Mitoxantrone, teniposide, chlorambucil and prednisone (MVLP) for relapsed non-Hodgkin's lymphoma. The impact of advanced age and performance status.

Fifty-seven patients with relapsed non-Hodgkin's lymphoma (NHL) of low, intermediate and high-grade malignancy were treated with mitoxantrone, teniposide (Vm26), chlorambucil (Leukeran) and prednisone (MVLP). The median age was 71 years; none of the patients was excluded due to poor performance status (PS). Out of 44 patients with PS (according to WHO) < or = 2, 38 responded with a median progression free survival (PFS) of 21.5 months. Of 13 patients with PS > 2, 6 responded with a median PFS of 8.2 months. Haematopoietic toxicity was related to PS rather than to dose intensity or bone marrow involvement. Three patients died within a short time due to toxicity; another two died later as a result of cardiac failure probably due to accumulated toxicity of adriamycin and mitoxantrone. MVLP chemotherapy is effective and feasible and has only moderate toxicity in patients with relapsed NHL and PS < or = 2, despite advanced age.

Longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia using archived blood smears.

We performed a longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia and a follow-up of at least 2.5 years after diagnosis. Point mutations at codons 12, 13, and 61 of the N-ras oncogene were analyzed after in vitro amplification of N-ras specific sequences followed by dot-blot hybridization. Lysed cells scraped from archived blood and bone marrow smears were used as template for a polymerase chain reaction. In 3 of 90 patients tested (3.3%), a mutation in codon 12 could be detected in the most recent blood smears. All available blood and bone marrow samples of these patients were subsequently analyzed for the occurrence of that particular mutation. In all three cases the mutation was not detectable at diagnosis, but was acquired later during the course of the disease. In two of these patients this event was associated with rapid deterioration and transformation to acute leukemia. However, the third patient showed a protracted course during a period of 5 years after acquisition of the mutation. These results indicate that activation of the N-ras protooncogene in these three patients represents a secondary phenomenon associated with disease progression in some cases, but compatible with stable disease in others.

The effect of anticoagulants on the size of platelets in blood smears in the course of time.

In this study we measured platelet size in blood smears using the Kontron Mop Videoplan (Kontron Electronic Group, Weesp, Holland). The blood smears were prepared at different times after phlebotomy; samples were collected in three different anticoagulants and 100 consecutive platelets were measured in each smear. A number of platelet parameters were determined, some of which were based on the log normal distribution of the platelet area. We found that the size of platelets in blood smears is also dependent on the time after phlebotomy and the anticoagulant used. This may be important for the comparison of platelet areas, a characteristic of various disorders. Our data indicate that the optimal interval after phlebotomy for preparation of blood smears is 2-5 min.

On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group.

We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.

Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases.

The utility and prognostic significance of the FAB classification was studied in 237 patients with a myelodysplastic syndrome. No significant differences in actuarial survival and probability of transformation to acute leukaemia were found in patients with RA, AISA or CMML. The median survival time for the RA group was 50 months, for the AISA and CMML subclasses more than 60 months. The probability of transformation for the RA, AISA and CMML subgroups showed a linear trend with a probability of 25% for the RA, 16% for the AISA and of 18% for the CMML groups after a 5 year observation period. A uniformly poor prognosis was found for the RAEB and RAEB/t subgroups with median survival times of respectively 9 and 6 months. Chromosomal abnormalities were found in 68 out of 155 patients (44%). Patients with only normal metaphases or with abnormal metaphases together with karyotypic normal cells had a longer median survival time and a lower probability for transformation as compared to those with only abnormal metaphases. The most important factor in prognosis is the number of blast cells in blood and bone marrow. Age and sex, and certain quantitative and qualitative abnormalities in the peripheral blood appear of limited prognostic value for patients with RA, AISA and CMML. The longer life expectancy of 35 patients with CMML as compared to other series seems to be related to the percentage of blast cells at the time of diagnosis.

Significance of in vitro cultures in myelodysplastic syndromes.

Bone marrow samples from 20 controls, 41 patients suffering from various types of myelodysplasia and 19 suffering from ANLL were investigated by in vitro cultures. The cultures were stimulated by various concentrations of leucocyte conditioned medium (LCM) and PHA-stimulated conditioned medium (PCM) and were examined after 7 and 14 d. We found that, in clinically stable MDS, growth patterns and dose-response to CM's were mostly within the normal range. With progressive blastic transformation, these features became abnormal with an increase in cluster growth. Clusters responding to a high dose of LCM, persisting after 14 d and enhanced by PCM may represent 'early' clonogenic cells. These clusters were found in progressive MDS with increased numbers of blast cells. Clusters formed by 'late' clonogenic cells were found in normal bone marrow and stable MDS. In ANLL the disturbance of proliferation and maturation seems to be much more pronounced than in progressive MDS with blastic transformation. We conclude that the interpretation of in vitro bone marrow culture data in terms of a disorderly arrangement of clonogenic cells in MDS and ANLL is facilitated by comparing different conditioned medium stimulations and by scoring after different time intervals.

The preleukemic syndrome. II. Cytogenetic findings.

Out of 151 patients with preleukemic syndrome, bone marrow chromosome studies were carried out in 88 during the preleukemic phase and in 10 after blastic transformation. Out of 54 cases studied without banding techniques, 13 (24%) were abnormal, while 17 (50%) out of 34 banded cases showed abnormalities. This highly significant increase in yield of aberrations was not restricted to structural abnormalities. During the preleukemic phase of the disease, only 5 of the abnormal patients had no normal metaphases in their bone marrow. Four types of chromosome aberrations were observed more than once: -Y, +8, del 5q and del F or del 20q. They are all frequently observed in myeloproliferative disorders. After blastic transformation, 15 out of 19 patients were abnormal and the abnormalities were more complex. It seems, therefore, that a qualitative and quantitative difference exists between this group of patients and the published series of patients with ANLL. Small abnormal cell lines with the same chromosome abnormalities as in the bone marrow were observed in PHA-stimulated blood cultures of 9 patients. Unstimulated cultures of the same blood sample did not show any mitosis. It is suggested that small subpopulations of lymphocytes arose from the same pluripotent stem cell as the leukemic myelogenous cells, although there may be other explanations.

The preleukemic syndrome. I. Clinical and hematological findings.

A long-term prospective study including 151 patients with preleukemia was performed in 1958--79. The series comprised 78 women and 73 men with a mean age of 79 and 72 years, respectively. Acute leukemia was the cause of death in 35 patients, 61 died of infections and/or hemorrhage or of unrelated causes. The mean interval between the initial diagnosis and death from acute non-lymphocytic leukemia was 36 months (range 2--121). Pitfalls in diagnosis are extensively discussed. The most striking was the advanced age of the patients. The presence of pancytopenia at the time of diagnosis was not predictive for subsequent blastic transformation.