Karel A. Dicke

Autologous bone-marrow transplantation in relapsed adult acute leukaemia.

Abstract 24 cases of adult acute leukaemia, of which 21 were evaluable, were treated in irreversible relapse with high-dose piperazinedione and supralethal total-body irradiation (T.B.I.) in conjunction with autologous marrow transplantation (A.B.M.T.). The grafted marrow cells had been collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated on discontinuous albumin gradients in an attempt to separate normal cells from residual leukaemic cells. 11 patients achieved complete remission (C.R.); 7 other patients had signs of engraftment but died before C.R. The median remission duration was 4 months (2-14). 6 of 9 acute myeloblastic leukaemia patients, in whom bone-marrow transplantation was the first treatment of relapse, achieved C.R. 4 of 5 patients with acute lymphoblastic leukaemia, whose bone-marrow cells were collected during first remission, reached C.R. Autologous bone-marrow transplantation is a valuable first treatment for acute myeloblastic leukaemia in relapse and acute lymphoblastic leukaemia in second relapse.

High‐dose combination chemotherapy with autologous bone marrow transplantation in adult solid tumors

In order to determine whether high‐dose combination chemotherapy was active in chemotherapy resistant patients, 19 patients, (9 with small cell bronchogenic carcinoma, 6 with embryonal cell carcinoma, 2 with diffuse histiocytic lymphoma, 1 with Hodgkins disease and 1 with chondrosarcoma), 18 of whom had had extensive prior chemotherapy and failed, received 23 courses of high‐dose chemotherapy with autologous bone marrow infusion (ABMT). Three patients received four courses of cytoxan (2–6 g/m2) and VP‐16 (500–600 mg/m2) and 16 patients received 19 courses of cytoxan and VP‐16 in these doses plus BCNU (300 mg/m2). Activity was observed in 6 of 8 evaluable small cell bronchogenic carcinoma patients (1 complete response (CR), 4 partial responses (PR), 1 < PR), in 6 embryonal cell carcinoma patients (3 CR, 2 PR, 1 < PR), in both patients with diffuse histiocytic lymphoma (1 CR, 1 < PR), in the patient with Hodgkins disease (1 PR); and in the patient with chondrosarcoma (stable). Only 2 patients who had received prior cytoxan and VP‐16 extensively showed resistance to these programs. The median response duration was 11 weeks (range = 4–55+ weeks). Major toxicity consisted of bacterial infections. Two patients died from treatment related causes. Neutrophils recovered to levels of ⩾ 1.5 × 109/liter by days 20–42 (median, day 27) and platelets to levels of ⩾ 100 × 109/liter by days 21–56 (median, day 32) without any delayed BCNU toxicity. High‐dose combination chemotherapy with ABMT causes acceptable toxicity and high response rates of relatively short duration in tumors refractory to conventional chemotherapy.

In vitro agar culture patterns in preleukemia and their clinical significance

Nineteen patients with preleukemia were studied by in vitro agar culture to determine if this method could predict their clinical outcome. As in oligoleukemia, five growth patterns were identified: (1) Category (Cat) I-A with low plating efficiency, normal cluster/colony ratio and normal cell differentiation in the colonies; (2) Cat I-B with high plating efficiency, normal cluster/colony ratio and normal cell differentiation in the colonies; (3) Cat II with low colony and high cluster incidence and normal cell differentiation in the colonies; (4) Cat III-A with growth of excessive number of clusters (3–20 cell size) only, containing predominantly blast cells; and (5) Cat III-B with excessive number of clusters (3–39 cell size) and a few blast cell colonies. Growth patterns II, III-A and III-B are characteristic of acute myeloid leukemia and therefore called leukemic growth patterns. Twelve of 19 patients had a Cat I-A (non-leukemic) growth pattern. Five patients were identified with a leukemic growth pattern (two in Cat II, two in Cat III-A and one in Cat III-B), and two patients with Cat I-B. Survival was significantly longer (P = <0.05) in Cat I-A than in the other categories. Progression to leukemia was more common (67) and faster (median 20 weeks, range 2–32 weeks) in Cat I-B, II, III-A and III-B as compared to Cat I-A (1 of 12 at 40 weeks). Of seven patients who progressed to leukemia, four presented with a leukemic culture pattern. Of the three patients with a non-leukemic culture pattern, two were followed sequentially. In one, change from I-A to III-A occurred 16 weeks in advance and in the other from I-B to III-A simultaneously with leukemic progression. Patients with preleukemic syndrome who, in in vitro culture, reveal leukemic growth patterns, may represent true preleukemia and progress rapidly to overt leukemia.

The treatment of advanced testicular carcinoma with high dose chemotherapy and autologous marrow support

Abstract Thirteen patients with disseminated nonseminomatous germ cell carcinoma, failing to respond to extensive prior chemotherapy including cis -platinum, were treated with high dose chemotherapy. Cyclophosphamide (4.5g/m 2 ) and epipodophyllotoxin (VP-16) (600 mg/m 2 ) were given followed by autologous bone marrow transplantation. In some cases 1,3 bis (β-chloroethyl)- 1 -nitrosourea (BCNU), adriamycin or platinum were also administered. Of 10 patients evaluable for response 9 responded; 4 patients achieved a complete remission and 3 a partial remission. Median response duration was 15 weeks (range 4 to 20+ weeks ). Four patients died from treatment-related infections; 2 of whom entered the program already with fever and 3 of whom died after hematopoietic recovery. Major toxicities were bacterial and fungal infections. In patients treated with cyclophosphamide and VP- 16 only, no fever was seen in 3 out of 9 courses. Granulocyte transfusion was given in only 1 of 9 courses. Neutrophils recovered to greater than 1.5 × 10 9 /liter by day 18–35 (median 23 ) and platelets greater than 100 × 10 9 /liter by day 16 to 42+ (median 21 ). Further experience with high dose cyclophosphamide and VP- 16 followed by autologous bone marrow transplantation is needed to evaluate its value in the management of patients with disseminated nonseminomatous germ cell tumor failing front line conventional chemotherapy.

