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"Larson, R A"
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European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
Journal Article
Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial
In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients’ long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR
4.5
;
BCR-ABL
⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.
Journal Article
Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (
n
=553) or interferon-α (IFN) plus cytarabine (
n
=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88%––or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
Journal Article
Diverse coral communities in mangrove habitats suggest a novel refuge from climate change
Risk analyses indicate that more than 90% of the world's reefs will be threatened by climate change and local anthropogenic impacts by the year 2030 under \"business-as-usual\" climate scenarios. Increasing temperatures and solar radiation cause coral bleaching that has resulted in extensive coral mortality. Increasing carbon dioxide reduces seawater pH, slows coral growth, and may cause loss of reef structure. Management strategies include establishment of marine protected areas with environmental conditions that promote reef resiliency. However, few resilient reefs have been identified, and resiliency factors are poorly defined. Here we characterize the first natural, non-reef coral refuge from thermal stress and ocean acidification and identify resiliency factors for mangrove–coral habitats. We measured diurnal and seasonal variations in temperature, salinity, photosynthetically active radiation (PAR), and seawater chemistry; characterized substrate parameters; and examined water circulation patterns in mangrove communities where scleractinian corals are growing attached to and under mangrove prop roots in Hurricane Hole, St. John, US Virgin Islands. Additionally, we inventoried the coral species and quantified incidences of coral bleaching, mortality, and recovery for two major reef-building corals, Colpophyllia natans and Diploria labyrinthiformis, growing in mangrove-shaded and exposed (unshaded) areas. Over 30 species of scleractinian corals were growing in association with mangroves. Corals were thriving in low-light (more than 70% attenuation of incident PAR) from mangrove shading and at higher temperatures than nearby reef tract corals. A higher percentage of C. natans colonies were living shaded by mangroves, and no shaded colonies were bleached. Fewer D. labyrinthiformis colonies were shaded by mangroves, however more unshaded colonies were bleached. A combination of substrate and habitat heterogeneity, proximity of different habitat types, hydrographic conditions, and biological influences on seawater chemistry generate chemical conditions that buffer against ocean acidification. This previously undocumented refuge for corals provides evidence for adaptation of coastal organisms and ecosystem transition due to recent climate change. Identifying and protecting other natural, non-reef coral refuges is critical for sustaining corals and other reef species into the future.
Journal Article
Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib
Dasatinib, a potent inhibitor of BCR–ABL
in vitro
, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (
N
=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1–18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.
Journal Article
Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase
Nilotinib is a selective inhibitor of BCR-ABL approved for use in newly diagnosed and imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase. In this study, 400 mg of nilotinib was administered twice daily to the patients with myeloid (MBP,
n
=105) or lymphoid blastic phase (LBP,
n
=31) CML. After a minimum follow-up of 24 months, major hematologic responses were observed in 60% (MBP) and 59% (LBP) of patients. Major cytogenetic responses (MCyR) were attained in 38% (MBP) and 52% (LBP) of patients; and complete cytogenetic responses in 30% and 32%, respectively. Median duration of MCyR was 10.8 (MBP) and 3.2 months (LBP). Median overall survival was 10.1 (MBP) and 7.9 (LBP) months with 12- and 24-month survival of 42% (MBP 44%, LBP 35%) and 27% (MBP 32%, LBP 10%), respectively. Twelve MBP patients and two LBP patients received subsequent stem cell transplantation. Myelosuppression was frequent, with grade 3/4 neutropenia, thrombocytopenia, and anemia in 68%, 63% and 47% of patients, respectively. Grade 3/4 hypophosphatemia, hyperbilirubinemia and lipase elevation were observed in 15%, 11% and 11% of patients, respectively. Nilotinib has significant efficacy in patients with BP CML, but given the limited long-term survival of these patients, novel agents are needed.
Journal Article
Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy
Nilotinib is a highly selective Bcr–Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for second-line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international phase II study of nilotinib was conducted in CML patients (39 chronic phase (CP), 21 accelerated phase (AP)) after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematological response and major cytogenetic response (MCyR) rates in CP were 79% and 43%, respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematological response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients were progression-free. Median overall survival for both populations has not been reached, and the estimated 18-month survival rate in CML-CP was 86% and that at 12 months for CML-AP was 80%. Nilotinib is an effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.
Journal Article
Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720
Untreated
de novo
(
n
=421) and secondary (
n
=189) acute myeloid leukemia (AML) patients ⩾60 years received intensified chemotherapy, including daunorubicin 60 mg/m
2
and etoposide 100 mg/m
2
during days 1, 2, 3 with cytarabine 100 mg/m
2
during days 1–7, with a second induction if needed and one consolidation course with these drugs and doses for 2, 2 and 5 days, respectively. In all, 287 (47%) achieved complete remission (CR), 136 (22%) died and 187 (31%) were non-responders. CR rates were 27, 44 and 52% for complex karyotypes, rare aberrations and neither (
P
<0.001), 52 and 37% for
de novo
and secondary AML (
P
=0.003), and 53 and 42% for age 60–69 and ⩾70 years (
P
=0.015). In multivariable analysis, CR predictors included non-complex/non-rare karyotypes (
P
<0.001),
de novo
AML (
P
<0.001), better performance status (PS) (
P
<0.001) and younger age (
P
=0.001). Disease-free (DFS) and overall (OS) survival medians were 6.8 (95% CI: 6.2, 7.8) and 7.2 (95% CI: 6.4, 8.6) months. In multivariable analysis, DFS was shorter for complex karyotypes (
P
<0.001) and increasing white blood count (WBC) (
P
<0.001) and age (
P
=0.038), and OS for complex karyotypes (
P
<0.001), increasing WBC (
P
=0.001) and age (
P
<0.001), poorer PS (
P
<0.001) and secondary AML (
P
=0.010). Outcomes and prognostic factors were similar to those in previous Cancer and Leukemia Group B studies.
Journal Article
A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes
Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m
2
/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity <20% and blasts <10%). Marrow cellularity (
P
<0.0001) and blast% (
P
=0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3–4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1–21), relapse was 29% (95% CI: 13–46) and OS was 71% (95% CI: 51–85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21–58) and 2 year OS was 31% (95% CI: 14–48). Disease at the nadir correlated with inferior OS after HCT (HR=1.22 for each 10% marrow blasts, 95% CI: 1.02–1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days,
P
=0.3) and OS (375 vs 195 days,
P
=0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.
Journal Article