The Effectiveness of Tyrosine Kinase Inhibitors and Molecular Monitoring Patterns in Newly Diagnosed Patients With Chronic Myeloid Leukemia in the Community Setting.

BACKGROUND: Clinical outcomes of patients with chronic myeloid leukemia (CML) treated in clinical trials, including response to therapy, may not be representative of those treated in a community setting. Thus, we sought to determine the real-world effectiveness of first-line tyrosine kinase inhibitors in CML by evaluating response rates, all-cause discontinuation, and adherence. Response monitoring patterns were also analyzed. PATIENTS AND METHODS: This retrospective observational study, using the McKesson Specialty Health/US Oncology Network (MSH/USON) iKnowMed electronic health record database and medical charts, identified newly diagnosed CML patients who received first-line imatinib, dasatinib, or nilotinib from July 2007 to March 2011, and were then followed for ≥ 18 months. RESULTS: Three hundred patients met study criteria (222 imatinib-treated, 34 dasatinib-treated, and 44 nilotinib-treated in the first-line). Molecular and cytogenetic response assessments were conducted less frequently than recommended (40% never had cytogenetic or molecular monitoring at any time). Patients treated with either dasatinib or nilotinib experienced higher response rates by 6, 12, and 18 months, faster time to major molecular response, and a significantly lower rate of all-cause treatment discontinuation within 18 months relative to imatinib-treated patients. Approximately 56% of all patients were adherent to tyrosine kinase inhibitor therapy. CONCLUSION: Dasatinib and nilotinib were more effective than imatinib as first-line therapy for CML in a community setting, as observed in descriptive and univariate analyses. The frequency of cytogenetic and molecular monitoring was lower than that recommended by current guidelines, including patients with no molecular or cytogenetic assessments during the 18-month follow-up. Therefore, MSH/USON is working toward improving compliance with response monitoring guidelines.

A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia.

BACKGROUND: Uncontrolled studies comparing pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR) to fludarabine plus C+R (FCR) suggest similar efficacy with fewer infectious complications with PCR. We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia (CLL). TREATMENT: FCR (F 20 mg/m(2) Days 1-5, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (28-day cycles) or PCR (P 4 mg/m(2) Day 1, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (21-day cycles). Dose 1 of R: 100 mg/m(2) was given on Day 8 Cycle 1 and the remainder on Day 9; in subsequent cycles the entire dose was given on Day 1. RESULTS: Ninety-two patients were randomly assigned to each group (N = 184). Groups were balanced; ~20% had received prior chemotherapy. The infection rate (FCR/PCR) was 31%/36%, the infective event rate was 38%/45%; 30 (35%)/37 (44%) patients were hospitalized; total hospitalization days was 271/404. 12 (14%)/6 (7%) patients achieved complete remissions (CR); the overall response rate (ORR) including CR+nodular PR (nPR)+PR was 59%/49%. Grade 3-4 treatment related AEs: neutropenia (69%/57%), leukopenia (34%/17%), thrombocytopenia (13%/6%). Grade 3-4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related. CONCLUSIONS: PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity. ORRs were lower than expected; the CR rate was higher (NS) with FCR. This trial did not demonstrate a lower infection rate with PCR.

Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma.

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

Purine analogue combinations for indolent lymphomas.

Indolent lymphomas are a group of lymphoid malignancies with differing patterns of behavior and responses to treatment. The progress in treating patients with hairy cell leukemia (HCL) using nucleoside analogues can be used as a model for other indolent B-lymphoproliferative disorders, such as follicular lymphoma. Recent advancements in therapeutic options available for these patients include combination therapy with agents that have differing mechanisms of action and non-overlapping toxicity. It has been shown that patients who are candidates for aggressive therapy might receive benefit, including disease-free survival and overall survival, from combination purine analogue therapy. Using these more aggressive therapeutic approaches earlier in the disease course and as maintenance therapy may further enhance outcomes. With the advent of these new therapies along with the molecular evaluation of these regimens, we may be nearing the time where the goal for more advanced indolent lymphoma will be to achieve a cure.

