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Thirty-one patients with a diagnosis of refractory acute myelogenous leukemia received homoharringtonine as their first (15 patients) or second (16 patients) salvage therapy. Homoharringtonine was given as a continuous infusion of 2.5 mg/m2 daily for 15 to 21 days to 13 patients (schedule 1), and of 3.0 mg/m2 daily for 15 days in 18 patients (schedule 2). Overall, one patient achieved complete remission (3%), and three (10%) had a hematologic improvement with normalization of the marrow and peripheral blood picture except for persistent thrombocytopenia. Six patients (19%) demonstrated prolonged myelosuppression, three (23%) on schedule 1 and three (17%) on schedule 2. Cardiovascular complications were minimal consisting of hypotension in one patient (3%) and supraventricular arrhythmias in two patients (6%). Hyperglycemia was observed in 42% of patients and was significant in 10%. The authors conclude that homoharringtonine, at the dose schedule investigated, has definite but low antileukemic efficacy. The low-dose continuous infusion schedule was associated with prolonged myelosuppression but no serious cardiovascular complications. The role of such therapy in myeloproliferative disorders, especially chronic myelogenous leukemia, deserves consideration.

Leukemic blasts from 40 consecutively admitted adults with untreated acute lymphoblastic leukemia (ALL) were examined for myeloid surface antigen expression. Of these, 14 (35%) were reactive with one or more myeloid monoclonal antibodies. Each example of myeloid surface antigen-positive (My+ ALL) met the standard morphologic and cytochemical criteria for ALL. In addition, none of the 13 samples studied for ultrastructural evidence of myeloperoxidase met the criteria for acute myelocytic leukemia (AML). All patient samples reacted with lymphoid monoclonal antibodies: CD10+ (8 patients), CD19+ CD10- (2 patients), T cell+ (2 patients), and T cell+ CD10+ (2 patients). Coexpression of myeloid and lymphoid determinants was established by two-color immunofluorescence studies using flow cytometry in five of five samples analyzed. Cytogenetic abnormalities that have been associated with myeloid and mixed leukemias were common, including t(9;22), 7q-, abnormalities of 11q with or without a translocation, 20q-, and -5. Blasts from seven patients were studied at the molecular level. Immunoglobulin heavy chain gene rearrangements were detected in five of five samples with B cell+ T cell- phenotypes. One sample that was T cell+ CD10+ was germline for the immunoglobulin heavy chain and the T cell receptor gamma- and beta-chain genes. The other patient with T cell+ CD10+ blasts relapsed with AML following allogeneic bone marrow transplantation. The leukemia cells at the time of diagnosis and the cells at relapse demonstrated similar cytogenetics and the same immunoglobulin gene rearrangement, suggesting a clonal relationship. As a group, the My+ ALL patients had a significantly decreased complete remission rate when compared to My- ALL patients. Further studies at the molecular level will be required to determine the significance of karyotype abnormalities in My+ ALL.

We investigated the light and ultrastructural morphology of 37 patients with acute nonlymphocytic leukemia (ANLL) and inv(16)(p13q22) or del (16)(q22) with specific emphasis on the changes in the eosinophils (EOS). All but one of the 37 patients were classified as French-American-British M4 with eosinophilia (FAB M4-E) on the basis of the monocytoid nature of the leukemic cells and the presence of large EOS with interspersed basophilic-staining granules. A median of 92% of the blasts were peroxidase positive, and Auer rods were found in 71% of cases. Only 27% of the cases had sufficient alpha-naphthyl butyrate positivity to confirm the diagnosis of FAB M4, but electron microscopy demonstrated a sufficient monocytic component to support this classification in all cases examined. Electron microscopy also demonstrated nuclear blebs both in the blasts and notably, in the EOS of all cases examined (16 of 16). Nuclear blebs in EOS were found in only 1 of 13 cases of ANLL that showed eosinophilia but lacked abnormalities of chromosome 16. This case was also classified as FAB M4-E. The finding of nuclear blebs in EOS in FAB M4-E suggests that the EOS may be derived from the malignant clone in this leukemia. These blebs are also of diagnostic in value classifying a leukemia as FAB M4-E.

