Search

Here we describe how we detected the BCR/ABL fusion gene on the short arm of der(9) combining classical GTG banding and Fluorescence In Situ Hybridization (FISH) in a case of chronic myeloid leukemia (CML). To our knowledge, variant translocations involving the short arm of chromosome 9, in literature, are almost rare in chronic myeloid leukemia. It is not clear if this complex genetic translocation represents clonal evolution or a unique, initial presentation variant of the Philadelphia chromosome (Ph).

Background and Objectives: The prognosis of elderly patients with acute myelogenous leukemia (AML) is usually dismal, while the true survival of older patients not included in clinical trials is not known. We retrospectively evaluated the impact on survival of an aggressive versus a non-aggressive approach in 1005 patients aged >60 years registered in the database of the GIMEMA cooperative group., Design and Methods: Group A patients (n=621) received aggressive treatment, while group B patients (n=384) underwent non-aggressive therapy. The groups were different for risk factor distribution: the patients in group B had a higher median age, worse performance status (PS) and a higher proportion of previous myelodysplastic disease., Results: The overall median survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At multivariate analysis the following factors were associated with a significantly shorter survival: age >71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95% CI=1.24-1.68), white cell count > 10,000 mL (RR=1.37; 95% CI=1.06-1.75), and heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference in survival was associated with aggressive or non-aggressive treatment (RR=1.1; 95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a white cell count > 10,000/mL showed a significantly better survival when treated aggressively (median survival 7 vs 3 months, p = 0.011)., Interpretation and Conclusions: Despite an obvious selection of patients with a worse prognosis in group B, the difference in survival between the two groups was marginal. Multivariate analysis failed to demonstrate a significant survival benefit in aggressively treated patients. All these considerations indicate that elderly patients with AML are overall unlikely to benefit from aggressive treatment, so that this should be offered only to selected patients.

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.

Background and Objectives: Spontaneous remission (SR) in de novo myelodysplastic syndromes (MDS) is a rare event, which has been so far described only in children with monosomy 7. The phenomenon is extremely heterogeneous, perhaps depending on different pathogeneses of the disease., Design and Methods: We retrospectively evaluated the outcome of 564 consecutive adult patients with primary MDS diagnosed at our Institution in a 12-year period. SR was defined as an unexpected improvement lasting more than 1 year without concomitant treatments other than vitamins or low-dose steroids (in patients with platelets < 50 x 10(9)/L)., Results: Nine cases of SR were observed in 3 males and 6 females (median age 38.7 years). At diagnosis, all patients had Hb levels < 10 g/dL and 8/9 required packed red cell transfusions. The median time from diagnosis to SR was 18 months (range 4-46) and all patients had normalization of peripheral blood parameters: in 2 out of 3 patients with karyotypic abnormalities at onset, a cytogenetic remission was documented. The median duration of SR was 56 months; 5 patients are still in SR and 4 patients have relapsed (1 as MDS and 3 as acute myeloid leukemia)., Interpretation and Conclusions: SR is a rare (less than 2% in our experience) but possible event also in adult MDS patients. It should be kept in mind in the evaluation of experimental treatments for MDS in which very low rates of complete responses are expected.

