Granulocytopoietic precursor cells and regulatory factors in irradiated human bone marrow.

The effects of irradiation on committed granulopoietic progenitor cells (CFU-C) and granulopoietic humoral regulators were studied in 17 X-ray treated patients with carcinoma of the breast or of the prostate. After 45 or 70 Gy, the CFU-C decreased to 14 +/- 10% in irradiated areas. This remaining CFU-C population probably reflects a combination of radioresistance and survival in situ, and migration of CFU-C from protected marrow areas. The frequency of peripheral blood CFU-C did not change after irradiation. Endogenous colony stimulating activity (CSA), i.e., release of CSA within the marrow cell population, in post-irradiation bone marrow persisted on roughly the same level, indicating a fairly low radiosensitivity of the CSA-producing cells in the bone marrow. Colony stimulating activity in peripheral blood cells and serum remained unchanged, but there were great interindividual variations, and some of the patients with hypercellularity and CFU-C increase in nonirradiated marrow areas also had increased CSA. Serum lipoprotein inhibitors were higher in the post-treatment patients than in healthy control patients.

Philadelphia chromosome negative acute lymphoblastic leukemia preceding Philadelphia positive chronic myelogenous leukemia.

A patient with Philadelphia chromosome (Ph) negative acute lymphoblastic leukemia (ALL, FAB type L1) developed Ph-positive chronic myelogenous leukemia (CML) after more than 2 years in complete remission. Subsequently, Ph-positive lymphoblastic transformation occurred, which was again successfully treated. Thereafter, the CML state was interrupted twice more by blast crisis. The additional chromosomal abnormalities were atypical for Ph-positive CML. The course is interpreted as a possible example of the multistep development of CML. Blastic transformation occurring prior to the Ph chromosome has been reported in only two cases previously.

t(6;9) in bone marrow cells in two patients with sarcoidosis and acute myeloid leukemia.

A t(6;9) was seen in bone marrow aspirates from two patients with sarcoidosis who developed acute myeloid leukemia. This is a new observation not previously reported.

Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia.

A total of 44 adults aged 18-78 years were allocated to an open randomized study whose aim was to compare the efficacy and toxicity of mitoxantrone with those of daunorubicin in previously untreated patients presenting with acute myeloid leukemia. In one arm, induction treatment consisted of mitoxantrone plus cytarabine given on a 3- plus 7-day schedule. Post-induction treatment consisted of two courses of mitoxantrone plus cytarabine given on a 2- plus 5-day schedule. In the control arm, mitoxantrone was replaced by daunorubicin. In all, 14 of 21 eligible and evaluable patients in the mitoxantrone arm achieved a complete remission (CR). In the control arm, 14 of 20 subjects attained a CR. The median survival was 365 days for patients randomized to mitoxantrone-cytarabine and 401 days for those given daunorubicin-cytarabine. The efficacy and toxicity of mitoxantrone were similar to those of daunorubicin.

Treatment of acute nonlymphoblastic leukemia in adults with daunorubicin-DNA complex: a preliminary report.

Forty-four adult patients under 60 years of age with acute nonlymphoblastic leukemia were randomized for induction treatment with one of the following three regimens: R 1 = courses of daunorubicin on day 1 + ARA-C on days 1--5; R 2 = courses of daunorubicin on days 1 and 2 + ARA-C on days 4--8; R 3 = courses of daunorubicin-DNA complex on days 1--2 + ARA-C on days 4--8. Out of 14 patients, 9 went into remission on R 1, 6 out of 14 on R 2, and 8 out of 16 on R 3. The preliminary results suggest that daunorubicin-DNA complex has the same efficacy for inducing remission as daunorubicin alone, if the same time intervals and dosages are used.

Outcome for patients with leukemia, multiple myeloma and lymphoma who relapse after high dose therapy and autologous stem cell support.

