Response to recombinant interferon alpha in patients with chronic myelogenous leukemia in a single center: results and analysis of predictive factors.

To improve the management of chronic myeloid leukemia (CML) in a single center, we used interferon alpha (IFN alpha) to treat newly diagnosed CML patients and investigated the factors predictive of a major cytogenetic response. Fifty-two patients (pts) with a median age of 51.5 years (16-68), were given interferon alpha (IFN alpha) (5 millions/m2/day, subcutaneously). The median interval between diagnosis and IFN alpha was 41.5 days (0-160). The doses of INF alpha were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 24), intermediate (n = 19) and high risk (n = 9). A complete hematological response (CHR) was achieved in 42 cases (80.7%). A partial response was present in nine; only one patient did not respond. By multivariate logistic regression analysis, only the age at diagnosis was found to influence the CHR rate (P = 0.06). Cytogenetic response was evaluated in 46 responder patients. Twenty-three patients achieved a major cytogenetic response (MCR) which was either partial ( > or = 65% pH negative cells) (n = 3) or complete (CCR) (n = 20). By univariate analysis, two disease-related variables were found to influence the MCR rate in 40 evaluable CHR patients: spleen size at diagnosis and peripheral blood blast percentage. However, using either univariate or multivariate analysis, the most significant factor was the achievement of CHR within 3 months (P < 0.0004 and P < 0.0002, respectively). These results show that IFN alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within 3 months could be useful to identify early, those patients who will not respond to IFN alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.

Flow cytometric study of idarubicin and daunorubicin accumulation and the effect of verapamil in leukemic cell lines and fresh cells from patients with acute non-lymphoblastic leukemia.

By using flow cytometry, the intracellular accumulation (Acc) of idarubicin (IDA) and daunorubicin (DNR) and the effect of verapamil (VRP) on both anthracycline accumulation (VRP index) were studied in leukemic cell lines (K562 and HL60 and their two DNR-resistant subclones) and fresh leukemic cells. IDA accumulated more than DNR in both parental (K562: p < 0.03 and HL60: 0.09) and resistant cell lines (p < 0.01 for both cell lines) irrespective of whether or not they were treated with VRP. VRP index was higher for DNR than for IDA (p < 0.05). Similar results were observed in fresh leukemic blasts from 25 patients with ANLL (IDA Acc superior to DNR Acc: p < 0.0001; higher VRP index for DNR than for IDA: p < 0.01). The higher Acc of IDA than DNR seen in fresh leukemic cells could explain the better clinical efficacy of IDA reported in patients with ANLL.

High response rate using recombinant interferon-alpha in patients with newly diagnosed chronic myeloid leukemia.

To improve the management of chronic myeloid leukemia (CML) in a single center, we have used interferon-alpha (IFN-alpha) to treat newly diagnosed Ph-positive CML patients and investigated the factors predictive of a major cytogenetic response. Eighty-one patients with a median age of 50.5 y (17-70) were given IFN-alpha (5 x 10(6)/sqm/day, s.c.). The median interval between diagnosis and IFN-alpha was 45 days (0-160). IFN-alpha doses were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 39), intermediate (n = 32) and high risk (n = 10). A complete hematological response (CHR) was achieved in 66 cases (81.5%). Cytogenetic response was evaluated in these 66 responders. Thirty-six patients (44.4%) achieved a major cytogenetic response (MCR) (> or = 65% Ph-negative cells), 31 of them having a complete cytogenetic response. The 5-y transformation-free survival (TFS) of the 81 patients was 77 +/- 14% (95% CI) and was statistically influenced by the CHR rate at three months (p = 0.008) and the achievement of MCR or CCR (p < 0.0009 and p < 0.0005, respectively). Moreover, we found that the MCR or CCR were significantly influenced by the obtaining of CHR at three months (p < 0.001 and p < 0.0001, respectively). These results show that IFN-alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within three months could be useful to identify early those patients who will not respond to IFN-alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.

