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Daniela Diverio

Publications and source records attributed to Daniela Diverio.

25 records · Page 2Linked to original sources
PubMed2004

Clinico-biological features and outcome of acute promyelocytic leukemia patients with persistent polymerase chain reaction-detectable disease after the AIDA front-line induction and consolidation therapy.

BACKGROUND AND OBJECTIVES: Front line treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and chemotherapy (CHT) results in molecular remission in approximately 95% of patients tested after consolidation. The small fraction of patients with persistence of molecular disease (i.e. those in whom polymerase chain reaction (PCR) is positive for PML/RARalpha) after such therapy are thought to have a dismal prognosis but has not yet been investigated in detail. DESIGN AND METHODS: We analyzed the clinico-biological features at presentation of APL patients who showed PCR-detectable residual disease and compared them to those of patients achieving molecular remission after AIDA induction and consolidation. Furthermore, we report the outcome of patients with molecularly persistent disease treated with salvage therapy. RESULTS: Patients attaining molecular remission (n=650) and patients who tested PCR+ve at the end of consolidation (n=23) were not statistically significantly different as regards median age, white cell and platelet counts, morphologic subtype (M3 or M3v), fibrinogen levels or PML/RARalpha transcript type. As to treatment outcome after salvage therapy, 7 patients were treated before morphologic relapse [3 with chemotherapy and autologous stem cell transplantation (SCT) and 4 with allogeneic SCT], and are alive after 64-118 months. Of 16 patients treated at the time of morphologic relapse, only 2 patients are alive, both of whom received an allogeneic SCT. INTERPRETATION AND CONCLUSIONS: Our findings indicate that APL patients who are molecularly resistant to the AIDA protocol have no distinguishing features at presentation. Their outcome suggests the need for early therapeutic intervention with aggressive treatment prior to the occurrence of hematologic relapse.

Adolescent↗
PubMed2003

The importance of molecular monitoring in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) is characterized by a unique genetic marker in virtually 100% of cases, i.e. the PML/RARalpha fusion gene which is readily amplified by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Several international groups reported the prognostic significance of minimal residual disease (MRD) assessment in APL, indicating that sequential PCR analysis should be used as a guide to therapy. In fact, such evaluation offers the possibility of identifying, after front-line treatment, either patients requiring additional therapy or patients at low risk who are presumably cured and who may be spared unnecessary toxicity. In this view, the terms molecular remission and molecular relapse are now widely employed to define a more advanced therapeutic objective and a condition necessitating anticipated salvage, respectively. The introduction of quantitative PCR through automated technologies is likely to further improve standardization of the method and comparison of results obtained in the context of large clinical trials.

Combined Modality Therapy↗
PubMed2003

Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count.

Extramedullary relapse occurs infrequently in acute promyelocytic leukaemia (APL) but has been increasingly reported after the advent of all-trans retinoic acid (ATRA) treatment, probably as a consequence of improved patient survival. We describe our single centre experience of six APL patients who had disease localization in the central nervous system (CNS). In three patients, clinical symptoms (headache and/or nausea) that presented during follow-up led to the performance of a lumbar puncture and detection of overt CNS infiltration. Two of these patients had simultaneous haematological relapse and one was in molecular remission when CNS leukaemia was documented. One patient with no local symptoms showed CNS infiltration at the time of molecular relapse. Following the introduction of routine lumbar puncture, carried out after front-line induction in all newly diagnosed patients with white blood cell count (WBC) greater than 10 x 109/l, two additional patients in molecular remission with no local symptoms were found to have initial APL localization in the CNS. Presenting features included in 6/6 patients an elevated WBC count (> 10 x 109/l) and a predominance of the PML/RAR bcr3 type (5/6 patients) and of microgranular morphology (5/6 patients). Our findings highlight the importance of carrying out lumbar puncture in APL patients presenting with high-risk features.

Adult↗
PubMed2002

PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors.

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations resulting in fusion proteins of the retinoic acid receptor (RAR). Here, we report a novel murine model system for APL, based on the transduction of purified murine hematopoietic progenitors (lin(-)) using high-titer retroviral vectors encoding promyelocytic leukemia-RAR (PML-RAR), and the green fluorescent protein (GFP) as a marker. PML-RAR-expressing lin(-) cells were impaired in their ability to undergo terminal myeloid differentiation and showed increased proliferative potential in vitro. Inoculation of transduced lin(-) cells into syngeneic, irradiated mice resulted in the development of retinoic acid-sensitive promyelocytic leukemias at high frequency (> 80%) and short latency (approximately 4 months). Morphologic and immunophenotypic analysis revealed no gross abnormalities of the preleukemic bone marrows. However, hematopoietic progenitors from PML-RAR preleukemic mice showed a severe impairment in their ability to undergo myeloid differentiation in vitro. This result, together with the monoclonality or oligoclonality of the leukemic blasts, supports a "multiple-hit" model, where the fusion protein causes a "preleukemic" phase, and leukemia occurs after additional genetic lesions. This model system faithfully reproduces the main characteristics of human APL and represents a versatile tool for the in vitro and in vivo study of mechanisms of leukemogenesis and the design of protocols for differentiation treatment.

Animals↗
PubMed2002

Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in vivo studies.

Acute leukemia with the t(11;17) expressing the PLZF-RARalpha gene fusion is a rare variant of acute promyelocytic leukemia (APL) that has been associated with poor clinical response to all-trans retinoic acid (ATRA) treatment. However, some recent reports have put into question the absolute refractoriness of this leukemia to ATRA. We describe here a patient with PLZF/RARalpha APL who was treated at relapse with ATRA and low-dose hydroxyurea. Complete hematologic remission was obtained through differentiation of leukemic blasts, as proven by morphologic, immunophenophenotypic, and genetic studies carried out in sequential bone marrow samples. Moreover, in vitro studies indicated that blast differentiation was potentiated by the addition of the histone deacetylase inhibitor tricostatin A, but not of hydroxyurea, to ATRA. Our findings indicate that the maturation block may be overcome and terminal differentiation obtained in this leukemia subset and support the view that sensitivity/refractoriness of this form to ATRA should be revisited.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Molecular monitoring of hematologic malignancies: current and future issues.

Genetic markers associated with hematologic malignancies such as acute promyelocytic leukemia (APL) can be detected with high sensitivity and specificity using the reverse-transcription polymerase chain reaction (RT-PCR). This procedure can be applied to monitor minimal residual disease. In patients with APL, RT-PCR is now being used to detect molecular relapse, and a strong association has been found between outcome and the treatment of molecular as opposed to hematologic relapse. In APL, results from PCR assays are also being used to guide therapy. Prognostic groups can be defined using molecular and clinical characteristics of the disease as well as patient characteristics. In the future, PCR monitoring strategies may be adapted to the risk of relapse of individual patients. Patients at high risk of relapse may be monitored much more rigorously than patients at low risk of relapse. Although RT-PCR is in routine use as a clinical tool, the lack of standardization of techniques in different laboratories has resulted in some difficulties in interpretation of results. There is a real need for an international consensus on standardization of PCR techniques.

Hematologic Neoplasms↗