Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Drug Resistance, Neoplasm , Leukemia, Myeloid, Accelerated Phase/drug therapy , Leukemia, Myeloid, Accelerated Phase/pathology , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Dasatinib/administration & dosage , Dasatinib/adverse effects , Humans , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Accelerated Phase/mortality , Neoplasm Staging , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Randomized Controlled Trials as Topic , Retreatment , Treatment OutcomeABSTRACT
Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.
Subject(s)
Graft vs Host Disease/drug therapy , Janus Kinases/therapeutic use , Pyrazoles/therapeutic use , Adult , Aged , Chronic Disease , Female , Graft vs Host Disease/pathology , Humans , Janus Kinases/pharmacology , Male , Middle Aged , Nitriles , Pyrazoles/pharmacology , PyrimidinesABSTRACT
The prognosis of chronic phase chronic myeloid leukemia (CML) has improved so that life expectancy for patients responding to tyrosine kinase inhibitors (TKIs) is now equivalent to age-matched controls. Attention should be paid to comorbidities that impact survival. The success of TKI therapy can be easily and reliably assessed at well-accepted time points using quantitative polymerase chain reaction (PCR) standardized to the international scale. Patient-reported outcome (PRO) tools are readily available for use in the clinic and provide complementary information on the tolerance of TKIs. Effectively managing adverse events of TKIs can improve compliance and quality of life. Discontinuation of TKIs is the next frontier in CML. In select patients with sustained deep molecular remission, a discontinuation of TKI is associated with a durable treatment-free remission in approximately 50%. Patient engagement in their discontinuation can be achieved through a provider multi-team coaching, is complementary to the available guidelines, and may provide an additional safety net so that these discontinuations remain safe when applied in general practices.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Medical Oncology/trends , Protein Kinase Inhibitors/therapeutic use , Disease Management , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Prognosis , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with "reduced frequency" molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482-88. © 2017 American Cancer Society.
Subject(s)
Deprescriptions , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Neoplasm Recurrence, Local/blood , Protein Kinase Inhibitors/therapeutic use , Watchful Waiting/methods , Adult , Aged , Aged, 80 and over , Aniline Compounds/therapeutic use , Dasatinib/therapeutic use , Female , Humans , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Male , Middle Aged , Neoplasm Recurrence, Local/genetics , Nitriles/therapeutic use , Quinolines/therapeutic use , Remission Induction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Young AdultABSTRACT
BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.
Subject(s)
Hematopoietic Stem Cell Transplantation/mortality , Leukemia, Myeloid, Acute/mortality , Mutation/genetics , Survivors , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Allografts , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival Rate , Young AdultABSTRACT
Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Harringtonines/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Blast Crisis/drug therapy , Codon , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Harringtonines/chemistry , Harringtonines/pharmacology , Homoharringtonine , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Accelerated Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/drug therapy , Mutation , Treatment OutcomeSubject(s)
Blast Crisis/pathology , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/pathology , Protein Kinase Inhibitors/administration & dosage , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Chronic-Phase/enzymology , Remission InductionABSTRACT
The management of chronic myeloid leukemia (CML) in accelerated or blast phase (advanced phase) remains a significant challenge despite the introduction of very effective tyrosine kinase inhibitors (TKIs). The biology of advanced-phase CML is complex and engages several pathways that are not optimally targeted by TKIs. Allogeneic stem cell transplantation remains the only potentially curative therapy, but the effectiveness of this conventional approach is limited. New strategies are required to improve the outlook for these patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Chronic-Phase/therapy , Protein Kinase Inhibitors/therapeutic use , Blast Crisis/therapy , Consolidation Chemotherapy/methods , Disease Management , Humans , Leukemia, Myeloid, Chronic-Phase/pathology , Molecular Targeted Therapy/methodsABSTRACT
BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.