In vitro and in vivo studies were conducted to obtain basic information on the activity of gamma interferon (IFN-gamma) in acute myelogenous leukemia (AML). In a selected case of AML, recombinant IFN-gamma, but not IFN-alpha, induced differentiation of primary leukemic blasts in vitro. Similarly, IFN-gamma inhibited leukemic colony formation in vitro. This contrasted with IFN-alpha which was inactive. In one case of AML (M2), partially purified IFN-gamma given intravenously caused a shift of the WBC profile from immature blasts to maturing myeloid cells and neutrophil granulocytes. Intravenous IFN-gamma treatment of another patient who had AML as a second malignancy resulted in a complete hematologic remission, normalization of marrow granulocyte-macrophage colony-forming cell in vitro growth, and conversion of marrow cytogenetics from 95% hyperdiploid clone with complex abnormalities into 100% diploid. The results indicate a potential use of IFN-gamma in the treatment of selected patients with AML and the possibility of in vitro pretreatment evaluation of these patients' leukemic response to IFNs.

Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.

Forty-one previously untreated patients with a diagnosis of acute myelogenous leukemia (AML) were entered on a study using early intensification followed by a short-term maintenance chemotherapy. Induction and early intensification consisted of three to four cycles of doxorubicin, vincristine, cytosine arabinoside (Ara-C) and prednisone (ADOAP) in escalating dosages. Maintenance therapy used three cycles of Ara-C thioguanine (AT), followed by three cycles of cyclophosphamide and rubidazone with vincristine and prednisone (CROP). Median total duration of therapy was 9 months. The overall complete remission (CR) rate was 73%. Tolerance to chemotherapy and dose escalation were better for patients who received their induction and early intensification in the protected environment. The overall median survival was 75 weeks. Compared to a historical control group treated with long-term maintenance chemotherapy, patients achieving CR on the current study had similar median remission (52 versus 65 weeks; P = 0.3) and survival durations (94 versus 98 weeks). This regimen using early intensification and short-term maintenance chemotherapy did not improve the overall prognosis of this AML population.

The thesis of this paper is that knowledge acquired from historical data collected in a clinical research program may be used for planning future clinical trials and evaluating the effect of treatment. In a breast cancer study comparing adjuvant, treatment with FAC-BCG to control treatment Cox's regression model including number of involved nodes, stage of disease, and menopausal status was used to demonstrate that FAC-BCG patients have superior disease-free survival. A logistic regression model for acute leukemia involving age, cytogenetics, prior hematologic abnormality, temperature, serum creatinine, and hemoglobin was obtained by fitting to 325 previously untreated adult patients who received treatment between March, 1973 and April, 1977. The model was validated by prospective application to 107 patients treated between May, 1977 and December, 1978. Results in this trial will be compared with those in similar patients for the historical control series.

Ftorafur, a possible sustained-release formulation of 5-fluorouracil, was administered to 27 patients with metastatic cancers. The majority of patients had adenocarcinoma, most of which (60%) arose from the gastrointestinal tract. Ftorafur was given i.v. at doses ranging from 1 to 3 g/sq m/day for 5 days, repeated every 2 to 3 weeks. Gastrointestinal (68%) and neurological (17%) toxicities were the most common side effects encountered in this study and became dose limiting at doses greater than 2 g/sq m/day for 5 days. Myelosuppression (7%) was infrequent. Other toxicities included weakness (20%), chills and fever (8%), and phlebitis (1%). Of 24 evaluable patients, 4 (17%) responded (1 complete and 3 partial remissions). Responses were seen in 1 of 8 carcinomas of the lung, 1 of 5 carcinomas of the stomach, 1 of 3 carcinomas of the colon, and 1 of 1 carcinoma of the jejunum. The duration of response ranged from 4 to 58 weeks. The results of this study resemble somewhat those obtained with the laborious 5-day continuous i.v. infusion of 5-fluorouracil. Daily doses of 2 g/sq m for 5 days, repeated every 3 weeks, produced significant antitumor effect and tolerable toxicity.

