Successful induction chemotherapy for childhood RAEB-T with VP-16: a case report

A one-year-old boy diagnosed as refractory anemia with excess of blasts in transformation is reported. Hematological examination revealed anemia, thrombocytopenia and the presence of blasts in both peripheral blood (3.5%) and bone marrow (20.1%) specimens. Chromosomal analysis showed abnormal karyotype; 48, XY, +21, +marker, r (7). Analyses with cytochemical stainings, electronmicroscopy and monoclonal antibodies to cell surface markers could not define the lineage of blasts. Induction chemotherapy was started with VP-16 (230 mg/m2 x 5 days) as a single agent and complete remission was achieved. Thereafter, he had been treated for 11 months with the intensive chemotherapy which consisted of VP-16, cytosine arabinoside, daunorubicin, vincristine, vinblastine, 6-mercaptopurine, prednisolone, mitoxantrone and CNS prophylaxis. He has been in complete remission for 18 months. The usefulness of VP-16 to MDS in pediatric patients is documented.     

Leukemogenic risk of hydroxyurea therapy in polycythemia vera,essential thrombocythemia,and myeloid metaplasia with myelofibrosis

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13–14%. This risk has been estimated to be 1–5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993–1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-α(IFN-α). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL in the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-α, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P = 0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further. © 1996 Wiley-Liss, Inc.     

Treatment of myelodysplastic syndromes with retinoic acid and 1 alpha-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. The Scandinavian Myelodysplasia Group (SMG)

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.     

Etoposide, cyclophosphamide and fractionated total body irradiation as a preparative regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study.

Thirty-seven patients with advanced hematologic malignancy were entered into a phase I study designed to define a maximum tolerable dose (MTD) of etoposide (VP-16) and cyclophosphamide (CY) combined with 12 Gy fractionated total body irradiation (TBI) as preparation for marrow transplantation from an HLA-identical sibling (n = 13) or with cryopreserved autologous marrow (n = 24). Dose levels ranged from 36 mg/kg of VP-16 combined with 67 mg/kg of CY to 52 mg/kg of VP-16 combined with 103 mg/kg of CY followed by 12 Gy TBI. The MTD for allogeneic marrow recipients was 36 mg/kg of VP-16 + 52 mg/kg of CY followed by 12 Gy TBI and for autologous marrow recipients 44 mg/kg of VP-16 + 103 mg/kg CY followed by 12 Gy TBI. Pulmonary and liver toxicities were dose limiting. All of 31 evaluable patients transplanted in relapse achieved a complete remission. However, in all but three of these patients the disease relapsed 28-899 (median 110) days post-transplant. Currently, six of 24 autologous marrow recipients are surviving, three in remission 256, 340 and 764 days post-transplant. None of 12 allogeneic marrow recipients have survived. In conclusion, a preparative regimen combining 44 mg/kg of VP-16 + 103 mg/kg CY followed by 12 Gy TBI is well tolerated by autologous marrow recipients and 36 mg/kg VP-16 + 67 mg/kg CY followed by 12 Gy TBI is well tolerated by allogeneic marrow recipients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemopoietic stem cell transplantation for advanced polycythaemia vera or essential thrombocythaemia

Ten patients with polycythaemia vera (PV) and nine with essential thrombocythaemia (ET) received a haemopoietic stem cell transplant (HSCT) at the Fred Hutchinson Cancer Research Center between May 1988 and March 2000. HSCT was performed because of progression to the spent phase of the disease with myelofibrosis and splenomegaly in 10 patients and evolution into a myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) in nine patients. Patients were 18-59 years old (median 43). The interval from diagnosis to HSCT was 77-300 months (median 170). Seven patients were splenectomized before transplantation, and all but five had been treated with cytotoxic agents. Eleven patients received a transplant from a related, and eight from an unrelated, donor following conditioning with chemotherapy only or chemotherapy plus total body irradiation regimens. All evaluable patients achieved sustained engraftment. Twelve patients are surviving 5-116 months (median 41) after transplant, 10 in continued complete remission, one in haematological remission with residual marrow fibrosis and one with mixed haemopoietic chimaerism currently receiving therapy with interferon. Seven patients (six with AML/MDS and one with myelofibrosis) died of transplant-related complications. These data show that HSCT can provide curative therapy for patients with PV and ET with advanced disease.     