Subject(s)
Aminopyridines , Antineoplastic Agents , Hematologic Neoplasms/drug therapy , Phenylurea Compounds , Protein Kinase Inhibitors , Aged , Aminopyridines/adverse effects , Aminopyridines/pharmacokinetics , Aminopyridines/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Aurora Kinases/antagonists & inhibitors , Azacitidine/adverse effects , Azacitidine/pharmacokinetics , Azacitidine/therapeutic use , Female , Hematologic Neoplasms/metabolism , Humans , Male , Maximum Tolerated Dose , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Receptors, Vascular Endothelial Growth FactorABSTRACT
BACKGROUND: Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic-phase chronic myeloid leukemia (CP-CML) is unknown. We hypothesized that finding aberrant cells with FC in CP-CML may predict early blast-phase (BP) transformation. METHODS: Results for FC performed at the time of diagnosis for adult and pediatric patients with CP-CML who were referred to our institution were reviewed, and they were correlated with outcomes. RESULTS: FC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP-CML. Aberrant populations, representing a median of 2% (range, 0.3%-15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first-line treatment. With a median follow-up of 43 months (range, 2-113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4-72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31). CONCLUSIONS: In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP-CML appears to be associated with early progression to lymphoid BP.
Subject(s)
Blast Crisis/immunology , Blast Crisis/pathology , Immunophenotyping/methods , Leukemia, Myeloid, Chronic-Phase/immunology , Leukemia, Myeloid, Chronic-Phase/pathology , Adult , Child , Female , Flow Cytometry/methods , Humans , Male , Predictive Value of TestsABSTRACT
Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCη, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
Subject(s)
Benzamides/therapeutic use , Drug Resistance, Neoplasm/drug effects , Fusion Proteins, bcr-abl/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Molecular Targeted Therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Animals , Benzamides/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Disease Progression , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Knockdown Techniques , Genes, Neoplasm , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mice , Mitogen-Activated Protein Kinase Kinases/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Phosphorylation/drug effects , Piperazines/pharmacology , Protein Kinase C/metabolism , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , RNA, Small Interfering/metabolism , Survival Analysis , Up-Regulation/drug effects , raf Kinases/metabolismABSTRACT
OBJECTIVE: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta. METHODS: Cases reported to the Georgia Comprehensive Cancer Registry and the national Surveillance Epidemiology and End Results cancer registry between 1999 and 2008 were analyzed. Age-adjusted incidence rates were calculated for all of the counties and public health regions and were compared with national rates calculated using Surveillance Epidemiology and End Results 17 data. Cases of adult acute myeloid leukemia served as controls. RESULTS: Age-adjusted incidence rates of adult ALL (0.8/100,000) and acute myeloid leukemia (4.6/100,000) were comparable to the national rates (0.9 and 5.2, respectively). The age-adjusted incidence rate of ALL in northern Georgia was 1.1 (95% confidence interval 0.8-1.5) and was not affected by race. CONCLUSIONS: The observed increase in cases of ALL at our tertiary center results from a referral pattern rather than heterogeneous distribution of adult ALL across Georgia.
Subject(s)
Leukemia, Erythroblastic, Acute/epidemiology , Adult , Georgia/epidemiology , Humans , Referral and Consultation , RegistriesABSTRACT
Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians', and increasingly patients and families' preference, patients' comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.
Subject(s)
Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Nitriles/pharmacology , Nitriles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Drug Approval , Humans , Molecular Targeted Therapy , Nitriles/adverse effects , Nitriles/pharmacokinetics , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/genetics , Quinolines/adverse effects , Quinolines/pharmacokinetics , United States , United States Food and Drug AdministrationABSTRACT
Bosutinib is an orally bioavailable SRC/ABL tyrosine kinase inhibitor with activity against all phases of resistant chronic myeloid leukemia that do not express the T315I or V299L ABL kinase domain mutations. Bosutinib has a unique toxicity profile that is manageable. This paper provides an overview of bosutinib, covering pharmacodynamics and pharmacokinetic properties, results of treatment in newly diagnosed and previously treated chronic myeloid leukemia patients, as well as common side effects.
ABSTRACT
The SRC-ABL inhibitor bosutinib is one of the five tyrosine kinase inhibitors currently approved for the treatment of Philadelphia chromosome-positive leukemias. Bosutinib has shown activity against all phases of resistant chronic myeloid leukemia that do not harbor the T315I or V299L ABL kinase domain mutations. Bosutinib is overall well tolerated; transient diarrhea is the most common side effect. This article summarizes the pharmacokinetics, pharmacodynamics, safety and efficacy of bosutinib for the treatment of Philadelphia chromosome-positive leukemias.
