Int. .I. Radiation Oncology Bid. Phys., 1976, Vol. 1, pp. 301-304. Pcrgmmn Press.
Printed in the U.S.A.
NEUTROPENIA AND INFECTION FOLLOWING CANCER CHEMOTHERAPYt GERALD P. BODEY, M.D., VICTORIO RODRIGUEZ, M.D., KENNETH B. MCCREDIE, M.D. and EMIL J. FREIREICH, M.D. Department of Developmental Therapeutics, The University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston, TX 77025,U.S.A. Chemotherapy, Acute leukemia, Neutropenia, Systemic candidiasi~, Antibiotic therapy. Many of the infections which occur in cancer patients are caused by impairment of host defense mechanisms resulting from the malignancy or its therapy. Cancer chemotherapy frequently is administered in short courses at several week intervals. Recovery from the immunosuppressive effects of intensive short courses of chemotherapy usually is quite prompt, whereas the onset of myelosuppressive toxicity usually is more gradual and recovery requires a longer period of time.“” For chemotherapeutic agents and combinations with myelosuppressive toxicity, the interval between treatment courses is often dictated by the time required for recovery from this toxicity. Most of the infectious complications associated with chemotherapy occur during this period of myelosuppression. A study in patients with acute leukemia demonstrated the important relationship between the frequency of infection and the level of circulating neutrophils.3 The per cent of days spent with infection was determined in 54 patients who were followed from the onset of their disease until death; this was related to the neutrophil count (Fig. 1). Not only was the frequency of infection much higher at low neutrophil levels, but the propoi-tion of severe infection (major organ or disseminated infection) was higher. Patients with neutropenia are unable to produce an adequate inflammatory response at sites of infection.13 Consequently, infection disseminates widely and rapidly in these tThis work was supported in part by Grants CA 10042 and CA 05831 from the National Cancer
100
1
Fig. 1. Relation between neutrophil count and infection in patients with acute leukemia. From, Bodey, G.P., Rodriguez, V., Whitecar, J.P.:9 Courtesy of Excerpta Medica Foundation. patients. An autopsy study of pneumonia in 40 children who died of cancer illustrates this problem.5 None of the 18 children with neutrophil counts above lOOO/mm’developed septicemia in association with pneumonia, whereas, 64% of the 22 children with neutrophil counts less than 1000/mm3 developed septicemia. A majority of the episodes of septicemia at our institution occur in patients with neutropenia. In a study of 67 episodes of Pseudomonas septicemia, the neutrophil counts were less than 1000/mm3in 81% of the Institute, National Institutes of Health, U.S.P.H.S., Bethesda, MD 20014, U.S.A.
301
Radiation Oncology 0 Biology ??Physics
302
patients; neutrophil counts were less than 100/mm3 in 36% of patients.16 Similarly, in a study of 152 episodes of Klebsiella septicemia, neutrophil counts were less than lOO/mm” in 50% of the patients.15 Recovery from most severe infections is related to the patients’ ability to respond with an increased production of neutrophils (Fig. 2).
0 lnitld
omnucocrn CaJw-‘loo Chnage-
Nme
400 MI
‘looo Rix
‘loo0
mu
Fig. 2. Fatality rate from severe infection related to neutrophil count in patients with acute leukemia. From, Bodey, G.P., Rodriguez, V., Whitecar, J.P.? Courtesy of Excerpta Me&a Foundation. The effectiveness of some antibiotics in neutropenic patients is related to the patient’s ability to respond to infection with an increased production of neutrophils. The broad spectrum aminoglycoside antibiotic, gentamitin sulfate, is an example. In a study of cancer patients, 63 patients with infections which were caused by a single species of aerobic gram negative bacillus received gentamicin sulfate.’ During 32 episodes, the patients had persistent neutropenia or their neutrophil count decreased. The response rate for this group of patients was only 31%. During 31 episodes, the patients maintained an adequate neutrophil count. The response rate among this group of patients was 74%: Adequate serum activity has been demonstrated in neutropenic patients who failed to respond to gentamicin sulfate therapy. Serum specimens have been obtained from patients before and during infusions of the antibiotic, and two-fold serial dilutions have been tested in vitro against the patients’ organisms. These
Vol. 1. No. 3-4
organisms have been inhibited by 1:4 or greater dilutions of the serum. In vitro sensitivity tests indicated that the organisms did not develop resistance to gentamicin sulfate during therapy. None of these neutropenic patients had localized abscesses where poor perfusion might have been responsible for failure. Furthermore, a’ S&150% increase in the dose of drug did not improve the results. Unlike the’ aminoglycosides, penicillins have been very effective even in neutropenic patients. Methicillm caused a prompt reduction in the number of fatal staphylococcal infections in these patients.’ A recent important addition to this family of antibiotics is carbenicihin. Thus drug has extended the spectrum of the penicillins to include Pseudomonas aeruginosa, indole positive Proteus sp., and some Enterobacter sp.” The drug has been used in the treatment of Pseudomonas infections in cancer patients.” The cure rate was 76% among the 29 patients whose neutrophil count fell during the fhst week of infection. It was 8% among the 22 patients whose neutrophil count increased in response to their infection. Hence, the activity of this drug does not depend upon the patient’s neutrophil level. Fungal infections are common in cancer patients. Systemic candidiasis is the most frequent serious fungal infection in these patients. Although multiple factors play a role in predisposing the cancer patient to candidiasis, neutropenia is one of the major contributing factors. Amphotericin B is seldom effective in neutropenic patients. In a series of 71 systemic Candida infections in patients with acute leukemia, only 5 were cured.’ Of 16 patients who received amphoteritin B, 4 recovered; however, all four patients simultaneously achieved remission of their leukemia and had recovery of their neutrophil counts. Amphotericin B did not prolong the survival of patients with systemic candidiasis who did not achieve remission and who had persistent neutropenia when compared to untreated patients. Prompt therapy of infection in the cancer patient with neutropenia is important to prevent dissemination and death. Further-
Neutropenia and infection following cancer chemotherapy 0 G. P. BODEY et al.
more, neutropenia induced by chemotherapy is reversible if the patient can survive long enough for the bone marrow to recover. The safest approach is to assume that all febrile episodes (temperature of 101°F or greater, without obvious other cause) in the neutropenic patient result from infection; over 80% of febrile episodes in these patients are eventually proved to be caused by infection. Often no clinical signs and symptoms are present other than fever because these patients have an inadequate inflammatory response. For example, in a series of patients with acute leukemia, only 40% of major pulmonary infections found at autopsy were recognized antermortem.* The initial evaluation of fever in neutropenic patients should include a careful physical examination, urinalysis, chest X-ray film and cultures of blood, urine, throat, and other appropriate sites. Blood cultures should be obtained at least once each day as long as fever persists, since the infecting organism may not be isolated from the initial specimen. Even when the etiologic agent has been identified, persistent or recurrent fever may indicate super-infection. Culture specimens from other sites should be obtained twice weekly as long as fever persists. Since most infections occurring in neutropenic patients are caused by gram negative bacilli, broad spectrum antibiotics should be utilized as initial therapy. No antibiotic combination has been uniformly effective in these patients. Probably the best regimen for initial therapy is the combination of carbenicillin and cephalothin; this can be revised when the etiologic agent is identified. A major concern is the management of the neutropenic patient in whom antibiotic therapy has‘been initiated but the cause of the fever c¬ be ascertained. We recently completed a study which suggests that if the patient responds to this antibiotic regimen, it should be continued for 7-10 days.14 Although infection can be proved in only 20% of these patients, some of them will die if the antibiotic therapy is discontinued prematurely. Patients with fever which persists for three to four days despite therapy tManufactured
303
with carbenicillin and cephalothin should have the carbenicillin replaced with gentamicin sulfate. Nearly 50% of these febrile episodes are eventually proved to result from infection. Most of these infections are resistant to both carbenicillin and cephalothin but respond when gentamicin sulfate is administered. Since many antibiotics are only minimally effective for the treatment of infections in neutropenic patients, white blood cell transfusions have been utilized in an attempt to control infection. Unfortunately, the half life of leukocytes in the blood is only about 6 hr; in order to achieve an increment of 1500 neutrophils per mm3 blood, 10” cells must be transfused. Chronic myelogenous leukemia patients with high peripheral white blood counts have been used as donors for white blood cell transfusions. The leukocytes are collected by leukapheresis, returning the plasma and erythrocytes to the donor. The transfusion of 10” leukocytes results in the defervesence of fever in over 50% of neutrophenic recipients.‘* Among patients with gram negative bacilli bacteremia, over 60% become afebrile and 40% are cured of their infection when leukocyte transfusions are administered along with antibiotics. Over 100 transfusions of leukocytes collected from normal donors have been given to cancer patients with neutropenia; 75% of the recipients responded to leukocyte transfusion with reduction of fever and clearing of infection. Since the management of infectious complications in cancer patients with neutropenia is often difficult, a prophylactic program, utilizing patient isolation units (Life Islandst, laminar air flow rooms) and antibiotic regimens has been under investigation in recent years.6 The proportion of days spent with infection was related to the neutrophil count for 33 patients with acute leukemia who were undergoing chemotherapy while on this prophylactic program.4 A control group of same patients receiving the similar chemotherapy was selected for comparison. At every level of circulating neutrophils, the former patients spent less time with infection
by T. M. Matthews Research, Inc., Alexandria, Virginia.
