steroids in patient with advanced HD [16-20], two of whom included very few patients [16,20], and of two reports using the combination of gemcitabine with cisplatin and steroids (Table 3) [21,22]. In all except one [20] was gemcitabine administered using short infusion (30-60 min). A prolonged infusion, over 4h, was used in the latter. This approach is superior from a pharmacokinetic standpoint and could be more effective but also more toxic [23]. We have not used it since it is not the standard way of administering gemcitabine. It is difficult to compare results of published reports because of differences in patient characteristics, most importantly the extent of prior treatment. In studies using combination therapy patients were generally less heavily pretreated and were not autotransplanted. Responses were also seen in patients completely refractory to chemotherapy and in those failing ASCT. This indicates that gemcitabine is probably not cross-resistant with standard treatment for HD. However, except in formidable exceptions, gemcitabine does not seem to be curative and treatment should probably be continued until transplantation, progression or the appearance of unacceptable toxicity. Heavily pretreated patients with HD are generally unable to tolerate standard doses and schedules of gemcitabine due to hematological toxicity. An alternative approach designed to reduce hematological problems might be to start with a lower dose, e.g. 800 mg/m2 once every two to three weeks, and then increase the dose and frequency of administration in those that are able to tolerate it. In our cohort non-hematological, non-infectious toxicity was very mild. Specially, neither we, nor the other groups have seen any cases of pulmonary toxicity, confirming the fact that severe lung toxicity seen with the BAGCOPP (bleomycin, doxorubicin, gemcitabine, cyclophosphamide, vincristin, procarbazine, prednisone) and ABVG (doxorubicin, bleomycin, vinblastin, gemcitabine) regimens in HD was due to an unfortunate synergistic effect of the combination of bleomycin and gemcitabine [24,25]. The combination of gemcitabine and steroids is active and well tolerated in HD. Activity is also seen in patients with unfavorable prognostic factors relapsing after ASCT, refractory to previous treatment or with a high IPI. It can be given safely to previously irradiated patients. This treatment should be tried in patients with HD failing standard treatment options. Acknowledgements Supported by grants 108007 & 108511 from the Croatian Ministry of Science and Technology. Presented in part at the 8th EHA meeting in Lyon, France, 2003. REFERENCES 1.Dugann DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP, Peterson BA. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkins disease: report of an intergroup trial. 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Severe pulmonary toxicity in patients with advanced-stage Hodgkin's disease treated with a modified bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP) regimen is probably related to the combination of gemcitabine and bleomycin: a report of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 2004; 22:2424-9. 25.Friedberg JW, Neuberg D, Kim H, Miyata S, McCauley M, Fisher DC, Takvorian T, Canellos GP. Gemcitabine added to doxorubicin, bleomycin, and vinblastine for the treatment of de novo Hodgkin disease: unacceptable acute pulmonary toxicity. Cancer 2003; 98:978-982. Table 1. Patients characteristics Gender F / M 7 / 7Age median / range 29 / 17-46 yearsHD type NS / MC / LP 10 / 3 / 1Interval from diagnosis to treatment median / range 32 / 6-90 monthsNo. of previous treatment lines median / range 4 / 1-7Front line chemotherapy COPP-ABVD / COPP-ABV / ABVD / OPPA 3 / 7 / 2 / 2Extranodal disease localization bone marrow / lungs / liver / pelvis 2 / 8 / 3 / 1 * NS = nodular sclerosis MC = mixed cellularity LP = lymphocyte predominance, diffuse type * the total is higher than 11 because some patients had multiple extranodal localizations Table 2. Hematological toxicity of gemcitabine in patients with refractory or relapsed Hodgkins disease No. of patients with toxicity (total no. of pts. = 14)Grade III Grade IVAnemia 4 0Granulocytopenia 8 1Trombocytopenia 2 3 Table 3. Published reports on the use of gemcitabine in Hodgkins disease ReferenceNo. of pts.CR/PRRR ScheduleGemcitabine (G) monotherapy +- steroids17232 / 736%G 1g/m2 days 1,8,15 every 4 weeks18142 / 443%G 1g/m2 days 1,8,15 every 4 weeks19270 / 622%G 1g/m2 days 1,8 every 3 weeksthis paper146 / 464%G 1g/m2 days 1,8 every 3 weeksGemcitabine (G) + cisplatin (C) + steroids21234 / 1270%G 1g/m2 days 1,8 + C 75 mg/m2 day 1 every 3 weeks22205 / 1180%G 1g/m2 days 1,8, 15 + C 100 mg/m2 day 15 every 4 weeks Only studies with more than three patients are included. FIGURE LEGENDS Figure 1. Response rates in patients with refractory or relapsed Hodgkins disease treated with gemcitabine. Figure 2. Overall survival and time to treatment failure in patients with refractory or relapsed Hodgkins disease treated with gemcitabine. Triangles indicate censored patients. 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