Dasatinib at 100 mg daily continues to demonstrate durable efficacy in second-line therapy in a proportion of patients.
—Neil P. Shah, MD, PhD
Nearly 5,000 scientific abstracts were presented at the 2014 American Society of Hematology (ASH) Annual Meeting and Exhibition in San Francisco. Along with our targeted coverage of the meeting’s key newsmakers, The ASCO Post provides you with these brief reports of other interesting presentations.
Choosing Wisely List
ASH announced its second list of five tests, treatments, and procedures in hematology that should be questioned for routine use as part of the Choosing Wisely campaign, an initiative of the American Board of Internal Medicine Foundation. The first list from ASH was published in 2013; the new list was published just prior to the 2014 ASH meeting.1
The new Choosing Wisely recommendations include:
The goal of the campaign is to reduce unnecessary spending while maintaining evidence-based quality care. Since the launch of the campaign in April 2012, more than 100 national and state medical specialty societies, regional health collaborative organizations, and consumer partners have climbed aboard. Studies are underway to determine the impact of these recommendations.
The recommendations, as well as the evidence supporting them, are available at www.hematology.org/choosingwisely.
Upfront Treatment of CLL
FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) remains the standard of care for upfront treatment of medically fit CLL patients, withstanding a challenge from BR (bendamustine [Treanda] and rituximab) in a head-to-head phase III study.2 However, BR may be a better choice than FCR in elderly and/or less medically fit patients with regard to the toxicity profile, according to the authors of the German CLL Study Group (GCLLSG) CLL10 study.
CLL10 was designed to show noninferiority of front-line BR vs FCR in patients with active CLL without del (17p) who were deemed medically fit. Patients were randomly assigned to six cycles of FCR (n = 284) or BR (n = 280), with the primary endpoint of progression-free survival.
Front-line FCR was significantly superior to BR on several measures. Median progression-free survival was 55.2 months for FCR vs 41.7 months for BR (P < .001). In younger patients (≤ 65), progression-free survival with FCR was also significantly superior to BR: 53.6 months vs 38.5 months, respectively (P < .001). The difference in progression-free survival favoring FCR was not statistically significant in patients older than 65 years.
The rate of complete remission was significantly better in the FCR-treated group: 39.7% vs 30.8% for BR (P = .034). Overall response rate was similar between the two arms, and there was no difference in overall survival between groups at 3 years: 90.6% vs 92.2%, respectively.
Final results of CLL10 were presented by lead author Barbara Eichhorst, MD, of University Hospital in Cologne, Germany.
7-Year Follow-up With Dasatinib in CML
After 7 years of follow-up, collective data on safety and efficacy continue to support the use of dasatinib (Sprycel) in patients with chronic-phase chronic myeloid leukemia (CML) who are resistant to or intolerant of first-line imatinib (Gleevec).3
“This is the longest follow-up for safety and efficacy of any second-generation BCR-ABL tyrosine kinase inhibitor,” said lead author Neil P. Shah, MD, PhD, University of California, San Francisco.
Study CA180-034 was designed to compare four different doses of dasatinib in patients with chronic-phase CML resistant to or intolerant to imatinib; 662 patients were randomly assigned to 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. After 2 years, patients randomized to twice-daily dosing were allowed to switch to once-daily dosing. The primary endpoint of the study was molecular cytogenetic remission.
Over 7 years of follow-up, the dose of 100 mg was generally well tolerated. Cumulative rates of drug-related pleural effusion increased over time. Cardiovascular events occurred at low rates in all four groups, and most occurred during the first year of therapy.
“Dasatinib at 100 mg daily continues to demonstrate durable efficacy in second-line therapy in a proportion of patients,” Dr. Shah said. More than 20% of heavily pretreated patients continued therapy for at least 7 years. No newly described BCR-ABL mutations were reported over the follow-up period. In patients who achieved BCR-ABL expression ≤ 10%, overall survival and progression-free survival were significantly improved at 3 years compared with patients who did not reach that milestone.
Deaths due to disease progression occurred in 12% of patients across all four dosage groups.
