Emil J. Freireich

Pulmonary complications of acute leukemia

The lungs of 50 consecutive autopsied cases of acute leukemia were studied and cultures were obtained from 36. Thirty‐one patients had major pulmonary lesions. Most of these were not recognized antemortem. Infection was the most common pulmonary complication. Pulmonary disease was present in 95% of those cases with abnormal chest x‐rays but 59% of the patients with normal chest x‐rays also had pulmonary pathology. Leukemic involvement was identified microscopically in 64% of the lungs. Peribronchial infiltrates were found most frequently. Patients with high levels of circulating abnormal cells had more severe leukemic involvement of the lung. Pulmonary hemorrhage was found in 54% of the lungs and was severe in 12%. The incidence of pulmonary hemorrhage was higher in patients with severe thrombocytopenia. Thirty‐one major and 29 minor pulmonary infections were found in 40 of the patients. Many of these were unrecognized clinically and the offending organism was seldom isolated antemortem. The most frequently identified pathogens were Pseudomonas sp., Candidia sp., and Aspergillus sp.

The effect of chemotherapy on acute leukemia in the human.

Abstract A study has been made of 178 patients with acute leukemia admitted consecutively to the Chemotherapy Service of the National Cancer Institute between Oct. 22, 1953, and Oct. 20, 1958. Response to chemotherapy and survival varied markedly according to the age of the patient and the morphologic type of leukemia. For patients with acute lymphocytic leukemia, both the frequency of hematologic response and survival were better for children (under age 20) than for adults (age 20 and over). For patients with acute myelocytic leukemia, the frequency and extent of response did not vary with age. The response and survival for these patients with myelocytic leukemia was similar to that of adults with lymphocytic leukemia. However, for patients having a complete remission, the median duration of the remissions was significantly longer for patients with myelocytic leukemia, than for adults with lymphocytic leukemia. The survival time for patients who had a response was substantially longer than that for patients who did not. However, if the total time each patient received chemotherapy which resulted in a response was subtracted from the survival time, the resulting survival curves were similar to those for patients who failed to respond to therapy, and similar to the survival pattern reported prior to 1948. Thus the risk of death during periods of active disease has not changed during the past 10 years and the improved survival can be attributed directly to the duration of the hematologic responses resulting from chemotherapy. The duration of hematologic response was directly related to the extent of the response. The response to subsequent courses of therapy was found to be independent of response to the first course of therapy. There was a trend toward shorter survival the higher the white count at the time of diagnosis, but there was no relation between presenting symptoms or time from symptoms to diagnosis and survival. These data document the alterations in the natural history of acute leukemia resulting from currently available chemotherapy and can be useful for comparison with data accumulated in the future when newer forms of therapy are available.

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.

Effectiveness of Platelet Transfusion in Leukemia and Aplastic Anemia

Hemorrhage resulting from thrombocytopenia in patients with acute leukemia and aplastic anemia can be controlled by platelet transfusions. Severe gross hemorrhage was rarely observed when platelet counts were higher than 20,000 per cu. mm. Transfusion of 1 × 1011 platelets produced an average increment of 12–14,000 platelets per cu. mm./square meter (m2) of body surface in acute leukemia. One unit of platelet rich plasma (PRP) contains an average of 1 × 1011 platelets and 4 PRP/m2 twice weekly will maintain the platelets above 20,000 per cu. mm. most of the time. When very large doses of platelets are required in a small volume then platelet concentrates (PC), prepared by centrifuging PRP and removing most of the plasma, are used. PC are 80 to 90 per cent as effective as PRP in elevating the platelet count if prepared from plasma with a pH of 6.8 or less, achieved by the addition of citric acid.

Effect of Storage up to 48 Hours on Response to Transfusions of Platelet Rich Plasma

The effect of in vitro storage of platelet rich plasma (PRP) on the circulating platelet count following platelet transfusion was evaluated in patients with thrombocytopenia and acute leukemia. PRP was obtained by plasmapheresis using ACD anticoagulant. There was little or no decline in response to PRP up to seven hours after donation whether kept at room temperature or at 4 C. In order to study the effect of storage at 4 C. for 24 and 48 hours, a protocol was designed which limited donor‐patient variables. PRP stored 24 and 48 hours was 62 per cent and 37 per cent, respectively, as effective as fresh PRP in elevating the platelet count in the recipient one hour after transfusion.

