Vincristine as treatment for recurrent episodes of thrombotic thrombocytopenic purpura.

The clinical course of thrombotic thrombocytopenic purpura has dramatically improved after the introduction of plasma-based therapy, including plasma exchange and plasma infusion. However, a considerable number of patients still experience relapse after initial successful treatment. In this study, vincristine (VCR) was given as salvage treatment in 12 episodes of recurrent thrombotic thrombocytopenic purpura in seven patients, concomitantly with short-term plasma infusion. Complete remission (CR) was defined by normal platelet, hemoglobin, and serum lactic dehydrogenase (LDH) values as well as by absence of clinical signs. Of 12 patients, 12 achieved CR following therapy with VCR. The median duration of CR was 15 months (range: 2-16). Toxicity was mild consisting of paresthesias in three cases, leukopenia in one case, and autonomic neuropathy leading to paralytic ileus in one case. We conclude that VCR is remarkably effective for recurrent thrombotic thrombocytopenic purpura with acceptable toxicity.

High-dose idarubicin and busulphan as conditioning for autologous stem cell transplantation in acute myeloid leukemia: a feasibility study.

INTRODUCTION: Between 30 and 50% of patients with acute myeloid leukemia still relapse after autologous stem cell transplantation. We investigated the feasibility of a new conditioning regimen consisting of high dose IDA plus oral busulphan in patients undergoing autologous transplantation. MATERIALS AND METHODS: Patients (n = 13) were given three days continuous infusion IDA, followed by four days conventional dose oral busulphan as conditioning. Peripheral blood stem cells were used in all cases. Eleven patients were in CR1. Patients with t(8;21) and inv(16) as well as those with acute promyelocytic leukemia were excluded from the study. The median of CD34+ cells infused was 6.2 x 10(6)/l (2.6-16.1). RESULTS: No case of transplant-related mortality occurred. The median number of days to neutrophil (>0.5 x 10(9)/l) and platelet (>20 x 10(9)/l) recovery was 10 (7-21) and 20 (9-26), respectively. Patients needed a median of 3 platelet units (1-6) and 3 blood units (0-12), respectively. Left ventricular ejection fraction remained unmodified after ASCT. Twelve out of 13 patients (92%) had variable grade of mucositis (two grade 2, five grade 3 and five grade 4). Total parenteral nutrition was needed in nine patients (69%). After a median follow-up of 14 months from ASCT, 11 patients out of 13 (85%) are alive in continuous CR; the other two patients experienced relapse at 12 and 14 months. CONCLUSION: Our data demonstrate the feasibility of a conditioning regimen based on high-dose IDA plus Busulphan in AML. Results concerning antileukemic efficacy are promising, but need confirmation on larger series with longer follow-up.

Treatment of chronic myeloid leukemia in the blastic phase with fludarabine, cytosine arabinoside and G-CSF (FLAG).

The present study was undertaken to evaluate the efficacy of the association of fludarabine plus Ara-C and G-CSF (FLAG) in the treatment of 15 patients with chronic myeloid leukemia in the blastic phase (CML-BP). Patients achieving a partial remission (PR) after the first course received a second FLAG. Complete remission (CR) was consolidated with another FLAG regimen. Patients were then submitted to an individualized program of treatment depending on age and suitable donors. Overall seven patients achieved CR (46.7%), three (20%) showed a primary resistant disease, while three (20%) died during remission induction therapy. Five of them received a consolidation therapy; in two cases further treatment was not performed because of severe toxicity. Median overall survival and disease-free survival were of 7.5 and 4.5 months, respectively. FLAG proved to be effective in achieving a high CR rate in patients with CML-BP. Median overall survival and disease-free survival were not significantly improved compared to previous studies. Nevertheless, the treatment was well tolerated even in a group of heavily pretreated patients, allowing further transplantation opportunities in younger patients.

Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura.

Vincristine (1.4 mg/m(2) on day 1, followed by 1 mg on days 4 and 7) was given to eight patients with thrombotic thrombocytopenic purpura (TTP) who were refractory to plasma exchange (n=4) or plasma infusion (n=4). Seven of eight patients (87%) achieved a complete response; one was refractory to treatment and died within a few weeks. After a median follow-up of 50 months, all responding patients are alive and well. Two patients relapsed and were successfully retreated with vincristine. Toxicity was mild, consisting of two episodes of leukopenia and one of autonomic neuropathy leading to paralytic ileus in a patient aged 70 years. We conclude that vincristine is highly effective in the treatment of patients suffering from refractory TTP, with negligible toxicity.

Complete remission of refractory anemia following a single high dose of cyclophosphamide.

We describe a case of stable complete remission in a patient with refractory anemia complicated by severe autoimmune hemolytic anemia, achieved with a single high dose (4 g/m2) of cyclophosphamide (cyclo). Concomitantly, an effective mobilization of CD34-positive cells was induced. Other immunosuppressive approaches including high-dose methylprednisolone, high-dose immunoglobulin, and cyclosporine had been ineffective. This finding suggests that, in selected cases, an immunologic mechanism may mediate cytopenia in myelodysplastic syndromes (MDS). In addition, it demonstrates that successful mobilization of peripheral blood stem cells can be induced with high-dose cyclo in MDS.

