A phase I trial of gemcitabine plus cladribine in patients with advanced hematologic malignant diseases

Cancer Chemother Pharmacol. 2004 Dec;54(6):553-61. doi: 10.1007/s00280-004-0857-3. Epub 2004 Sep 2.


Purpose: Gemcitabine and cladribine (2CdA) are nucleoside analogues that decrease DNA synthesis via inhibition of ribonucleotide reductase; the combination could be additive or synergistic. We conducted a dose escalation study to establish the maximum tolerable doses (MTD) of gemcitabine and 2CdA when given in combination in patients with advanced hematologic malignancies and to describe the toxicity profile of this combination.

Patients and methods: A total of 45 patients with advanced hematologic diseases were enrolled into two groups. Group A had adequate baseline hematopoiesis, defined as absolute neutrophil count (ANC) >1 x 10(9)/l and platelet count >50 x 10(9)/l. Group B did not meet these criteria. Hematologic dose-limiting toxicity (DLT) for group A was defined as grade 4 neutropenia or thrombocytopenia lasting >28 days; group B was not evaluated for hematologic toxicity. Nonhematologic DLT was defined similarly for both groups. Death occurring during the first cycle of treatment was considered a DLT event only if it was related to drug toxicity. Gemcitabine was administered as a 4-h intravenous infusion once every 28 days. 2CdA was administered over 1 h daily for the first 3 days of each 28-day cycle.

Results: The MTD was not reached in either group. Myelosuppression was common, but not dose-limiting. Febrile neutropenia and infections were also common, particularly in group B, and judged in most cases to be due to bone marrow failure at baseline. Nonhematologic toxicities were generally mild, and skin rash, the most frequently observed, was dose-limiting in one patient enrolled in each group. Four deaths (three during the first cycle of treatment) occurred at the highest dose level tested in group B (gemcitabine 5000 mg/m2 and 2CdA 16 mg/m2). Although only one of these deaths was dose-limiting by stated criteria, this dose level did not appear to be safely tolerated in this patient population. Several responses were observed in patients with Hodgkin's disease.

Conclusions: The combination of gemcitabine and 2CdA is feasible in patients with hematologic malignancies. Phase II studies of this combination should be considered, particularly in patients with Hodgkin's disease.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cladribine / administration & dosage*
  • Cladribine / adverse effects
  • Deoxycytidine / administration & dosage*
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Drug Administration Schedule
  • Fatigue
  • Feasibility Studies
  • Female
  • Hematologic Neoplasms / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Neutropenia / chemically induced
  • Thrombocytopenia / chemically induced


  • Deoxycytidine
  • Cladribine
  • gemcitabine