Relapses after autologous transplantation are a serious clinical problem in patients with haematological diseases. The decision making for handling of such patients is difficult and the aim of this retrospective analysis of posttransplant relapses was 1) to obtain information of practical importance for the management of future relapses and 2) to evaluate the basis for clinical phase I-II trials of salvage therapy combined with biological modifiers. Included in the study were 283 patients with acute leukemia, multiple myeloma and malignant lymphoma who relapsed after autologous transplantations during a five year period from 1989 to 1994. Chemo- and radiotherapy was given to 229 patients after relapse or due to progressive disease and the response evaluated after 90 days. Fifty four patients (24%) obtained a complete remission and 44 patients (19%) partial responses. The overall median survival from relapse was 5 months. In the group given salvage treatment the median survival was 7 months and in the 54 patients who obtained remission the median survival was 15 months. So far 6 of 14 patients in continuous complete remission have a remission time after relapse longer than the time in remission after transplantation. Survival after relapse depended upon the time from transplantation to relapse, primary disease and if salvage therapy was given. In conclusion posttransplant relapses can be treated but the strategy has to be evaluated in future clinical trials.

The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988.

During the 17-year period 1972 through 1988, a total of seven cases of agranulocytosis associated with the use of dapsone for the treatment of dermatitis herpetiformis were reported in Sweden. The median age of the patients involved was 61 years; three of them were male. The median duration of dapsone treatment was 7 weeks and the daily prescribed dose was 100 mg. Based on sales and prescription data, the crude relative risk of agranulocytosis during dapsone treatment of dermatitis herpetiformis was 50, and the total risk was one case per 3000 patient years of exposure to dapsone. In relation to the number of new cases of dermatitis herpetiformis, agranulocytosis was estimated to develop in 1 of 240 to 425 patients receiving dapsone therapy. Patients should be instructed to seek medical care immediately in case of fever.

Priming with r-metHuSCF and filgrastim or chemotherapy and filgrastim in patients with malignant lymphomas: a randomized phase II pilot study of mobilization and engraftment.

SCF has been shown to synergize with G-CSF to mobilize CD34(+) PBPCs. In this study we report results from this combination after a phase II trial of 32 patients with malignant lymphoma randomized to receive recombinant methionyl human SCF (ancestim, r-metHuSCF) in combination with recombinant methionyl human G-CSF (filgrastim, r-metHuG-CSF) (experimental arm A) or routine chemotherapy plus filgrastim (conventional arm B). The primary objective was to evaluate the side effects and toxicity during priming and mobilization. The secondary objectives were efficacy by the level of blood-circulating PBPCs, the number of harvest days and the time to three-lineage engraftment after autografting. First, during priming 5 patients had 8 serious events, 4 in each arm. A summary of all adverse events revealed 30 (94%) patients suffering from 132 events of all grading. Second, neutropenia and thrombocytopenia was documented in arm B. Third, 9/14 (64%) patients in arm A reached the target of 5 million CD34(+) cells/kg body weight (bw) compared with 13/15 (87%) in arm B. The results represent the first randomized trial of growth factor plus chemotherapy priming and indicate that a formal phase III trial very unlikely may challenge chemotherapy plus r-metHuG-CSF priming in candidates for high-dose therapy.

Prognostic implications of in vitro colony studies and clonal chromosomal aberrations in adults with acute leukaemia.

A comparison was made between in vitro colony culture parameters and chromosomal abnormalities in 44 adult patients with acute leukaemia, with special reference to prognosis. The presence of clonal chromosomal aberrations in some (AN) or all (AA) metaphases of bone marrow cells was a fairly strong indication of poor prognosis, while the absence of abnormal metaphases (NN) was a favourable prognostic sign. 6 of 7 patients in the NN group entered complete remission (CR), as did 8 of 20 in the AN + AA group and 8 of 17 in the group with random loss of chromosomes (NNA). The median survival time for AN + AA patients was 4 months, while for patients without clonal aberrations (NN + NNA) it was 9 months. Of the cultural parameters studied, colony-stimulating activity (CSA) of peripheral leucocytes had the strongest correlation to prognosis. CSA greater than 1 was related to remission (P less than 0.01) and longer survival (P less than 0.05 at 4 months), while 8 patients with CSA less than or equal to 1 were all dead at 8 months. However, very high CSA values (greater than 20) indicate a poor prognosis. Although both chromosome analysis and CSA were of prognostic value, combining the 2 parameters did not improve the prognostic information, mainly because of covariation of NN and CSA greater than 1.