A myelo dysplastic syndrome (refractory anemia with excess of blasts) occurred in a patient with small cell lung cancer during complete response

A myelo dysplastic syndrome (MDS), refractory anemia with excess of blasts (RAEB), that occurred in a patient with small cell lung cancer (SCLC) during a period of complete response (CR) was reported. A 66-year-old female patient was diagnosed as SCLC in March, 1985. Induction chemotherapy (CDDP, ADM, VCR, VP-16) achieved CR in May, 1985. She had received maintenance chemotherapy (CDDP, ADM, VCR (or VDS), VP-16) and chest irradiation (48.6 Gy) until May, 1988. The hematologic findings revealed MDS and she was admitted in June, 1989. She died one month after onset of MDS because of pneumonia. An autopsy showed no evidence of recurrence of small cell carcinoma in the primary site and other organs. There is a possibility of the risk of secondary leukemia following long term chemotherapy and irradiation in patients with SCLC, and the role of treatment after the achievement of CR in patients with SCLC remains to be clarified.     

Anti-CD33 monoclonal antibodies enhance the cytotoxic effects of cytosine arabinoside and idarubicin on acute myeloid leukemia cells through similarities in their signaling pathways

OBJECTIVE: Chemotherapy agents (CA) such as cytosine arabinoside (ara-C), idarubicin (IDA), and etoposide (VP-16) are widely used in the treatment of acute myeloid leukemia (AML) However, their effects on signaling pathways leading to cytotoxicity have only been described recently. Ligation of the leukemia-associated antigen CD33 by anti-CD33 monoclonal antibody (mAb) also results in signaling events that induce a downregulation of cell growth. We examined the possibility that anti-CD33 mAb and CA might cooperate in mediation of growth inhibition in primary AML samples and AML cell lines. MATERIALS AND METHODS: We investigated two AML cells lines and 14 primary AML samples for their proliferative response ((3)H-thymidine incorporation), colony formation, and biochemical (Western blot analysis) to anti-CD33 mAb treatment combined with chemotherapy agents. RESULTS: CD33 ligation induced a significant increase in ara-C- or IDA- but not VP-16-or Bryostatin-mediated inhibition of proliferation and colony formation. Ara-C and IDA induced SHP-1 and SHP-2 protein tyrosine phosphatase (PTPs) phosphorylation and Lyn/SHP-1 complex formation, while VP-16 and Bryostatin did not. CD33 ligation, however, mediated phosphorylation of these PTPs and Syk/SHP-1 complex formations. Combined treatment of AML cells by ara-C or IDA with anti-CD33 mAb resulted in higher levels of SHP-1 phosphorylation. Reduction in SHP-1 by short interfering RNA abrogated these effects. CONCLUSION: These data suggest that combined incubation of leukemia cells with anti-CD33 mAb and ara-C or IDA, but not VP-16 or Bryostatin, independently triggers similar events in the downstream signaling cascade, and therefore leads to additive antiproliferative effects and enhanced cytotoxicity.     

Elderly non-Hodgkin's lymphoma presenting with pulmonary squamous cell carcinoma as a complication of chemotherapy for malignant lymphoma]

The authors report a case of pulmonary squamous cell carcinoma which occurred after chemotherapy of non-Hodgkin's lymphoma (NHL). A 76-year-old man, who was admitted to our department because of swelling of cervical lymph nodes, was diagnosed as having NHL (follicular mixed cell lymphoma). He was treated with 11 courses of CHOP therapy. Thereafter, chemotherapy including ifosfamide was carried out for approximately three years. In June, 1991, he was readmitted to our department because of swelling and pain in his left thigh and an abnormal shadow on chest X-ray. Chest CT demonstrated a cavitated shadow (about 5 cm in diameter) with an irregular margin in right S1, which was suggested to be lung cancer or pulmonary infiltration of malignant lymphoma. Bronchoscopy, which was carried out on July 12, showed bloody sputa from the right B1 ramus and markedly reddened mucosa at the orifice of the right upper bronchus. Sputum cytology revealed no malignancy. ACVP-16 chemotherapy including ara-C, CBDCA and VP-16 was initiated on July 14 because of enlarged superficial lymph nodes. On July 18, he fell out of bed and fractured his left femur. He also suffered from respiratory failure. He died of pulmonary haemorrhage on July 26. Autopsy revealed pulmonary squamous cell carcinoma. The occurrence of pulmonary squamous cell carcinoma is rare after the chemotherapy of malignant lymphoma.     