Novel Regimen in T-Cell Lymphoblastic Lymphoma
The phase II open-label GRAALL-LYSA LL-03 study is one of the largest ever conducted in adults with T-cell lymphoblastic lymphoma, enrolling 131 patients to evaluate an adapted pediatric-inspired GRAALL treatment, which has yielded good results in adults with acute lymphoblastic leukemia (ALL). Outcomes with this protocol were reported by French investigators.4
The pediatric-inspired ALL treatment included a corticosteroid prephase, a five-drug induction with sequential cyclophosphamide, high-dose consolidation, late intensification, central nervous system prophylaxis and cranial irradiation, and a 2-year maintenance phase. Allogeneic stem cell transplantation was offered to complete responders with high-risk disease.
Of 131 patients, 119 (91%) reached a complete or unconfirmed complete response; 30 patients needed a salvage course, and 34 relapsed. At 3 years, event-free survival was 63%, disease-free survival was 72%, and overall survival was 69%.
The four-gene profile of NOTCH1/FBXW7/RAS/PTEN, as well as level of lactate dehydrogenase, were the strongest prognostic indicators for treatment outcome.
“The study confirms the good response rate and outcomes achieved in these patients when using a pediatric-like ALL chemotherapy,” said lead author Stephane
Lepretre, MD, of Henri Becquerel Center in Rouen, France.
Predicting Relapse After Stopping Imatinib
CML patients treated with first-line imatinib achieve a complete cytogenetic response in more than 70% of cases and a major molecular response in 18% to 58%. However, a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay is unable to ensure eradication of disease, even in the setting of undetectable BCR-ABL. The newer digital polymerase chain reaction (dPCR) can detect one BCR-ABL–positive cell out of 107 cells and is 100 times more sensitive than quantitative RT-PCR. The use of dPCR could potentially separate patients with minimal residual disease from those in whom CML has been completely eradicated.
The global Imatinib Suspension and Validation study aimed to evaluate relapse after discontinuation of imatinib and to validate the capability of dPCR to predict these relapses in CML patients with negative quantitative RT-PCR results.5 The study included 112 patients treated with imatinib for more than 2 years who were in complete molecular remission at the time of enrollment for at least 18 months. The median duration of imatinib treatment was 103 months, median time from first evaluation of complete molecular remission to imatinib discontinuation was 26 months, and median time from CML diagnosis to imatinib discontinuation was 108 months.
At a median follow-up of 22 months, 48% of patients relapsed after discontinuing imatinib. Of these, 68% were dPCR-positive and 43% were dPCR-negative. Of the 108 patients analyzed by dPCR, 23% were dPCR-positive and 77% were dPCR-negative (33% of relapsed patients were dPCR-positive and 67% were dPCR-negative). More than 73% of the relapses occurred within the first 9 months after imatinib discontinuation. Age younger than 45 and dPCR positivity were significantly associated with relapses. No case of CML progression was observed.
The authors concluded that dPCR positivity and young age are predictive of relapse. The presence of patients whose quantitative RT-PCR remained positive but at levels < 0.1% “remains scientifically unexplained and requires particular clinical attention,” said Silvia Mori, PhD, of the University of Milano-Bicocca in Monza, Italy. ■
Disclosure: Drs. Lepretre and Mori reported no potential conflicts of interest. Dr. Eichhorst is on the advisory boards of and receives honoraria from Janssen, Gilead, Mundipharma, GlaxoSmithKline, has received scientific grants from Roche and Mundipharma, and has received honoraria from Roche.
1. Hicks LK, Bering H, Carson KR, et al: Five hematologic tests and treatments to question. Blood. December 4, 2014 (early release online).
2. Eichhorst B, Fink AM, Busch R, et al: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) shows superior efficacy in comparison to bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German GLL Study Group (GCLLSG) (CLL10 study). 2014 ASH Annual Meeting. Abstract 19. Presented December 6, 2014.
3. Shah NP, Rousselot P, Schiffer C, et al: Seven-year follow-up of patients with imatinib-resistant or –intolerant chronic phase chronic myeloid leukemia receiving dasatinib in study CA180-034, final study results. 2014 ASH Annual Meeting. Abstract 520. Presented December 8, 2014.
4. Lepretre S, Touzart A, Vermeulin T, et al: Pediatric ALL-like therapy for adults with T-cell lymphoblastic lymphoma: Results of the Graall-Lysa LL03 study. 2014 ASH Annual Meeting. Abstract 371. Presented December 8, 2014.
5. Mori S, Vagge E, le Coutre P, et al: The risk of relapse in CML patients who discontinued imatinib can be predicted based on patients age and the results of dPCR analysis. 2014 ASH Annual Meeting. Abstract 813. Presented December 9, 2014.