1 Klinik I für Innere Medizin, Universität zu Köln, Köln; 2 II. Medizinische Klinik, Carl-Thiem-Klinikum, Cottbus; 3 Abteilung für Hämatologie, Onkologie und Tumorimmunologie, Max-Delbrück-Centrum für Molekulare Medizin, Campus Buch, Humboldt-Universität Berlin, Berlin-Buch; 4 Klinik für Hämatologie und Onkologie, Medizinische Klinik III, Klinikum HannoverSiloah, Hannover; 5 Abteilung Onkologie und Hämatologie, Medizinische Klinik, Universitätskrankenhaus Eppendorf, Hamburg, Germany
Received 29 October 2001; revised 11 February 2002, accepted 11 March 2002
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Abstract |
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An important variable affecting outcome in relapsed and refractory Hodgkins disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 34 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkins lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD.
Patients and methods:
Patients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 14, cisplatin 100 mg/m2 i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m2 i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 µg/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT.
Results:
The median age of the 102 patients included was 34 years (range 2164 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 06) and 48% (mean duration 1.4 days, range 011) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 x 106/kg CD34+ cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients.
Conclusions:
A brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.
Key words: Hodgkins disease, relapse, salvage chemotherapy
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Introduction |
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Several studies have been performed with conventional salvage regimens before the administration of HDCT [48]. Although response rate (RR) and toxicity profile of salvage chemotherapy are different, detailed analyses comparing various regimens are difficult due to the generally small number of patients and the heterogeneous patient population, i.e. patients with primary progressive and relapsed disease. No randomized trial exists comparing the effectiveness of different conventional salvage chemotherapies. Due to the lack of randomized studies, the selection of conventional salvage chemotherapy should be based on the potential to induce high RRs with low toxicities allowing the majority of patients to proceed to the final myeloablative regimen.
The most important variables affecting outcome in HDCT studies are chemosensitivity to conventional salvage chemotherapy and the remission status before HDCT [complete remission (CR) > partial remission (PR) > no change] [812]. Recent clinical studies demonstrated a clear relationship between chemotherapy dose intensity and tumor response in HD [13]. There are two principal ways to enhance dose intensity. Doses of cytotoxic drugs can be intensified by increasing individual drug dose, or shortening the interval between treatments, or both. The use of granulocyte colony-stimulating factor (G-CSF) for interval shortening has made this approach feasible. The introduction of accelerated chemotherapy regimens by interval shortening with growth factor support has shown promising results in first-line chemotherapy regimens for patients with aggressive HD and non-Hodgkins lymphoma (NHL) [14, 15].
In the present study, our objective was to determine the efficacy and toxicity of dexamethasone/cisplatin/cytarabine (DHAP) in relapsed and refractory HD while shortening the intervals between the cycles using G-CSF. We show that this approach is feasible, effective and well-tolerated in patients with relapsed and refractory HD.
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Patients and methods |
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All patients had received COPP/ABVD (cyclophosphamide/oncovin/procarbazine/prednisone alternating with doxorubicin/bleomycin/vinblastine/darcarbazine), ABVD (doxorubicin/bleomycin/vinblastine/darcarbazine), BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/oncovin/procarbazine/prednisone) or similar regimens as front-line chemotherapy. Primary progressive/refractory disease was defined as disease progression during first-line chemotherapy, or only transient response (CR or PR lasting 90 days) after induction treatment. Progressive disease required the following: (i)
5% increase from nadir in the sum of the products of the greatest diameter of any previously identified abnormal node for partial responders or non-responders; (ii) appearance of any new lesion during or
90 days after the end of therapy. Relapsed HD was defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy for
3 months. Early relapse required a CR lasting
3 months to 12 months. A CR in late relapses must last
12 months. All patients had biopsy-proven relapsed or refractory HD.
DHAP salvage chemotherapy and G-CSF administration
All patients received two cycles of DHAP as salvage treatment in order to reduce tumor volume before HDCT. DHAP consisted of dexamethasone 40 mg i.v. day 14, cisplatin 100 mg/m2 i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m2 i.v. over 3 h 12q day 2. Hydration (250 ml/h) was started 62 h before cisplatin infusion. Corticosteroid eye drops were given topically beginning 12 h before and continuing for 2 days after administration of cytarabine to prevent conjunctivitis. To minimize nausea and vomiting, patients were given ondansetrone 8 mg i.v. on day 1 and 2. Twenty-four hours after the last dose of cytarabine, G-CSF was given at doses of 5 µg/kg/day subcutaneously until leukocytes increased to 2500/µl for 3 days.
Staging procedures
Before salvage chemotherapy, the extent of disease was assessed by chest X-ray, abdominal sonography, computed tomography, and bone marrow biopsy. Restaging was performed after two cycles of salvage therapy. After two cycles of DHAP all sites of initial disease manifestation were reassessed by adequate methods, including pathological restaging for patients who had bone marrow involvement before salvage therapy.
Definition of response and statistics
CR was defined as the disappearance of all clinical and radiographic evidence of disease for at least 1 month. PR was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting >1 month. Any response less than PR was considered as treatment failure. Demographics and disease characteristics were summarized using descriptive statistics. The significance of differences in the RR according to various features was calculated by chi-square testing [16].