The role of vincristine in the treatment of childhood acute leukemia

In a study of 117 patients under the age of 20 with acute leukemia, vincristine (VCR), at 2 mg. per square meter body surface per week, produced complete remissions in 55 per cent and partial remissions in 15 per cent. The drug also induced second remissions. Patients entering complete remission with VCR were randomly allocated to maintenance therapy with VCR or placebo. The median duration of remission was short: 9 weeks for VCR compared with 6 weeks for placebo. The probability of serious neurological toxicity computed according to the time of exposure to VCR, based on the supposition that VCR was not used for maintenance therapy, indicated that the minimal theoretical risk of toxicity for the highest complete remission rate occurred at 4 weeks (38 per cent remissions with 5 per cent toxicity). At 6 weeks, the corresponding probabilities were 54 and 16 per cent.

Clinical trials of hydroxyurea in patients with cancer and leukemia

Hydroxyurea (HU) was studied in 53 patients with malignant disease. Toxicity at the tolerated dose of 25 to 50 mg. per kilogram (0.75 to 1.5 Gm. per square meter) was mainly myelosuppression and was rapidly reversible upon drug withdrawal. HU or its metabolites interfere with normal as well as leukemic hemopoietic cells. HU can produce beneficial effects in chronic myelogenous leukemia (CML) as manifested by a fall in white blood count, decrease in hepatosplenomegaly, improvement in anemia and M/E ratio. In patients with acute leukemia, HU regularly causes a decrease in leukemiG cells, but rarely induces remission. No significant antitumor activity was seen in the 13 patients with nonleukemic neoplasms. From this study, it is suggested that the drug has potential application in the treatment of C M L and for the rapid lowering of the high white blood cell count of patients with blastic crisis and acute leukemia. Studies pertaining to the made of action of the drug are briefly reviewed.

Complement‐Fixing Platelet Iso‐Antibodies in Serum of Transfused Persons. Correlation of Antibodies with Platelet Survival in Thrombocytopenic Patients

Sera from 172 patients who had received an average of 34 transfusions per patient were assayed for platelet antibodies using a complement fixation technic. Fifteen patients formed a total of 31 antibodies. Eighteen of these were identified as reacting with six specific platelet antigens which were present in from 3 to 49 per cent of the general population. The antigens are common to leukocytes, but not erythrocytes, and are genetically determined. No antibodies were found in serum from 55 non‐transfused persons. The probability of antibody formation increased with repeated antigen exposure. Stored whole blood was at least as effective as platelet concentrates in provoking antibodies. There was a significant relationship between the presence of complement fixing platelet antibodies and the occurrence of “fever‐chill” transfusion reactions. In three patients it was possible to correlate the efficacy of platelet transfusion therapy with the antigen content of infused platelets.

Repeated Leukapheresis of Patients with Chronic Myelocytic Leukemia

The technic of plasmapheresis has been employed repeatedly to obtain large numbers of granulocytes from patients with chronic myelocytic leukemia. Up to 20 liters of blood from a single donor could be processed by centrifugation in one week without changes in the patients clinical condition or his blood proteins as long as the plasma and red cells were both returned. The major limiting factor was the chronic removal of small amounts of red cells with each unit, resulting in decrease in hemoglobin level with intensive and prolonged periods of plasmapheresis. Removal of granulocytes at rates up to 3 × 1011 per day produced little consistent decrease in peripheral white count unless it was continued for a week or more. Plasmapheresis is a safe and relatively simple technic for the collection of large numbers of leukocytes from donors with chronic myelocytic leukemia.

Disseminated histiocytosis associated with atypical lymphoid cells (lymphohistiocytosis)

Biopsy of a cervical lymph node from a 3 1/2‐year‐old Caucasian boy originally was diagnosed as malignant lymphoma, lymphocytic type. Following therapy with radiation and prednisone, the patient had transient pancytopenia but was free of apparent disease for the subsequent 15 months. At age 5 he presented with fever, induration and congestion of the lower abdomen and scrotum, splenomegaly, abnormal liver function, hepatomegaly, lymphadenopathy and progressive pancytopenia. Biopsies of axillary and abdominal adipose tissue, cervical and axillary lymph nodes, liver and bone marrow were suggestive of, but not diagnostic of, malignant lymphoma. Despite therapy with prednisone, cyclophosphamide, and vincristine, the patient had continued fever and progressive hepatosplenomegaly and expired on the sixty‐first hospital day. At autopsy there was no evidence of lymphocytic lymphoma but there was disseminated histiocytosis involving liver, spleen, bone marrow, lymph nodes, diaphragm and abdominal panniculus. In retrospect, occasional similar histiocytes were noted in lymph node sections from 2 years previously. The authors interpret this case as representative of disseminated lymphohistiocytosis, an apparently familial disease with distinctive clinicopathologic features.