Harold Glucksberg

Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.

Sixty-one evaluable patients, 19 with advanced aplastic anemia and 42 with end stage hematological malignancies, were conditioned for marrow grafting with total body irradiation or cyclophosphamide, or a combination of both. Marrow graft donors were siblings matched at the HL-A region and nonreactive in mixed leukocyte culture. All patients received methotrexate postgrafting to modify anticipated graft-versus-host disease (GVHD). Forty-three of the 61 patients developed clinically recognizable GVHD. In seven GVHD was limited to the skin. In the remaining patients, skin involvement was more severe and was followed by gastrointestinal involvement manifested by anorexia, nausea, diarrhea, abdominal pain, and malabsorption and/or liver involvement manifested by hepatomegaly, rises in serum glutamic oxaloacetic acid transaminase, and bilirubin. The severity of GVHD showed no correlation with the underlying disease, the conditioning regimen, or the day of onset after grafting. Fourteen of 25 patients without GVHD or with only skin involvement are alive. By contrast, only 5 of 36 with severe GVHD are alive. Twenty-six of the 36 patients with severe GVHD succumbed to infection, whereas only 4 of 25 without GVHD or with only skin involvement did so. The results show that despite histocompatibility matching and methotrexate therapy, GVHD remains a serious and often fatal complication of marrow transplantation.

INTERSTITIAL PNEUMONIA AND CYTOMEGALOVIRUS INFECTION AS COMPLICATIONS OF HUMAN MARROW TRANSPLANTATION1

SUMMARY A retrospective analysis of interstitial pneumonia and cytomegalovirus infection (CMV) was carried out on a group of 50 patients undergoing marrow transplantation for hematological malignancy or aplastic anemia. Interstitial pneumonia was a serious complication of transplantation, occurring in the first 4 months following marrow engraftment in 20 patients with a fatal outcome in 14 cases. In nine patients with interstitial pneumonia there was histological, cultural, or serological evidence of infection with CMV. No other pathogen was clearly associated with any of the fatal pneumonias. Review of available data indicated a minimum of 31% of patients achieving a functional transplant showed evidence of an active CMV infection. These data also suggested that patients with poor or absent serological responses to CMV tended to develop disseminated infection with fatal pneumonia while those with marked rises in antibody titers to CMV showed either no clinical symptoms attributable to CMV or developed only transient pneumonia. A prospective study is required to confirm this observation.

Disappearance of pH1-Positive Cells in Four Patients with Chronic Granulocytic Leukemia after Chemotherapy, Irradiation and Marrow Transplantation from an Identical Twin

Four patients (21, 41, 13 and 38 years of age) with a history of chronic granulocytic leukemia for 12, 10, 11, and 106 months, respectively, were treated with dimethyl busulfan, cyclophosphamide, 920 rads of total-body irradiation and intravenous marrow infusion from normal, genetically identical twins. Serial chromosome analyses were performed on marrow aspirates cultured without mitotic stimulants. No Ph1-positive cells were detected in the marrows from the normal twins, whereas just before therapy, all 100 metaphases examined from each patient were Ph1-positive. Chromosome analyses were performed three to five times per patient after transplantation, and not a single Ph1-positive cell was detected. The patients remain hematologically normal 22, 23, 26 and 31 months after transplantation. The results show that the Ph1-positive clone can be eradicated by vigorous therapy and that the marrow in chronic granulocytic leukemia can be repopulated by stem cells from normal twins.

High-dose combination chemotherapy for acute nonlymphoblastic leukemia in adults.

One hundred thirty‐nine consecutive unselected adults with acute nonlymphoblastic leukemia were treated with a high‐dose chemotherapeutic remission‐induction regimen consisting of daunomycin (70 mg/m2 IV on days 1, 2, 3), cytosine arabinoside (100 mg/m2 IV every 12 hours), 6‐thioguanine (100 mg/m2 orally every 12 hours), prednisone (40 mg/m2 daily), all given on days 1 through 7, and vincristine (1 mg/m2 IV on days 1 and 7). Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and prophylactic platelet transfusions. The complete remission (CR) rate was 60%. The median number of days to CR was 30. Fifty‐eight of 77 (75%) patients under age 50 and 26 of 62 (42%) patients over age 50 attained CR. Despite the use of a relatively large dose of daunomycin and monthly maintenance chemotherapy, the median remission duration was only 39 weeks and the median survival 64 weeks. Most patients who failed to achieve CR died early—77% of deaths occurred within the first six weeks. Infections accounted for the increased mortality in patients over age 50. Thirty‐seven percent of patients over age 50 died of infections whereas only 10% under age 50 did so (P < 0.001). Seven percent of the patients died of fungal infection during attempted remission induction. The incidence of resistance of the leukemia to the remission‐induction regimen was low (8%).

Cure of Hematologic Neoplasia with Transplantation of Marrow from Identical Twins

IN 1974, we reported1 on 16 patients with refractory hematologic neoplasia who were treated with high-dose cyclophosphamide, supralethal total-body irradiation, bone-marrow transplantation from a n...

Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes. A southwest oncology group study

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L‐PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42‐month median and 30‐month minimum follow‐up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L‐PAM (P = 0.002). Disease‐free survival times were significantly longer with CMFVP than with L‐PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1–3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre‐ and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L‐PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L‐PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L‐PAM in decreasing recurrences and increasing survival in both pre‐ and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

Intensification therapy for acute nonlymphoblastic leukemia in adults

Thirty‐nine adults with acute nonlymphoblastic leukemia (ANL) in complete remission (CR) for six months were considered for intensification therapy. All patients had received a high dose chemotherapeutic remission‐induction regimen consisting of daunorubicin, cytosine arabinoside, 6‐thioguanine, prednisone, and vincristine, followed by one consolidation course of the same drugs at reduced doses and then monthly maintenance course of low‐dose chemotherapy. The intensification therapy consisted of the same intensive chemotherapy regimen utilized for remission induction in place of the sixth and 12th monthly courses of postremission induction chemotherapy. Twenty‐three of the 39 patients received intensification therapy, whereas 16 patients refused or were not offered such therapy for medical reasons and, therefore, received only monthly therapy. The median remission duration of the 23 patients who received intensification therapy was 157 weeks, and 9 remain in continuous first remission at 176–285 weeks. The remission duration of the 16 patients who did not receive intensification therapy was 73 weeks (P = 0.03). Kaplan‐Meier estimates of remission duration and survival from time of remission computed by including the patients who either relapsed or received bone marrow transplantation before the time of intensification (6 months) revealed a median remission duration and survival of 100 and 172 weeks for patients receiving intensification compared to 37 and 72 weeks, respectively, for patients not receiving intensification therapy. Since results in patients not receiving intensification therapy are consistent with our previous results in patients receiving the same induction and consolidation regimens without intensification, this nonrandomized study suggests that intensification therapy prolongs remission duration and survival in adults with ANL. Cancer 52:198‐205, 1983.

Adjuvant therapy of breast cancer: The Southwest Oncology Group experience

SummaryThe Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CVFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) to two years of intermittent L-phenylalanine mustard (L-PAM) in women with operable breast cancer with histologically positive axillary lymph nodes. In fully and partially evaluable patients with a 68-month median follow-up, treatment failures have occurred in 27% of 172 receiving CMFVP and 47% of 186 women given L-PAM (p = 0.002). The advantage for women receiving CMFVP was seen for all subsets regardless of menopausal status except among women who were premenopausal and had 1–3 positive nodes. Based on this study, a second study was implemented using both the estrogenreceptor (ER) content of the primary tumor and axillary nodal status to select therapy.