Subject(s)
Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia/drug therapy , Leukemia/genetics , Nitriles/therapeutic use , Philadelphia Chromosome , Protein Kinase Inhibitors/therapeutic use , Quinolines/therapeutic use , Aniline Compounds/adverse effects , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Approval/legislation & jurisprudence , Humans , Leukemia/pathology , Neoplasm Staging , Nitriles/adverse effects , Nitriles/chemistry , Nitriles/pharmacology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinolines/adverse effects , Quinolines/chemistry , Quinolines/pharmacology , Treatment OutcomeABSTRACT
Patients with cancer are at high risk for developing venous thromboembolism (VTE), and the presence of a central venous catheter (CVC) further increases this risk. CVC-related VTE has serious implications related to the loss of vascular access, development of pulmonary embolism, recurrent VTE, infections and post-thrombotic syndrome. The pathogenesis of CVC-related VTE is complex and multifactorial, with risk factors associated with the catheter, the vessel selected for insertion and the underlying cancer as well as the anti-cancer therapy. Clinical presentation of CVC-related VTEs is often non-specific, and ultrasonography is the most commonly used radiological diagnostic test. Management of CVC-related VTE in patients with cancer requires a balance between the need for venous access, the risk of VTE recurrence and the risk of bleeding from treatment-induced thrombocytopenia. Effective VTE prophylaxis methods have yet to be defined. Ongoing studies are evaluating the role of newer oral antithrombotic agents and alternative interventional strategies for the prevention and treatment of CVC-related VTE in patients with cancer.
Subject(s)
Catheterization, Central Venous/adverse effects , Neoplasms/complications , Venous Thrombosis/etiology , Anticoagulants/therapeutic use , Humans , Incidence , Premedication , Risk Factors , Venous Thromboembolism/diagnosis , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Venous Thromboembolism/therapy , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiology , Venous Thrombosis/prevention & control , Venous Thrombosis/therapyABSTRACT
The presence of leukemic blasts detected by light microscopy in cerebrospinal fluid (CSF) establishes the diagnosis of leukemic meningitis in acute lymphoblastic leukemia/lymphoma (ALL). Flow cytometry immunophenotyping (FCI) is a very sensitive method that detects a minute number of aberrant cells, and is increasingly performed on CSF samples. We sought to determine the sensitivity and specificity of CSF FCI for the diagnosis of leukemic meningitis in ALL. Between November 2007 and August 2011, 800 CSF samples from 80 patients with ALL were available from diagnostic lumbar punctures (LPs; n = 80), follow-up LPs (n = 687) and at the time of relapse (n = 33). FCI was performed on 267 samples, and only identified aberrant cells in cytologically confirmed cases of leukemic meningitis. A blinded review of all cases with detectable CSF nucleated cells confirmed these findings. We conclude that CSF FCI has a 100% sensitivity and specificity for the detection of lymphoblasts. However, additional studies are needed to define the role this procedure plays in the diagnosis of leukemic meningitis.
Subject(s)
Flow Cytometry , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/secondary , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adolescent , Adult , Aged , Female , Follow-Up Studies , Humans , Immunophenotyping , Male , Meningeal Neoplasms/cerebrospinal fluid , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/cerebrospinal fluid , Recurrence , Sensitivity and Specificity , Young AdultABSTRACT
Treatment of chronic myeloid leukemia (CML) has evolved dramatically with the development of tyrosine kinase inhibitors (TKIs). This past decade also witnessed major advances in the field of allogeneic hematopoietic stem cell transplantation (alloHSCT) that led to better patients' outcomes. Progress in the exploitation of alternative sources of stem cells, development of novel conditioning regimens, discovery of innovative graft-versus-host prophylactic strategies, and advances in supportive care as well as positioning of alloHSCT in the overall management of CML are discussed in this article.
Subject(s)
Hematopoietic Stem Cell Transplantation/trends , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Comorbidity , Hematopoietic Stem Cells/cytology , Humans , Immunosuppression Therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Transplantation, HomologousABSTRACT
Bosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia. This review of bosutinib summarizes the mode of action, pharmacokinetics, efficacy and safety data, as well as the patient-focused perspective through quality-of-life data. Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia, especially in the chronic phase, with resistance or intolerance to prior tyrosine kinase inhibitors. Bosutinib has distinct but manageable adverse events. In the absence of T315I and V299L mutations, there are no absolute contraindications for the use of bosutinib in this patient population.