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.

A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma.

BACKGROUND: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear. METHODS: We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'. RESULTS: Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009). CONCLUSIONS: The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

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.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy.

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.

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.

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.

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, 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.

Cardiovascular toxicity is increased, but manageable, during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients aged 60 years and older.

High-dose therapy (HDT) for non-Hodgkins lymphoma (NHL) and multiple myeloma (MM) is considered a feasible option for patients aged 60 years. This study compared the outcomes for all patients aged 60 years treated with HDT at the center to a matched cohort group aged <60 years. Results for patients who were 60 years at HDT between 1997--2002 were retrospectively analysed to assess efficacy and safety. Event-free (EFS) and overall survival (OS) rates were compared with a cohort group, matched by disease type, chemotherapy sensitivity, year of treatment and conditioning regimen. Patients with NHL were also matched by International Prognostic Index score. Forty patients aged 60 years were identified. Median age was 65 (range 60--76) with 22 MM and 18 NHL; 50% had 1 or more co-morbidity; 35% had cardiovascular co-morbidity vs. 18% of controls (p=0.075). Response rates (RR) following HDT for MM were: 4 (18%) complete responses (CR) and 18 (82%) partial responses (PR), giving an overall response rate (ORR) of 100%, vs. 77% for controls (p=0.02). For NHL patients there were: 8 CR (44%) and 4 PR (22%), giving an ORR of 67%, vs. 83% for controls (p=0.3). Transplant-related mortality was 8% compared to 5% in controls (p=0.6). Toxicities were similar with the exception of cardiac toxicity, which was significantly higher in patients aged 60 years vs. controls (50% grade 3 vs. 10%: p<0.0001). Atrial fibrillation was the most frequent cardiovascular toxicity (9 patients). At a median follow-up of 33 months, there is no significant difference between older vs. younger patients in median EFS (24 vs. 38 months: p=0.78) or OS (40 months vs. not reached: p=0.23). HDT is feasible and effective in selected patients 60 years with MM and NHL. Patients 60 years are more susceptible to cardiovascular toxicities, particularly atrial fibrillation, but have similar or better response rates following HDT and similar long-term outcomes to younger patients.

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.

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.

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.

Isolex 300i CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: We have previously reported that repeated cycles of high-dose therapy (HDT), can be supported by unmanipulated autologous PBPC. Here we investigate whether purified CD34+ cells, obtained by immunomagnetic separation using the Isolex 300i device, can support such therapy. METHODS: Twenty-nine consecutive patients with metastatic breast cancer had PBPC mobilized and harvested following chemotherapy and G-CSF (10 microg/kg per day). Patients with > 4.0 x 10(6)/kg CD34+ cells in the apheresis product underwent CD34-selection using the Isolex 300i (v2.0) device. All cells collected were equally divided into three aliquots and cryopreserved. Patients who did not achieve this threshold had unmanipulated cells collected and stored. Patients subsequently received three cycles of HDT with paclitaxel (175 mg/m2), thiotepa (300 mg/m2) and either ifosfamide (10 g/m2) or cyclophosphamide (4 g/m2). It was intended for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e 1/3 for each cycle) and to compare hemopoietic recovery between patients receiving CD34-selected cells or unmanipulated cells. RESULTS: Thirteen of the 29 patients (45%) did not mobilize sufficient CD34+ cells to undergo CD34-selection. The remaining 16 patients underwent CD34-selection with a median purity of 84.3% (range: 16.3-96.1%) and yield of 34% (range: 1-60%). Fifteen of these patients proceeded to HDT and 42 of the planned 45 cycles were administered. Nine patients had all three HDT cycles supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (range: 0.04-3.01). Three of the 15 patients required infusion of 'back-up' unmanipulated cells because of delayed neutrophil recovery. Of the 13 patients whose PBPCs did not undergo CD34+ cell selection, 11 proceeded to HDT with a median of 3.2 x 10(6)/kg (range: 2.0-4.4) unselected cells infused per cycle and 31 of 33 planned cycles were delivered. When hemopoietic recovery was compared between cycles of HDT supported by CD34-selected (n = 34) and unmanipulated cells (n = 31), there was a modest slowing in the patients receiving CD34-selected cells; time to ANC > 1.0 x 10(9)/L = 11 days versus 10 days (P = 0.0122) and platelets > 20 x 10(9)/L = 14 days versus 13 days (P = 0.0009). No difference in recovery to 50 x 10(9)/L was observed (P = 0.54). CONCLUSION: We have demonstrated that Isolex 300i CD34-selected cells are capable of supporting multiple cycles of HDT. However, we were unable to acquire sufficient CD34+ cells to perform this processing in 45% (13/29) of patients and further improvements in yield are required to overcome the modest delay in neutrophil and platelet recovery.

