A phase II study of dexamethasone, ifosfamide, cisplatin and etoposide (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma

Abstract

The 4-day combination of dexamethasone, ifosfamide, cisplatin, and etoposide (DICE) is a salvage regimen for lymphoma. We report a prospective phase II multi-center trial of a modified DICE regimen in relapsed or refractory Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), constituting a single day of intravenous administration followed by 3 days of oral administration, aimed at reducing inpatient days without losing efficacy. Forty patients (median age 56, range 25 - 79) were included: 28 (70%) NHL, 9 (23%) HL and 3 (8%) CLL. Fifty-three per cent had received 2 prior treatment regimens. International Prognostic Index (IPI) was 2 in 75% of NHL patients. Patients aged 55 and those with previous autologous stem cell transplantation (ASCT) started on a lower-dose regimen, with dose escalation possible in 2 patients. Overall response rate was 41%. Thirty-eight per cent of patients had stable disease. With a median of 3.1 years of follow-up, estimated progression-free survival (PFS) and overall survival (OS) rates at 3 years were 15% and 43% respectively. OS was longer in the < 55 compared to the 55 age cohort (P = 0.0091), longer for HL than NHL (P = 0.59 and 0.039 respectively) and longer for Low/Low-Int IPI than High/High-Int IPI (P = 0.0074 and 0.0009 respectively). Median duration of inpatient stay was 3 days. There were no treatment-related deaths. In conclusion, this modification of DICE is an effective and well tolerated salvage regimen, even in this poor prognosis group of patients. Further clinical studies of DICE in first relapse and in older patients, possibly with the addition of rituximab, are warranted.

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

“…The second arm in phosphoramide mustard can react with a second guanine moiety in an opposite DNA strand or in the same strand to form crosslinks. non-small-cell lung carcinoma (NSCLC) [313][314][315][316], breast cancer [317][318][319], ovarian cancer [320,321], bladder cancer [322][323][324], cervical cancer [325], osteosarcoma [326], neuroblastoma [327,328], leukemia [329,330], multiple myeloma [331], and lymphomas [332,333]. IFO could be used in both single agent and combination therapy with many other cytotoxic agents in clinical practice, such as etoposide, doxorubicin and mitomycin.…”

Hydroxylation andN-Dechloroethylation of Ifosfamide and Deuterated Ifosfamide by the Human Cytochrome P450s and Their Commonly Occurring Polymorphisms

“…It is the structural isomer of the more commonly used antineoplastic and immunosuppressive agent cyclophosphamide (CPA) (Zhang et al, 2006). Toxicities associated with IFO treatment limit its use, even though the drug has proven more effective than CPA in a wide range of malignant diseases (Buda et al, 2003;Sorio et al, 2003;Donfrancesco et al, 2004;Pocali et al, 2004;Biagi et al, 2005;Kosmas et al, 2007). IFO-induced toxicities include moderate-to-severe nephrotoxicity, which occurs in ;30% of the patient population, and neurotoxicities, which occur in ;20% of the patient population (Loebstein et al, 1999;Klastersky, 2003;McCune et al, 2005).…”

Exploring Old Drugs for the Treatment of Hematological Malignancies

“…Thalidomide in the treatment of MM is another good example. As we stated earlier, thalidomide is teratogenic by inhibiting VEGF signaling thus disrupting angiogenesis during the formation of limbs [30,31]. Angiogenesis is proposed as an important factor in myeloma development because increased bone marrow vascularity and angiogenesis-associated signals of IL-6, VEGF, FGFR are frequently seen in myeloma [49].…”

“…Dexamethasone is now the backbone in the prescription of multiple myeloma treatment. Recently, dexamethasone was introduced to the treatment of chronic lymphoid leukemia [29,30] and relapsed lymphoma [31]. Our recent study demonstrated that not only dexamethasone and prednisolone, but all other glucocorticoids display anti-myeloma activity for cells bearing c-maf and cyclin D2 [58].…”