Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II Gemia protocol

BACKGROUND AND OBJECTIVE: High-dose cytarabine (HDAra-C), mitoxantrone and etoposide are the mainstay of several active regimens against relapsed or refractory acute myelogenous leukemia (AML). We designed a phase II study to assess the efficacy and side effects of a time sequential application of mitoxantrone plus intermediate-dose Ara-C followed by HDAra-C plus etoposide (GEMIA) in adult patients with refractory or relapsed AML. DESIGN AND METHODS: Patients with refractory or relapsed AML were eligible for GEMIA salvage therapy, which comprised mitoxantrone 12 mg/m2/day on days 1-3, Ara-C 500 mg/m2/day as a 24-hour continuous infusion on days 1-3, followed by HDAra-C 2 g/m2/12-hourly on days 6-8 and etoposide 100 mg/m2/12-hourly on days 6-8. Granulocyte colony-stimulating factor was started on day 14. In patients above the age of 55 the dose of Ara-C in the first sequence (days 1-3) was reduced to 250 mg/m2. RESULTS: Twenty patients were included, of whom 12 achieved complete remission after GEMIA (60%, 95% CI 40-80%), one was refractory and five died early from infection. Two additional patients achieved partial remission after GEMIA and complete remission after consolidation chemotherapy, for a final CR rate of 70% (95% CI 48-88%). Neutrophils recovered at a median of 27 days (range, 22-43) and platelets 46 days (range, 25-59) after the start of treatment. The median duration of remission was 133 days (range, 36-417+) whereas overall survival time lasted for a median of 153 days (range, 13-554+). Treatment-associated toxicity was comprised predominantly of infection, mucositis and diarrhea that reached World Health Organization grades III-V in 40%, 40% and 30% of patients, respectively. Despite the intention to rapidly proceed to a hematopoietic stem cell transplant in patients in remission, only five patients reached the transplant. INTERPRETATION AND CONCLUSIONS: The GEMIA time sequential chemotherapy regimen appears effective in obtaining remissions in refractory and relapsed adult AML. The high toxicity seen, however, suggests that its design is amenable to further improvements, especially in more elderly patients. Since remissions are short-lived, more innovative post-remission strategies are needed.     

Intensive salvage chemotherapy for primary refractory or first relapsed adult acute lymphoblastic leukemia: results of a prospective trial.

BACKGROUND AND OBJECTIVE: Adults with primary refractory or relapsed acute lymphoblastic leukemia (ALL) have a very poor prognosis with current salvage chemotherapies. Complete remissions (CR) can be obtained with intensive regimens in 40-60% of cases, but they are short-lived. In an effort to obtain high CR rates and prolong their duration and achieve long-term survival in a substantial number of patients, we designed an intensive combination salvage regimen (RELAL-88). In this protocol, chemotherapy was to be followed by an allogeneic or autologous stem cell transplant (SCT) within three months from CR. DESIGN AND METHODS: Forty-five patients with primary refractory (n=17) or first relapsed ALL (n=28) were treated with the RELAL-88 five-day induction regimen comprising vindesine, mitoxantrone, cyclophosphamide, intermediate-dose Ara-C, prednisolone and methotrexate. Twenty-eight patients received granulocyte colony-stimulating factor (G-CSF), 16 patients from day 6 (early G-CSF group) and 12 from day 14 of therapy (delayed G-CSF group). RESULTS: Thirty-four patients (74%) achieved CR (95% CI 60-87), two died in aplasia due to infection and nine were non-responders. No pretreatment variable analyzed was predictive of the chance of obtaining CR. Recovery of neutrophils occurred at a median of 29 days from the start of chemotherapy without G-CSF and 20 days with G-CSF (p = 0.005), without differences between the early and late G-CSF groups. Non-hematologic side effects were usually well tolerated and consisted mainly of infections and mucositis. Twenty-three of 34 patients (68%) who achieved CR reached the planned SCT (nine autologous and 14 allogeneic). The median overall survival was 5.7 months, and the median disease-free survival for those achieving CR was 4.6 months. Of the variables analyzed for their influence on overall survival among the 34 patients who achieved CR, only the availability of an HLA-compatible sibling was associated with a prolonged survival (p = 0.03). INTERPRETATION AND CONCLUSIONS: The RELAL-88 intensive salvage regimen produces a very high rate of CR in poor-risk adult ALL. Non-hematologic toxicities were tolerable, and most eligible patients could undergo the planned SCT. G-CSF significantly shortened the period of neutropenia by about eight days, irrespective of whether it was started early or late after chemotherapy. However, as with other currently available salvage therapies, remissions were short-lived, and more effective post-remission treatment strategies are needed. In our experience, only allogeneic SCT offered the chance of long-term survival.     

