W. Hiddemann

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVE To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. DESIGN Retrospective comparison of two cohorts of patients. SETTING Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. PATIENTS Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. MAIN RESULTS Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. CONCLUSIONS These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Differential pattern of DNA-Aneuploidy in human malignancies

The differential pattern of DNA-aneuploidy, detected by flow cytometry (FCM) regarding its frequency, grade and multiclonality, was investigated and correlated to tumor type, malignancy grade, tumor stage and prognosis in a multi-institutional study at the University of Münster. High resolution measurements using admixed normal blood reference cells were undertaken in 2413 cases of 13 different malignant diseases and in 776 benign lesions or samples. The incidence of DNA-aneuploidy was highest in melanomas, carcinomas, testicular tumors, sarcomas (75%-95%) and myelomas (65%). Acute leukemias showed an intermediate DNA-aneuploidy rate of 40% with special subgroups represented by common ALL (44%), p less than 0.05) and myelomonocytic/monocytic AML (47%, p less than 0.01). The lowest DNA-aneuploidy-rate was found in basal cell skin carcinomas (19%) and congenital melanocytic nevi (9%). No case of DNA-aneuploidy was observed in the 776 benign lesions or samples.--DNA-indices giving the grade of DNA-aneuploidy with 1.0 for normal diploid G1/0 cells were found distributed predominantly between 1.0 and 2.0 in the solid tumors, except testicular tumors, clustering around a triploid maximum at 1.5. DNA-indices of myelomas and acute leukemias generally ranged below 1.25 with lower DNA-aneuploidy grades in AML than in ALL (p less than 0.01).--In melanomas the aneuploidy rate was higher (86%) in metastases than in the primary tumors (54%, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cytosine arabinoside in the treatment of acute myeloid leukemia: The role and place of high-dose regimens

SummaryCytosine arabinoside (AraC) is one of the most active drugs in the treatment of acute leukemias and is widely applied at all phases of therapy. In spite of extensive clinical and experimental investigations, its intracellular metabolism and especially its mechanism of action are still not fully elucidated. Controversy also continues about the most appropriate way and dose of administration; which differs by more than 100 fold in clinical studies ranging from low-dose, over standard and intermediate dose regimens, to high-dose protocols.The present review is focused on the role and place of high-dose AraC treatment in acute myeloid leukemia (AML). Based on available clinical and experimental data, the following conclusions can be drawn: Not considering possible but not yet demonstrated beneficial long-term effects, the incorporation of high-dose AraC intoinduction therapy has not resulted in an improvement of overall remission rate, with the possible exception of patients with slow initial cytoreduction after a first course of conventional treatment. Promising results, however, emerge from high-dose AraC-basedconsolidation protocols, which need confirmation in prospectively randomized comparative trials. Inrelapsed and refractory AML, higher than conventional doses undoubtedly enhance the efficacy of AraC salvage therapy. The question of whether the antileukemic activity of intermediate-dose regimens with 500–1,000 mg/m2 AraC is equivalent to that of high-dose protocols applying 2,000–3,000 mg/m2 AraC, however, remains open but may soon be answered by ongoing controlled clinical and pharmacologic investigations.

Treatment of advanced chronic lymphocytic leukemia by fludarabine. Results of a clinical phase-II study.

SummaryIn a clinical phase-II study fludarabine phosphate was given to 20 patients with advanced chronic lymphocytic leukemia who had failed on prior conventional therapy. Fludarabine was administered at a dose of 25 mg/m2/d for 5 days. Treatment cycles were repeated every 4 weeks until maximal response, followed by two cycles for consolidation. Four of the 20 patients achieved complete remission and seven patients partial remission, resulting in an overall response rate of 55% (11/20). Fludarabine therapy was well tolerated, with mild myelosuppression and secondary infections comprising the predominant side effects. These data warrant further confirmation and a randomized comparison of fludarabine with established regimens, which is currently underway.

Tumor heterogeneity in osteosarcoma as identified by flow cytometry

Measurements of the cellular DNA content by flow cytometry were carried out in 25 untreated osteosarcomas to identify the frequency of DNA aneuploidies and heterogeneous DNA stemlines in relation to histopathology. Analyzing multiple specimens from each single tumor (2–16; median, 4), highly malignant osteosarcomas were found to express DNA aneuploidies in 18 of 21 cases (86%) with multiple aneuploid DNA stemlines in 10 cases (48%). In three paraosteal osteosarcomas, no DNA aneuploidy was detected and a significantly lower proportion of cells in S‐phase was observed as compared to the highly malignant osteosarcomas (mean 8.6% vs. 18.8%; P <0.05). Like in the paraosteal osteosarcomas, no DNA aneuploidy and a low fraction of cells in S‐phase was found in the predominant cell population of one of the very rare sclerosing small cell osteosarcomas, which also revealed a second DNA stemline with a DNA index of 2.0. These results demonstrate a high degree of DNA stemline heterogeneity in highly malignant osteosarcomas. The data emphasize the usefulness of DNA measurements for the characterization of bone tumors and indicate the possibility of discriminating highly malignant from low‐grade osteosarcomas. Cancer 59:324–328, 1987.

Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara‐C (AC) (NOAC) was active in refractory non‐Hodgkins lymphoma (NHL) but myelosuppression was dose‐limiting. In a pilot study, we investigated the effects of recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM‐CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were > 3.0/nl for 3 consecutive days. Twenty‐three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM‐CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM‐CSF, the median duration of severe neutropenia (< 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM‐CSF (P = 0.0058), and that of thrombocytopenia (<20.0/nl), 3 days versus 7 days (P> 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM‐CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM‐CSF. The following side effects were associated with the administration of rhGM‐CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM‐CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM‐CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM‐CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.

