Dharmvir S. Verma

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.

Autologous bone marrow transplantation in patients with adult acute leukemia in relapse.

SUMMARY Nine patients with adult acute leukemia were treated in relapse with piperazinedione plus supralethal total body irradiation in conjunction with autologous marrow infusion. Bone marrow cells were collected and stored in first remission. Storage time varied from 3 to 23 months. Before storage, marrow cells were separated using density albumin gradients in order to reduce the number of leukemic cells in the graft. Three patients died before day 14 after transplantation because of complications already present at the time of transplantation. In six patients, hemopoietic recovery started to occur within 14 days after transplantation. In four patients leukemia-free periods were obtained, lasting 60+ days. The three patients with the longest leukemia-free period after transplantation (range 75 to 220+ days) are reported in more detail. One patient is still alive without evidence of leukemia, with full hematological recovery 220+ days after transplantation. Recently progress has been made in increasing rates of remission in adult acute leukemia using combination chemotherapy, but only 25 to 30% of the patients survive for 2 years or longer (1). Allogeneic bone marrow transplantation, using HLA-identical mixed leukocyte culture-negative related donors in combination with chemotherapy and total body irradiation (TBI), has been used as therapy in relapsed leukemia patients. Allogeneic marrow transplantation, however, is limited to only 25% of relapsed leukemia patients because of the low frequency of compatible marrow donors. Autologous bone marrow cells collected in remission may offer an alternative to allogeneic marrow cells for transplantation in relapse. In this paper we report the overall results of nine patients, and more specifically the data of three patients with adult acute leukemia who were treated at the time of relapse with high-dose chemotherapy and TBI, followed by autologous marrow infusion. The marrow cells to be used for transplantation were collected and subsequently stored in first or second remission. The patients were grafted in relapse when chemotherapy alone failed to induce a remission. In order to reduce the number of transplanted leukemia cells in the graft, the bone marrow cell suspensions were fractionated using discontinuous albumin density gradients before storage (2).

High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults

High-dose methylprednisolone (HDMP) was used to treat 18 episodes of severe (grades III and IV) acute graft-versus-host disease (GVHD) that developed after allogeneic bone marrow transplantation in 12 patients with acute leukemia and in 2 with aplastic anemia. Most of the patients showed rapid improvement in GVHD, with complete resolution of the skin and gut manifestations. However, the response of liver disease to the treatment was slow and incomplete. Complications seen were interstitial pneumonia and fungal and viral infections. Seven patients survived for more than two months following the treatment of acute GVHD. Five of these became long-term survivors with a median survival of 22+ months (range 11-38 months); all five long-term survivors developed chronic GVHD and are alive at the time of this report. It appears that HDMP is an effective treatment for severe acute GVHD. However, its true efficacy can only be ascertained in a randomized study comparing high-dose and conventional-dose methylprednisolone.

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 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.