Logistic regression methods were applied to derive a set of models relating achievement of CR to prognostic characteristics in a group of 300 adult acute leukemia patients treated with cytosine arabinoside, vincristine, and prednisone combined with adriamycin (ADOAP) or rubidazone (ROAP). These models were tested prospectively in an independent group of 107 subsequent patients treated with ADOAP or ROAP therapy, by comparing observed outcomes to predictions of response based on the models. Several models were able to identify subgroups of patients with good, intermediate, and poor prognoses. A model regarded as clinically useful and which provided a good fit to both the population from which it was derived and the test population included the pretreatment factors age, history of an antecedent hematologic disorder, temperature, blood urea nitrogen, hemoglobin, and liver size.

A prospective randomized trial was conducted comparing the addition of iv hyperalimentation (IVH) to Corynebacterium parvum, isophosphamide, and adriamycin (CIA) chemoimmunotherapy in 26 patients with extensive squamous cell lung cancer. Thirteen patients were entered in each treatment arm of the study and IVH was administered before and after the first course of CIA for a total of 31 days. The major dose-limiting toxic effect of CIA was leukopenia. Less myelosuppression was observed for the patients receiving IVH. The difference in the lowest recorded leukocyte and neutrophil counts between the two groups was significant (P = 0.03 and 0.01, respectively). Also, a significant decrease (P = 0.06) in nausea and vomiting associated with chemotherapy administration was found for the IVH gorup. The differences in toxic effects between each group were not maintained over subsequent courses of therapy when both groups received CIA alone. The prevention of the toxic effects of chemotherapy by IVH suggests a means of giving higher chemotherapy doses with the intent of increasing tumor response and patient survival.

The effects of alpha-difluoromethylornithine (DFMO), an ornithine analogue which is an ornithine decarboxylase inhibitor, on the actions of the topoisomerase II-reactive agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide (VP-16) were investigated in 2 murine L1210 leukemia lines and 2 human HL-60 leukemia lines. One of the human lines was resistant to the cytotoxic and DNA cleaving effects of m-AMSA (HL-60/AMSA). In all 4 lines, alpha-DFMO depleted cellular putrescine and spermidine to nondetectable levels. VP-16-induced DNA cleavage (quantified using alkaline elution) was decreased in all lines following alpha-DFMO treatment. The m-AMSA-induced DNA cleavage was decreased in one of the L1210 lines and in the HL-60 line sensitive to m-AMSA; m-AMSA-induced DNA cleavage was increased in the other L1210 line. The low frequency of m-AMSA-induced DNA cleavage produced in HL-60/AMSA was unaffected by alpha-DFMO treatment. Alterations in drug-mediated DNA effects induced by alpha-DFMO could not be uniformly explained by alpha-DFMO-induced alterations in m-AMSA or VP-16 cellular uptake, as indicated by direct measurements of cell-associated drug or results of DNA cleavage assays in nuclei isolated from alpha-DFMO-treated cells. Exogenous putrescine prevented the effects of alpha-DFMO on drug-induced DNA cleavage, substantiating polyamine depletion as the cause of the altered frequency of DNA cleavage. Cytotoxicity assays in 2 of the lines demonstrated that drug-induced reductions in colony-forming ability paralleled drug-induced DNA cleavage. (2R,5R)-6-heptyne-2,5-diamine, a putrescine analogue which is also an ornithine decarboxylase inhibitor, was also used to deplete polyamine levels in HL-60. (2R,5R)-6-heptyne-2,5-diamine was more potent than alpha-DFMO and produced effects on m-AMSA- and VP-16-induced DNA cleavage and cytotoxicity identical to those produced by alpha-DFMO.