An open-label pilot study of pentostatin, mitoxantrone, and rituximab in patients with previously untreated, Stage III or IV, low-grade non-Hodgkin lymphoma.

BACKGROUND: In a previous study, the authors demonstrated that the combination of pentostatin (P) and rituximab (R) was well tolerated and was active in patients with low-grade non-Hodgkin lymphoma (NHL). In the current study, mitoxantrone (M) was added to P + R to evaluate the toxicity and efficacy of this three-drug combination (PMR). METHODS: Twenty-four previously untreated patients with histologically proven, Stage III or IV, low-grade NHL were registered between April and September, 2002. Patients received P (4 mg/m2), M (10 mg/m2), and R (375 mg/m2) every 28 days (M on Day 1; P and R on Days 1 and 8; in Cycle 1, R was given on Day 8 only). Eighty-three percent of patients had Stage IV disease, the median patient age was 62 years (range, 4-81 years), and the performance status was 0-2. RESULTS: Responses included 9 patients who achieved complete remission (CR) (38%), 3 patients with unconfirmed CR (CRu) (12%), 8 patients who achieved partial remission (33%), and 4 patients who achieved stable disease (17%); the overall response rate (CR + CRu + PR) was 83%. PMR appeared to result in comparable activity in all histologies. The median response duration was 10.0 months (range, 3.5-15.1 months). Patients received a median of 5 cycles (range, 1-10 cycles). Eighteen patients (75%) required dose reduction or delay due to toxicity, mainly neutropenia (the administration of growth factors was not permitted). Three patients died (two patients died of disease progression, and one patient died from unrelated cardiopulmonary arrest). Grade > or = 3 drug-related toxicities included neutropenia (67%), leukopenia and febrile neutropenia (17% each), and sepsis (8%), and 38% of neutropenic episodes occurred in Cycles 1 and 2. CONCLUSIONS: In this study, PMR was active and well-tolerated in patients with low-grade NHL, and the combination is deserving of further study.

Results of a phase II multicenter trial of single-agent gemcitabine in patients with relapsed or chemotherapy-refractory Hodgkin's lymphoma.

This study's objective was to determine the efficacy and safety of gemcitabine in patients with relapsed or chemotherapy-refractory Hodgkin's lymphoma (HL). Twenty-nine patients were enrolled. Eight of the first 10 patients received intravenous gemcitabine (1250 mg/m2) days 1, 8, and 15 every 4 weeks. Two patients withdrew consent before treatment. Because of toxicity, the remaining 19 patients received 1000 mg/m2 on days 1 and 8 every 3 weeks. Of the 29 treated patients, 16 (55.2%) were male, the median age was 43 years (range, 20.9-77.3), and 89.7% of them were white. Twelve patients (41.4%) had an Eastern Cooperative Oncology Group performance status (PS) of 0, 14 (48.3%) had a PS of 1, and 3 (10.3%) had a PS of 2. All patients had >/= 2 prior chemotherapy regimens. Eighteen patients (62%) had a relapse following bone marrow transplantation. Of 27 evaluable patients, 6 (22%) had partial response, 14 (52%) had stable disease, and 7 (26%) had progressive disease. The median time to progression for all patients was 6.4 months (range, 1.1-21.9). The median survival for all patients was 26.9 months (range, < 1-28.4). All patients have discontinued treatment because of disease progression or relapse. Grade >/= 3 toxicity occurred in 14 patients (48.3%): thrombocytopenia (33.3%), neutropenia (29.6%), anemia (7.4%), increased alanine aminotransferase, reduced cardiac function, and fever (3.7% for each event). This study confirms the activity of gemcitabine in relapsed and highly refractory HL. Dose and schedule may be modified in the future to optimize responses. As gemcitabine is active in highly refractory/relapsed HL, future studies should consider incorporating gemcitabine in combination regimens as first-line therapy for patients with high-risk HL.