A reversible monoamine oxidase inhibitor, toloxatone: Structural and electronic properties

Toloxatone is a reversible MAO_A-inhibitor, marketed as antidepressant (Humoryl^®), with an original chemical structure. It differs from first generation irreversible MAOIs, known to induce covalent bonds with the enzyme active site. In order to understand the mechanism of the reversible inactivation of the MAO, as a first step, a detailed structural and electronic analysis was undertaken. An X-ray diffraction-crystallographic study showed that toloxatone is a planar molecule and brought to light hydrogen bonds and π-π interactions. MO calculations confirmed the planar structure as energetically favoured. Electronic analysis demonstrated a delocalization of both ring systems. The combined results give evidence for the potential of toloxatone to participate in reversible, long distance interactions with an appropriate partner.     

Non-secretory multiple myeloma presenting as primary plasma cell leukaemia.

A case of non-secretory multiple myeloma presenting as primary plasma cell leukaemia in a 65 year old woman is presented. Bone pain was the initial clinical manifestation. Laboratory analysis showed 20% of circulating immature plasma cells. Despite the presence of osteolytic lesions, no M-component could be demonstrated in serum protein electrophoresis, and serum and urine immunoelectrophoresis. Bone marrow aspirate demonstrated an 83% infiltration of plasma cells showing various degrees of immaturity. Immunofluorescence with monoclonal antisera demonstrated intracytoplasmic kappa light chains in a high percentage of plasma cells. Immature plasma cells without cellular capacity to synthesize and excrete complete immunoglobulins could be more aggressive, leading to an initial leukaemic process. Previous work regarding possible pathogenetic mechanisms, clinical and laboratory features, and response to treatment of this extremely rare association are reviewed.     

Analysis of two new leukemia-associated antigens detected on human T- cell acute lymphoblastic leukemia using monoclonal antibodies

Two monoclonal antibodies (anti-3-3 and anti-3-40) were produced, which identify two new leukemia-associated antigens. Both antibodies reacted with most cell lines derived from patients with T lymphoblastic leukemia (T-ALL), but were not detected on suspensions of normal hematopoietic cells (including thymocytes) by cytotoxicity, absorption, or indirect immunofluorescence assays. Analysis of fresh leukemic cells indicated that anti-3-3 only reacted with T-ALL cells, while anti-3-40 also reacted with some non-T, non-B ALL cells and a few acute myelocytic leukemia (AML) cells. The 3-40 antigen was also found histopathologically in frozen sections of several normal tissues, including the epithelial cells and a few lymphoid cells of the thymus, and some malignant tissues. The 3-3 antigen was not found in any tissue studied. A "double absorption"assay provided additional serologic evidence that the two antibodies identify different antigenic determinants. Biochemical analysis indicated that the molecules immunoprecipitated by anti-3-3 and anti-3-40 have molecular weights of 35,000-40,000 daltons. This study demonstrated that the 3-3 and 3-40 antigens are markers for human T-ALL and can be used along with the normal T-lymphocyte antigen, 3A1, to discriminate T-ALL from cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia (ATL), and T-cell chronic lymphocytic leukemia (T-CLL).     

Spontaneous splenic rupture as the initial manifestation of acute lymphoblastic leukaemia: Immunophenotype and cytogenetics

Summary Spontaneous splenic rupture is a rare, though life-threatening complication of some hematological malignancies and is even more infrequent as the initial symptom of acute lymphoblastic leukemia. We describe the fourth case, to our knowledge, of acute lymphoblastic leukemia presenting as splenic rupture, and for the first time the immunophenotype and cytogenetic pattern observed.     

Changes in circulating cytokines and markers of muscle damage in elite cyclists during a multi‐stage competition

The purpose of this study was to determine the changes in the basal and post‐exercise plasma markers of muscular damage, lipid peroxidation and cytokines in eight male well‐trained semiprofessional cyclists, in response to a three consecutive‐day cycling competition. Serum markers of oxidative and muscular damage – creatine kinase activity, lactate dehydrogenase activity, myoglobin and malondialdehyde (MDA), creatinine and nitrite levels – followed a sawtooth‐type representation throughout the competition. MDA showed an accumulative pattern, evidenced in the post‐race values of the third stage which were significantly higher with respect to the values of the first stage. Cortisol levels were significantly influenced by an interaction between the exercise and the stage factors, with higher values on the 4th day. Plasma cytokine levels were only determined before the first stage and post‐race, after the third stage. The exercise increased TNFα, IL6, IL2 and IFNγ levels, whereas IL1β was unchanged. In conclusion, cyclist stages induced oxidative and cellular muscle damage which is partially recovered to basal values by the next morning. Repetitive stages during the cycling competition accumulated plasma muscular damage and lipid peroxidation markers and pro‐inflammatory cytokines, probably as a result of local inflammatory responses.