Increased stem cell dose, as obtained using currently available technology, may not be sufficient for engraftment of haploidentical stem cell transplants

The best strategies for haploidentical stem cell transplants are not known. We used a standard myeloablative pretransplant conditioning regimen (30 mg/kg VP-16, 120 mg/kg cyclophosphamide, and 12 Gy of TBI in six fractions), an increased peripheral stem cell dose of > 10 x 10(6) CD34+ cells/kg, T cell depletion (with CD34+ cell selection and CD4/CD8 depletion steps) to < 1 x 10(5) CD3+ cells/kg and cyclosporine post transplant. Ten patients (7M/3F, median age 11 (3-33) years) with high-risk leukemia (AML in 4, MDS in 2, CML in 1 and T-ALL in 3) received a hemopoietic stem cell transplant (HSCT) from a haploidentical father or sibling. The median number of CD34+ cells was 12.9 (9.5-45.7) x 10(6) cells/kg; median number of CD3+ cells was 0.41 (0.09-1.89) x 10(5) CD3+ cells/kg. All patients initially achieved 0.5 x 10(9)/l neutrophils at a median 12 (10-21) days. Graft failure in two consecutive patients out of four on the original protocol led to a modification adding ATG pretransplant and OKT3 post transplant. Graft failure was observed in one out of six subsequent patients. Acute GVHD > or = grade II was observed in three patients. Three of 10 patients are alive in CR at > 24 and >3 (2) months after transplant. Seven patients died: four of transplant related complications and three of relapse. Increased stem cell dose (> or = 10 x 10(6) CD34+ cells/kg) as obtained using currently available technology may not be sufficient to ensure stable engraftment in patients with high-risk leukemia using standard myeloablative conditioning regimens.     

Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continuous-infusion high-dose ara-C + daunorubicin: comparison to patients treated without GM-CSF.

We gave 56 patients with newly diagnosed acute myelogenous leukemia (AML) granulocyte-macrophage colony-stimulating factor (GM-CSF) 20 or 125 micrograms/m2 once daily subcutaneously before (for up to 8 days or until GM-CSF-related complications developed) and during, or only during (patients presenting with blast counts greater than 50,000 or other leukemia-related complications) ara-C (1.5 g/m2 daily x 4 by continuous infusion) and daunorubicin (45 mg/m2 daily x 3) chemotherapy. Because results seemed independent of GM-CSF schedule, we compared results in these 56 patients with results in 176 patients with newly diagnosed AML given the same dose and schedule of ara-C without GM-CSF (110 patients ara-C alone, 66 patients ara-C + amsacrine or mitoxantrone). Comparison involved fitting a logistic regression model predicting probability of complete remission (CR) and a Cox regression model to predict survival (most patients in all three studies were dead) with treatment included as a covariate in both analyses. After adjusting for other prognostically significant covariates [presence of an antecedent hematologic disorder, an Inv (16), t(8;21), or abnormalities of chromosomes 5 and/or 7, performance status, age, bilirubin], treatment with ara-C + daunorubicin + GM-CSF was predictive of both a lower CR rate and a lower survival probability. There were no treatment-covariate interactions, suggesting that the negative effect of this GM-CSF treatment regime was not an artifact of some imbalance in patient characteristics. The unadjusted Kaplan-Meier hazard rate of the ara-C + daunorubicin + GM-CSF group was not uniquely high during the initial 4 weeks after start of therapy, but was highest among the three treatment groups throughout weeks 5 to 16, suggesting that the negative effect of this treatment was not caused by acute toxicity. Patients who did not enter CR with this treatment tended to have persistent leukemia rather than prolonged marrow aplasia, suggesting that this treatment and, in particular, GM-CSF may increase resistance of myeloid leukemia cells to chemotherapy. To date, relapse rates are similar in all three groups (P = .43) (as are survival rates once patients are in CR) but much of the remission duration data is heavily censored, unlike the survival data. Our results suggest caution in the use of GM-CSF to sensitize myeloid leukemia cells to daunorubicin + ara-C chemotherapy.     

