Edward S. Henderson

Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD

BACKGROUND AND METHODS MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkins disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkins disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen. RESULTS Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose. CONCLUSIONS In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkins disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Normal Granulocyte Transfusion Therapy: Treatment of Septicemia Due to Gram-Negative Bacteria

Abstract Ninety-six granulocyte transfusions were given from compatible normal donors to 39 neutropenic patients receiving appropriate antibiotics for documented septicemia due to gram-negative bacteria. A matched group of 37 patients treated concurrently with appropriate antibiotics alone served as a control. Eleven of 37 patients (29.7 per cent) in the control group survived the episode of sepsis. Eighteen of the 39 patients (46.1 per cent) receiving transfusions survived; however, 12 patients receiving four or more consecutive daily granulocyte transfusions from compatible donors had complete recovery (100 per cent). In contrast only five of 19 control patients (26 per cent) surviving long enough to receive four transfusions (more than five days) recovered. These studies indicate that compatible granulocyte transfusions (as defined by absence of recipient leukoagglutinins and lymphocytotoxic antibodies against donor leukocytes) can be effective in the clinical management of septicemia due to gram-negat...

Cardiac ultrastructural changes induced by daunorubicin therapy

To elucidate the mechanisms of the cardiotoxicity induced by daunorubicin (DNR), histologic and ultrastructural studies were made of the hearts of six patients with acute leukemias. Three of these patients had received relatively high total doses (455, 460, and 500 mg/m2) of DNR; one patient had received a relatively low total dose (120 mg/m2) of DNR; two patients who had not been treated with this drug served as controls. Histologic changes observed only in the hearts of the three patients who had received relatively high doses of DNR consisted of scattered foci of damaged, degenerating, and atrophic muscle cells. These changes were more widespread in the patient who had received the highest dose of DNR and developed clinical signs of cardiotoxicity. Alterations of chromatin were observed in 10% of nuclei of cardiac muscle cells in the three patients treated with relatively high doses of DNR. These changes consisted of transformation of variable amounts of chromatin into thick fibers, 160‐200 Å in diameter, intermediate‐sized fibers, 70‐100 Å in diameter, and thin filaments, 30‐40 Å in diameter. These alterations were interpreted as representing various stages of uncoiling and unraveling of chromatin and were considered to be related to the phenomenon of intercalation of DNR into DNA. DNR cardiotoxicity may be related to the inability of non‐dividing cardiac muscle cells to repair DNR‐induced alterations in DNA.

Filtration leukapheresis for granulocyte transfusion therapy. Clinical and laboratory studies.

To study the clinical efficacy of granulocytes obtained by filtration leukapheresis, patients with clinically evident infection and granulocyte counts of smaller than 500 per cubic millimeter were randomly assigned to receive conventional therapy alone or with a granulocyte transfusion obtained from a single donor each day for four days. Five of 19 control patients survived to day 20, and 15 of 17 in the transfused group survived. Comparison of the two populations for variables such as age, disease, and severity and type of infection revealed no other factor that could account for the difference in survival. Outcome was not demonstrated to be related to HL-A match, post-transfusion counts, or presence of leukocyte antibodies. Functional studies of granulocytes obtained by filtration leukapheresis showed only minor differences although appearance was altered. Granulocytes so obtained can be used safely and efficaciously as adjunctive therapy for infection associated with granulocytopenia.

An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).

Autopsy data on 1,206 children and adult patients with acute myelocytic leukemia (AML) (585), chronic granulocytic leukemia (CGL) (204), acute lymphocytic leukemia (ALL) (308), and chronic lymphocytic leukemia (CLL) (109) obtained from 1958 to 1982 were reviewed. This analysis has shown that, whereas the proportion of patients with residual AML at any anatomic site decreased significantly and uniformly over the entire study period, significant corresponding decreases in patients with CGL and ALL occurred only since 1976 and 1978, respectively. No significant corresponding decreases were noted in patients with CLL at any time. Significant decreases were also noted over time in the rates of extramedullary site involvement by AML, CGL, and ALL. Whereas the lymphoreticular organs, kidneys, adrenals, and pituitary were most often involved at autopsy by CLL, the testes, leptomeninges, dura mater, uterus, large bowel, and pancreas were most often involved by ALL. In general, patients with AML and CGL showed the lowest relative rates of involvement of the various organs by leukemia during the 24‐year period. Whereas patients with AML and ALL showed significant decreases in the rates of involvement of nearly all anatomic sites during the most recent study periods, those with CGL and CLL showed corresponding decreases in only a few organ sites. The lower rates of organ involvement in patients with AML and ALL attest to the more aggressive eradication of leukemic cells by therapeutic regimens in these diseases over time. In particular, the significant decrease in the rate of meningeal involvement by ALL during the most recent period is probably attributable to central nervous system prophylaxis.