We have shown that short-term incubation (45 min) of peripheral blood lymphocytes of normal donors with OKT3 monoclonal antibody (MoAb), directed against T-cell-associated antigen CD3, resulted in an acquisition of lytic activity against fresh leukemic cells. Induction of such antileukemia activity was specific for OKT3, since Leu-1 MoAb (directed against another T cell surface molecule, CD5) did not induce a lytic effect. The OKT3-generated antileukemia effect was displayed against various types of leukemia including chronic myelogenous leukemia and acute myelogenous leukemia of various histological subtypes (M1, M2, M5). We furthermore demonstrated that OKT3 MoAb substantially enhanced leukemia killing by interleukin-2 (IL-2)-activated killer cells obtained from peripheral blood of patients with leukemia. Of most importance was the observation that the combined treatment of effector cells with IL-2 and OKT3 MoAb resulted in the highest levels of lysis of both autologous and allogeneic fresh leukemic cells that have been observed in leukemic patients to date. Of importance was to note that OKT3 treatment was effective in induction of cytotoxic activity also in patients whose effector cells were unresponsive to stimulation with IL-2 alone. All of these observations suggest that IL-2-activated and OKT3-MoAb-treated effector cells may represent the most aggressive population of antileukemia-directed killer cells and may play a significant role in the treatment of human leukemia.

Philadelphia chromosome-positive (Ph1) acute leukemia is a heterogeneous subset of acute leukemia with a poor prognosis. We studied five patients to determine the potential for phenotypic and molecular heterogeneity. Cellular characterization studies included light myeloperoxidase (L-MPO), terminal deoxynucleotidyl transferase (TdT), ultrastructural MPO (U-MPO), and immunophenotyping by flow cytometry using T11, T3, T4, T8, Leu 1, B1, Leu 12, HLA-DR (la), CALLA (J5), OKM1, My4, My7, My8, My9, and My10. DNA was analyzed for rearrangements of the breakpoint cluster region (bcr), immunoglobulin heavy chain, joining region (JH), immunoglobulin kappa light chain constant region (C kappa), and T cell receptor (TcR beta). RNA dot blots were hybridized by using molecular probes for MPO and TdT. We found that four of five cases were acute mixed-lineage leukemia (AMLL). One patient had acute unclassifiable leukemia. Of the four patients classified as having AMLL, three showed myeloid and lymphoid features, with one patient showing myeloid, T cell, and B cell features. The last case showed T cell and B cell features only. In one patient MPO/RNA was positive in spite of insufficient L-MPO or U-MPO to diagnose acute myelogenous leukemia (AML), thereby suggesting significant MPO gene expression before the production of sufficient MPO protein to meet the French-American-British criteria for AML. Three of the five patients showed rearrangement of bcr (cases 1, 2, and 5). Studies of these five patients support the concepts of molecular and phenotypic heterogeneity in Ph1 acute leukemia, demonstrate a high incidence of AMLL in this subset of acute leukemia, and support the use of lineage-associated molecular probes to define lineage at an earlier stage than previously possible.

For the past 34 months, a combination of 5-fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC-BCG) was evaluated as adjuvant treatment in stage II and III breast cancer patients with positive axillary nodes. In the group of 131 patients receiving FAC-BCG, the estimated proportion remaining disease-free at 2 years from surgery was 91% compared to an estimated 69% in a group of 151 historical control patients (p less than .01). This advantage was statistically significant in all subgroups except for patients with primary tumor less than 3 cm and for patients with less than 4 positive nodes. Estimated 2-year survival rates were 9,6% for FAC-BCG patients and 86% for control (p = .02). Treatment was well tolerated. Adjuvant FAC-BCG seems effective in prolonging disease-free interval and early survival in patients with stage II and III breast cancer. Its long term efficacy will require longer follow-ups.

Phase I studies were conducted in 58 adult cancer patients with Baker's Antifol (BAF), a new active-site directed inhibitor of dihydrofolate reductase. Dose escalation ranged from 10 to 250 mg/m2/day X 5 days and courses of treatment were repeated every 2-3 weeks. Biologic effects were observed mostly at doses greater than 100 mg/m2/day X 5 days. The patients developed myelosuppression during 19% of the trials. Other types of toxicity were dermatitis in 12 to 30% and stomatitis in 7 to 38% of the trials. Toxicity was directly related to the impairment of the patient's liver function. Two partial responses (in a patient with adenocarcinoma of the lung and a patient with transitional cell carcinoma of the bladder) occurred. BAF is an active new chemotherapeutic agent which deserves further clinical trials in patients with various malignancies.

