Axel R. Zander

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.

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.

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.

Antibody-dependent cell-mediated cytotoxicity in human cancer: characterization of patient leukocyte activity and treatment effects.

Antibody‐dependent cell‐mediated cytotoxicity (ADCC), mediated by peripheral blood Hypaque‐Ficoll separated mononuclear cells, was studied in humans using chicken erythrocytes (HRBC) incubated in a 1:1200 dilution of rabbit anti‐CRBC and human B erythrocytes (HRBC) incubated in a 1:20 dilution of isoantibody. At the optimal target effector ratio of 3:1, ADCC to both CRBC and HRBC was significantly higher than normal in 27 lung cancer, 18 malignant melanoma, and seven colon cancer patients, but not in 20 breast cancer patients. Chemotherapy (single‐agent or combination) in 12 patients did not affect ADCC in vitro but significantly suppressed ADCC to both targets after only four or five days of therapy in vivo (ADCC to CRBC, 47.4 to 24.1% lysis: ADCC to HRBC, 48.1 to 16.3% lysis). Immunotherapy with intravenous (IV) corynebacterium parvum or IV methanol extraction residue of BCG (MER) boosted ADCC to both targets within four to seven days of the first dose. It was found that ADCC to HRBC but not to CRBC was completely absent in three cases of active hairy cell leukemia but was present in two cases in remission. The ADCC to HRBC showed an age‐dependent increase in both the 51 normal subject and the cancer patients. This was not observed for ADCC to CRBC. The ADCC to CRBC was mediated mainly by an Fc‐receptor‐positive, nonadherent, small lymphocyte, and ADCC to HRBC was mediated entirely by an adherent monocyte. The ADCC did not correlate significantly with the H3 thymidine incorporation of peripheral blood mononuclear cells, cultured without stimulation for either one or seven days. It also did not correlate with the number of residual granulocytes in the mononuclear cell suspensions. Measurement of ADCC is a useful method of characterizing host defense in malignant disease and its modification by therapy.

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 mechanism of lithium carbonate-induced augmentation of colony-stimulating activity elaboration in man☆

Lithium carbonate (Li) has been reported to elevate granulocyte counts in patients with certain neutropenic disorders and to improve chemotherapy-induced granulocytopenia. To investigate the mechanisms involved in the increase in myelopoiesis, the effect of Li on monocytemacrophage (M phi)- and T-lymphocyte (TL)-derived colony-stimulating activity (CSA) were studied in vitro. Li induced a dose-related increase in both M phi- and TL-derived CSA over that in non-Li-stimulated cell populations. However, the increase was significant (p less than 0.007) only at a higher concentration of Li (2 mEq/l). The results of co-incubating TL with M phi with or without Li indicated that Li significantly enhanced synergistic CSA production by the two cell populations (p less than 0.02). We further demonstrated the presence of a larger proportion of M phi with TL rosettes in the presence of Li (62%) than in its absence (21%). Further experiments with concanavalin A (Con-A)-inducible suppressor TL suggested that Li effectively blocks the suppressor TL-mediated suppression of CSA. These data suggest that Li enhances M phi and TL interaction which results in an augmented CSA elaboration. Further, Li would be more effective in those neutropenic disorders associated with enhanced suppressor TL activity. For an optimal effect, however, Li would require appropriately functioning M phi and non-suppressor subsets of TL and an intact stem cell pool.

The kinetics of colony-stimulating activity elaboration from human bone marrow cells by immunoadjuvants: Interactions between light density adherent and nonadherent cells in vitro☆

To examine the myelopoietic activity of immunoadjuvants like Bacillus Calmette Guerin (BCG), methanol extraction residue of BCG (MER), Corynebacterium parvum and Pyran, we performed experiments to delineate their action on human marrow cells. Whole light-density (<1.077 g/ml) cells (LD) (2 × 106/ml and 2 ml/dish), adherent (Ad) cells, and nonadherent (N-Ad) cells alone (derived from 4 × 106 LD cells/dish) from human marrow were incubated with and without the above agents. The conditioned media (CM) were harvested at 24, 72, 96 and 168 h and colony-stimulating activity (CSA) assayed against light-density nonadherent human marrow cells (0.5 × 105or 1.0 × 105 per dish). Maximum CSA elaboration was shown to occur after 72 or 96 of incubation, and an invariable drop in the activity was noted after an incubation of 168 h. The optimal concentrations elaborating maximum CSA for BCG, MER and C. parvum were 1000, 100 and 10 μg/ml, respectively. The CM prepared with higher concentrations were less active. Pyran-produced CM were found to be inactive for CSA. The CSA elaborated from LD cells was always more than additive to that from Ad and N-Ad cells when incubated separately. However, when Ad and N-Ad cells were incubated together (ratio 1:3), the CSA in CM was as potent as from LD cells. Immunoadjuvants themselves had no colony-stimulating effect on N-Ad target cells in the presence of CSA source. On the other hand, they inhibited colony growth at higher concentrations. This inhibition seems to be due partly to the products of the cycloxigenase pathway of arachidonic acid metabolism.

Myelopoietic Modulation by Lithium: in vitro Experiments on its Mechanisms of Action in Man

Various reports have described consistent elevation of granulocytes accompanying lithium administratioin in psychiatric patients (Mayfield and Brown, 1966; O’Connell, 1970; Shopsin et al., 1971). in 1975 Gupta et al. reported that lithium increased the leukocyte count in patients with Felty’s syndrome. They also documented increase in colony stimulating activity (CSA) active against murine bone marrow cells in the urine of these patients (Gupta et al., 1976). Recently, several authors have reported that lithium, when administered to patients with various malignancies, may ameliorate chemotherapy induced myelosuppression (Catane et al., 1976; Greco et al., 1976; Stein et al., 1977; Tisman, 1974; Tisman and Wu, 1977) and reduce the duration of granulocytopenia induced by chemotherapy in acute myeloid leukemia (Charron et al., 1977). Lithium has also been used to elevate leukocytes, platelets and hemoglobin levels in aplastic anemia with some success (Barrett et al., 1977).