Remission rate and survival in acute myeloid leukemia: impact of selection and chemotherapy.

113 patients with acute myelogenous leukemia (AML), representing 82% of the total cohort of AML patients within the geographical area of northern Sweden, were recorded. The total complete remission (CR) rate was 47.8%, and median survival was 4 months. The probability of long-term survival for all patients without exclusions was only 5%. Thus, the results from this study differ strongly from data on patient outcome in most therapy studies in AML, where the influence of patient selection on the results is larger. The median age in our patients was 63 years, which is also higher than in most other studies. Elderly patients had a low CR rate (24% in patients greater than or equal to 70 yr), but remission duration was similar in the different age groups. Patients treated according to "high-dose" protocols had a CR rate of 64%, while only 14% of less aggressively treated patients achieved remission. A better response rate after more aggressive chemotherapy was evident also in elderly patients. CR rate was 81% in patients below 60 yr of age who had no antecedent blood disorder and who had had symptoms for less than 3 months. Other variables with prognostic implications were: cytogenetic subgroup, antecedent hematological disease, and level of serum ferritin. High serum ferritin was associated with short CR duration. Ferritin is produced by the leukemic cells and could be regarded as a marker for leukemic activity.

In vitro culture of peripheral blood and bone marrow cells in patients with sarcoidosis with and without special preparations of Kveim antigen.

Colony-forming cells (CFC) and colony-forming ability in peripheral blood and bone marrow were studied in 22 patients with different stages of sarcoidosis, with or without the addition of different Kveim preparations. The study showed no statistical differences between the colony growth in healthy persons compared to patients with sarcoidosis in stages I and II. The counts in these groups were, however, lower than in patients with sarcoidosis in stage III (P < 0.01). The lowest counts of CFC were found in the highly active cases suffering from fever, joint pains and erythema nodosum, and these counts were also lower than generally found in normal cases. After stimulation with mononuclear cells from healthy controls the number of colonies in the acute stages, however, reached normal values. This suggests either a low autostimulation or a neutralization of an inhibiting factor in the blood. It is suggested that if an inhibiting factor is present it is principally localized to the sarcoid granuloma. A pronounced inhibition of colony growth was seen when the Kveim membrane fraction prepared from sarcoid lymph nodes and spleen, was added to the cell cultures.

CCNU toxicity after an overdose in a patient with Hodgkin's disease. Effects on colony-forming cells (CFU-C) and colony-stimulating activity (CSA).

An overdose of CCNU (600 mg over a 15-d period) was unintentionally ingested by a patient with advanced Hodgkin's disease subjected to combination chemotherapy. A severe bone marrow depression occurred 3 weeks after the start of the CCNU treatment. The nadir of the platelet count was reached after 4 weeks and that of the granulocyte count after 5 weeks. At the nadir of the white blood cell count, colony-forming cells (CFU-C) were found in significantly reduced numbers in the bone marrow, and were not found at all in the peripheral blood; the amount of colony-stimulating activity (CSA) produced by peripheral blood cells was reduced. However, the cells producing CSA recovered earlier than the CFU-C, and the CSA peak value was reached about 1 week before the peak value for CFU-C in the bone marrow. Thus, in vivo CSA-producing cells appeared to be more resistant to CCNU than were CFU-C, and their recovery appeared to be a prerequisite for the recovery of CFU-C and myelopoietic cells.

Myelodysplastic syndromes--a population-based study on transformation and survival.

A retrospective analysis was done on 113 patients (median age 73 years) with myelodysplastic syndromes (MDS), consecutively diagnosed at our center during a 10-year period. Patients with refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) had significantly longer survival than patients with refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML) or refractory anemia with excess blasts in transformation (RAEB-T). Thirty-seven patients (33%) subsequently developed acute myelogenous leukemia (AML). The percentages of AML transformation for the subgroups were: RA: 26%, RARS: 14%, RAEB: 38%, CMML: 25% and RAEB-T: 69%. A total of 9 patients received high-dose chemotherapy, 7 of them already at the time of MDS diagnosis. Six of the RAEB-T patients entered complete and two partial remission. The median age in the group of RAEB-T patients was significantly lower (62 years) than in the other MDS subgroups. It seems that high-dose chemotherapy, at least in RAEB-T, may induce complete remission and improve survival time.