The effect of the adenosine deaminase inhibitor, 2'-deoxycoformycin, on cellular nucleotides during therapy with continuous infusion of 9-beta-D-arabinofuranosyladenine (ara-A) has been investigated. In three courses of treatment using increasing doses, the active 5'-triphosphate of ara-A, 9-beta-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP) accumulated in leukemic cells and erythrocytes from a patient treated for acute lymphocytic leukemia in proportion to the dose of ara-A. The cellular ara-ATP concentration increased more than 5-fold after the injection of a single, nontoxic, but pharmacologically active dose of 2'-deoxycoformycin 24 hr after initiation of ara-A infusion. However, this response was associated with a concomitant increase in the cellular deoxyadenosine triphosphate concentrations to levels equal to or greater than those of ara-ATP throughout the three treatment courses studied. Consistent with previous results using cell-free systems, it was demonstrated that a competitive relationship exists between deoxyadenosine triphosphate and ara-ATP for the inhibition of DNA synthesis in cultured human lymphoblastoid cells and that the ratio of the cellular concentrations of these nucleotides could predict the extent of inhibition of DNA synthesis. Application of this rationale to the nucleotides in the leukemic cells of the patient suggested that administration of 2'-deoxycoformycin may create a cellular biochemical milieu that could be antagonistic to the inhibition of DNA synthesis by ara-ATP.

Forty-seven adults with advanced malignant lymphoma (the majority in stage IV) were treated with a combination of cyclophosphamide, hydroxyldaunorubicin (Adriamycin), vincristine (Oncovin), prednisone, and bleomycin (CHOP-Bleo). The complete remission (CR) rate was 66%. The overall response (complete + partial remission) was 92%. The CR rate in patients with diffuse histiocytic lymphoma (DHL) was 69%. Only 3 of the 18 patients with DHL in CR have relapsed; the projected median duration of response was calculated to be greater than 2 yr. In patients with nodular poorly differentiated lymphocytic lymphoma (NPDL), the CR rate was 62%. One of the eight patients with NPDL in CR has relapsed; the projected median duration of complete response will be greater than 4 yr. The median survival for all patients entered in this study has not been reached; however, it was estimated that it will be greater than 3 yr. The survival curves became flat at 70 wk for the patients with DHL and at 1 yr for the patients with NPDL. Major complications during chemotherapy with CHOP-Bleo were myelosuppression and alopecia. Only six severe infections occurred during myelosuppression. No hemorrhagic problems were observed. This study indicates that combination chemotherapy with these agents is effective in increasing the CR rate and survival in patients with diffuse histiocytic lymphoma. In patients with NPDL, further observation will be needed to assess the effect of this combination on survival.

Twenty-eight patients with advanced adenocarcinoma were treated with a combination of thymidine, 5-FU, and PALA. PALA (1 g/m2) was given on the first day, followed on the second day with 30 g of thymidine and 150-300 mg/m2 of 5-FU given simultaneously through two iv sites. Responses were seen in two of 17 patients (12%) with colorectal adenocarcinoma. One response was complete and one was partial. The gastrointestinal tract and CNS were the sites of dose-limiting toxic effects. Myelosuppression was observed only at 5-FU doses of 250 and 300 mg/m2.

Ifosfamide was given in i.v. doses of 600 to 1200 mg/sq m/day for 5 days to 32 cancer patients, refractory to prior therapy, in an attempt to investigate the possibility of reducing toxicity by dose fractionation. Microscopic hematuria occurred in 14% and gross hematuria in only 10% of the patient trials. Azotemia did not occur in any patient on this study. Reversible myelosuppression was comparable to that found by other investigators. Other side effects such as nausea and mental confusion occurred infrequently. Ifosfamide produced antitumor effect in 7 of 27 evaluable patients. This study indicates that the renal and bladder toxicity of ifosfamide can be substantially reduced if the drug is administered in i.v. infusions of 1 to 2 hr daily for 5 days.