Plasma basic fibroblast growth factor and bone marrow fibrosis in clonal myeloproliferative disorders

Basic fibroblast growth factor (bFGF) is an important growth factor involved in clonal hematopoietic expansion, neoangiogenesis, and bone marrow fibrosis, all of which are important pathobiologic features of clonal chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS). The aim of this study was to assess circulating bFGF concentrations in patients with CMPD and MDS with respect to the presence of bone marrow fibrosis in histopathologic examination. The study group comprised 18 patients with CMPD (six female, 12 male; median age 50 years), seven patients with MDS (one female, six male; median age 66 years) and 10 healthy adults as controls (four female, six male; median age 29 years). CMPD group included six chronic myelogenous leukemia (CML), seven essential thrombocythemia (ET), three polycythemia vera (PV), two agnogenic myeloid metaplasia (AMM). All seven MDS patients were the FAB subtype of refractory anemia (RA). Bone marrow biopsy sections stained with hematoxylin and eosin (H & E) and for reticulin were examined for the presence of fibrosis. The median plasma bFGF level was 18.2 pg/ml (interquartile range, IQR: 15.2-26.7) in patients with CMPD, 18.0 pg/ml (IQR: 15.8-26.4) in patients with MDS, 13.6 pg/ml (IQR: 9.9-20.0) in the control group. The bFGF levels were significantly higher in patients with CMPD in comparison with the healthy control group (P = 0.031). Circulating bFGF tended to be significantly lower in relation to the development of marrow fibrosis (P = 0.028). The complicated interactions of bFGF and fibrosis in the context of CMPD may be either 'cause' or 'effect'. The bFGF might represent an important link between angiogenesis, fibrosis, and clonal neoplastic hematopoiesis during the development of CMPD.     

Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity

BACKGROUND AND OBJECTIVES: According to the recently published WHO-classification essential thrombocythemia with ringed sideroblasts (ET/RS) remains an ambiguous category which may be considered as myelodysplastic/myeloproliferative disease, unclassifiable. Because until now only case reports or very small series of patients have been described, a more systematically performed study is warranted. DESIGN AND METHODS: A retrospective evaluation was carried out on 38 patients with the diagnosis of ET/RS and more than 15 % ringed sideroblasts on smears. Simultaneously performed bone marrow biopsies, follow-up examinations and survival data were also available. RESULTS: Based on cytological features and particular bone marrow findings including immunohistochemistry three patterns could be determined. These were associated with different clinical features and in particular prognosis. Group I included six patients whose diagnosis was consistent with ET, group II comprised 21 patients revealing prefibrotic and early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally 11 patients (group III) displayed myelodysplastic syndromes (MDS). Follow-up studies revealed that no patient with ET showed a fiber increase but eight CIMF patients developed overt myelofibrosis and four patients of the MDS group developed secondary acute myeloid leukemia. In comparison with a control group of 39 patients with true ET, prognosis was significantly different because our cohort showed a median survival of 100 months that contrasted significantly with the 170 months in the patients with true ET. INTERPRETATION AND CONCLUSIONS: Ringed sideroblasts are not a pathognomonic feature of MDS, but may indicate a dysplasia probably associated with a primary or secondary disturbance of iron metabolism in a variety of disorders. For this reason, a more accurate classification of so-called ET/RS patients is warranted by evaluation of smears and in particular bone marrow biopsy specimens. According to our findings these patients should be classified as having either ET, CIMF or MDS and show a significantly different survival pattern.     

Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents.

