John E. Curtis

Cutaneous and mucosal neoplasms in bone marrow transplant recipients.

Fifty‐six long‐term survivors of bone marrow allografts were followed for a minimum of 40 months after bone marrow transplantation (BMT) to determine the frequency of secondary malignancies. The 56 patients included ten with severe aplastic anemia (SAA), 16 with acute myeloblastic leukemia (AML), 11 with acute lymphoblastic leukemia (ALL), and 19 with chronic myelogenous leukemia (CML). All patients received a preparative regimen combining high‐dose chemotherapy with total body irradiation (TBI). Three patients developed a malignancy of the skin or oral mucosa. Two were diagnosed as squamous cell carcinoma and one as a malignant melanoma. All three patients had chronic graft versus host disease (GvHD) and were treated for prolonged periods with immunosuppressive medications. The lesions of all patients developed in areas involved by chronic GvHD.

Neurologic disorders in patients with small cell lung cancer

In a series of 641 patients with small cell lung cancer, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the cancer. The total number of neurologic disorders was 210, which included brain metastases (75.7%), meningeal carcinomatosis (6.7%), intramedullary metastases (2.4%), epidural metastases (11.0%), hyponatremia producing CNS symptoms (3.3%), and Eaton‐Lambert syndrome (1.0%). The most common signs and symptoms were motor dysfunction and confusion. The overall survival of patients with any neurologic disorder was compared to that of patients without neurologic problems. There was no difference between the survival curves for the first year and a half, but patients without neurologic complications had a greater probability of long‐term survival (log‐rank P = 0.03). There were no statistically significant differences when this comparison was made according to stage of disease. When a neurologic disorder related to cancer occurred, the survival time from the date of that diagnosis was usually short. The neurologic disorder was the immediate cause of death in the majority of cases. In patients who achieved a complete remission, the administration of prophylactic cranial irradiation (PCI) significantly reduced the risk of developing brain metastases as the initial site of the relapse (log‐rank P = 0.0034). After adjustment for performance status and extent of disease, the survival of complete responders treated with and without PCI was not significantly different. We conclude that neurologic complications are a frequent and serious problem in patients with SCLC.

Contributions of Host- and Disease-Related Attributes to the Outcome of Patients with Acute Myelogenous Leukemia

Three sequential trials of treatment for acute myelogenous leukemia (AML) involving 173 patients were analyzed to identify clinical and myeloblast-cell progenitor properties in culture related to outcome. The latter, including self-renewal capacity expressed as plating efficiency (PE2) and drug sensitivity, were determined for a representative group of 45 patients. Despite increasingly intensive remission induction therapy, similar response rates were achieved in the three trials and no increase in the duration of survival was observed. Clinical attributes at presentation by multivariate analyses were not consistently predictable of outcome. Of the blast cell attributes, only PE2 was predictive of duration of survival (p less than 10(-6)). For patients in remission the relapse rate during the first year was 0.63 compared with 0.15 in subsequent years. The percentage marrow myeloblasts at presentation, a measure of disease activity, was significantly higher for the patients having remissions lasting less than one year. These studies demonstrate the importance of disease-related attributes on the outcome of patients with AML.

High-dose cytosine arabinoside in the treatment of acute myelogenous leukemia: contributions to outcome of clinical and laboratory attributes.

High-dose cytosine arabinoside (HDAra-C) has been used for remission induction, and in conventional doses for maintenance in a trial of single-agent therapy in 43 previously untreated patients with acute myelogenous leukemia (AML). Rationale for the trial was provided by the observed decrease in leukemic blast cell self-renewal in culture following exposure to Ara-C. Compared with a previous trial of 57 patients treated with multidrug therapy, single-drug Ara-C was associated with a significantly improved complete remission rate (P = .010), although the survival time was not increased. All patients with low self-renewal responded to HDAra-C in contrast to the previous trial where some patients with this phenotype failed remission induction. The clinical observations are consistent with the view that the antileukemic effect of Ara-C has some specificity for cellular events required for self-renewal of blast cells. Exposure in vivo to Ara-C was associated with an increase in blast stem cell renewal at relapse, indicating that maintenance with other drugs should be tested. The study demonstrates the importance of biological attributes in design and analysis of clinical trials.