Selection of Unrelated Compatible Platelet Donors by Lymphocyte HL-A Matching

Abstract Thrombocytopenic patients who are refractory to transfusions of platelets obtained from random donors will respond to platelets from HL-A-identical siblings. The efficacy of using HL-A lymphocyte typing to select unrelated compatible platelet donors, however, has not been well documented. In this study, three patients who were not responding to random donor platelets were transfused with platelets obtained from selected unrelated persons matched for HL-A. The median response in circulating platelets (increment times body-surface area per unit) measured at 20 hours was 11.2, 9.1 and 17.0 (X 103) as compared to 0, 0 and 2.2 (X 103), respectively, to nonmatched platelets. These observations indicate that alloimmunization in multi-transfused patients is primarily due to HL-A antigens and that lymphocyte HL-A typing can be used to select unrelated compatible platelet donors for refractory patients.

Hepatotoxic effects of methotrexate

Hepatotoxicity of methotrexate (MTX) therapy was studied in 22 patients. During intensive MTX therapy, values for SGOT, SGPT, LDH and BSP were 140 μ, 315 μ, 753 μ and 13% with control values of 13.5 μ, 20.5 μ, 379 μ and 4%, respectively. During intermittent therapy these values were 50 μ, 110 μ, 544 μ and 10% with controls of 13 μ, 15 μ, 355 μ and 3%. Other liver function tests remained normal. After cessation of intermittent therapy, recovery occurred in one month. Liver biopsies revealed a chronic portal inflammatory reaction in 7/10. Methotrexate can be used in nonmalignant disorders provided that careful control of its toxic side effects is maintained.

Cerebrospinal fluid perfusion for central nervous system neoplasms

CENTHAL NERVOUS system neoplasms have long defied effective treatment.1-4 The functional anatomy has limited the surgical approach.2,4,5 The unique physiology and microscopic anatomy implied in the concept of a “blood-brain barrier,” limits the entrance of many chemotherapeutic agents from blood to brain+-s and, by so doing, makes systemic chemotherapy inadequate.9 Local arterial perfusion, which is promising in some anatomical sites, does not circumvent the “blood-brain barrier” and is in addition fraught with prohibitive toxicity.10-12 The unique anatomy, physiology, and pharniacology of the central nervous system can, however, be beneficially utilized and their previously frustrating limitations advantageously applied. It has been shown recently that lipid insoluble and highly ionized organic moleculeslx can pass, by diffusion, from cerebrospinal fluid to brain,GJ4Jb while the “bloodbrain barrier” limits movement of such substances in the opposite direction, that is, from brain to blood. Accordingly, a system was devised utilizing cerebrospinal fluid pathways for the continuous and restricted delivery of high concentrations of chemotherapeutic agents from ventricular and spinal fluid to brain.l(;J7 The great disparity in deoxyribonucleic acid (DNA) metabolism between normal brain and malignant tissue should make these tumors an ideal target for chemotherapeutic agents.lx-’O

Gastrointestinal "sterilization" in the treatment of patients with acute leukemia.

In preliminary studies, a combination of gentamicin, vancomycin, and nystatin in conjunction with either sterile or reduced‐bacterial diets consistently resulted in bacterially “sterile” stools and an apparent reduction of infection in granulocytopenic patients receiving myelosuppressive chemotherapy. the ease and economy of the approach recommends it to chemotherapy centers which lack elaborate isolation facilities. Studies are in progress to more precisely compare the relative effectiveness of physical isolation, air filtration, diet, and prophylactic antibiotics in reducing the infectious complication of cancer chemotherapy.

Cytogenetic studies in 77 patients with chronic lymphocytic leukemia: correlations with clinical, immunologic, and phenotypic data.

Cytogenetic analyses by G-banding and/or Q-banding techniques of polyclonal B cell mitogen-stimulated peripheral blood lymphocytes in 77 patients with chronic lymphocytic leukemia were carried out in the present study. Adequate metaphases were obtained in 65 patients (84%). Of 29 patients with abnormal karyotypes, ten (34%) had trisomy 12 as the sole abnormality, eight (28%) had trisomy 12 in combination with other karyotypic changes, and the remaining 11 had various karyotypic changes other than trisomy 12. There was a significant relationship between the abnormal karyotype and disease status, clinical stage, lymphocyte count, bone marrow infiltration pattern, monoclonal IgM gammopathy, and urinary monoclonal-free light chain status. Six of seven patients (87%) with trisomy 12 only had stage 0-11 disease, whereas all eight patients with trisomy 12 with other changes had stage III or IV disease (P less than .02). However, of nine patients with other karyotypic changes without trisomy 12, five had stage 0-II and four had stage III or IV disease. These observations suggest that trisomy 12 may be the primary or the earliest karyotypic change in a majority of aneuploid patients with chronic lymphocytic leukemia, and that other karyotypic changes in addition to trisomy 12 may develop as a result of clonal evolution, dedifferentiation, or therapy. Of nine patients in whom autopsy studies were carried out, four were found to have diffuse histiocytic lymphoma or Richters syndrome (three with trisomy 12 in combination with other chromosome changes and one with normal karyotype). Our findings clearly demonstrate that cytogenetic study may be of value in the clinical and prognostic evaluation of patients with chronic lymphocytic leukemia.