In vitro exposure of acute promyelocytic leukemia cells to arsenic trioxide (As2O3) induces the solitary expression of CD66c (NCA-50/90), a member of the CEA family.

Arsenic trioxide (As2O3) is a useful drug for the treatment of acute promyelocytic leukemia (APL), acting through a complex mechanism involving the induction of apoptosis. We investigated by flow cytometry whether in vitro treatment of APL leukemic cells with As2O3 determined specific surface membrane changes. Twelve APL bone marrow aspirates were analyzed following 7 days of in vitro treatment with As2O3 (0.25, 0.5 and 2.5 microM) with regard to the expression of a series of differentiation antigens. Twelve acute myeloid leukemia (AML) samples of non-APL morphotype were analyzed as controls. Exposure of APL as well as non-APL samples to any concentration of As2O3 did not affect the expression of beta2 integrins (CD11a and CD11b), CD45 isoforms (RA, RB and R0), CD44/H-CAM, CD33 and the CEA-related antigen family members CD66ade and CD66b, thus failing to disclose any maturating effect. Of interest, in all APL samples (but not in AML) every tested dose of As2O3 determined a dramatic upregulation of CD66c display; intermediate concentration (0.5 microM) of As2O3 increased the median percentage of CD66c+ cells from 5% in control cultures (25th-75th percentile 2-12%) to 80% in drug-exposed cultures (25th-75th percentile 58-90%) (P<0.001). The induction of solitary expression of CD66c is a new finding which demonstrates As2O3 capability of generating phenotypic changes absolutely restricted to APL cells Moreover, these results provide experimental basis for considering the involvement of the newly described CD66 signalling pathway in As2O3-driven programmed cell death.

Immunophenotypic analysis enables the correct prediction of t(8;21) in acute myeloid leukaemia.

Immunophenotypic findings from 14 patients affected by acute myeloid leukaemia (AML) with t(8;21) were compared to those obtained from 79 AML patients with normal or other aberrant karyotypes. Classic lineage markers, adhesion molecules, surface enzymes, stem-cell-related antigens and HLA-DR were investigated. Following evaluation by the Mann-Whitney test, we found that t(8;21) AMLs showed a significantly higher expression of CD19, CD34, CD56, CD45RA and CD54. Conversely, blasts from patients in the control group significantly expressed higher levels of CD45RO, CD33, CD36, CD11b and CD14. In order to split the data at the best cut-off point to achieve the most homogeneous subset with regard to cytogenetic pattern, i.e. t(8;21) or not, the CART (Classification and Regression Trees) method was applied. In the univariate analysis by CART, statistically significant differences were found when CD19 was dichotomized at 10%, CD34 at 37%, CD45RA at 84%, CD54 at 21%, CD56 at 12%, CD36 at 14%, CD45RO at 25%, CD11b at 18% and CD14 at 12%. Once cut-off points were established by CART, we applied the logistic regression model to establish which combination of two or more antigens was most predictive for t(8;21). The combination CD19-CD34 at the cut-off points indicated above correctly classified 92/93 cases (98.9%). The addition of any other antigen combination to the CD19/CD34 model failed to improve the level of prediction. We conclude that AML with t(8;21) displays an exclusive immunophenotype that is highly predictive of the cytogenetic pattern.

Therapeutic options and treatment results for patients over 75 years of age with acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: Acute myeloid leukemia (AML) is a prevalent disease of the elderly. Given the progressive aging of the general population, the frequency of the disease will further increase, especially in very old individuals. In a cohort of 70 consecutive AML patients aged over 75 years, we investigated the clinico-hematological characteristics and treatment results. DESIGN AND METHODS: Seventy patients aged > 75 were diagnosed at our institutions as having AML between January 1987 and December 1996. This figure represents 8% of the whole AML patient population observed during the same period. These patients were studied concerning the main clinical and hematological features at presentation, therapeutic approach and clinical outcome. RESULTS: A myelodysplastic syndrome preceded the onset of AML in 10 patients (14%). Trilinear myelodysplasia was present in 28 patients (40%). Hypocellular leukemia was diagnosed in 12 cases (17%). An active infection was found in 12 patients (17%). Aggressive chemotherapy was given to 22 patients (31%), low-dose ARA-C (LDARA-C) to 7 patients (10%), while 41 (58%) were managed with supportive care and/or hydroxyurea (HU). Therapeutic choice was significantly influenced by performance status (p = .03), infections (p = .0001), severe co-morbid disease (p = .0001), and hypocellular AML diagnosis (p = .0001). Complete remission (CR) was obtained in 7/22 patients aggressively treated (32%), 0/7 in the LD-ARA-C group, and in one patient treated with HU. The median survival for the whole patient population was 18 weeks. There was no significant difference among the three treatment groups. However, patients achieving CR experienced significantly longer survival as did those with hypocellular leukemia. INTERPRETATION AND CONCLUSIONS: In spite of a relevant selection at diagnosis, intensive chemotherapy is not appropriate for the majority of very old patients with AML. However, since a minority of patients takes substantial advantage from an aggressive approach, any effort should be made to preliminarily identify this subset at diagnosis.