A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation

L. Choon-Kee, Margarida De Magalhaes-Silverman, Raymond J. Hohl, Masaki Hayashi, Annette Schlueter, Roger D. Gingrich

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Patients with primarily refractory lymphoma (PrR) or in refractory relapse (RR) rarely show sensitive responses to conventional chemotherapy (CCT). The dose intensity of CCT is known to affect response rates, despite no apparent increase in survival. In the present study, we conducted dose escalations of ifosfamide and mitoxantrone to see whether a 2-3 fold increase in the conventional dose could improve the response rates, thereby increasing the chances of subsequent transplant therapy (TT) for potential long-term survival. The regimen has 3 cycles (Cls): 1st Cl with methylprednisolone 500 mg/d x 4, ara-C 2 g/nr and fixed doses of ifosfamide 2 g/m2/d x 3 and mitoxantrone 12 mg/m2; 2nd and 3rd Cls consisting of cisplatin 30 mg/m2/d x 3, methylprednisolone 500 mg/d x 4, ara-C 3 g/m2 q 12h x 2 and the classic dose escalation of ifosfamide (2.5; 3.75; 5 g/m2/d x 3) and mitoxantrone (16; 20; 24; 28 mg/m2) over 6 levels. To prevent serious pancytopenia, G-CSF-primed stem cells were collected prior to the 2nd Cl and > 3x 106 CD34 cells/kg were infused 2 days after the 2nd and 3rd Cls. Pts then went on to receive myeloablative therapy with TT. Since 1997, 17 patients completed therapy; median age 37 yr (20-56 yr); 3F, 14M; 7 PrR Hodgkin's disease (HD), 2 RR HD, 7 PrR diffuse large cell lymphoma, 1 PrR diffuse small cleaved cell lymphoma. Oliguric acute renal failure as dose limiting toxicity occurred at the level 3 of ifosfamide 5 g/m2/d x 3 and mitoxantrone 16 mg/m2. 3 pts completed level 1 and 12 pts completed level 2. Durations of neutropenia were 7d, 11 d, and 9d after each 1 st, 2nd, and 3rd Cls. 53% pts had platelet <2 x lOVmcl lasting 7d (3-15d) after 2nd and 3rd Cls. 33% suffered from infectious episodes; 58% from moderate GI toxicity; 9% from mild CNS toxicity. There was no hepatic, or cardiopulmonary toxicity before TT. Of 14 pts who completed 3 Cls, 6 achieved CR; 4PR. 13 pts received TT; 4 allogeneic; 9 autologous. 3 pts who had received prior chest radiation died of interstitial pneumonitis post-TT. 1 pt had relapse 72 days after TT. Currently 7 pts are alive without relapse, with the Kaplan-Meier event free survival of 39% and a median follow-up of 190 days.In the study, we have identified the MTD of ifosfamide at 3.75 g/m2 x 3 and mitoxantrone at 16 mg/m2. Although preliminary, the regimen shows reasonable activity that warrants further clinical trials.

Original languageEnglish (US)
Pages (from-to)371b
Issue number11 PART II
StatePublished - Dec 1 2000

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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