Kinetics of hematopoietic progenitor release and peripheral blood stem cell harvest
Surface phenotype analysis using flow cytometry was performed as reported previously [17]. Mononuclear cells were stained with fluorescein isothiocyanate- and phycoerythin-conjugated CD34 (anti-HPCA-2) monoclonal antibodies with mouse IgG as negative control. More than 20 000 cells were analyzed with flow cytometry using a FACScan flow cytometer (Becton Dickinson, Basel, Switzerland) with Lysis II software.
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Results |
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Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP (Table 4).
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Stem cell mobilization
Peripheral blood stem cells (PBSCs) were collected after the first DHAP cycle in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a peak on day 12. A mean of 6.1 x 106/kg CD34+ cells (range 3.159.4 x 106/kg) were collected by apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT (cyclophosphamide or etoposide) in the remaining patients. PBSC harvest was successful in 96% of all patients.
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Discussion |
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An important variable affecting outcome in patients with relapsed or refractory HD is the potential of conventional salvage chemotherapy to reduce tumor volume before HDCT [8, 19]. Patients who relapse after chemotherapy but respond to subsequent conventional salvage therapy make up most of the long-term survivors in transplantation programs. Nevertheless, the role of conventional salvage chemotherapy before HDCT has not clearly been defined in relapsed or refractory HD. Different regimens have been used in the past for initial tumor reduction thereby evaluating chemosensitivity often while logistic arrangements are underway for HDCT.
Since 1985, a number of new salvage chemotherapy regimens have been investigated incorporating drugs not used in first-line treatment. Because most first-line treatment programs employ MOPP (mustine/vincristine/procarbazine/prednisone), ABVD, or combinations of both, new salvage regimens have been designed anticipating resistance to previously used drugs in patients who have relapsed [2025]. Table 5 lists second-line salvage regimens for HD published since 1985. However, a detailed analysis and interpretation is difficult because generally the number of patients is small and the clinical status of patients is highly variable. In addition, the duration of first remission is heterogeneous and a large number of these patients also received subsequent HDCT plus ASCT. No randomized trial exists comparing the effectiveness of different conventional salvage regimens.
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In view of the results reported in our study and lack of a prospective randomized trial, the benefit of adding more cytotoxic drugs to the DHAP regimen has not become clear. Considering dose intensity, an alternative to dose escalation of single cytotoxic drugs or adding new drugs to established salvage regimens is the use of colony-stimulating factors (CSFs) to shorten treatment intervals. Pfreundschuh et al. [29] recently reported the results of a prospective randomized trial in patients with relapsed or refractory HD. Patients were randomized to receive the dexa-BEAM regimen with escalating etoposide doses supported by placebo or GM-CSF. The increase in dose intensity provided was small and the authors concluded that the use of CSF for interval reduction rather than dose escalation is a more effective strategy for dose intensification.
In the present study, 102 patients with relapsed or refractory HD were treated with the DHAP regimen plus G-CSF to shorten the intervals between each cycle. The median time between the first and second cycle of DHAP was 16 days (range 1231 days). This represents a dose escalation by a factor of 1.8 compared with DHAP given at 28-day intervals. The second DHAP cycle was administered between 12 and 17 days after starting the first course in 74% of cycles. All cycles could be administered at the full calculated dose. The RR after two cycles of DHAP was 89% (21% CR, 68% PR) and thus at least comparable with results observed with other salvage regimens. The RR for patients with late, early and multiple relapsed HD were not different (91%, 93% and 92%, respectively). However, the RR for patients with progressive HD was only 65%. Using chi-square testing for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors for response to DHAP. The toxicity profile was excellent with WHO grade 4 leukocytopenia and thrombocytopenia occurring in 43% (mean duration 1.1 days, range 06) and 48% (mean duration 1.4 days, range 011) of all courses. Neither severe infections nor TRM occurred.
The potential to mobilize PBSCs is an important requirement for a pre-ASCT cytoreductive regimen. Since the initial study protocol included both HD and aggressive NHL, PBSCs were collected after the two DHAP cycles during sequential HDCT. Subsequently, PBSCs were collected in eight patients with relapsed HD after the first cycle of DHAP. A mean of 6.1 x 106/kg CD34+ cells (range 3.159.4 x 106/kg) were harvested. These results are in accord with previously published results by Oliveri et al. [30] using DHAP plus G-CSF for priming of PBSCs in patients with lymphoma.
In conclusion, a brief tumor-reducing program with DHAP supported by G-CSF is a very effective and well-tolerated approach before HDCT in patients with relapsed and refractory HD. The regimen is also suitable for collecting PBSCs. As a direct consequence of the present study, DHAP was implemented into the new prospectively randomized HDR-2 study. Here, the German Hodgkin Lymphoma Study Group together with the European Group for Blood and Marrow Transplantation and the European Organization for Research and Treatment for Cancer are comparing two cycles of DHAP plus G-CSF followed by BEAM with two cycles of DHAP followed by a sequential HDCT and BEAM in patients with relapsed HD [31].
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Acknowledgements |
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Footnotes |
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Participating Centers Listed in Acknowledgements.
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References |
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