Pegylated liposomal doxorubicin as single-agent treatment of low-grade non-Hodgkin's lymphoma: a phase II multicenter study.

The purpose of this study was to determine the objective response rate, median duration of response, time to disease progression, and survival time and to evaluate the safety of pegylated liposomal doxorubicin in previously treated patients with low-grade non-Hodgkin's lymphoma. Thirty-two patients with low-grade non-Hodgkin's lymphoma were treated and analyzed. Pegylated liposomal doxorubicin 30 mg/m2 was administered intravenously as a single dose on day 1 of each 3-week cycle. Patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had stage II-IV disease. The median baseline left ventricular ejection fraction was 60%, and the median age was 68 years. In 29 evaluable patients, there were 3 (10%) complete responses, 6 (21%) partial responses, 11 (38%) patients with stable disease, and 9 (31%) with progressive disease. The median number of cycles was 4 (range, 1-22 cycles). The median duration of response (complete response plus partial response) was 11.0 months (range, 2.3-37.0 months). The estimated median time to progression was 5.6 months (range, 1.1-40.5 months) and the estimated median survival was 29.6 months (range, 3.9-41.6 months). Treatment-related toxicities grade = 3 included neutropenia (25%) and palmoplantar erythrodysesthesia (9%). Only 1 clinically significant cardiac toxicity was observed. There were 17 deaths; none were treatment related. Single-agent pegylated liposomal doxorubicin 30 mg/m2 every 3 weeks, is associated with antitumor activity in the treatment of low-grade non-Hodgkin's lymphoma, as shown by an objective response of 31%, and produced no significant cardiac or hematologic toxicity. Based on these results, pegylated liposomal doxorubicin should be further evaluated in combination with other agents in low-grade non-Hodgkin's lymphoma.

Results of a phase II multicenter trial of pentostatin and rituximab in patients with low grade B-cell non-Hodgkin's lymphoma: an effective and minimally toxic regimen.

This study explored the efficacy and toxicity of the combination of pentostatin and rituximab, effective single agents in low-grade non-Hodgkin's lymphoma (NHL). Sixty patients with previously treated low-grade NHL were enrolled. Except for day 1, both drugs were administered weekly for 4 weeks, with week 5 off. During week 1 (day 1) only rituximab was given; subsequent weekly treatments included both drugs. Patients received a minimum of 2 five-week cycles in order to be evaluable for efficacy. Responses were evaluated on week 5 of cycle 2. If partial response (PR) or stable disease (SD) responses were noted, 2 additional cycles were administered. Final evaluations were done on week 5 of cycle 4. Of 60 patients, 58.3% had an Eastern Cooperative Oncology Group performance status (PS) of 0, and 41.7% had PS of 1; 31.7% and 51.7% had stage III or stage IV disease, respectively. Histology included follicular center, follicular, grade I (45%), II (21.7%), III (1.7%), and small lymphocytic (31.7%). Seventeen patients had prior chemotherapy, but no patients had received prior pentostatin or rituximab. Median age was 60.3 years (range, 32.5-84.7 years). Among 57 evaluable patients, 77% responded (22.3% complete response [CR], 3.5% unconfirmed CR, 35.1% PR, and 10.5% unconfirmed PR); 19.3% had SD, and 8.8% progressive disease (PD). Response rate among previously untreated patients was 83% versus 63% in previously treated patients. Median duration of response was 11 months (range, 2.3-22.2 months); median time to progression was 15 months (range, < 1-25 months). Neutropenia was the only adverse event experienced by >/= 10% of patients. Six deaths were caused by PD, and one death each was caused by acute respiratory distress, possibly related respiratory failure, and cardiac toxicity. These results suggest the combination of pentostatin/rituximab is well tolerated and active in low-grade lymphoma.