Treatment of acute lymphocytic leukemia by high-dose intravenous methotrexate.

A pharmacokinetic study of methotrexate levels in blood and cerebrospinal fluid was performed in 42 patients who received one or more courses of high-dose methotrexate at 500 mg/sq m infused i.v. over a 24-hr period. Methotrexate level in the lumbar cerebrospinal fluid reached 1.2 x 10(-7) M at 0.5 hr and remained constant at that level for the 1st 24 hr. Similar methotrexate levels were noted in the ventricular fluid obtained through an Ommaya device on three patients with brain tumors treated with high doses of methotrexate. Preliminary clinical results using high-dose methotrexate combined with simultaneous intrathecal methotrexate in 23 children with newly diagnosed acute lymphocytic leukemia indicate that this treatment program is safe to administer and to date appears effective in the prevention of central nervous system leukemia.

Profound radiosensitivity in "leukemic" T-cell lines and T-cell-type acute lymphoblastic leukemia demonstrated by sodium [51Cr]chromate labeling.

Radiation sensitivity was determined by measuring spontaneous release from 51Cr-labeled cells in various lymphoid cell populations. Among six leukemia T-cell lines originating from acute lymphoblastic leukemia, four such lines were found to be highly radiosensitive. In contrast, two of the leukemic T-cell lines and four normal control B-cell lines were not radiosensitive. Thymocytes from six patients and leukemia T-cell blasts from three patients with T-cell leukemia were likewise found to be highly radiosensitive, whereas leukemic blasts from six patients with null-cell (non-T, non-B-cell) acute lymphoblastic leukemia were not radiosensitive. Normal peripheral blood lymphocytes and mitogen-induced normal lymphoblasts were found not to be radiosensitive. The results indicate that measurement of the radiation sensitivity of acute leukemic blasts may have a therapeutic significance in coping with the heterogeneous nature of individual leukemia cases.

Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity.

Twenty-two patients with newly diagnosed nonmetastatic osteosarcoma of the extremity were treated with an adjuvant chemotherapeutic regimen consisting of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin. Fourteen of the 22 patients remain continuously disease free for 65+ to 113+ months, with a median time on study of 70+ months. The 72-month disease-free survival estimate is 64%. Pulmonary metastases occurred in six patients, an isolated stump recurrence was seen in one patient, and one patient had a local recurrence following a limb-salvage procedure. For those patients in whom pulmonary metastases developed, the onset was late in three of six, and the number of metastases was three or fewer in all patients. Two patients with pulmonary metastases and one with a stump recurrence have apparently been salvaged, thus resulting in a 77% 72-month survival. Toxicity observed in patients treated with this regimen was in keeping with previous reports. This chemotherapeutic regimen is effective in the adjuvant therapy of nonmetastatic osteosarcoma of the extremity. It should be incorporated into other adjuvant protocols in an effort to continue to improve the outcome in patients with osteosarcoma.

Determining prognosis in childhood acute lymphoblastic leukemia by phytohemagglutinin (PHA) stimulated lymphocytes.

The cellular immunity of 49 children between the ages of five months and 17 years with acute lymphoblastic leukemia (ALL) in remission was studied in vitro by stimulating the lymphocyte cultures with phytohemagglutinin (PHA). The mitogenic responses of the lymphocytes were followed for seven days in short term tissue culture and the maximum peak days were correlated to the disease-free period. The patients who had the maximum mitogenic response on day five or later had a significantly better prognosis than patients who peaked on day four or earlier.

Chemotherapy of osteosarcoma.

