Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of ...resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
•Most cases of ibrutinib-resistant CLL were due to mutations in BTK and/or PLCG2 and often composed of multiple independent subclones.•High sensitivity testing identified resistance mutations up to 15 months before manifestation of clinical progression.
This phase 1 study treated 119 patients with imatinib-resistant chronic myelogenous leukemia (CML) with nilotinib, an inhibitor of BCR-ABL tyrosine kinase. The drug had a relatively favorable safety ...profile and was active in patients who were in the blastic or accelerated phases of CML and in the chronic phase of CML with resistance to imatinib.
Nilotinib had a relatively favorable safety profile and was active in patients who were in the blastic or accelerated phases of CML and in the chronic phase of CML with resistance to imatinib.
The chimeric
BCR-ABL
gene, created by the formation of the Philadelphia chromosome (Ph), encodes a fusion protein, BCR-ABL. The unregulated activity of the ABL tyrosine kinase in BCR-ABL is the cause of chronic myeloid leukemia (CML). Imatinib mesylate, an inhibitor of the BCR-ABL tyrosine kinase, improves the outcome in CML.
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,
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However, the annual progression rate during treatment of chronic-phase CML with imatinib is 4 percent.
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Imatinib is active alone or in combination in newly diagnosed Ph-positive acute lymphoblastic leukemia (ALL).
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Nilotinib (AMN107, Novartis) is a new, orally active, aminopyrimidine-derivative tyrosine kinase inhibitor that is more potent against CML . . .
GOALSWe investigated whether measurement of serum levels of the microRNAs (miRNAs) miR-16, miR-195, and miR-199a, alone or in combination with conventional serum markers, can help to differentiate ...hepatocellular carcinoma (HCC) from chronic liver diseases (CLDs).
BACKGROUNDRecent reports suggest a link between aberrant expression of miRNA, and HCC.
STUDYThis retrospective analysis was conducted using sera from 105 HCC patients, 107 CLD patients, and 71 normal control subjects. The miRNAs were measured using real-time reverse transcription-polymerase chain reaction. The conventional HCC markers α-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3%), and des-γ-carboxyprothrombin (DCP) were measured with commercial kits.
RESULTSSerum levels of miR-16 and miR-199a were significantly lower in HCC than in CLD patients or control subjects (P<0.01). As a single marker, miR-16 had the highest sensitivity for HCC, followed by miR-199a, AFP, DCP, AFP-L3%, and miR-195. The combination of miR-16, AFP, AFP-L3%, and DCP yielded the optimal combination of sensitivity (92.4%) and specificity (78.5%) for HCC, overall and when analysis was restricted to patients with tumors size smaller than 3 cm. As a second-line HCC marker, miR-16 yielded positive HCC predictions in 18 of the 26 (69.2%) HCC patients with negative results on all 3 conventional markers, most of whom had tumors size smaller than 3 cm; miR-16 was falsely positive in only 12 of 96 (12.5%) CLD patients.
CONCLUSIONSThe addition of miR-16 to conventional serum markers improved sensitivity and specificity for HCC. Use of miR-16 for second-line testing in cases considered negative on the basis of conventional HCC markers should be explored in larger, prospective studies.
Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 ...mg/m(2) administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices.
Patients were treated with decitabine 20 mg/m(2) by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were > or = 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score > or = 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety.
Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses CR plus 15 marrow CRs mCRs), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6).
Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration-approved inpatient regimen.
Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A ...chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%.
We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC.
The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin.
FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).
Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector
of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing ...pathways. A phase 2 trial was conducted to determine the efficacy
and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies.
Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute
infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics,
pharmacodynamics, and antitumor response were assessed.
Results: Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome
and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine
agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell
leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five
(10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease
was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores,
fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic
syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus.
Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed.
Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with
selected hematologic malignancies.
The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic ...lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response.
One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m(2) day 1 of course 1 and 500 mg/m(2) day 1 of courses 2 to 6; fludarabine 25 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks.
CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival.
The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.
Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by cytopenia and a propensity to develop acute myeloid leukemia (AML). The management of lower-risk (LR) MDS with ...persistent cytopenias remains suboptimal. Eltrombopag (EPAG), a thrombopoietin receptor agonist, can improve platelet counts in LR-MDS and tri-lineage hematopoiesis in aplastic anemia (AA). We conducted a phase 2 dose modification study to investigate the safety and efficacy of EPAG in LR-MDS. EPAG dose was escalated from 50 mg/day, to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a PNH clone, marrow hypocellularity, thrombocytopenia with or without other cytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with previous EPAG studies in AA; no patients discontinued drug due to adverse events. Three patients developed reversible grade-3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued EPAG after achieving a robust response (median time 16 months); four of them reinitiated EPAG due to declining counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to AML on study. In conclusion, EPAG was well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.
Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In
this phase I study, LBH589 was administered i.v. as a 30-minute ...infusion on days 1 to 7 of a 21-day cycle.
Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic
leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m 2 ): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation
were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed.
Results: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m 2 and one at 11.5 mg/m 2 . QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included
nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8
of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period.
H3 acetylation increase was significant in B-cells (CD19 + ; P = 0.02) and blasts (CD34 + ; P = 0.04). The increase in H2B acetylation was highest in CD19 + and CD34 + cells 3.8-fold ( P = 0.01) and 4.4-fold ( P = 0.03), respectively. The median acetylation of histones H2B and H3 in CD34 + and CD19 + cells significantly increased on therapy as did apoptosis in CD14 + cells. Area under the curve increased proportionally with dose with a terminal half-life of ∼11 hours.
Conclusion: Intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m 2 with consistent transient antileukemic and biological effects.
Purpose: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which
regulates many aspects of cell growth and division. A phase I/II ...study was done to determine safety and efficacy of everolimus
in patients with relapsed or refractory hematologic malignancies.
Experimental Design: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine
the maximum tolerated dose of everolimus to be used in the phase II study.
Results: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle
cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus.
No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia
(7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring
a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration.
A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation
of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in
six of nine patient samples, including those from the patient with a major platelet response.
Conclusions: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome.
Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol
3-kinase/Akt/mTOR pathway are warranted.
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