Emergence of central nervous system myeloma in the era of novel agents.

Although multiple myeloma (MM) remains an incurable disease, considerable improvements in survival have been made with the introduction of autologous stem cell transplantation and new drugs. Central nervous system (CNS) MM is a rare complication associated with poor survival. Historically, CNS disease developed early in the course of MM; however recently, patients often present with CNS disease following multiple lines of therapy. It is hypothesized that exposure to novel agents (thalidomide, lenalidomide and bortezomib) changes the natural history of MM, increasing the lifetime risk of CNS disease. We analysed the baseline characteristics, treatment and outcome data of patients who presented with CNS MM at Peter MacCallum Cancer Centre between 2001 and 2010. Seven patients were identified, from 2005 onwards. All patients were Durie-Salmon stage IIIA or IIIB and International Staging System Scores I to III at baseline. All had received at least three lines of therapy, including high-dose chemotherapy with autologous stem cell transplantation and a novel agent, prior to developing CNS MM. Median time from diagnosis to CNS disease was 24 months (range 10-42). All patients died after developing CNS disease with median survival post-CNS disease of 2 months (range 1-23). The incidence of CNS MM is increasing, and time to development of CNS manifestations is prolonging, associated with increased use of high-dose chemotherapy and novel agents. Whether this is due to improved overall survival or specific characteristics of these therapies is not clear. Despite the availability of novel agents, survival after CNS MM remains poor.

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features.

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4-26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1-58) from diagnosis, with a crude incidence of 6.5% and 5-year actuarial incidence of 5 +/- 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2-9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0.0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.

Superior quality and duration of responses among patients with mantle-cell lymphoma treated with fludarabine and cyclophosphamide with or without rituximab compared with prior responses to CHOP.

Sixteen patients with relapsed mantle-cell lymphoma (MCL) were treated with the combination of fludarabine and cyclophosphamide (FC) with or without rituximab. All patients had received prior CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) chemotherapy, with a response rate of 63.5% (25% complete response), and a median duration of response of 10 months (range 1-32 months). Subsequent treatment with FC +/- rituximab produced a response rate of 75% with a higher complete response rate (56% P = 0.07 vs. CHOP), and a median duration of response of 11 months (4-25+ months). This study demonstrates that FC is a highly active regimen in patients relapsing following CHOP chemotherapy.

Fludarabine combination therapy is highly effective in first-line and salvage treatment of patients with Waldenström's macroglobulinemia.

Alkylating agents or single-agent purine analogues are modestly effective as front-line therapy for Waldenstrom's macroglobulinemia (WM), but response rates of < 50% are exhibited in the salvage therapy setting. Fludarabine combination therapy may be more effective, but no large studies exploring these regimens specifically in WM are available. We report our results of 18 cycles of fludarabine combination therapy: FC (fludarabine 25 mg/m2 for 3 days plus cyclophosphamide 250 mg/m2 for 3 days; n = 9), FM (fludarabine 25 mg/m2 for 3 days plus mitoxantrone 10 mg/m2 for 1 day; n = 3), FCR (FC plus rituximab 375 mg/m2; n = 5), or fludarabine/rituximab (n = 1). Four patients had previously untreated disease, and 14 had pretreated disease; 67% had elevated serum levels of beta2-microglobulin, and 86% had hemoglobin levels < or = 12 g/dL. Patients received a median of 4 cycles (range, 1-6 cycles), with grade > or = 3 neutropenia and infection complicating 25% and 4% of cycles, respectively. Objective responses (all partial) were attained in 13 patients (76%). Response rates did not significantly differ by regimen, previous treatment, age, performance status, beta2-microglobulin level, hemoglobin level, time from diagnosis, previous fludarabine exposure, or alkylator refractoriness. Median remission duration was 38 months; no previously untreated patient had died at a median of 37 months of follow-up, and the actuarial 5-year survival rate was 55% for pretreated patients. No cases of secondary myelodysplasia or leukemia were encountered.

Fludarabine based combinations are highly effective as first-line or salvage treatment in patients with Waldenström macroglobulinemia.

Treatment with single-agent chemotherapy or rituximab (R) is safe and moderately effective for patients with Waldenström macroglobulinemia (WM). We analyzed the efficacy and toxicity of fludarabine (F)-combinations. Twenty-nine treatment episodes were administered to 27 patients, including FC (F 25 mg/m(2) days 1-3, cyclophosphamide [C] 250 mg/m(2) days 1-3; n = 7), FCR (FC + R 375 mg/m(2) day 1; n = 18), FM (F + mitoxantrone [M] 10 mg/m(2) day 1; n = 3), and FR (n = 1). Patient characteristics were median age 57 years (36-89), 83% male, 10 previously untreated (34%). In total, 123 cycles were administered, a median of four (2-6) per patient. Grade ≥ 3 neutropenia and infections complicated 28% and 3% of cycles, respectively. Responses were achieved in 26 cases (90%), one complete, 23 partial, and two minor. The median progression-free survival was 43.1 months, and at a median follow-up of 66.5 months the actuarial 5- and 10-year overall survival-rates were 88% and 75%, respectively. All 10 previously untreated patients responded (one CR, nine PR), and were alive at a median follow-up of 50 (6-106) months. Three heavily pretreated patients subsequently developed AML/MDS (one fatal) at 56, 61, and 91 months post F-based treatment. F-combination therapy is highly active in WM, both untreated and alkylator-refractory. However, a possible contribution to the cumulative risk of treatment-related MDS/AML requires ongoing monitoring.

