Rituximab in B-cell disorders other than non-Hodgkin's lymphoma.

Rituximab is a human/mouse chimeric monoclonal antibody that binds to the CD20 antigen and is expressed at all stages of B-cell development. Rituximab has demonstrated efficacy as monotherapy and in combination with chemotherapy in the treatment of both indolent and aggressive non-Hodgkin's lymphoma (NHL). Rituximab treatment results in rapid depletion of B-cells and this has led to the consideration of other B-cell disorders as candidates for rituximab therapy. Recent studies have demonstrated the efficacy of rituximab in a variety of such disorders, including chronic lymphocytic leukemia (CLL), post-transplant lymphoproliferative disorder (PTLD), Waldenström's macroglobulinemia (WM), multiple myeloma (MM), idiopathic thrombocytopenic purpura (ITP), hairy-cell leukemia (HCL) and cold agglutinin disease (CAD). In patients with CLL, increasing the dose and/or frequency of rituximab treatment has given improved response rates compared with the standard dose schedule used in NHL, and combination immunochemotherapy has yielded an overall response rate of 92% (with a 60% complete response rate). Clinical trials have also demonstrated evidence of efficacy for rituximab in PTLD, WM and relapsed or refractory ITP. Efficacy of rituximab in CAD and relapsed or refractory HCL has also been demonstrated in small studies and case reports. Available data thus indicate that rituximab can be an effective therapy in a wide range of CD20+ lymphoid disorders

Regulation of the bone marrow microenvironment by G-CSF: Effects of G-CSF on acute lymphoblastic leukaemia

<div><p>It has been suggested that disruption of the lymphoid niche by G-CSF may be of therapeutic benefit to patients with acute lymphoblastic leukaemia. We used a xenograft model to determine the effect of G-CSF on ALL progression in a minimal residual disease setting. Consistent with the effects on normal murine B cell progenitors, G-CSF slowed disease in the majority of ALL xenografts tested, suggesting that G-CSF may provide benefits beyond neutrophil recovery for ALL patients. However, two of eight xenografts demonstrated accelerated disease progression. G-CSF could be detrimental for these patients due to expansion of the malignant clone.</p></div

Patient information for xenografts.

<p>Patient information for xenografts.</p

Effect of G-CSF on the in vitro growth of ALL xenograft cells.

<p><b>(A)</b> Expression of the G-CSFR on ALL cells as determined by flow cytometry. The fine line is the isotype control and the heavy line the G-CSFR specific antibody. <b>(B)</b> The lack of response of ALL cells to G-CSF (added at 0, 10 or 50 ng/ml) in <i>in vitro</i> cultures in the presence of human (hTERT Stroma).</p

Additional file 1: of Sphingosine kinase 2 supports the development of BCR/ABL-independent acute lymphoblastic leukemia in mice

Additional Data: Table S1, Figures S1-4. (DOCX 6406 kb

An imatinib-only window followed by imatinib and chemotherapy for Philadelphia chromosome-positive acute leukemia: long-term results of the CMLALL1 trial

We report long-term results in 40 patients with Philadlephia chromosome-positive (Ph +) acute leukemia who received an imatinib monotherapy window to evaluate in vivo effects on BCR-ABL signaling prior to induction chemotherapy. The first 25 patients (cohort 1) received the LALA-94 protocol without further imatinib (newly diagnosed Ph + acute lymphoblastic leukemia [ALL]) or induction chemotherapy followed by single-agent imatinib. Subsequent patients (cohort 2) continued imatinib concurrently with either LALA-94 (newly diagnosed Ph + ALL) or other intensive chemotherapy regimens. Cohort 2 had a complete response (CR) rate of 93% and 5-year survival of 69%. For newly diagnosed Ph + ALL, survival was superior in cohort 2 compared with cohort 1. Toxicity was similar to that expected for chemotherapy alone. Among 10 evaluable patients, rapid loss of phospho-CRKL occurred during the imatinib window in seven patients (all achieved CR) and incomplete inhibition in three patients (none with CR). In summary, a pharmacodynamic window design permitted biomarker assessment of BCR-ABL targeting without compromising clinical outcomes