Isophosphamide was administered to 27 patients with acute leukemia and to 15 patients with malignant lymphoma refractory to primary therapy. The starting dose of isophosphamide was 1200 mg/m2 administered as a daily continuous infusion x 5 days; the courses of treatment were repeated every 2-3 weeks. Of the 27 patients with acute leukemia, four achieved complete remission, two achieved partial remission, and two achieved hematologic improvement. However, no responses occurred in ten patients with acute myelogenous leukemia (AML). Thus, the response rate was 47% (eight responses among among 17 patients, in patients with acute lymphoblastic leukemia and acute undifferentiated leukemia. Seven of the 15 patients with malignant lymphoma responded. Most responses (five of six patients) occurred in patients with diffuse histiocytic lymphoma. Twenty-one of the 42 patients had received prior therapy with cyclophosphamide and 12 of these patients (two with leukemia and ten with lymphoma) responded, thus suggesting that as in the treatment of L1210 leukemia, isophosphamide is effective for tumors resistant to prior cyclophosphamide therapy. No significant genitourinary toxicity occurred; however, myelosuppression became the dose-limiting toxicity. Isophosphamide is active in malignant lymphomas and acute leukemias (except AML) and may have a role in combination regimens for such diseases.

Vindesine, a newer vinca alkaloid derivative, underwent a phase I clinical evaluation in 68 humans with advanced, refractory malignancies. Patients received single total doses ranging from 2 to 12.5 mg, repeated every 1-2 weeks. Dose-limiting myelosuppressive, gastrointestinal, and neurologic toxic effects were observed at higher doses. They consisted predominantly of neutropenia, constipation leading, on occasion, to paralytic ileus, and peripheral neuropathy. Total doses of 7.5-10 mg (equivalent to 4-5 mg/m2), repeated every 2 weeks, well-tolerated. There were two partial remissions in patients with acute leukemia and prior vincristine therapy, two minor responses in patients with renal cell carcinoma, one minor response in a patient with squamous cell carcinoma of the esophagus, and one minor response in a patient with squamous cell carcinoma of the lung. Vindesine is well-tolerated by man, although it shares some of the toxic manifestations of vinblastine and vincristine. Its efficacy in some patients who were no longer responsive to vincristine therapy suggests a lack of clinical cross-resistance between these compounds.

Tumor antigens and specific tumor immunity have been well-documented in several human malignant diseases [3]. There have also been several studies which have indicated that the degree or type of tumor immunity relates to the prognosis of the tumor-bearing patient [8]. Therefore if a patient’s general immunocompetence is impaired, his tumor immunity is also likely to be impaired and his prognosis will be poor. Several studies have suggested that this is indeed true. Thus, several investigators [2, 7, 8, 11] have found that immunological evaluation of solid tumor and lymphoma patients prior to treatment could identify patients with a good prognosis on the basis of their immunocompetence.

The therapy of acute leukemia has improved rapidly in the last two decades. Using available therapeutic agents, complete clinical and hematological remission can be achieved regularly in children with acute lymphocytic leukemia. The choice of chemotherapeutic agent, management of complications of hemorrhage and infection, and recognition of prognostic factors are important for the induction of a hematological remission. While patients in complete hematological remission are free of evidence of disease they still have residual leukemic cells, but in our present state of knowledge and with available techniques, we are unable to detect these. For this reason it is important to treat patients while in remission. The importance of dosage schedule for remission maintenance chemotherapy is stressed.In patients studied to date, regardless of the treatment used, the disease has recurred eventually. Available therapeutic agents are highly effective and highly selective, but they still fall short of providing ideal control of the disease. The continuing search for new chemotherapeutic agents is aided by the knowledge gained and techniques developed with current agents.