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Autophagy is a cell recycling process the molecular apparatus of which has been identified over the past decade. Autophagy allows cells to survive starvation and inhospitable conditions and plays a key role in numerous physiological functions, including hematopoiesis and immune responses. In hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. In addition, autophagy is involved in other important aspects of blood cancers as it promotes immune competence and anti-cancer immunity, and may even help enhance patient tolerance to standard treatments. Approaches exploiting autophagy, either to activate or inhibit it, could find broad application in hematologic malignancies and contribute to improved clinical outcomes. These aspects are discussed here together with a brief introduction to the molecular machinery of autophagy and to its role in blood cell physiology.

A case of chronic myelomonocytic leukemia with a reciprocal translocation (12;13)(p13;q14) and other numerical and structural abnormalities is described. Most of the metaphases examined showed duplication of the der(13)t(12;13), leading to trisomy of the translocated segment of chromosome 12. Using fluorescence in situ hybridization we observed that the breakpoint on chromosome 13 is centromeric to the retinoblastoma gene. Since other cases with apparently similar t(12;13) have recently been reported, we conclude that this structural rearrangement may be a rare but non random event in hematologic disorders.

Background: Elderly patients with acute myeloid leukemia (AML) those refractory to induction chemotherapy and those with so-called secondary leukemia have unfavorable prognoses and require innovative therapeutic approaches. Fludarabine allows an increased accumulation of Ara-CTP in leukemic cells and inhibits DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone results in a synergistic effect., Materials and Methods: From May 1993 to February 1996, fludarabine-containing regimens (FLAG and FLANG) were employed as induction therapy in 51 high-risk AML patients. Diagnosis of AML in 22 patients was preceded by a myelodysplastic syndrome lasting more than six months; 8 of the 29 de novo AML cases (28%) were refractory to previous chemotherapy, 9 (31%) were treated for early relapse, 12 (41%) presented poor prognostic factors at diagnosis. The median age was 64 (range 33-76) years and the FAB subtypes were the following: M0 3, M1 5, M2 28, M4 7, M5 8. Forty-eight per cent of patients showed poor prognosis chromosomal abnormalities. FLAG (24 patients) consisted of both fludarabine 30 mg/sqm over 30 minutes followed 4 hours later by Ara-C 2 g/sqm over 4 hours (for 5 days) and G-CSF 300 micrograms/day administered 12 hours before fludarabine, for a total of 5 doses. FLANG (27 patients) had a shorter duration (3 days), reduced Ara-C dosage (1 g/sqm) and administration of mitoxantrone (10 mg/sqm) at the end of Ara-C infusion., Results: Recovery of both neutrophils (PMN > 0.5 x 10(9)/L) and platelets (Plt > 20 x 10(9)/L) required a median of 16 days from the end of therapy. Overall, 30 patients (59%) achieved CR, 6 (11%) PR and 10 (20%) were refractory; 5 (10%) experienced early death (cerebral hemorrhage or infection). The length of complete response ranged from 2 to 26 months with a median follow-up of 8 months. De novo and secondary AML registered 62 and 54% CR rates, respectively. Eight out of 10 patients refractory to conventional schemes achieved CR (80%) but only 3 out of 10 treated for relapse obtained CR (30%)., Conclusions: FLAG and FLANG showed similar activity and toxicity while proving to be highly effective and relatively well-tolerated treatments for high-risk de novo AML. Secondary leukemias seemed to be responsive as well, but the presence of an unfavorable karyotype alteration lowered the response rate.

Background: Several methods for the recruitment of circulating progenitor cells (CPC) to be used for hemopoietic rescue after myeloablative therapy have been described. The present study was designed to verify the effectiveness and safeness of one of such procedures, involving the administration of high-dose cyclophosphamide (HD-CTX) and granulocyte-macrophage colony-stimulating factor (GM-CSF)., Methods: Eight tumor patients were treated with HD-CTX (7 g/m2), followed by GM-CSF (7 mcg/Kg/day, continuous infusion) from day +2 to the completion of leukocyte recovery, when aphereses for CPC harvesting were performed. CPC were evaluated by clonogenic assay for granulocyte-macrophage colony-forming units (CFU-GM), megakaryocyte colony-forming units (CFU-Meg) and erythrocyte burst-forming units (BFU-E) before therapy as well as during the hemopoietic recovery., Results: In each patient, a significant increase of trilineage CPC was observed, at a mean of 14 days from HD-CTX, with peak increment of 224, 268 and 230-fold for CFU-GM, CFU-Meg and BFU-E respectively. The mean duration of leukocyte count < or = 0.5 x 10(9)/l was 6.6 days, with severe thrombocytopenia (grade 4 WHO) lasting 2.8 days in 5 patients. GM-CSF infusion was well tolerated without any need for dose reduction or discontinuation., Conclusion: The administration of HD-CTX and GM-CSF induces a significant enhancement of CPC including CFU-Meg other than CFU-GM and BFU-E. The procedure is suitable for the recruitment of CPC in patients with CTX sensitive tumors.