Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m 2 per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m 2 (n ‫؍‬ 177) or placebo (n ‫؍‬ 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/ placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P ‫؍‬ .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/ placebo (11% vs 2%; P ‫؍‬ .016; 54 days vs 34; P ‫؍‬ .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.

The article is concerned with incidence, clinical features, response to therapy, and prognosis of patients with hypocellular myelodysplastic syndromes. Bone marrow (BM) cellularity <30% (or <20% in patients >70 yr) was found in 24 of 236 (10.2%) trephine biopsies. Median age was 61 yr, with significant male predominance (M/F=3.0) At diagnosis, median hemoglobin was 83 g/L, median platelet and neutrofil counts were 31x109/L and 1.2x109/L, respectively. According to FAB classification, 17 patients had RA, 6 had RAEB, and only 1 had RAEB-t. Beside marrow hypoplasia, the most prominent PH finding was megakaryocyte hypoplasia and dysplasia, found in two-thirds of cases, each. Comparison between hypocellular and normo/hypercellular MDS cases regarding clinicopathological features showed younger age, more severe cytopenia, less blood and BM blast infiltration, MK hypoproliferation, and more pronounced stromal reactions in former cases. Karyotypic abnormalities were present in 12.5% hypocellular cases, in contrast to 44.6% normo/hypercellular cases (p=0.0025). Eleven patients were treated with supportive therapy alone, six with danazol or androgens, six with immunosuppressive therapy, and one with LDARAC. However, complete or partial response was achieved in only four patients treated with danazol or androgens. None of the patients developed leukemia. Eleven patients died, so marrow insufficiency was the main cause of death. Median survival was 33 mo for hypocellular MDS, and 19 mo for normo/hypercellular MDS (p=0.09). The results confirm the existence of hypocellular variant of MDS, which seems to have better prognosis than those patients with normo/hypercellular disease.

In a retrospective study of 236 patients with primary myelodysplastic syndromes (MDS), 130 cases (55.1%) revealed myelofibrosis in bone marrow biopsies. It was observed that fibrosis mostly occurs focally or patchy, and collagen deposits were found very rarely (only four patients). The histopathology of bone marrow biopsies revealed several differences between fibrotic and non-fibrotic MDS: cellularity is significantly higher, dysmegakaryopoiesis is more pronounced, plasmocytes and mast cells are more often increased, and disturbance of marrow topography (particularly of the MK- and G-line) can be found more frequently in MDS with myelofibrosis. Reticulin fibrosis occurred in all subtypes of MDS; however, there was a higher incidence in chronic myelomonocytic leukemia. The frequency of abnormal growth of GM-progenitors was significantly higher in the MDS cases with myelofibrosis, compared to the cases without fibrosis. Clinical data showed significantly higher WBC, more frequent presence of immature granulocytes, and higher percentage of myeloblasts in peripheral blood and bone marrow in MDS with myelofibrosis compared to cases without myelofibrosis. Life expectancy was reduced to 13 mo, compared with 35 mo in MDS without fibrosis (p=0.00055). Time to leukemic transformation was 32 mo in MDS with fibrosis, compared with >56 mo in MDS without fibrosis (p=0.015). Myelofibrosis therefore seems to herald a poor prognosis.

Cytogenetic analysis has proven to be a mandatory part of the diagnosis of myelodysplastic syndromes (MDS) as well as a major indicator for predicting clinical course and outcome. Aside from the 5q-syndrome, no specific clinico-cytogenetic entity has been reported. To determine the incidence and clinical significance of acquired abnormalities of chromosome 17 in adult primary MDS, we reviewed the cytogenetic features of 271 patients detected at our institution during a 10-year period. Clonal cytogenetic abnormalities were identified in 109 cases. Among them, abnormalities of chromosome 17 were identified in 13 patients (11.9%). Five patients had "single" defects, while in eight patients abnormalities of chromosome 17 were associated with other chromosomal rearrangements ("complex" defects). After chromosomes 5, 7, 8 and 1, abnormalities of chromosome 17 were the most frequent chromosomal rearrangements in our patients with MDS. Following "single" defects of chromosome 17 were identified: del(17)(p12) in two cases, and i(17)(q10), del(17)(q21;q23) and del(17)(q12;q22) in one case each. Two patients with del(17p), one with RAEB-t and the other one with CMML, had an aggressive course of the disease with accelerated leukemic transformation and short survival. Patient with i(17q) had RARS subtype and died soon after diagnosis, while other two cases with interstitial deletions of the long arm of chromosome 17 had RAEB subtype and stable, no progressive course of the disease. Among "complex" karyotypes with abnormalities of chromosome 17 we identified der(17) in four, monosomy 17 in two, and del(17p) and l(17q) in one case each. Most of these patients transformed to acute leukemia and had very short survival. The results of this study suggest that abnormalities of chromosome 17 are frequent finding in MDS. Loss of genetic material in 17p, both in "single" and "complex" defects, seems to be closely related to poor prognosis of MDS patients.

Biological and clinical significance of growth pattern of hematopoietic progenitors were investigated in 117 patients with primary myelodysplastic syndromes (MDSs) at referral. Abnormal (i.e., "leukemic" or absent) growth of GM colonies (CFU-GM) and GM clusters was found in 47% of patients with "advanced" MDS (RAEB, RAEB-t, and CMML) and in 15% of "low-risk" (RA/RARS) patients. In vitro erythropoiesis was decreased in most of the patients, with significantly lower number of BFU-E in "advanced" MDS than in RA/RARS patients. Megakaryocyte progenitors (CFU-MK) were very low or absent in almost all the patients, regardless of the FAB type. Significant correlation was demonstrated between the number of BFU-E and hemoglobin concentration and between number of CFU-MK and platelet count. Growth capacity of GM progenitors appears to be in proportion to "myeloproliferative" capacity of the malignant clone. T-cell depletion had no influence on growth capacity of hematopoietic progenitors, nor did colony growth respond in a dose-dependent manner to different concentrations of LCM. Growth capacity of MDS hematopoietic progenitors was independent of Bournemouth score, of the presence and type of cytogenetic abnormality, and of the expression of CD95 and caspase-3 antigens on bone marrow cells. However, in patients with "abnormal" growth of GM progenitors, CD34 antigen expression was significantly higher than in patients with "normal" growth. "Abnormal" GM growth was found to be independently predictive regarding the survival and the risk for AML development. In contrast, the prognostic value of erythroid and megakaryocyte cultures was found to be limited.