We report nine children with relapsed (n = 8) or high-risk (n = 1) peripheral T-cell lymphoma (PTCL) who underwent autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). These children received transplants as part of a prospective phase I/II study of thioTEPA (TT) and total body irradiation (TBI) with escalating doses of VP-16. The median age of these patients at time of BMT was 6.5 years (range 2.5 years to 14 years). Three were transplanted with active disease after failing salvage chemotherapy. Of the other six, one was transplanted in first complete remission (CR) and five in second or subsequent CR. Of these nine patients, eight are free of disease a median of 25 months after BMT (range, 6 to 48 months), with an estimated 2-year relapse-free survival (RFS) of 89%. Six of these eight patients have been followed for 12 or more months after BMT, and in each their current remission exceeds their longest previous remission duration. The toxicity of the TT/TBI +/- VP-16 regimens was significant but manageable, predominantly consisting of severe mucositis. For a comparison, we reviewed retrospective data on the six additional children and adolescents with PTCL who underwent BMT during the 3-year period preceding this phase I/II study. The median age at BMT of these six patients was 19 years (range 15.5 years to 20 years). These patients were prepared for BMT with a variety of other regimens. One had no response to BMT and the other five relapsed at 1.5 to 5 months after BMT (median, 3 months) with an RFS of 0%. Our data suggest that thioTEPA plus TBI, with or without VP-16, is an effective preparative regimen for BMT for young patients with relapsed or high-stage PTCL and leads to prolonged RFS.     

Mobilization kinetics of peripheral blood progenitor cells after IAPVP-16 salvage chemotherapy plus G-CSF in lymphoproliferative disorders

We have explored the efficacy of salvage chemotherapy combination, IAPVP-16 (ifosfamide 5 g/m2 on day 1; VP-16 100 mg/m2 on days 1-3; ara-C 1.2 g/m2/12 h on days 1 and 2; methylprednisolone 80 mg/m2 on days 1-5) plus G-CSF for PBPC mobilization. This protocol was used in 45 patients with relapsed or refractory lymphoproliferative diseases who underwent 85 leukaphereses. In 41 patients > 2 x 106/kg CD34+ cells were obtained after a median of two procedures. The median number of CD34+ cells harvested was 3.2 x 106/kg per apheresis and 8.4 x 106/kg per patient. Seven of 10 patients who had failed previous mobilization attempts achieved more than 2 x 106 CD34+ cells/kg in a maximum of three aphereses. A history of previous mobilization failure and a low platelet count (<150 x 109/l) negatively influenced the CD34+ cell yield in univariate and multivariate analyses. A good correlation was found between the circulating CD34+ cells/microl and the CD34+ cells and CFU-GM in the leukaphereses products (r = 0.93 and r = 0.73, P < 0.001), and > or =17 CD34+ cells/microl predicted the achievement of > 2 x 106/kg CD34+ cells in a single leukapheresis in more than 90% of cases. IAPVP-16 plus G-CSF may be specially indicated in tandem transplantations or CD34+ selection and in patients who have failed previous mobilization attempts.     

Myelodysplastic features in patients with long-term HIV infection and haemophilia

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL(-1), and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL(-1), while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL(-1) received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS. These data suggest that bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute the entity for which the name HIV-myelopathy has been proposed in the literature.     

Long-term follow-up of de novo myelodysplastic syndromes treated with intensive chemotherapy: incidence of long-term survivors and outcome of partial responders

The percentage of long-term survivors after intensive chemotherapy and the outcome of MDS patients who achieve partial remission (PR) with intensive chemotherapy (IC) are not known.
Between 1981 and 1996 we treated 99 patients with de novo MDS who had high-risk MDS or progression to AML, with IC. 41 (41%) achieved CR, 16 (16%) achieved partial remission (PR), 26 (26%) had failure, and 16 (16%) died in aplasia. Eight of the patients who achieved CR were autografted, three were allografted and the remaining cases received moderate consolidation chemotherapy.
After IC, the 16 PR patients fulfilled the criteria for RA in 15 cases and CMML in one case. Median PR duration was 17 months, and three PR were > 3 years (39, 50+, 82+ months). Median actuarial survival of patients who achieved PR and CR was 18 months and 20 months from the onset of IC, respectively (difference not significant).
Of the 71 patients treated before 1993, with sufficient follow-up, 10 (14%) had survived > 4 years (long-term survivors). Four of them were alive in first CR after 49+ to 110+ months and probably cured, two were alive in PR after 50+ and 82+ months and four had died after 49–78 months. Long-term survivors were characterized by a significantly higher incidence of RAEB-T at diagnosis, and with normal or favourable cytogenetic findings. In patients with RAEB-T at diagnosis included before 1993, 8/23 (35%) cases who had no unfavourable karyotype had survived > 4 years.
Our findings suggest that MDS patients who achieve PR with IC, and not only those who achieve CR, can benefit from this type of treatment. The percentage of long-term survivors remains low, however, and is almost restricted to patients with RAEB-T at diagnosis and no unfavourable karyotype.     