Subgroups of oligoleukemia as identified by in vitro agar culture.

Abstract Sixty-five patients with a diagnosis of oligoleukemia (myeloid leukemia with 20 cell size with or without colonies consisting predominantly of blast cells. Culture patterns of Cat III-A and III-B resemble those observed in acute myeloid leukemia and therefore are called leukemic culture patterns. Patients in Cat I-A (non-leukemic culture pattern) survive longer (P =

Cyclic neutropenia and T lymphocyte suppression of granulopoiesis: Abrogation of the neutropenic cycles by lithium carbonate

To investigate the mechanisms of cyclic neutropenia, we studied the capacity of a patients T lymphocytes (TLp) to interact with monocyte-macrophages from her normal HLA-identical sibling (MOb) in the elaboration of colony-stimulating activity (CSA). TLp obtained at the time of decreasing neutrophil counts, increased CSA elaboration (p less than 0.056) when incubated at a 1:1 ratio with MOb. Increasing the TLp to MOb ratios to 3:1 or 5:1 progressively decreased CSA. Also, lithium carbonate, which ordinarily prevents concanavalin A activation of suppressor TL, failed to do so, suggesting that preactivated suppressor TL were present in the patient while neutrophil levels were falling. In similar experiments performed while neutrophil levels were rising these activated suppressor TL were absent. These data suggest that some patients with cyclic neutropenia may have a cyclic increase in suppressor TL activity. As predicted by our in vitro experiments, lithium carbonate administration did not abrogate the first neutropenic cycle, but it did mitigate subsequent cycles.

Prostaglandin E1-mediated augmentation of human granulocyte-macrophage progenitor cell growth in vitro

Abstract In vitro clonal growth of granulocyte-macrophage progenitor cells (GM-CFC) is stimulated by colony-stimulating factor(s) (CSF). Monocyte-macrophage-derived CSF elaboration has been demonstrated to be associated with the synthesis and release of prostaglandins of the E series (PGE). In this study, we have demonstrated that PGE 1 treatment of human marrow cells prior to their in vitro culture, significantly augments (approx. two-fold) the GM-CFC growth, and this is achieved by the stimulation of the non-cycling (G 0 or long G 1 ) GM-CFC fraction to enter that of actively proliferating GM-CFC. This phenomenon may provide a physiological means of preventing exhaustion by CSF-stimulated proliferation and differentiation of the actively dividing GM-CFC compartment.

The Use of the Robinson in vitro Agar Culture Assay in Adult Acute Leukemia

Previous in vitro classification of adult acute leukemia incorporating morphology has been complex and difficult to understand. We have devised a simplified classification based solely on leukemic proliferation in vitro. Forty-four patients with adult acute leukemia previously untreated were included in this study and received identical chemotherapy. Three in vitro groups were recognized. The complete remission rate (CR) was 77% in the 13 patients with no leukemic growth in vitro (Group 1), 81% in 16 patients with leukemic cell growth but aggregated of 20 cells or less (Group 2) and only 27% in the 15 patients with aggregates of greater than 20 (Group 3). There was a highly significant difference in complete remission rates between Group 3 and the other 2 groups (p less than 0.01). Linear logistic regression analysis demonstrated the independence of the in vitro growth from other prognostic variables. The cause of death in failures suggested that this system detects resistance to the chemotherapy. Similar multifactorial analysis including in vitro agar culture may help to predict for chemotherapy response in preleukemia and leukemia with a low blast cell infiltrate when cytotoxic therapy is clinically indicated.

Significance of PHA Induced Clonogenic Cells in Chronic Myeloid Leukemia and Early Acute Myeloid Leukemia

A technique for cloning myeloblastic leukemic cells in semi-solid agar, after prior PHA stimulation, was studied in all phases of chronic myeloid leukemia. Phytohemagglutinin responsive cells were found in blast crisis and accelerated phase. In a small number of patients in the benign phase of their disease, colony growth with PHA was detected. A group of patients with early acute leukemia was also examined by this technique. The incidence of PHA colonies appeared to correlate with the progression of the disease. The potential application of this assay for early detection of leukemic clones and possible prediction of the rapidity of progression of the leukemic process is discussed.

The Early Detection of Remission in Acute Myelogenous Leukaemia by in Vitro Cultures

Twenty‐eight cases of acute myeloid leukaemia without normal myeloid colony growth in vitro were serially cultured by an in vitro agar culture method during remission induction therapy. Colony formation frequently returned before morphological evidence of remission. Without early return of colony formation drug induced aplasia was prolonged and fatal. Analysis of the pattern of return of in vitro colony forming cells may be of value in designing the chemotherapy schedule.