Emil J. Freireich

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

Doxorubicin (Adriamycin) was administered by continuous infusion to reduce peak plasma levels and thus lessen cardiac toxicity. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electronmicroscopy. Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control patients treated by standard intravenous injection. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. The median cumulative dose for those receiving continuous infusion was 600 mg/m2 body surface area (range, 360 to 1500 mg/m2) compared with 465 mg/m2 (range 290 to 680 mg/m2) in the control group (p = 0.002). Fourteen of the 30 patients in the control group showed severe morphologic changes in the biopsy specimens, precluding further doxorubicin administration, as compared with two of 21 patients receiving the drug by continuous infusion (p less than 0.02). The mean pathologic score for the infusion group, 0.9, was lower than the mean for the control group, 1.6 (p = 0.004). Antitumor activity was not compromised. Decreasing peak plasma levels of doxorubicin by continuous infusion reduces cardiotoxicity.

The prognosis of patients with cancer is largely determined by the specific histological diagnosis, tumor mass stage, and host performance status. The management of neoplastic disease with the currently available treatment armamentarium may be further advanced if individual patients' risk factors could be better defined. Some of the determinants of tumor response seem to be expressed at the cellular level in terms of degree of tumor cell differentiation, growth kinetics, and hormone receptor expression, which are not readily appreciated by descriptive morphology. Quantitative cytology in the form of flow cytometry has greatly advanced the objective elucidation of tumor cell heterogeneity by using probes that discriminate tumor and normal cells and assess differentiative as well as proliferative tumor cell properties. Abnormal nuclear DNA content is a conclusive marker of malignancy and is found with increasing frequency in leukemia (23% among 793 patients), in lymphoma (53% among 360 patients), and in myeloma (76% among 177 patients), as well as in solid tumors (75% among 3611 patients), for an overall incidence of 67% in 4941 patients. The degree of DNA content abnormality varies according to disease type, with a predominant excess of 10 to 20% in the hematological cancers, whereas ploidy levels in solid-tissue neoplasms span the entire range from almost haploid to hyperoctaploid abnormalities, with near-triploid mean and median DNA content values. The proportion of cells in the S phase of the cell cycle increases with increasing DNA excess in a number of different solid tumors and in acute leukemia. This cytokinetic parameter permits discrimination of low- and high-grade malignant lymphomas. Several reports demonstrate increasing morphological immaturity to be associated with increasing DNA content abnormality and increasing S percentage, all of which adversely affect prognosis. Among phenotypic tumor cell markers, surface membrane antigens have been extensively studied in lymphoid and myeloid neoplasms by the use of hybridoma-generated monoclonal antibodies, which have recently also found in vitro and in vivo therapeutic application. Cellular RNA content is useful for the objective discrimination of acute leukemias and of multiple myeloma. Newer applications of flow cytometry concern studies in the areas of cytoenzymology and cellular pharmacology. Current research is dedicated to the identification of neoplastic marker probes for DNA-diploid disease ( e.g. , nucleolar antigen) and additional phenotypic ( e.g. , hormone receptors) and cytokinetic ( e.g. , cycle traverse rate, growth fraction) parameters. From a patient management perspective, a role for flow cytometry is emerging as a tool for diagnosis of cancer (abnormal DNA content), specific histopathological diagnosis (RNA for hematological cancers; surface markers for lymphoid and myeloid neoplasms), prognosis (adverse impact of aneuploidy and high S percentage), and treatment (cytokinetically oriented, monoclonal antibodies, drug pharmacology). The pace of past progress justifies the hope that cytometry may soon provide “fingerprinttype” information of an individual patient's tumor which, if proven prognostically relevant, may provide the basis for treatment selection in the future.

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.