Recent advances in the use of chemotherapy for treatment of osteosarcoma have altered out pessimism in this disease. Results are presented from 3 groups of investigators using different agents as adjuvant chemotherapy following immediately upon amputation of the primary. The Roswell Park Memorial Institute began a regime, immediately after amputation, of adriamycin 30 mg/M2 for 3 doses and given every 4-6 weeks. This study was subsequently expanded in a cooperative group (ALGB) and the results on 20 patients analyzed. At 19 months approximately 75 per cent are free of any pulmonary metastases compared with 10-25 per cent expected from amputation alone. Similar results have been obtained by other Centers using different chemotherapeutic agents. In Boston Children's Hospital high dose Methotrexate with citrovorum factor is used. In 12 of these patients local control of the primary by surgery was obtained and of these only 1 developed pulmonary metastases during an observation time of 23 months. At the M. D. Anderson Hospital multi-drug combinations were used including Cyclophosphamide, Vincristine, L-Phenylalamine Mustard and Adriamycin. They reported a survival rate of 55 per cent (10 out of 18). All of these neoplastic agents have toxic side effects but when carefully used these effects are minimized and the quality of life is quite good. Many questions must be answered by future controlled long term follow-up studies.

Human thymus cells. Excellent responders but poor stimulators in 'One Way' mixed lymphocyte reaction.

Human allogeneic 'one-way' mixed lymphocyte reactions between thymus cells and thymus cells were entirely absent. Of twenty-one mixed lymphocyte reactions between peripheral blood lymphocytes as responding cells and thymus cells as stimulating cells, only eleven had a weak but significant reaction. In contrast, a highly significant response was observed in each of eighteen mixed lymphocyte reactions between thymus cells as responding cells and peripheral blood lymphocytes as stimulating cells and in each of eleven mixed lymphocyte reactions between peripheral blood lymphocytes and peripheral blood lymphocytes. These findings indicate that the thymus cells (T lymphocytes) possess excellent proliferative capacity, with little or no stimulating capacity, while peripheral blood lymphocytes (T and B lymphocytes), on the other hand, are good responders, as well as good stimulators, in the mixed lymphocyte reaction.

Receptors for sheep erythrocytes (E) and erythrocyte-antibody-complement complexes (EAC) on the lymphoblasts of childhood acute lymphocyblastic leukemia.

Two cell-surface markers, rosette formation with sheep erythrocytes (E-rosette) as a T-cell marker and rosette formation with bovine erythrocyte-antibody-complement complex (EAC-rosette) as a B-cell marker were determined on peripheral blood lymphocytes and lymphoblasts from normal and 89 children with acute lymphoblastic leukemia (ALL). In the majority of the patients (12/15 untreated patients and 6/11 patients in relapse), lymphoblasts exhibited neither E- nor EAC-rosette formation. Lymphoblasts from one untreated patient with mediastinal mass displayed E-(50%) and EAC-rosette formation (15%). In 3 of 11 patients in relapse, lymphoblasts displayed an increase in EAC-rosette formation with progressive disease. In the remaining patients with active disease, a small and variable proportion of lymphoblasts expressed E and/or EAC-rosette formation. In 63 patients in remission, percentages of E- and/or EAC-rosette were similar (p greater than 0.05) to those of control. The results indicate a wide heterogeniety with respect to expression of lymphocyte membrane markers in lymphoblasts and in normal lymphocytes in patients with active ALL.

The treatment of primary childhood acute lymphocytic leukemia with intermediate dose methotrexate.

Fifty-four consecutive children with acute lymphocytic leukemia (ALL) were treated from August 1974 until December of 1976 at Rosewell Park Memorial Institute (RPMI) according to a protocol which substituted cranial irradiation with systemic intermediate dose methotrexate (IDM) 500 mg/m2 each 3 weeks for a total of 3 courses immediately following induction. Of 54 patients, 52 went into remission (96%). There were 35 standard risk and 17 increased risk patients according to age and presenting white blood count (WBC). As of September 1979 9 of the 35 standard risk patients had relapsed: (five central nervous system (CNS), three systemic, and one testicular. The overall disease control is comparable to other published methods of therapy involving cranial irradiation but has the added advantage of not exposing these children to the long range side effects currently being observed in children who had previously been treated with prophylactic cranial irradiation.

Human thymus cells: blastogenic response to mitogens, antigens and allogeneic cells.

