Ascorbic acid inhibits antitumor activity of bortezomib in vivo.

Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.

Pulsed ATRA as single therapy restores long-term remission in PML-RARalpha-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study.

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.

High-dose therapy in multiple myeloma: effect of positive selection of CD34+ peripheral blood stem cells on hematologic engraftment and clinical outcome.

BACKGROUND AND OBJECTIVE: Positive selection of peripheral blood stem cells (PBSC) has been investigated in multiple myeloma (MM) with the aims of reducing plasma cell (PC) contamination of the leukaphereses and improving clinical outcome of autografted patients. DESIGN AND METHODS: In our center 39 untreated patients with stage II and III MM, younger than 65 years, started high-dose therapy consisting of 4 VAD cycles, collection of PBSC mobilized by 7 g/m(2) cyclophosphamide + G-CSF, and myeloablative treatment with 12 mg/kg busulfan plus 120 mg/m(2) melphalan. The leukaphereses from 23/39 patients (59%) were processed for positive selection of CD34(+) cells using an avidin-biotin immunoaffinity device. RESULTS: A reduction of PC contamination of as much as 2 log was found in the post-selection products by a flow-cytometric technique using the monoclonal antibody CD 138 alternatively coupled with CD38 and cytoplasmatic k or l light chains in separate samples. Hematologic reconstitution and clinical outcome of the 23 patients reinfused with selected CD34(+) cells (SEL group) were compared with those of the 16 patients reinfused with unselected cells (UNSEL group). No significant differences were observed between the 2 groups with regards to the median duration of neutropenia and thrombocytopenia, the hematologic support required, the incidence of febrile episodes and bacteremias. At a median follow-up of 18 months (range 5-34) after ASCT, there were 7/23 (32%) continuous complete remissions (CR) in the SEL group and 4/16 (25%) in the UNSEL group; there were 10/23 (44%) continuous partial remissions (PR) and 5/16 (31%) in the SEL and UNSEL groups, respectively. Two patients in the UNSEL group and one patient in the SEL group died of progressive disease. INTERPRETATION AND CONCLUSIONS: Our data show that positive selection allows rapid engraftment of hematopoiesis and low morbidity. Although no significant difference was detected between the two groups in the frequency of CR and PR 3 and 18 months after ASCT, a longer follow-up is needed to evaluate definitively the effect of CD34(+) selection on the clinical outcome after ASCT.

The therapy of primary adult systemic CD30-positive anaplastic large cell lymphoma: results of 40 cases treated in a single center.

The outcome of a series of adult patients, affected by primary systemic CD30-positive anaplastic large cell lymphoma (ALCL), treated with a sequential intensive therapeutic program, has been analyzed and all data available in the literature have been reviewed. Forty consecutive, unselected patients with ALCL were treated with the F-MACHOP regimen, followed by radiotherapy (RT) for residual mediastinal disease (15 cases) and by autologous stem cell transplantation (ASCT) conditioned with BAVC (29 cases). Eighty-nine percent (32/36) of the patients younger than 60 years were eligible for completing the sequential treatment. Since then, 3 patients in CR refused ASCT, 1 was excluded for cardiac toxicity and 3 progressed and died of disease. Thus, 29 have been so far submitted to the transplant procedure. CR and PR rates were 40% and 45% respectively after CHT; 52.5% and 35% after RT; 80% and 5% after ASCT, with 78% of patients transplanted in PR convertin to a CR. Actuarial overall survival is 85% at 48.5 months (93% at 66 months for the 29 transplanted patients) and disease free survival is 100% at 54 and 64 months respectively, with no relapses observed among patients who reached a CR. Considering our data and those of the literature, it can be concluded that although the role of ASCT in the therapy of ALCL must not be considered as definitive, its efficacy in converting PR into CR and in preventing relapses, suggests that a randomized trial comparing CHT alone vs CHT+ASCT should be undertaken.

Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia.

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.

Neutralizing anti-interferon-alpha antibodies and response to treatment in patients with Ph+ chronic myeloid leukaemia sequentially treated with recombinant (alpha 2a) and lymphoblastoid interferon-alpha.

Neutralizing anti-IFN alpha antibodies (nIFN alpha Abs) occur in a significant proportion of patients with hairy cell leukaemia, hepatitis or solid tumours treated with recombinant IFN alpha (IFN alpha 2a or IFN alpha 2b), but information on their incidence in chronic myeloid leukaemia (CML) is scanty and their clinical relevance is not yet completely defined. By using an IFN alpha antiviral neutralization bioassay, the frequency of nIFN alpha 2a Abs was evaluated in 67Ph+ CML patients during IFN alpha 2a therapy at doses ranging from 6 to 9 MU/d. 15 patients (22%) developed nIFN alpha 2a Abs (titre ranging from 1:40 to 1:20480) and 11/15 (73%) were haematologically and/or karyotypically unresponsive to treatment. 52 patients did not develop antibodies and 11 of them (21%) were unresponsive. The negative relationship between the positivity for nIFN alpha 2a Abs and the response to treatment was highly significant (P = 0.0001). In nine nIFN alpha 2a Abs positive patients, treatment was changed from recombinant IFN alpha 2a to lymphoblastoid IFN alpha (IFN alpha-ly), at the same dose and schedule. After 9 months of IFN alpha-ly treatment a haematological response was achieved in 4/7 cases who were non-responsive to prior IFN alpha 2a therapy and was maintained in the other two patients previously responsive to IFN alpha 2a. However, no karyotypic response was observed. This data shows that a significant proportion of Ph+ CML patients receiving treatment with IFN alpha 2a can develop neutralizing antibodies and that these antibodies are associated with a loss of IFN alpha 2a efficacy. Changing the patients to treatment with lymphoblastoid IFN alpha may restore haematological response but it is not likely to induce a karyotypic response.

[Therapy and iron supplements with ferritin iron during pregnancy. Randomized prospective study of 458 cases]. / Terapia e supplemento marziale con ferro ferritinico durante la gravidanza. Studio prospettico randomizzato di 458 casi.

A randomized polycentric study was programmed to establish the effects of daily administration of ferritin iron from early pregnancy to puerperium. 254 women with normal iron balance at the beginning of their pregnancy were randomized receiving no supplements or 40 mg iron daily. At the end of pregnancy iron balance was still normal only in one third of the pregnant women of the first group versus two third of the second group. 204 women who were iron-deficient received daily 40 or 120 mg of iron; in this group anemia developed less frequently (13% versus 29%) and iron balance normalized in one subject on four; the great majority of these women remained iron-deficient. Unwanted effects of minimal or mild relevance, and almost always sporadic were observed in 6.5% of cases and with the reduction or withdraw of the treatment in only 1.4% of cases. These results showed that daily administration of ferritin iron during pregnancy is effective and well tolerated; furthermore they suggest that the treatment must be done with at least 60 mg daily in women with normal iron balance and protracted also after the puerperium in iron deficient subjects.