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.

Treatment-related myelodysplasia following fludarabine combination chemotherapy.

Although myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) are rare following fludarabine monotherapy, the risk of these diseases may potentially be increased when fludarabine is combined with cyclophosphamide or mitoxantrone due to synergistic effects on the inhibition of DNA repair. Among 137 patients treated with fludarabine combination regimens, ten patients developed MDS/sAML, including one who had received no other therapy. Six patients had abnormalities of chromosomes 5 and/or 7. The crude rate of MDS/sAML was 2.5% for previously untreated patients, and 9.3% for pretreated patients (p=0.28). The rate of MDS/sAML following fludarabine combination therapy is higher than that previously reported for fludarabine monotherapy.

Dose-reduced fludarabine, cyclophosphamide and rituximab is well tolerated in older patients with chronic lymphocytic leukemia and has preserved therapeutic efficacy.

Despite its efficacy in prospective trials, full dose fludarabine, cyclophosphamide and rituximab (FCR) may be too toxic for elderly patients with chronic lymphocytic leukemia (CLL) in clinical practice. We retrospectively reviewed the impact of dose reductions in FCR therapy on the outcomes of 42 consecutive patients aged 65-87 (median 72) years. Despite a median cumulative fludarabine dose reduction of 50% from full dose, the objective response and complete response rates were 86% and 38% respectively (frontline 94%/59%; previously treated 80%/24%). Dose reductions of 25-75% were not significantly associated with inferior progression free survival compared to minimal reductions (≤25%) (p=0.49), and did not preclude deep responses, including six cases (14%) of minimal residual disease negativity. Although hematological and infectious toxicities were common, treatment limiting adverse effects were infrequent. Dose attenuated FCR appears to have preserved efficacy and may be a viable therapeutic option for elderly patients with CLL.

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.

BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration.

The onset of accelerated phase or blast crisis of chronic myelocytic leukemia (CML) is usually associated with the acquisition of new chromosome abnormalities in addition to the t(9;22)(q34;q11) that is characteristic of the chronic phase CML. We describe the cytogenetic and molecular genetic findings in two cases of myelocytic blast crisis of CML, one occurring 6 months after commencing treatment with the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571, Glivec, or Gleevec) and the second treated with imatinib mesylate for established blast crisis. In both cases, multiple secondary cytogenetic abnormalities were observed at transformation, with homogeneously staining regions that were shown to contain BCR/ABL amplification by fluorescence in situ hybridization appearing after imatinib mesylate administration. BCR/ABL amplification is emerging as an important mechanism of acquired resistance to imatinib mesylate.

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.

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma.

BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FC-R) shows significant in vitro synergism and may improve patient outcome with little overlapping toxicity. METHODS: Between December 2000 and June 2005, 77 patients completed therapy after a median of 4 cycles of FC-R (fludarabine at a dose of 25 mg/m2 intravenously [i.v.] on Days 1-3, cyclophosphamide at a dose of 250 mg/m2 i.v. on Days 1-3, and rituximab at a dose of 375 mg/m2 on Day 1). The median age of the patients was 59 years, 65% were male; 31% had previously untreated disease; and 44% had chronic lymphocytic leukemia (CLL), 29% had follicular lymphoma, and 27% other indolent lymphoid malignancies. In addition to standard disease response criteria, patients underwent evaluation using flow cytometric and/or molecular studies. RESULTS: Objective responses (OR) and complete responses (CR) were observed in 83% and 42%, respectively, of evaluable patients (n=76), respectively. For patients with CLL, the respective OR and CR rates were 100% and 67% as firstline therapy, and 95% and 14% as salvage therapy. For patients with follicular lymphoma, the respective OR and CR rates were 100% and 86% as firstline therapy, and 87% and 67% as salvage therapy. Responders who had no detectable disease on flow cytometric and/or molecular studies experienced prolonged remissions with no recurrences reported at a median 25 months of follow-up. Peripheral stem cell collection using stem cell factor plus granulocyte-colony-stimulating factor was successful in 10 of 13 patients who underwent mobilization (77%). CONCLUSIONS: FC-R is highly active as initial or salvage therapy in patients with CLL or indolent non-Hodgkin lymphoma. Collection of autologous stem cells during molecular remission is feasible and may facilitate future exploration of high-dose therapy in these patients.

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.