Over 90 per cent of the thymus cells from each of twenty-six donors were T lymphocytes, identified by E-rosetting and less than 3 per cent of the cells were B lymphocytes identified by EAC-rosetting. With advancing age, the proportion of T lymphocytes decreased while that of B lymphocytes increased. The degree of (3H)thymidine incorporation of thymus cells was inversely proportional to the age of the thymus-cell donor. The PHA or PWM- induced blastogenic response of thymus cells gradually increased with advancing age when the response was expressed as the stimulation index. However, the actual rate of (3H)thymidine incorporation in all three groups was rather similar when cells were cultured with mitogens. The difference in stimulation index was due to the variation in incorporation rate in cultures without stimulants. The PHA response was approximately four-fold higher than that of PWM response. Thymus cell response to allogeneic lyphocytes, on the other hand, had no correlation with the age of thymus donor. The most surprising result in the present study was that the thymus cells from each of ten donors, aged 1-14 years, were incapable of responding to all four different recall antigens. Peripheral blood lymphocytes from nine to ten randomly selected age-matched children responded very well to one or more antigens.

High-dose methotrexate in acute lymphocytic leukemia.

A pharmacokinetic study of methotrexate (MTX) was performed in 60 patients who received high-dose MTX at 500 mg/m2 infused over 24 hours. MTX levels reached 1.2 X 10(-7) M in the cerebrospinal fluid (CSF) within 10 minutes and remained constant at that level for 24 hours. Forty of these 60 patients were children with acute lymphocytic leukemia. In these 40 patients, simultaneous intrathecal MTX was given along with high-dose MTX. The resultant CSF levels (lumbar area) were higher than those obtained with either high-dose MTX alone or simultaneous intrathecal MTX alone. To date, there have been one systemic and one central nervous system relapse in these 40 children, and the treatment program appears safe to administer.

The influence and reliability of neurologic assessment and Karnofsky performance score on prognosis.

The neurologic examination is important in the early diagnosis of brain tumors in children. Only in brain stem gliomas may the neurologic examination be better than computed tomographic scans in determining the progression. However, in general, the traditional neurologic examination has little or no value for prognosis. Reversible, associated features of brain tumors such as seizures or increased intracranial pressure may alter the patient's ability to function neurologically, but may not influence the prognosis regarding the tumor status. The Karnofsky functional status, to a large extent, reflects an adult's ability to work and has prognostic value but is largely inapplicable to children. Thus, a quality-of-life scale for children is needed.

Liposomal methotrexate in the treatment of murine L1210 leukemia.

To assess the therapeutic effectiveness of methotrexate (MTX) when administered in a liposome carrier, mice bearing intracranial L1210 leukemia were tested with liposomal MTX, free MTX, or saline. Single i.p. injections of liposomal MTX at doses of 5 mg/kg and 2.5 mg/kg prolonged survival of mice bearing intracranial L1210 leukemia. The same doses of the free drug did not prolong survival of the tumor-bearing mice. This system may have clinical application not only for MTX, but also other polar anticancer agents in the treatment for central nervous system malignancy.

Intermediate dose methotrexate (IDM) in childhood acute lymphocytic leukemia (ALL).

We employed three courses of intermediate dose Methotrexate (IDM) added onto a standard induction and maintenance program with the concept of both central nervous system (CNS) prophylaxis and simultaneous systemic intensification. Cranial radiation (RT) was not employed as CNS prophylaxis. Fifty of 52 patients (to age 18) achieved complete remission. Time on study now ranges from 22-68 months with a median time of 33 months. We separated the children into standard risk and increased risk. We defined increased risk as a WBC over 30 000/mm3 at presentation and an age of less than two years or greater than 10 years at presentation. There have been 15 relapses on these 50 patients; 11 occurred in increased risk patients (of 22 increased risk patients) and four occurred in standard risk patients (of 28 standard risk patients). There were seven CNS relapses, six systemic relapses, one simultaneous systemic and CNS relapse and one testicular relapse. Toxicity to the IDM was small with the worst problem being mucositis. No leukoencephalopathy occurred. The control of hematological relapse is excellent and the avoidance of potential long-term complications notes is even of greater importance.