Efficacy and toxicity of a high-dose G-CSF schedule for peripheral blood progenitor cell mobilization in healthy donors

An interim report evaluating the feasibility of myeloablative therapy followed by peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is presented. In the last 2 years 19 patients >60 years old with several oncological conditions, mostly hematological, underwent PBSC autotransplant either as salvage therapy following relapse or resistance to conventional treatment, or as consolidating therapy as a part of a well defined protocol. There were 13 males and six females; the mean age was 66.9 years (range 61-76 years); nine patients had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma, busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients with the combination of high-dose CTX and G-CSF with collections between 2.83 to 19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained in 15 of 16 patients evaluable for response and eight patients entered CR; overall eight patients are in CR, five are alive with disease, five are dead from disease progression and one is dead because of congestive heart failure 7 months following PBSC autotransplant. No early deaths following the procedure occurred; major side-effects were grade I-II mucositis (58%), fever with documented sepsis (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function was evaluated before and after myeloablative therapy by VEF in all patients; no significant modifications were necessary. In conclusion, our experience demonstrates that myeloablative therapies in older selected patients can be feasible; the feasibility of introducing PBSC autotransplantation following myeloablative therapy as a front-line treatment in patients aged >60 years, needs accurate guide lines for selection of appropriate patients.     

Inefficacy of cisplatin and etoposide as salvage therapy for children with recurrent or unresponsive soft tissue sarcoma

Cisplatin (CPDD) and etoposide (VP-16) have activity as single agents in children with recurrent soft tissue sarcoma, with response rates approximating 20%. Sixteen evaluable patients with soft tissue sarcoma, 0.9 to 16 years of age, were treated with a combination of CPDD (75-100 mg/m2 iv X 1) and VP-16 (100-150 mg/m2/day iv X 3-5) every 3 weeks after recurrence or failure to respond to standard therapy. Toxicity consisted of vomiting and myelosuppression. There were no complete responses, and only two children (12.5%) had partial responses lasting 6 weeks. Every patient died of progressive tumor. CPDD and VP-16, as given on this study, had minimal activity.     

Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.     

Essential Thrombocythaemia: A Single Institution Experience of 16 Years

This presentation is a clinical narrative and long term follow up (6–16 years) of 21 prospectively studied patients with essential thrombocythaemia (ET) in Kuwait. The median age (55.9 years) is younger than reported by others. Two patients were below the age of 40 years with one of them presenting as post-polycytheamia ET at 16 years of age. Twelve patients (57.1 %) remained asymptomatic throughout the period of follow up. Four patients complained of erythromelalgia, three (19 %) suffered from thrombotic episodes and only one (4.3 %) had excessive bleeding. Four patients presented with splenomegaly. Intensity of thrombocytosis or duration of very high platelet count had no relationship with these complications. Two patients transformed to post-ET myelofibrosis and one patient developed chronic myeloid leukaemia (CML). None transitioned to acute leukaemia. All patients are still alive after follow up for 6–16 years. Janus kinase 2 mutation was positive in eight (38 %) patients. It had no bearing on transition of our ET patients to post-ET myelofibrosis or CML. Platelet aggregation tests were performed in 14 patients. Six (42.9 %) showed defective response to ADP. Only one of these patients suffered from bleeding. All patients were given aspirin (81 mg/day). Cyto-reductive therapy with hydroxyurea was taken by six (42.9 %) subjects. Two patients who were treated with anagrelide and one with alpha-interferon did not continue treatment for long.