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 Hohl, Masaki Hayashi, Annette Schlueter, Roger D. Gingrich

Research output: Contribution to journalArticle

Abstract

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)
JournalBlood
Volume96
Issue number11 PART II
StatePublished - 2000

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Salvaging
Transplants
Chemotherapy
Stem Cell Transplantation
Mitoxantrone
Ifosfamide
Stem cells
Refractory materials
Lymphoma
Drug Therapy
Toxicity
Cytarabine
Methylprednisolone
Recurrence
Therapeutics
Hodgkin Disease
Granulocyte Colony-Stimulating Factor
Platelets
Pancytopenia
Cisplatin

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Choon-Kee, L., De Magalhaes-Silverman, M., Hohl, R., Hayashi, M., Schlueter, A., & Gingrich, R. D. (2000). A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation. Blood, 96(11 PART II).
Choon-Kee, L. ; De Magalhaes-Silverman, Margarida ; Hohl, Raymond ; Hayashi, Masaki ; Schlueter, Annette ; Gingrich, Roger D. / A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation. In: Blood. 2000 ; Vol. 96, No. 11 PART II.
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title = "A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation",
abstract = "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.",
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Choon-Kee, L, De Magalhaes-Silverman, M, Hohl, R, Hayashi, M, Schlueter, A & Gingrich, RD 2000, 'A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation', Blood, vol. 96, no. 11 PART II.

A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation. / Choon-Kee, L.; De Magalhaes-Silverman, Margarida; Hohl, Raymond; Hayashi, Masaki; Schlueter, Annette; Gingrich, Roger D.

In: Blood, Vol. 96, No. 11 PART II, 2000.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase-I, dose escalation study for salvage chemotherapy for patients with refractory lymphoma, prior to myeloablative therapy with stem cell transplantation

AU - Choon-Kee, L.

AU - De Magalhaes-Silverman, Margarida

AU - Hohl, Raymond

AU - Hayashi, Masaki

AU - Schlueter, Annette

AU - Gingrich, Roger D.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

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