M. Tribalto

FISH analysis for CML monitoring

Abstract Conventional cytogenetics is considered the gold standard for evaluating CML during interferon (IFN) treatment. Drawbacks to this approach are the small number of metaphases available during IFN therapy and the impossibility of scoring interphase cells. We applied, besides cytogenetics, double-color FISH (dc-FISH) detection of BCR-ABL gene fusion to monitor 20 CML patients on IFN. dc-FISH easily detected 200 cells per specimen, while with cytogenetic examination a mean of 16.1 mitoses per sample were scored. Though the correlation of dc-FISH and cytogenetic data was good (r=0.77, p<0.001), the discrepancy between the two methods as regards the proportion of leukemic cells in the marrow was often important. dc-FISH detected a relevant proportion of BCR-ABL+ cells in three patients classified as complete cytogenetic responders and showed that, after 9–12 months of IFN treatment, a significant reduction of BCR-ABL+ cells was present in all the 20 patients tested. This might suggest that all CML patients are potentially responsive to IFN. Though more data are required, we think that dc-FISH is more informative than cytogenetic analysis for CML monitoring. Notably because of the simplicity of the procedure, this method could be easily standardized among different laboratories, thus permitting cross-comparison in therapeutic trials.

A phase-II trial of all trans retinoic acid and low-dose cytosine arabinoside for the treatment of high-risk myelodysplastic syndromes

trans retinoic acid (45 mg/m2) and s.c. low-dose cytosine arabinoside (LDARAc) given at the dose of 20 mg twice per day. The courses were repeated monthly until response or progression; in the case of response, the therapy was administered until relapse. Morphologic diagnoses were refractory anemia with excess blasts (RAEB) in nine, RAEB in transformation (RAEB-t) in nine, and chronic myelomonocytic leukemia (CMMoL) in four patients; in all cases, bone-marrow blast infiltration was greater than 10% (median 20%, range 12–30%). When the international prognostic scoring system was applied, all the cases qualified as intermediate/high-risk categories. Nineteen patients were males and three were females; the median age was 69 years (range 25–90 years); three patients had previously been treated with conventional chemotherapy, and one of them had also undergone autologous bone-marrow transplantation. The criteria of response were defined as follows: (1) complete response: normalization of blood counts and bone-marrow blasts ( <5%), and (2) partial response: decrease in bone-marrow blast infiltration by 50%, and two of the following parameters – improvement in hemoglobin level by 1.5 g/dl or decrease by 50% in transfusional requirement, increase by 50% in absolute neutrophil count, and increase by 50% in platelet count. Overall, 7 (32%) of 22 patients achieved a response, with 5 (23%) being classified as complete responders and 2 (9%) as partial responders. Fifteen (68%) patients did not achieve any response, and 14 died of progressive disease or infectious disease. The overall median survival was 8 months (range 1–27 months), whereas the median survival of responders was 16 months (range 8–27 months); the median duration of response was 11 months (range 2–21 months). Moderate to severe hematological toxicity and infections were the most common side effects. In conclusion, it seems that the association of ATRA and LDARA-C may be effective in approximately 30% of HRMDS patients. Optimizing this approach might be pursued by selecting, on a biological basis, those cases more likely to respond or by incorporating other differentiating agents or growth factors.

All-trans retinoic acid plus low doses of cytarabine for the treatment of "poor-risk" acute myeloid leukemias.

SummaryThirteen refractory/resistant AML patients no suitable for additional aggressive chemotherapy, were treated with a combination including all -trans retinoic acid (45 mg/m2 sine die) and low doses of Ara-C (20 mg/m2 subcutaneously, twice in a day, days 1–10, every 28 days). Ten patients were évaluable; 8 of them achieved a complete remission, two patients with an important tumor burden, failed to achieve a response. One complete remission patient relapsed after 7 months but is still receiving the same therapy and is now in partial remission. We believe this combination effective as inducer of complete remission in those AML patients which cannot tolerate additional heavy treatments. The role of tumor burden in affecting response to therapy remains to be still evaluated.

Leukocyte Alkaline Phosphatase Score in Plasma Cell Dyscrasias: Correlation with Disease Severity and Circulating Levels of Granulocyte-Colony Stimulating Factor

In this study the leukocyte alkaline phosphatase (LAP) score in 106 patients with multiple myeloma (MM) in various phases of the disease (66 at diagnosis, 18 in plateau phase, 22 in relapse) was examined and compared with the score of 68 patients with monoclonal gammopathy of undetermined significance (MGUS) and 53 normal volunteers. In addition, the circulating levels of granulocyte-colony stimulating factor (G-CSF) were measured to explore the possible involvement of this cytokine in the pathogenetic mechanisms that lead to increased LAP activity. The results showed that the mean LAP score in patients with MGUS was comparable to normals and significantly lower than in MM (p < 0.001). Also, it increased with increasing tumor mass, and was lower in myelomas with stable disease than in those with active disease. G-CSF concentrations closely mirrored the behaviour of LAP score (r = 0.850, p < 0.001), significantly differing between each group of individuals. Its mean levels in MGUS were comparable to those of controls, whereas they were significantly increased in MM (p < 0.001), again with escalating values from cases with low tumor mass to advanced stages, and with lower concentrations in patients in plateau phase than in those in relapse. A significant correlation was found between G-CSF and neopterin levels (r = 0.578, p < 0.001), thus indicating an origin of the cytokine from monocytes and macrophages. These findings suggest that LAP scoring may assist in distinguishing benign from malignant paraproteinemias and may be used to follow the progression of plasma cell neoplasias.(ABSTRACT TRUNCATED AT 250 WORDS)