ABSTRACT
Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
Subject(s)
Clofarabine , Histiocytosis, Langerhans-Cell , Humans , Clofarabine/therapeutic use , Clofarabine/administration & dosage , Histiocytosis, Langerhans-Cell/drug therapy , Male , Female , Adult , Adolescent , Child , Middle Aged , Child, Preschool , Young Adult , Aged , Recurrence , Proto-Oncogene Proteins B-raf/genetics , Infant , Treatment Outcome , Salvage Therapy , Adenine Nucleotides/therapeutic use , Adenine Nucleotides/administration & dosage , Adenine Nucleotides/adverse effects , Arabinonucleosides/therapeutic use , Arabinonucleosides/administration & dosage , Arabinonucleosides/adverse effectsABSTRACT
A 17-year-old female with recently relapsed acute lymphoblastic leukaemia and a treatment course complicated by rhinocerebral mucormycosis infection developed severe peripheral neuropathy during the treatment for mucormycosis infection. This was felt to be a medication side effect. Her peripheral neuropathy was refractory to many well-established treatments, but ultimately responded dramatically and consistently to a novel therapy, topical doxepin cream (5%). This case report is the first published report of the application of topical doxepin cream for treatment of peripheral neuropathy in a paediatric patient.
Subject(s)
Doxepin/administration & dosage , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/drug therapy , Administration, Topical , Adolescent , Dosage Forms , Female , Humans , Mucormycosis/complications , Mucormycosis/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Severity of Illness IndexABSTRACT
A balance between survival and apoptotic signals regulates B cell development. These signals are tightly regulated by a host of molecules, including IL-7. Abnormal signaling events may lead to neoplastic transformation of progenitor B cells. Signal transduction inhibitors potentially may modulate these abnormal signals. Inhibitors of the mammalian target of rapamycin (mTOR) such as rapamycin have been used as immunosuppressive agents. We hypothesized that rapamycin might demonstrate activity against B-precursor acute lymphoblastic leukemia. We have found that rapamycin inhibited growth of B-precursor acute lymphoblastic leukemia lines in vitro, with evidence of apoptotic cell death. This growth inhibition was reversible by IL-7. One candidate as a signaling intermediate cross-regulated by rapamycin and IL-7 was p70 S6 kinase. Rapamycin also demonstrated in vivo activity in E mu-ret transgenic mice, which develop pre-B leukemia/lymphoma: E mu-ret transgenic mice with advanced disease treated daily with rapamycin as a single agent showed a >2-fold increase in length of survival as compared with symptomatic littermates who received vehicle alone. These results suggest that mammalian target of rapamycin inhibitors may be effective agents against leukemia and that one of the growth signals inhibited by this class of drugs in precursor B leukemic cells may be IL-7-mediated.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Interleukin-7/metabolism , Leukemia, B-Cell/drug therapy , Signal Transduction , Sirolimus/pharmacology , Animals , Apoptosis , Bone Marrow Cells/cytology , Cell Division , Cell Line , Cell Survival , Dose-Response Relationship, Drug , Flow Cytometry , Immunoblotting , Immunosuppressive Agents/pharmacology , In Vitro Techniques , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Neoplasm Transplantation , Phosphorylation , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Time FactorsABSTRACT
A primary focus of signal transduction in B cells, from the pre-B cell to the mature B cell, is the B cell receptor complex. Here we describe work demonstrating the importance of signaling via the pre-B cell receptor complex (pre-BCR) to the pre-B cell transition, the central checkpoint in B-cell development. We have shown tht pre-BCR complex components Igalpha and Igbeta are critical to allowing the pre-B cell to move through this transition, but may not be required for allelic exclusion. Pre-BCR expression also directly affects the response of leukemic cells to steroid treatment, suggesting that signals initiated by the pre-BCR complex may present therapeutic targets in acute leukemia. Additionally, interleukin-7 may also modulate the response of leukemic cells arising from early B-cell stages to treatment. This observation has lead directly to proposals to test drugs which may antagonize early B-cell growth signals, such as rapamycin, in acute lymphoid leukemia.
Subject(s)
B-Lymphocytes/immunology , Cell Differentiation/immunology , Lymphocyte Activation/immunology , Membrane Glycoproteins/immunology , Receptors, Antigen, B-Cell/immunology , Animals , Humans , Leukemia/immunology , Pre-B Cell Receptors , Signal Transduction/immunologyABSTRACT
Most childhood acute lymphoblastic leukemia (ALL) arises from early B-lineage cells,and response to steroid treatment is critical to successful ALL therapy. To investigate the effect of the pre-B cell receptor (pre-BCR) complex on the response of leukemic cells to steroids, cytoplasmic micro protein (cyto mu) was transfected into cyto mu-, steroid-resistant early B cell lines. The presence of cyto mu and the assembled pre-BCR complex conferred sensitivity to dexamethasone-induced apoptosis. Both intrinsic and extrinsic apoptosis pathways are involved in this cell death. However, if the transfected cyto micro protein is unable to assemble the pre-BCR complex, the cells remain resistant to dexamethasone. These findings suggest a role for the pre-BCR complex in the response of ALL cells to treatment and provide insight into the mechanism of steroid response in the treatment of pre-B ALL.