Alterations in the response of leukaemic cells to apoptosisinducing stimuli may account for resistance to chemotherapy and treatment failure, either by disruption of the apoptotic pathway itself or by altered DNA repair; quiescent cells and those with disrupted cell-cycle checkpoints may also display decreased apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and this led us to investigate whether the modulation of drug-induced apoptosis associated with differentiation might be a model for quiescence-associated resistance generally. We have demonstrated that resistance to idarubicin-induced apoptosis increased with greater duration of incubation of HL60 and U937 cells with ATRA and 1,25(OH) 2 D3 and that this protective effect correlated with the degree of G0/G1 accumulation. In addition, the cytoprotective effects held for other classes of cytotoxic drugs with different mechanisms of action to idarubicin. Prolonged exposure to idarubicin or vinblastine was associated with diminution of the protective effect and re-entry of cells into cycle. The full cytoprotective effect was restored by resupplementation with ATRA or 1,25(OH) 2 D3 during exposure to idarubicin, with concomitant persistence of G0/G1 accumulation. Differentiating agents prevented the accumulation of leukaemic cells at the G2/M checkpoint in response to low concentrations of idarubicin. Understanding how differentiating agents modulate these cell-cycle checkpoints, and how quiescent cells evade apoptosis, may allow the development of therapeutic strategies to limit such apoptosisinhibiting effects and maximise cell kill from chemotherapy. Leukemia (2000) 14, 620-628.

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Summary:We report a 45-year-old female with AML who underwent a T cell-depleted sibling allograft and relapsed a year later with extramedullary disease involving the lung parenchyma and presenting with the clinical and radiological features of interstitial pneumonitis. The patient was treated with donor lymphocyte infusion (DLI) resulting in complete resolution of the radiological signs. The unusual presentation and the management options are discussed. Keywords: granulocytic sarcoma; allogeneic bone marrow transplantation; interstitial pneumonitis; donor lymphocyte infusion; adoptive immunotherapy Extramedullary recurrence of acute myeloid leukaemia after chemotherapy or following bone marrow transplantation is unusual. We describe a unique case of diffuse intrapulmonary granulocytic sarcoma presenting as interstitial pneumonitis in a 45-year-old female who had undergone an allogeneic bone marrow transplant 12 months previously. Case reportA 45-year-old Indian female presented to her GP with a 2-week history of tiredness. The full blood count revealed anaemia and she was referred to the local hospital for further investigations. A bone marrow aspirate and trephine biopsy showed trilineage myelodysplasia with Ͻ2% blasts. Cytogenetics were normal. Three months later a regular follow-up showed blasts on the peripheral blood film and a diagnosis of AML was made on the bone marrow aspirate. Cytogenetics remained normal. She was treated according to the MRC AMLXII protocol with two courses of ADE (daunorubicin, etoposide, cytarabine), one course of MACE (amasacrine, cytarabine, etoposide) and one course of MIDAC (mitozantrone, cytarabine), achieving CR after the first course. Subsequently, she underwent a T cell-depleted bone marrow transplant from her HLA-identical sister. Conditioning consisted of CAMPATH 1G 20 mg/day for 5 days (day −9 to −5); thiotepa 5 mg/kg/day for 2 days (day −8 to −7) cyclophosphamide 60 mg/kg/day for 2 days (day −6 to −5) and total body irradiation, 1440 cGy in eight fractions (day −4 to −1). T cell depletion was performed ex vivo using Campath 1M. The patient had an uneventful post-transplant course. She engrafted on day +16 (neutrophils Ͼ0.5 × 10 9 /l). Recovery of platelets was achieved on day +22 (Ͼ50 × 10 9 /l). She did not experience any signs of acute GVHD and was discharged on day +23. On day +45 she tested CMV PCR positive in the blood for the second consecutive week and in accordance with the surveillance/treatment protocol was treated with 14 days of ganciclovir (5 mg/kg twice daily), rendering her CMV PCR negative. Follow-up was uncomplicated until day +365 when she was again admitted to the hospital with a 2-week history of non-productive cough and pyrexia. Extensive investigations failed to demonstrate any infectious cause for the pyrexia but a high resolution CT scan of the chest revealed generalised ground glass shadowing, with focal areas of reduced vascularity giving a mosaic perfusion pattern. Appearances suggested areas of bronchiolitis obliterans due to old infection wit...

SummaryHaemopoietic growth factors are involved in the production of the various blood cells from progenitors in the bone marrow, making them useful in a range of clinical situations. The genes for several of them have been cloned and their production engineered by recombinant technology, making them widely available. Myeloid growth factors are used to support patients in the aftermath of chemotherapy and bone marrow transplantation and have potential application in the treatment of infectious diseases. Erythropoietin is widely used for patients with anaemia due to failure of marrow production, having established its effectiveness in chronic renal failure. Thrombopoietin has recently been described and may provide a means to alleviate thrombocytopenia. Current indications and areas of recent reappraisal are addressed in this review.