Chemosensitive Disease Is Required To Achieve Benefit From Hdtasct

Two randomized studies comparing full-course salvage chemotherapy (SC) administered alone with curative intent with short-course SC followed by HDT and ASCT are reported. The British National Lymphoma

Investigation (BNLI) randomly assigned relapsed and primary refractory patients to either carmustine, etopo-side, cytarabine, and melphalan (BEAM) HDT followed by ASCT or up to three cycles of mini-BEAM with standard support.8 The German Hodgkin's Lymphoma Study Group (GHSG) randomly assigned patients with relapsed HL to either two cycles of dexa-BEAM (dexam-ethasone-BEAM) and BEAM and ASCT versus four cycles of dexa-BEAM.9 Each study demonstrated a statistically significant improvement in FFTF for the patients treated on the HDT arms, but neither was powered to show an overall survival (OS) advantage.

The importance of pretransplant cytoreduction with SC is demonstrated in numerous previous reports.10-13 In 1993, the lymphoma service at Memorial Sloan Kettering Cancer Center (MSKCC) published results using high-dose chemoradiotherapy in patients with biopsy-confirmed relapsed and primary refractory HL in first-generation clinical trials (MSKCC protocols 8597 and 86-86).1415 The program utilized accelerated fractionation radiotherapy either as total lymphoid irradiation (TLI) or as involved field radiation (IFRT), followed by high-dose chemotherapy and ASCT. One hundred and fifty-six patients with relapsed or primary refractory disease were treated; chemosensitive disease to SC was not a requirement for subsequent HDT. At a median follow-up of 11 years, the FFTF was 45%. After the introduction of G-CSF, overall mortality of the program decreased from 18 to 6%. In this study, patients with chemosensitive disease to SC had a marked OS advantage: 61% versus 14%. These results demonstrated the feasibility of incorporating doseintensive radiotherapy into HDT for HL and most importantly determined that patients with chemosen-sitive disease to SC had a marked improvement in FFTF compared to patients with refractory disease at the time of HDT.

As with aggressive non-Hodgkin's lymphoma (NHL), chemosensitive disease to SC is now suggested for transplant eligibility in the United States.16 There is limited information regarding the optimal SC regimen. The requirements for an SC regimen are adequate cytoreduc-tion in at least 75% of patients without extramedullary toxicity or severe bone marrow suppression, with subsequent ability to collect an adequate stem cell harvest.17 Specifically, in the phase III randomized German study described above, of the 161 patients enrolled, 13 could not be randomized secondary to dexa-BEAM-related mortality (eight patients) or severe infection.

In 2001, we reported the results of a comprehensive program for the treatment of 82 patients with relapsed and primary refractory HL (MSKCC protocol 94-68).18 All patients received SC with ifosfamide, carboplatin, and etoposide (ICE) and only responders were subsequently offered HDT and ASCT. All patients in this trial had biopsy-proven relapsed or refractory disease, and our data were analyzed by intent to treat. The response rate to ICE was 90%; there was no severe ICE-related extramedullary (nonhematologic) toxicity. The median number of CD34+ cells/kg collected was 7 X 106/kg. FFTF, at a median follow-up for surviving patients of 6 years, is 55%. In the subset of patients who received HDT/ASCT (75 of 82 patients), the FFTF is 61%.

Recently, two additional SC regimens were reported to have promising, although preliminary, results. Seventy-six patients with relapsed or refractory HL were treated on a phase I/II study with gemcitabine (G), vinorelbine (N, Vinorelbine), and liposomal doxorubicin (D) (GND). The objectives were to determine the maximally tolerated dose (MTD), response rates, and toxicity of this combination; 28 patients had a prior ASCT. At a planned interim analysis of the phase II portion of the study, the overall response rate was 58% [95% exact CI (0.34, 0.80)] for the first 19 patients without prior transplant [8 partial response (PR) 3 complete response (CR)] and 68% [95% exact CI (0.44, 0.87)] for the 19 patients with prior transplant (12 PR, 1 CR). The regimen was well tolerated and, importantly, is administered in the outpatient setting.19 IGEV consists of ifosfamide 2000 mg/m2 i.v. days 1-4; gemcitabine 800 mg/m2 i.v. days 1 and 4; vinorelbine 20 mg/m2 i.v. day 1; prednisolone 100 mg/m2 i.v. days 1-4, and G-CSF 300 ^g s.c. days 7-12 or up to peripheral blood progenitor cell (PBPC) harvest. Therapy consisted of four IGEV cycles at 3-week intervals followed by HDT in responding patients. The overall response rate was 84%, and all patients but one mobilized an adequate amount of PBPC. Grade III-IV neutropenia occurred in 34% of all IGEV courses, and was dose limiting. Nonhematologic side effects were negligible.20

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