High-Dose Versus Intermediate-Dose Cytosine Arabinoside Combined with Mitoxantrone for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia: Results of an Age-Adjusted Randomized Comparison

193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of either 3.0 versus 1.0 g/m2 in pts. < 60 years of age or 1.0 versus 0.5 g/m2 in older pts. Mitox was given to all cases at a dose of 10 mg/m2/d on days 3, 4, and 10, 11. Randomization was stratified for primary refractoriness against induction therapy and the length of first remission in relapsed cases (< 6 mths., 6-18 mths., > 18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates being 52% and 44% for the 3.0 versus 1.0 g/m2 AraC regimens in pts. < 60 years and 48% and 45% after 1.0 versus 0.5 g/m2 AraC in older pts. No differences between the respective regimens emerged either for the time to CR (median 46 days) nor remission duration (median 4.5 mths). Analysis of treatment failures, however, demonstrated a significantly higher rate of NR after the lower dose regimens in both age groups of 41% and 32% versus 11% and 14% in pts. receiving AraC at higher doses (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma

Mitoxantrone (Novantrone, NO) and high‐dose cytarabine (Ara‐C, AC) have each been shown in mono‐therapy trials to be active in non‐Hodgkins lymphoma (NHL). In the current study, a combination of the two drugs (NOAC) was administered to 31 patients with advanced NHL refractory to modern sequential chemotherapy regimens. Ara‐C was administered at 3 g/m2 as a 3 hour infusion every 12 hours on day 1 (2 doses) and mitoxantrone at 10 mg/m2/day on days 2 and 3. Of the 18 patients with high‐grade malignant NHL, six have attained a complete remission (CR) and two, a partial remission (PR). One CR and 5 PRs were achieved among the other 13 patients with intermediate or low‐grade NHL. The median time to relapse (TTR) of patients achieving CR was 7 months with a range from 4 to 17 months. Myelosuppression with subsequent infections was the major toxicity of this regimen. The median duration of severe neutropenia (< 0.5/nl) was 9 days with a range of 0 to 27 days and the median duration of severe thrombocytopenia (< 20/nl), 5 days with a range of 0 to 35 days. Infectious complications during cytopenia was seen in 45.3% of the courses administered and fever of unidentified origin was seen in 42.3%. About 63% of the patients were hospitalized for intravenous antibiotic or antimycotic treatment. Other side effects were mild and included nausea, stomatitis, and transient tachycardia of > 100/min. Thus, this regimen was active in refractory NHL with poor prognosis, and the toxic side effects were not excessive. Evaluation of the activity of this regimen at higher dose levels of Ara‐C is warranted.

Frequency and Clinical Significance of DNA Aneuploidy in Acute Leukemia

Analyses of the cellular DNA content were carried out in 446 patients with newly diagnosed acute myeloid (AML) and lymphoblastic (ALL) leukemias in order to assess the frequency of DNA aneuploidies and its relation to immunologic and morphologic subtypes as well as its prognostic relevance. Based on high resolution FCM analyses and standardized reference measurements, DNA aneuploidies were identified at a similar frequency in children and adults with AML (38.0% and 40.0%) and ALL (40.0% and 37.4%). In AML aneuploid DNA stemlines were significantly less frequent in FAB-M 1 cases as compared to the other morphologic subtypes (p less than 0.05), whereas the degree of DNA aneuploidy was significantly lower in M 1 and M 2 leukemias as compared to the M 4 and M 5 subgroups (p less than 0.05). In ALL non-T/non-B and C-ALL revealed a higher frequency of DNA aneuploidies than T- and Null-ALL cases (p less than 0.05). No differences in the response to induction therapy were found between patients with and without DNA aneuploidy in children or adults with AML or ALL. In the childhood ALL trial BFM 79/81, however, a significantly higher frequency of long term remissions was observed in children with DNA aneuploidy (0.91 versus 0.66 at five years, p = 0.053). A similar though not significant tendency was also revealed from the AML studies BFM 78 in children and 78/81 in adults. In the subsequent studies these differences could not be confirmed at present, possibly because of the considerably shorter observation time.

DNA aneuploidies in adult patients with acute myeloid leukemia. Incidence and relation to patient characteristics and morphologic subtypes.

Analyses of the cellular DNA content were carried out by flow cytometry (FCM) in 148 adult patients with acute myeloid leukemia (AML) to assess the incidence of DNA aneuploidies and its relation to patient characteristics and morphologic subtypes. DNA aneuploidies were found in 54 of 131 patients with de novo AML (41.2%) and in 4 of 17 patients with AML after preleukemic syndromes. Subclassification according to morphology revealed the lowest rate of DNA aneuploidies in M1 leukemias (25%) and a significantly lower degree of DNA aneuploidy in M1 and M2 cases as compared to M4 and M5 subtypes (P <0.05). Within the group of M4 and M5 leukemias, patients ≤ 40 years of age had a higher frequency of aneuploid DNA stemlines (71.4%) than older patients (33.3%) (P <0.025). No differences between patients with and without DNA aneuploidy were identified for the initial leukocyte count, serum LDH, bone marrow S‐phase index, bone marrow cell count/mm3 bone marrow nor the initial response to the induction regimen of 6‐thioguanine, cytusine arabinoside, and daunorubicin (TAD). For remission duration a tendency towards a higher proportion of long remissions was observed in patients with DNA aneuploidy.