NEW YORK (Reuters Health) Jul 25 - The combination of fludarabine plus cyclophosphamide and rituximab (FCR) can rapidly control Waldenstrom's macroglobulinemia, a generally indolent B-cell lymphoma, according to a July 5th online report in Cancer.
Although the multicenter study included some treatment-na�ve patients, lead author Dr. Alessandra Tedeschi said she now advises physicians to "avoid administering FCR in first line treatment because of the high rate of myelosuppression with long lasting neutropenias after the end of treatment."
She and her colleagues tested the FCR regiment in 43 symptomatic Waldenstrom's patients who were previously untreated or pretreated with one therapy. Patients who had received rituximab, or concurrent fludarabine and cyclophosphamide, were excluded.
Two thirds of the patients had intermediate-risk or high-risk disease.
The results showed that "with the FCR regimen, a high overall response rate may be achieved with good quality responses," Dr. Tedeschi, from Niguarda Ca'Granda Hospital, Milan, told Reuters Health in an email.
Patients received rituximab 375 mg/m2 IV on day one, and fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 IV on days two through four. The median number of FCR cycles was six - the same as the maximum number set in advance by the research team.
The overall response rate was 79%. Five patients (11.6%) had a complete remission. Nine patients (20.9%) had a very good partial response, i.e., more than a 90% reduction in serum IgM level. Eighteen (41.8%) had partial responses (reductions in serum IgM of 50% to 90%), and two patients (4.6%) had minor responses (i.e., their IgM dropped by 20% to 50%).
After a median interval of six months, four patients had improved further: one minor response converted to a partial response, and three very good partial responses evolved to complete remission.
At roughly three years, the median event-free survival was 50.1 months. Overall survival was 88.4% at 2 years, 69.1% at three years, and the same at 4 years.
Thirty-eight patients (88%) had at least one episode of grade 3/4 neutropenia, and 19 patients (44%) had neutropenia that persisted for a median of 7 months (range, 3-24 months).
Nine infectious episodes occurred during periods of neutropenia in the first six months of follow-up. Infections were fatal in two patients.
Three heavily pretreated patients developed myelodysplastic syndrome after 5, 24, and 60 months. Two patients had severe extrahematologic toxicity: cutaneous pemphigus vulgaris in one; hypotension and lipothymia in the other.
The FCR regimen is a reasonable option in cases with refractory and relapsed high risk disease, Dr. Tedeschi concluded.
"The inclusion of cyclophosphamide allowed us to achieve similar response rates while administering a lower cumulative dose of fludarabine without increasing infective toxicity," the researchers note.
"Because myelosuppression was the most common cause of early discontinuation and led to a high incidence of prolonged episodes of neutropenia, further studies are needed to optimize the doses and duration of this combined treatment regimen," they add.
"A good option could be to reduce fludarabine and cyclophosphamide dosages (FCR lite)," Dr. Tedeschi said.
Although the multicenter study included some treatment-na�ve patients, lead author Dr. Alessandra Tedeschi said she now advises physicians to "avoid administering FCR in first line treatment because of the high rate of myelosuppression with long lasting neutropenias after the end of treatment."
She and her colleagues tested the FCR regiment in 43 symptomatic Waldenstrom's patients who were previously untreated or pretreated with one therapy. Patients who had received rituximab, or concurrent fludarabine and cyclophosphamide, were excluded.
Two thirds of the patients had intermediate-risk or high-risk disease.
The results showed that "with the FCR regimen, a high overall response rate may be achieved with good quality responses," Dr. Tedeschi, from Niguarda Ca'Granda Hospital, Milan, told Reuters Health in an email.
Patients received rituximab 375 mg/m2 IV on day one, and fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 IV on days two through four. The median number of FCR cycles was six - the same as the maximum number set in advance by the research team.
The overall response rate was 79%. Five patients (11.6%) had a complete remission. Nine patients (20.9%) had a very good partial response, i.e., more than a 90% reduction in serum IgM level. Eighteen (41.8%) had partial responses (reductions in serum IgM of 50% to 90%), and two patients (4.6%) had minor responses (i.e., their IgM dropped by 20% to 50%).
After a median interval of six months, four patients had improved further: one minor response converted to a partial response, and three very good partial responses evolved to complete remission.
At roughly three years, the median event-free survival was 50.1 months. Overall survival was 88.4% at 2 years, 69.1% at three years, and the same at 4 years.
Thirty-eight patients (88%) had at least one episode of grade 3/4 neutropenia, and 19 patients (44%) had neutropenia that persisted for a median of 7 months (range, 3-24 months).
Nine infectious episodes occurred during periods of neutropenia in the first six months of follow-up. Infections were fatal in two patients.
Three heavily pretreated patients developed myelodysplastic syndrome after 5, 24, and 60 months. Two patients had severe extrahematologic toxicity: cutaneous pemphigus vulgaris in one; hypotension and lipothymia in the other.
The FCR regimen is a reasonable option in cases with refractory and relapsed high risk disease, Dr. Tedeschi concluded.
"The inclusion of cyclophosphamide allowed us to achieve similar response rates while administering a lower cumulative dose of fludarabine without increasing infective toxicity," the researchers note.
"Because myelosuppression was the most common cause of early discontinuation and led to a high incidence of prolonged episodes of neutropenia, further studies are needed to optimize the doses and duration of this combined treatment regimen," they add.
"A good option could be to reduce fludarabine and cyclophosphamide dosages (FCR lite)," Dr. Tedeschi said.
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