The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders.

BACKGROUND: Fludarabine-based combination chemotherapy regimens are highly effective in the treatment of patients with indolent lymphoproliferative disorders. Despite the prevalence of such disorders in older patients, the effect of increasing age on the deliverability of these regimes has not been assessed. METHODS: The authors analyzed the effect of increasing age on the deliverability and toxicity of 3 fludarabine-based regimens, all using fludarabine 25 mg/m2 per day for 3 days intravenously every 28 days, in 180 patients who were stratified into 2 age groups (age <60 years and age > or =60 years), with multivariate analysis to control for other differences between groups. The authors also explored the impact of age > or =70 years within the older cohort. RESULTS: Older patients were more likely to experience an episode of nonsevere hematologic or infectious toxicity, but there was no difference in the rate of severe toxicity. Toxicity rates per cycle did not differ between age groups. The rates of neutropenia (absolute neutrophil count [ANC], < 1.0 x 10(9)/L) and severe neutropenia (ANC, 0.5 x 10(9)/L) were 22% and 13%, respectively, in older patients versus 20% and 11%, respectively, in younger patients (P > .1 for both). The rates of thrombocytopenia (platelet count, <100 x 10(9)/L) and severe thrombocytopenia (platelet count, <50 x 10(9)/L) were 21% and 5%, respectively, in older patients and 16% and 5%, respectively, in younger patients (each P value > .1). The rate of infection was 18% per cycle in older patients and 15% per cycle in younger patients (P = .2), with no difference noted in severity. Other organ toxicities were uncommon and showed no difference between age groups. The treatment-related mortality rate was <1% in both cohorts (P > .5). In multivariate analysis, increasing age and performance status influenced the incidence of hematologic toxicity, whereas only performance status influenced the rate of infection and severe infection. CONCLUSIONS: Fludarabine-based combination chemotherapy regimens were well tolerated and can be delivered safely to older patients who have a good performance status with modestly increased myelosuppression but no increase in severe infectious complications or treatment-related mortality.

Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies.

BACKGROUND: Preclinical data have supported the use of fludarabine and cyclophosphamide (FC) in combination for the treatment of indolent lymphoid malignancies. Previously reported schedules were highly effective, but were complicated by significant myelotoxicity and infectious complications. In the current study, the authors analyzed their experience with an attenuated dose regimen to determine whether equivalent efficacy could be achieved with reduced toxicity. METHODS: Sixty-four patients with indolent lymphoid malignancies were treated with intravenous fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 250 mg/m(2), each given on Days 1-3 for a median of 4 cycles. The median age of the patients was 60 years. Nineteen percent of the patients were previously untreated, and 45% had refractory disease; the patients had received a median of 2 prior therapies. With regard to histology, 41% of the patients had chronic lymphocytic leukemia or its variants, whereas the remainder of patients had low-grade non-Hodgkin lymphoma, predominantly follicule center cell lymphoma. RESULTS: A total of 237 cycles were delivered. The principal toxicities reported were neutropenia (NCI CTC Grade 4 in 17% of cycles) and infection (Grade >/= 3 in 6% of cycles). The overall response rate and complete response rate were 86% and 29%, respectively. No significant difference could be discerned with regard to response rates for patients with untreated, recurrent, or refractory disease. CONCLUSIONS: The FC schedule used in the current study was found to be highly effective in patients with indolent lymphoid malignancies. Toxicity was lower compared with higher dose schedules, whereas efficacy appeared to be equivalent.

A new model for predicting infectious complications during fludarabine-based combination chemotherapy among patients with indolent lymphoid malignancies.

BACKGROUND: Fludarabine-containing combination chemotherapy regimens are increasingly used in the treatment of indolent lymphoid malignancies, with the associated risk of infection being the major toxicity. Predictors of infection during fludarabine-containing combination therapy are poorly defined and optimal strategies for infection prophylaxis are not known. The authors analyzed their experience with patients treated with the fludarabine-mitoxantrone (FM) or fludarabine-cyclophosphamide (FC) regimens to develop a predictive model for infections. METHODS: Ninety-two patients with indolent lymphoid malignancies were treated with FM (n = 29) or FC (n = 63). Baseline variables including age, gender, regimen, disease histology, previous therapy, time from diagnosis to current treatment, performance status, renal function, absolute neutrophil count (ANC), lymphocyte count, and immunoglobulin G levels were examined retrospectively for their association with risk of infectious complications during or within 4 weeks of therapy. RESULTS: Six risk factors were associated with infectious complications: age > 60 years, > or = 3 previous therapies, previous fludarabine exposure, time from diagnosis to current treatment of > 3 years, performance status > or = 2, and baseline ANC < 2.0 x 10(9)/L. Compared with patients with 0-2 risk factors, patients with > or = 3 risk factors had higher infection rates (26% vs. 7% per cycle, P < 0.0001), more Grade 4 neutropenia (41% vs. 8% per cycle, P < 0.0001), and more neutropenic sepsis (15% vs. 1% per cycle, P < 0.0001). CONCLUSIONS: Infection risk during fludarabine-containing combination chemotherapy was predicted with a model comprising six baseline risk factors. Patients predicted to be at high risk of infection were an appropriate group for consideration of prophylactic strategies.