Magnetic resonance imaging for monitoring relapse of acute myeloid leukemia

Magnetic resonance provides a non-invasive tool for monitoring normal and leukemic bone marrow. Measurements of the T1 relaxation times are elevated in acute myelogenous leukemia. However, interpatient variability diminishes the usefulness of MR measurements for diagnosing leukemia. In following the time course of individual patients, T1 relaxation time measurements appear to give an early and sensitive indication of leukemic relapse after remission and this may serve a clinical role in the management of leukemia by reducing the regularity of necessary marrow aspirates and biopsies.

Treatment of adults with severe aplastic anemia: Primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation

PURPOSE To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.

Comparison of outcomes and prognostic factors for two groups of patients with acute myeloblastic leukemia

Abstract Outcomes of the “practice” of groups of physicians working over two consecutive time intervals at the Princess Margaret Hospital have been compared. During the first interval (1970–1974), a remission induction regimen of cyclophosphamide, cytosine arabinoside and vincristine was used. During the second (1974–1976), the regimen consisted of adriamycin and cytosine arabinoside. The results of the analysis indicated that although the prognostic factors for the groups of patients differed slightly during the two study periods, the frequency of response to treatment and the survival curves for the two groups did not differ significantly. However, the quality of survival, as assessed by time spent in hospital, was significantly improved in the second interval. The major prognostic factors studied (age, platelet count and percentage of marrow blasts) appeared to be associated mainly with survival times less than the median, and to be predictive for a subgroup of patients with a poor prognosis, unlikely to achieve remission. These studies illustrate the need for ways to identify and salvage such high-risk patients.

A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA‐C) and all‐trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA‐C. In contrast to ARA‐C, paclitaxel dose responses were independent of cell culture method, the growth factors G‐CSF and GM‐CSF, and the ligands all‐trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of paclitaxel and ATRA on the ARA‐C dose responses of OCI/AML‐5: paclitaxel exposure was either before or after ARA‐C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA‐C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA‐C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA‐C. The studies justify trials combining ARA‐C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.

Response to hydrocortisone of blast progenitors in acute myeloblastic leukemia: an aspect of lineage infidelity.

The blast population in acute myeloblastic leukemia (AML) contains cells capable of forming blast-cell colonies in culture. The purpose of this study was to measure the effects of hydrocortisone on this process, using two end-points. First, we measured the effects of increasing concentrations of hydrocortisone on the primary plating efficiency of T-lymphocyte-depleted blast cell preparations from AML peripheral blood. Second, colonies forming in the presence or absence of the hormone were pooled and replated; changes in the plating efficiencies (secondary plating efficiency or PE2) of these suspensions reflected the effect of the hormone on blast progenitor self-renewal. For comparison, we measured the hydrocortisone dose response curves for normal granulopoietic and T-lymphocyte colony-formation. The latter showed little individual variation; T-lymphocyte colony-formation was regularly sensitive to the hormone while granulopoietic colony-formation was resistant. In contrast, wide variations were found in the hydrocortisone dose response curve for blast from 24 patients with AML (FAB 1-6). A significant association was found between successful remission induction and resistance to hydrocortisone in 24 treated patients. The association was maintained when the data was stratified by other risk factors, including PE2 and the presence of blasts bearing immunologically-defined markers of more than one differentiation lineage (lineage infidelity). We propose that sensitivity to hydrocortisone may reflect the passage of blast cells through lymphopoiesis-associated components of differentiation programs. From this point of view, the poor prognosis associated with sensitivity of blast progenitors to hydrocortisone may be similar to the response-failure of patients whose blasts exhibit lineaged infidelity when tested with immunological procedures.

Secondary acute myeloid leukemia 4 years after the diagnosis of hairy cell leukemia: case report and review of the literature

A 49-year-old man diagnosed with hairy cell leukemia (HCL) achieved a complete remission lasting 4 years after treatment with cladrabine and subsequently developed acute myeloid leukemia. Although a wide variety of second malignancies have been noted in HCL with an incidence of 8.7%, acute myeloid leukemia (AML) has been reported only once previously in a splenectomized patient who had been treated with alpha interferon.