Autologous blood stem cell transplantation followed by recombinant alpha interferon as treatment for patients with high-risk chronic myelogenous leukemia. A report of 32 cases.

Autologous blood stem cell transplantation (ASCT) was performed in 32 patients with high risk chronic myelogenous leukemia (CML). Prior to ASCT, the patients were given Busulfan and high-dose Melphalan. Peripheral blood stem cells collected at diagnosis were used to rescue hematopoiesis. Recombinant Interferon was administered after ASCT. In 24 patients transplanted in transformation, 23 achieved a complete hematological response and nine are still alive 9 to 73 months after ASCT. Eight other patients were transplanted in chronic phase for either the presence of bad prognostic factors (Sokal's classification) or no response to IFN. Seven are alive without transformation 16 to 48 months after ASCT. Although few patients presented a cytogenetical response (10/28), the survival observed in this series of patients compares favorably with that of patients treated conventionally. Thus, the place of ASCT in CML could now be tested prospectively.

Daunorubicin (DNR) accumulation in fresh leukemic cells: correlation with clinical and biological features.

The DNR accumulation (DNR Acc) and the verapamil (VRP) index (percent increase of VRP on DNR accumulation) was studied by using flow cytometry. Fresh leukemic mononuclear bone marrow blasts from 80 unselected ANLL patients' samples were incubated with DNR in the presence or absence of VRP. The DNR accumulation was determined by flow cytometry. The median DNR Acc was 28 (range: 4-101) and the median VRP index was 4% (range 0-53). VRP significantly enhanced DNR Acc in 42 of the ANLL samples (52.5%). DNR Acc or VRP index were not influenced by age, sex, or WBC counts. Only the FAB subclassification and the blast immunophenotyping were found to influence the parameters studied here. The lowest DNR Acc was found in M0 and M6 blast cells (15 range 0-46 and 10.5 range 8-13 respectively). M4 and M5 ANLL samples accumulated significantly more DNR than M0 and M6 blast cells. The VRP index was significantly higher in M0 compared with M1 and M2 samples, as well as in M4 compared with M1 samples. A slightly positive correlation was found between the percentage of CD34-positive cells in the CD34-positive samples and DNR Acc. In this study, DNR Acc and the VRP index were not significantly correlated with the response to chemotherapy or survival. In conclusion, this study shows that ANLL leukemic cells differ in anthracyclin accumulation and response to VRP in vitro.

[Sneddon's syndrome: review of the literature apropos of a case]. / Le syndrome de Sneddon: revue de la littérature à propos d'une observation.

The authors report the case of a young woman with Sneddon's syndrome and expose literature review. This rare entity is characterized by idiopathic livedo reticularis, ischemic stroke, and occasionally, mild arterial hypertension. Skin biopsy shows endarteritis obliterans of deep dermal arteries. The pathogenesis of this disorder is still unknown and the treatment is not clearly established.

Role of blast cell immunophenotyping for the diagnosis and prognosis of acute myeloid leukemia.

