Gemcitabine, Dexamethasone and Cisplatin Prove Effective for Recurrent Diffuse Non-Hodgkin’s Lymphoma

Abstract & Commentary

Synopsis: Standard treatment for recurrent, diffuse non-Hodgkin’s lymphoma remains to be established, but several studies have indicated that autologous stem cell transplant has resulted in improved survival. For those with bulky recurrence, pre-transplant, second-line chemotherapy is recommended. In this setting, an optimal regimen would not commonly produce severe marrow toxicity as mobilization of stem cells will be required for optimal reconstitution after transplant. In the current trial, gemcitabine, dexamethasone and cisplatin (GDP) administered in 21-day cycles resulted in an overall response rate (after 2 cycles) of 49%. Furthermore, after 2 cycles, stem cell mobilization was successful in 22 of 23 patients for whom such an approach was considered appropriate. Thus, GDP is an effective salvage regimen for recurrent large cell lymphoma, particularly in the pre-autologous stem cell transplant setting.

Source: Crump M, et al. Cancer. 2004;101(8): 1835-1842.

For patients with relapsed, aggressive non-Hodgkin’s lymphoma, second-line or salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation has been shown to improve progression-free and overall survival when compared to standard-dose chemotherapy alone.1,2 Non-marrow ablative standard dose regimens are desirable in this setting to preserve stem cell number while debulking tumor mass. In this light, a regimen including gemcitabine, dexamethasone and cisplatin offers theoretic appeal. Each of these drugs singly or used in other combinations has been shown to have therapeutic benefit, and with only modest effect on marrow function.

Accordingly, Crump and colleagues from the National Cancer Institute of Canada performed a phase II trial in which 51 eligible patients with recurrent or refractory diffuse large B-cell lymphoma or variants (per REAL classification), measurable disease, and one previous chemotherapy regimen were enrolled. Treatment consisted of gemcitabine 1000 mg/m2 intravenously (iv) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 75 mg/m2 on day 1, every 21 days, as an out patient. The primary end point was a response after 2 cycles. At that point, responding patients either proceeded to stem cell transplantation (SCT) or continued on the GDP regimen for up to 6 treatment cycles.

The median age of patients enrolled was 57 years (range, 18-84) and most had diffuse large-cell lymphoma. After 2 cycles, there were 8 complete responses (CR, 16%) and 17 partial responses (PR, 33%), for an overall response rate of 49% (95% confidence interval [CI], 37-63%). The response rate after completion of all protocol chemotherapy (including those who received > 2 cycles of GDP) was 53% (11 CR, 16 PR).

Grade 3 and 4 neutropenia occurred in 33% and 39% of patients, respectively. Grade 3 and 4 thrombocytopenia occured in 24% and 4% of patients respectively. Seven patients (14%) experienced febrile neutropenia. Of the 35 patients younger than 66 years of age, 22 (63%) proceeded to SCT. Non-hematological toxicity included grade 2 or greater nausea and vomiting occurred in 14 (27%) and 11 (22%) respectively. Grade 1 or 2 ototoxicity occurred in 13 (25%), and was attributed to cisplatin. Thromboembolic events occurred in 7 (14%) patients, including a fatal pulmonary embolism in one. Of the 51 patients enrolled, 17 (33%) required hospital admission for either a complication of treatment (febrile neutropenia, dehydration) or disease. As planned a subset of these patients went on to receive autologous stem cell collection. Of 23 patients in which this approach was attempted, mobilization of sufficient stem cell number was successful in 22 (96%). Of the 22 in whom there were sufficient stem cells for transplant, one patient had progressive disease before transplant and the procedure was cancelled, and 21 received high-dose chemotherapy and autologous stem cell infusion. The median time to neurtophil recovery was: > 0.5 ´ 109/L was 10 days (range, 8-24 days) and the median time to platelet recovery > 20 ´ 109/L was 13 days (range, 8-28 days).

Comment by William B. Ershler, MD

The results of this multicenter Phase II trial demonstrate the use of the GDP regimen in patients with recurrent, aggressive NHL, particularly if autologous stem cell transplantation is under consideration. The regimen was moderately well tolerated and response rates are comparable to other regimens, including ifosfamide, carboplatin, and etoposide (ICE), and dexamethasone, high-dose cytosine arabosinide (ara-C), and cisplatin (DHAP). The seeming advantage of GDP is the facility of administration (successfully administered as an outpatient in the great majority of patients in the current trial) and the relatively modest marrow toxicity, considering the aggressive disease being treated. The latter point is highlighted by the success at mobilizing stem cells in all but one of the patients for which this treatment was considered appropriate in this series.

The trial was small, and the results modest, yet the theoretical appeal of this combination and the relative ease of administration would seem to warrant a larger scale Phase III clinical trial, and it is encouraging to see that such a trial is currently underway (by the National Cancer Institute of Canada) comparing GDP and DHAP in this precise clinical setting (recurrent large cell lymphoma prior to stem cell transplant). In the meantime, practicing oncologists may feel familiar enough with the components of this regimen to use it under appropriate circumstances.

References

1. Phillip T, et al. N Engl J Med. 1995;333:1540-1545.

2. Kewalramani T, et al. Blood. 2000;96:2399-2404.

William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA, Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor of Clinical Oncology Alert.