Background and Objective: The successful use of differentiating treatment for patients with acute promyelocytic leukemia (APL) suggests that other acute myeloid leukemias (AML) may benefit from tailored and subtype-specific therapy. Despite the fact that new drugs specifically targeting AML genetic lesions have not yet been developed, distinct karyotypic categories have been identified which may deserve differentiated treatment. In addition, molecular assays to assess response to therapy more sensitively are now available for several AML subsets. In this review, we discuss the role of genetic characterization in the therapy of AML, and the investigative efforts which we believe are still needed for the design of tailored treatment for each and every patient with this disease., Design and Methods: The authors have been working in this field for many years and have contributed original papers, the data of which are incorporated in this article. In addition, the material analyzed in this overview includes articles and reviews covered by the Science Citation Index and Medline as well as some more recent unpublished personal observations., Results: Modern therapeutic approaches to AML tend to differentiate post-induction treatment intensity according to cytogenetically defined risk categories. Such prognostic categorization is largely unsatisfactory. In fact, following the advent of newly developed molecular assays (e.g. RT-PCR and FISH), specific and prognostically relevant lesions are frequently found in patients with an apparently normal karyotype, and these patients are, therefore, re-assigned to more appropriate prognostic categories. In addition, recent studies suggest that some patients may benefit from an increase in induction intensity; rapid genetic characterization will be needed for future differentiation of initial therapy. However, preliminary investigation of AML by integrated karyotypic/molecular analyses show that no specific abnormalities are detectable in at least half of the cases. Therefore, use of genetic criteria for prognostic stratification is currently feasible in only a proportion of patients., Interpretations and Conclusions: The prognostic role of genetic lesions, currently identified by karyotypic studies, needs to be validated in large series of AML patients prospectively characterized by advanced molecular/cytogenetic analyses and treated uniformly. In addition, searches for new clinically relevant genetic abnormalities, and diagnostic tools for their rapid identification are urgently needed to identify prognostic categories better. Elucidation of AML gene alterations should foster basic investigation aimed at developing new drugs targeted to the specific lesion in the individual patient. Before these more specific therapeutic agents are developed, diagnostic genetic characterization should add to other well-established prognostic factors to optimize the use of the presently available therapies.

Background: In order to determine whether recombinant human erythropoietin (rHuEPO) may play a role in treating anemia in idiopathic myelofibrosis (IMF), a pilot study using high doses of rHuEPO was conducted on patients with IMF., Methods and Results: From September, 1990 to December, 1992, 7 patients (6 males and 1 female, median age 68 years) affected by IMF entered the trial. RHuEPO was administered subcutaneously 5 days a week at a dosage of 160 U/kg daily for three months. Out of 7 patients, 4 obtained a response. These responders received additional maintenance treatment with rHuEPO until relapse. Response duration was 6, 7, 10+, and 16 months, respectively. Treatment was well-tolerated., Conclusions: Our data suggest that rHuEPO may play a role in the treatment of anemia in some IMF patients.

Background: It has recently been demonstrated that erythropoietin increases hemoglobin levels in anemia secondary to chronic renal failure. Some recent experiences have suggested a possible role in the treatment of anemia in patients with myelodysplastic syndrome (MDS)., Methods and Results: From April, 1990 to March, 1991, 16 patients (11 males and 5 females, median age 58.5 years) affected by low-risk myelodysplastic syndromes (MDS) were treated with recombinant human erythropoietin (rHuEPO) to ameliorate Hb levels and reduce transfusional requirement. All patients received high doses of rHuEPO (400 U/Kg s.c. twice weekly for 3 months). A partial response, defined as a stable increase in Hb levels > 1g/dL and/or a reduction in transfusional need > 50% lasting at least 3 months, was achieved by 5/16 patients. Those who responded received an additional course of treatment with rHuEPO at an increased dosage (600 U/Kg twice weekly for 3 months), and one of these five showed a progressive rise in Hb level up to normalization, while the other 4 remained stable. The treatment was well tolerated and no adverse reactions were observed., Conclusions: These results suggest that some patients with MDS may benefit from rHuEPO treatment.

From November, '85 to March, '87, 17 patients (12 males and 5 females, median 28 years) with resistant or relapsed ANLL received HiDAC (3 g/m2 c.i. 3 hs every 12 hs, day 1-4) + m-AMSA (100 mg/m2 i.v. day 5-7) as salvage therapy: 8/17 patients (47.1%) achieved CR, 7/17 (41.1%) were resistant and 2/17 (11.8%) died during induction; 8/10 relapsed patients achieved a 2nd CR, while all 7 primary resistant patients failed to. Median period of PMN less than 0.5 x 10(9)/l was 28 days, median period of PLTS less than 30 x 10(9)/l was 25 days. All patients had infections during aplasia. Median CR duration was 6.6 months, while median survival of responders was 10.6 months. Two patients with severe induction-related complications relapsed after 2 and 5 months, respectively: 1 patient underwent BMT and relapsed after 21 months; 5 patients, 4 of whom had received a prior ABMT during 1st CR, underwent ABMT: 3 died from ABMT related toxicity and 2 relapsed after 8 and 18 months, respectively. We conclude that HiDAC + m-AMSA is highly effective in relapsed, but not in resistant patients with acceptable hematologic and extra-hematologic toxicity. The role and modalities of ABMT in prolonging a 2nd CR are at present controversial.