Bone marrow blast cell antigen expression from 86 patients with de novo acute myeloid leukemias (AML) was studied and correlated with FAB classification and clinical outcome. Among a panel of 14 monoclonal antibodies routinely used for the diagnosis of acute leukemias we studied the expression of six antibodies (CD13, CD15, VIM2, CD33, CD14, CD34) of the granulomonocytic lineage and found that some of them were useful for diagnosis and/or prognosis. For FAB subclassification of AML, the CD13 or VIM2 antigen expression was of no benefit. Monocytic leukemias (M4 + M5PD + M5WD) more frequently expressed CD34 antigen (28/31) than granulocytic (M1 + M2 + M3) subtypes (33/53) (P < 0.01). Finally, the most striking differences were found with CD14 antigen expression: CD14 antigen was more frequently expressed in M4 + M5 leukemias (21/31) than in M1 + M2 + M3 subtypes (12/33) (P < 0.01). The mean percentage of CD14 positive blast cells was accordingly higher in monocytic leukemias than in granulocytic leukemias and the difference was highly significant (P < 0.0001). The CD15 antigen was more frequently expressed in differentiated leukemias (M2 + M3 + M4 + M5WD) (35/44) than in poorly differentiated forms (M1 + M5PD) (17/37) (P < 0.001). The statistical difference was higher when the mean percentage of CD15 positive blast cells were compared (P < 0.0003). Moreover these latter percentages were different in M1 and M2 subtypes (P < 0.003). The blast cell expression of CD13, CD14, CD15 or CD33 was not predictive of the length of CR or survival. Moreover, our results support previously published findings suggesting a longer overall survival duration for patients whose leukemic cells do not express the CD34 antigen (P < 0.01). We also confirm that patients with the more differentiated subtypes of AML (CD13-, CD34+) tend to survive longer than patients with the less differentiated subtypes of AML (CD13-, CD34+) (P < 0.001).

Autologous blood stem cell transplantation for chronic granulocytic leukaemia in transformation: a report of 47 cases.

Forty-seven patients with chromosome Philadelphia-positive (Ph1) chronic granulocytic leukaemia (CGL) in transformation underwent autologous transplantation of peripheral blood stem cells (ABSCT) collected at the original diagnosis before any treatment. They were treated with three consecutive strategies: single transplant (group I = 17 patients), double transplant (group II = 13 patients), double transplant followed by recombinant alpha interferon (group III = 17 patients). Forty-three patients were restored to a second chronic phase with a cytogenetic conversion (more than 10% Ph1-negative marrow metaphases) occurring in 14 of the 29 evaluable patients. Most patients had a recurrent transformation occurring 2-43 months after ABSCT and finally eight patients are still alive in second chronic phase 4-49 months after ABSCT (median = 24 months). The actuarial median duration of second chronic phase was 3 months, 10 months and 18 months for group I, group II and group III patients (P less than 0.0001). The encouraging results observed for group III patients prompt us to propose ABSCT for patients in chronic phase with initial prognostic factors, suggesting that recombinant alpha interferon will not be effective if administered as front-line therapy.

Treatment of acute myeloid leukemia in elderly patients: the influence of maintenance therapy (BGM 84 protocol).

Ninety-two elderly patients (ages 50-70) with "de novo" acute myeloid leukemia were given induction chemotherapy consisting of aclacinomycin-A (ACLA) (100 mg/m2/day x 3) and cytosine arabinoside (ARA-C) (100 mg/m2 day, continuous infusion, 7 days). Fifty-one patients (55%) achieved complete remission (CR), 8 patients exhibited drug resistance and 33 patients died during chemotherapy or aplasia. Three patients had severe cardiac toxicity. The only prognostic factor significantly affecting CR was the initial leukocyte count. After consolidation using ACLA (80 mg/m2/day x 2) and ARA-C (100 mg/m2/day x 5), 47 CR patients were randomly assigned to 2 different treatment arms: 23 patients (Group A) received intensive sequential chemotherapy consisting of 4 monthly courses of 8 different drugs while 24 other patients (Group B) were given ACLA and ARA-C at regular intervals, associated with continuous chemotherapy consisting of 6-mercaptopurine, methotrexate and androgens. The probability of disease-free survival at 2 years was significantly higher (33 +/- 22%) for Group B patients than for Group A (13 +/- 16%) (P less than 0.05). We conclude that continuous maintenance chemotherapy may be useful in increasing the number of long-term survivors, at least in the elderly who have not received very intense consolidation chemotherapy following CR.

Autologous stem cell transplantation versus chemotherapy for adult patients with acute myeloid leukemia in first remission: the BGMT Group experience.