Prognostic value of colony-stimulating and colony-forming cells in peripheral blood in acute non-lymphoblastic leukemia.

Colony-forming cells (CFC) and colony-stimulating activity (CSA) in peripheral blood cells have been studied before and repeatedly during treatment of 30 patients with acute non-lymphoblastic leukemia. WBC obtained after Isopaque-dextran separation were cultured in vitro by a double-layer agar technique. Before treatment 16 patients out of 30 had CSA and 22 out of 29 had CFC; both CSA and CFC were found in 15 patients. In follow-up studies during treatment, CSA was mainly unaffected during the leukopenic phase, while CFC were suppressed. No CFC were found at WBC counts below 900/mm3. This seems to imply that CFC are more sensitive to cytotoxic agents than colony-stimulating cells. Twelve patients entered remission; all of them had CSA and all the 11 who were investigated for CFC had CFC before treatment. Fourteen out of 18 non-responders lacked one or both types of cells. The presence of CSA and CFC in peripheral blood therefore appears to be a sign of favorable prognosis, while the absence of CSA and/or CFC implies lack of response to treatment.

In vitro colony studies in 87 patients with acute nonlymphoblastic leukemia. Prognostic value of colony-stimulating activity and colony-forming cells.

Colony-forming cells (CFU-C) in peripheral blood and bone marrow and colony-stimulating activity (CSA) in mononuclear peripheral white blood cells were studied at diagnosis in 87 patients with acute nonlymphoblastic leukemia (ANLL). Absence of CFU-C in peripheral blood was more frequent in patients who did not enter remission than in those who did, and survival was significantly shorter in CFU-C-negative than in CFU-C-positive patients. No correlation was found between CFU-C in the bone marrow and frequency of remission or survival time. Absence of CSA was significantly more frequent in patients who did not enter remission than in those who did. Only 4 of 28 patients who lacked CSA entered remission. Survival was significantly longer in CSA-positive than in CSA-negative patients. Thus, CSA synthesis in peripheral mononuclear blood cells appears to be a valuable prognostic factor in ANLL.

Outcome of a multicenter treatment program including autologous or allogeneic bone marrow transplantation for de novo acute myeloid leukemia.

The results of an intensive treatment program for patients 16-60 yr of age with de novo acute myeloid leukemia are presented. The patients were given conventional induction treatment with daunorubicin and cytarabine. Patients not entering complete remission (CR) after 1 course of daunorubicin/cytarabine were given 1 course of amsacrine/etoposide/cytarabine. Those entering complete remission received 3 consolidation courses using mitoxantrone, etoposide, amsacrine and cytarabine. One hundred and eighteen patients were enrolled. Complete remission was attained after 1-2 courses in 90 patients (76%). Another 6 patients reached CR after 3-4 induction courses for a total CR rate of 81%. If feasible, patients were offered either allogeneic or unpurged autologous bone marrow transplantation. Twenty-four patients underwent allogeneic bone marrow transplantation; 15 in first remission, 8 in second remission, 1 in early relapse. Thirty patients below 56 yr of age underwent autologous bone marrow transplantation in first remission. The overall probability of survival at 4 yr was 34%, and for patients below 40 yr of age 50%. Leukemia-free survival was 35% for the whole cohort of patients; 52% for patients below 40 yr of age. Patients undergoing allogeneic or autologous bone marrow transplantation in first remission had an overall survival of 86% and 47%, respectively, while the probability of leukemia-free survival in these groups was 87% vs. 40% at 4 yr. The CR rate and long-term results of this intensive treatment program compare favorably with other recent studies using intensive consolidation with allogeneic or autologous bone marrow transplantation or high dose cytarabine.