A short-term 51Cr-release assay was employed to investigate polymorphonuclear leukocyte (PMN) antibody-dependent (ADCC) and phytohemaglutinin-induced (PHA-ICC) cytotoxicity against chicken erythrocytes in 28 patients with myelodysplastic syndromes (MDS). MDS patients PMN-mediated ADCC and PHA-ICC were significantly reduced when compared to normal donors. When the patients were subdivided according to the revised FAB classification, a reduction in PHA-ICC from the RAEB group and a progressive impairment of ADCC from RA to RAEB-t patients was observed. These abnormalities may be ascribed to a reduced number of effector cells or to a metabolic impairment of their cytolytic capacity. These PMN functional deficiences may contribute to the increased susceptibility to infectious diseases, irrespective of the presence of granulocytopenia.

Seventy-four patients over 60 years of age with new cases of ANLL diagnosed between January, 1980 and December, 1986 were retrospectively evaluated. Twenty-nine (median age 63, range 60-70) received aggressive induction polychemotherapy: 15 achieved CR (52%), 10 were resistant (34.5%) and 4 died during induction (13.5%). Overall median survival was 6 1/2 months, median CR duration and median survival of responders were 9 and 13 months, respectively. Eight patients (median age 70.4, range 64-74) received low doses of Ara-C: 2 achieved CR, 5 were resistant and 1 died during induction, with an overall median survival of 6 1/2 months; 37 patients (median age 72, range 60-86) received only supportive care and cytostatic therapy for disease control with Hydroxyurea and 6-Mercaptopurine if WBC greater than 20 x 10(9)/l: overall median survival was 6 months and 2 patients are still alive after 18 and 26 months. Aggressive chemotherapy seems to be the treatment of choice in patients less than or equal to 70 years, while for those over 70 current supportive care may offer good survival and a good quality of life.

In an attempt to reduce the risk of leukemic relapse, different post-remission intensifications based on high-dose Ara-C (HiDAC) and autologous bone marrow transplantation (ABMT) were evaluated in patients with acute non lymphocytic leukemia in first remission and compared as to response and toxicity. Between September, 1985 and May, 1987, 34 patients in complete remission were eligible for our study. Induction therapy consisted of one or two courses of daunorubicin (DNR) and Ara-C (schedule 3 + 7). Fourteen patients receiving intensive post-remission chemotherapy with DNR + Ara-C (schedule 2 + 5), HiDAC + DNR, and ABMT following pretransplant BAVC conditioning entered the first pilot study. A high toxicity was observed and only 5 of them completed the full treatment plan. Thus the second pilot study used a single post-remission intensive course with HiDAC + m-AMSA and ABMT following cyclophosphamide plus TBI or BAVC. This approach was more feasible. The preliminary results show the usefulness of intensive post-remission therapy: in fact, all patients but one who completed the treatment program are still in continuous complete remission. A large number of patients and a longer follow-up are required to draw final conclusions.

Nine patients with recurrent acute promyelocytic leukemia have been treated between July, 1984 and November, 1987 with a combination therapeutic regimen consisting of amsacrine, cytosine arabinoside and thioguanine (AAT). Complete remission was achieved in 5/9 patients, one person died in aplasia of hepatic failure, and the remaining 3 died from heart failure with resistant disease. The 5 patients who achieved CR were successively treated with allogeneic (n = 2) or autologous bone marrow transplantation (n = 3). As of December, 1988 there were only 2 patients still alive and in CR, both underwent autologous bone marrow transplantation. The duration of the second complete remission in these two patients is 48+ and 29+ months, respectively. Moreover the overall survival duration for these two patients is 88+ and 41+ months, respectively. These data confirm that the AAT regimen is useful in treating recurrent acute promyelocytic leukemia, a disease otherwise characterized by a catastrophic clinical course during the recurrent phase.