The BGMT 87 study was designed to compare prospectively Allogeneic Bone Marrow Transplantation (AlloBMT), Autologous Stem Cell Transplantation (ASCT) and Chemotherapy (CT). Of the patients who could not undergo AlloBMT and were still in remission after two cycles of intensive CT were randomized for ASCT (n = 39) or CT (n = 38). The actuarial risk of relapse was 48.7 +/- 8.8% (95% ci) in the ASCT group and 61.1 +/- 8.4% (95% ci) in the CT group (p = NS). The estimated chance of surviving without disease at three years was similar in both groups (48.3 +/- 8.5% versus 38.9 +/- 8.4; p = NS).

A second case of trisomy 8 in Philadelphia chromosome (Ph)-negative cells during the course of Ph-positive chronic myelocytic leukemia.

A Ph-positive CML patient who had received a peripheral blood stem cell autograft in chronic phase demonstrated a transient regression of the Ph-positive clone with the concurrent appearance of another clone with trisomy 8. This latter clone disappeared when the patient received alpha-interferon.

Peripheral T-cell lymphoma in a chronically immunosuppressed renal transplant patient.

Non-Hodgkin large cell lymphomas occurs more commonly in organ-transplanted patients than in the general population. They are usually of B-cell origin whereas T-cell lymphomas are rare. We report a new case of peripheral T-cell lymphoma in an immunosuppressed renal transplanted patient. The patient presented a hepatosplenic mass with a widespread extension causing serious pancytopenia. It was classified as a pleomorphic medium and large cell type and corresponded to the "common" alpha beta-TCR type lymphoma. Lymphomatous cells exhibited an incomplete mature T-cell phenotype. T-cell receptor gene clonal rearrangement associated with a germline configuration of the immunoglobulin heavy chain gene confirmed a clonal T-cell genotype. By using both Southern blot analysis and polymerase chain reaction, we failed to demonstrate any association with Epstein-Barr virus or human T-cell lymphotropic virus type I or type II.

Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha.

In a single institution, we have used recombinant interferon- (IFN-) to treat 116 newly diagnosed Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients and analyzed the predictive factors for response and survival. The patients whose median age was 50.3 years (range, 9 to 70) were administered IFN- (5 million units/m2/d) subcutaneously. The IFN- dose was subsequently adjusted to maintain the white blood cell and platelet counts between 1.5 and 5 x 10(9)/L, 50 and 100 x 10(9)/L, respectively. At diagnosis, the Sokal score was used to classify the patients into three groups: low (n = 57), intermediate (n = 42), and high risk (n = 16). A complete hematological response (CHR) was achieved in 93 cases (80.2%). Of the 116 patients, 113 were available for cytogenetic evaluation. Fifty patients (43%) achieved a major cytogenetic response (MCR) (=65% marrow Ph- cells), 37 of them having a complete cytogenetic response (CCR). The estimated 5-year survival of the 116 patients was 68% +/- 11% (95% confidence interval [CI]) with a median follow-up of 42 months (range, 3 to 114) and 85% +/- 11% (95% CI) with a median follow-up of 30.9 (range, 3 to 111) when patients were censored at the time of transplantation. Event-free survival at 5 years (adding death and transplant as event) was 46% +/- 11% (95% CI). Using proportional hazards regression to study time-dependent variables, we confirmed that the most significant factor associated with survival was the cytogenetic response (MCR or CCR) (P <.0001). This factor was independent compared with the Sokal score and baseline variables used to calculate the Sokal score. Moreover, using either univariate or multivariate analysis, the achievement of CHR within 3 months was strongly correlated with MCR (P <.0001). Minimum cytogenetic response (mCR, ie, at least 5% of Ph- metaphases) at 3 months was also a significant predictive factor for MCR (P <.0001). These results show that IFN- can induce a high rate of hematological and cytogenetic response when administered in doses leading to myelosuppression. Factors such as the achievement of CHR and mCR within 3 months could be useful to identify early those patients who will not respond to IFN- and who need alternative treatments such as stem cell transplantation.