CliniMACS CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: Traditionally, following high-dose therapy (HDT), unmanipulated autologous PBPC are infused. Alternatively, purified CD34+ cells can now be obtained by immunomagnetic separation using the CliniMACS device. Limited data currently exist examining hemopoietic recovery with such cells. METHODS: Ten patients with advanced breast cancer had PBPC mobilized with docetaxel (100 mg/m2) and G-CSF (10 microg/kg per day), harvested and processed using the CliniMACS CD34-selection device and equally divided into three aliquots for cryopreservation. Unmanipulated 'back-up' cells were also collected on a separate day of the same mobilization, divided into three and cryopreserved. Patients subsequently received three cycles of HDT with cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2). The intent was for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e., 1/3 for each cycle). If, however, hemopoietic recovery was delayed after Cycle 1, 1/3 of the unmanipulated cells were infused following Cycle 2 and the remaining CD34-selected cells (2/3) were used to support Cycle 3. RESULTS: PBPC from 10 patients underwent CD34-selection with a resulting median purity of 93% (range: 76-98%) and yield of 62% (range: 16-93%). Of the 10 patients, only two were able to be supported with CD34-selected cells for all three cycles of HDT. The remaining eight patients required unmanipulated 'back-up' cells to support Cycle 2. Three patients also required infusion of 'back-up' unmanipulated cells because of persistent neutropenia (n = 1) or thrombocytopenia (n = 2) following cycles initially supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (0.7-2.6) (n = 20) and unselected cells was 1.7 (1.4-2.8) (n = 10). Comparing hemopoietic recovery between cycles of HDT supported by CD34-selected (n = 20) and unmanipulated cells (n = 10) there was a significant slowing with the CD34-selected cells; time to ANC > 1.0 = 13 days versus 10 days, platelets > 20 = 17 days versus 13 days, > 50 = 25 versus 17 days (all P values < 0.001). There was no correlation between the dose of CD34-selected cells infused and neutrophil/platelet recovery. DISCUSSION: We have demonstrated that, although unmanipulated PBPC achieve rapid hemopoietic recovery (at modest CD34 doses of < or = 2.8 x 10(6)/kg), CliniMACS-selected CD34+ cells (in the doses utilized in this study of < or = 2.6 x 10(6)/kg) result in significantly prolonged recovery.

Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate-grade non-Hodgkin's lymphoma.

Central nervous system (CNS) relapse of non-Hodgkin's lymphoma (NHL) is usually fatal despite therapy and effective prophylaxis is desirable. Patients at high-risk usually receive intrathecal (i.t.) prophylaxis, although its efficacy is unproven. We therefore analyzed the outcome of all patients with newly diagnosed "intermediate-grade" NHL receiving i.t. prophylaxis from 1991 to 1999. Twenty-six patients were identified and analyzed. All were free of CNS involvement at diagnosis with negative cerebrospinal fluid (CSF) cytology. Disease stage was IE in 7, and IV in 19, with a median of two extranodal sites involved. Serum lactate dehydrogenase was elevated in 65%, and the median International Prognostic Factors Index score was 3 (range 0-5). Anthracycline-based chemotherapy was used in all cases and included high-dose methotrexate +/- ara-C in six patients. The median number of i.t. treatments was 5 (range 1-12) and comprised methotrexate +/- steroid in 15, together with ara-C in 11. The actuarial 3-year CNS-relapse rate was 26 +/- 10%. Six CNS-relapses were observed and involved the spinal cord or brain parenchyma in two cases each, and the leptomeninges in four patients. Treatment-related variables associated with higher CNS-relapse rates (34-50%) were: delay of > or = 14 days from diagnosis to first i.t. injection, < 5 i.t. treatments, delay of i.t. prophylaxis until after attaining CR and systemic treatment lacking high-dose methotrexate +/- ara-C (each P < or = 0.17). I.t. CNS prophylaxis, as used here, was inadequate. Alternative approaches should be pursued.

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.

High-dose therapy and autologous transplantation for lymphoma: The Peter MacCallum Cancer Institute experience.

BACKGROUND: High-dose therapy (HDT) with autologous bone marrow or blood cell transplantation for the treatment of lymphoma commenced at Peter MacCallum Cancer Institute in 1986. AIM: To examine the patient characteristics and outcomes of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) treated with HDT and autologous transplantation at our Institute in the first 10 years of the service (1986-95). METHODS: A retrospective analysis was performed examining patient characteristics, prior chemotherapy regimens, pretransplant disease status, HDT regimen, source of stem cells, time for haematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and progression-free survival (PFS). RESULTS: Sixty-seven patients with NHL were treated with an estimated 5-year OS rate of 44% (95% confidence interval (CI) 32-56%) and PFS rate of 34% (95% CI 21-44%). Factors independently predictive of an unfavourable PFS on multivariate analyses were presence of constitutional symptoms at transplant (P < 0.002) and chemotherapy-resistant disease at transplant (P = 0.02). Twenty-three patients with HD were treated with a 5-year predicted OS rate of 74% (95% CI 56-92%) and PFS rate of 57% (95% CI 36-77%). There was no difference in PFS for HD patients who relapsed either within 12 months of completion of front-line therapy or after this time (P= 0.5). The transplant-related mortality for the entire cohort was 17%, with a progressive decrease over time. CONCLUSION: HDT with autologous transplantation achieves durable PFS and OS in patients with lymphoma. Improved patient selection, therapy modifications according to prognostic factors and ongoing improvements in supportive care should improve outcomes further.