304
Radiation Oncology 0 Biology 0 Physics
than the control patients, and most of these dilferences were statistically significant. Of the patients treated in the protected environ-
Vol. 1, No. 3-4
ment units, 45% never developed infection compared to 27% of the control patients.
REFERENCES 1. Bodey, G.P.: Infectious complications of acute leukemia. Med. Times 94: 1076-1085, 1966. 2. Bodey, G.P.: Fungal infections complicating acute leukemia. J. Chron. Dis. 19: 667-687, 1966. Buckley, M., Sathe, Y.S., 3. Bodey, G.P., Freireich, E.J.: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann. Intern Med. 64: 32%340,1966. 4. Bodey, G.P., Gehan, E.A., Freireich, E.J., Frei, E., III: Protected environment-prophylactic antibiotic program in the chemotherapy of acute leukemia. Am. J. Med. Sci. 262: 138-151, 1971. 5. Bodey, G.P., Hersh, E.M.: The problem of infection in children with malignant disease. In: Neoplasia in Childhood. Proceedings of the 12th AMWI Clinical Conference at the University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Texas. Chicago Year Book Publishers, 1969, pp. 135-154. 6. Bodey, G.P., Johnston, D.: Microbiological evaluation of protected environments during patient occupancy. AppL Microbial. 22: 828836, 1971. 7. Bodey, G.P., Middleman, E. Umsawasdi, T., Rodriguez, V.: Infections in cancer patients: results with gentamicin sulfate therapy. Cancer 29: 1697-1701, 1972. 8. Bodey, G.P., Powell, R.D., Jr., Hersh, E.M.,, Yeterian, A., Freireich, E.J.: Pulmonary complications of acute leukemia. Cancer 19: 781-793, 1%6. 9. Bodey, G.P., Rodriguez, V., Whitecar, J.P.: Severe infections in leukemic patients. An approach to antibiotic therapy. In: Advances and the Management of Pseudomonas and
10. 11.
12.
13.
14.
15.
16.
17.
Proteus Infections, ed. by Hoffman, F.: Proceedings of the Symposium, 12 July 1%9. New York, Excerpta Medica Foundation Publishers, 1970, pp. 65-78. Bodey, G.P., Terre& M.L.: In vitro activity of carbenicillin against gram negative bacilli. J. Bacreriol. 95: 1587-1590, 1968. Bodey, G-P., Whitecar, J.P., Middleman, E., therapy of Rodriguez, V.: Carbenicillin pseudomonas infections. J.A.M.A. 218: 62-66, 1971. Freireich, E.J., Morse, E.E., Bronson, W., Carbone, P.P.: Tranfusion of granulocytes from donors with chronic myelogenous leukemia to leukopenic recipients. In Proceed ings IX Congress Inremationai Sot. Hematology. Bethesda, National Cancer Institute, vol. 1, 1%2, pp_ 547-559. J&e, R.H.: Morphology of the inflammatory defense reactions in leukemia. Arch. Path. 14: 177-190, 1932. Rodriguez, V., Burgess, M.A., Bodey, G.P.: Management of fever of unknown origin in cancer patients with neutropenia. Cancer 32: 1007-1012, 1973. Umsawasdi, T., Middleman, E.A., Luna, M., Bodey, G.P.: Klebsiella bacteremia in cancer patients. Am. J. Med. Sci. 265: 473-487,1973. Whitecar, J.P., Bodey, G.P., Luna, M.: Pseudomonas bacteremia in cancer patients. Am. J. Med. Sci. 260: 216-223, 1970. Whitecar, J.P., Jr., Bodey, G.P., McCredie, K.B., Hart, J.S., Freireich, E.J.: Cyclophosphamide, Vincristine, Arabinosyl Cytosine and Prednisone (COAP) combination chemotherapy for adult acute leukemia. Cancer. Chemother. Rep. 56: 543-550, 1972.
Printed in the U.S.A.
NEUTROPENIA AND INFECTION FOLLOWING CANCER CHEMOTHERAPYt GERALD P. BODEY, M.D., VICTORIO RODRIGUEZ, M.D., KENNETH B. MCCREDIE, M.D. and EMIL J. FREIREICH, M.D. Department of Developmental Therapeutics, The University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston, TX 77025,U.S.A. Chemotherapy, Acute leukemia, Neutropenia, Systemic candidiasi~, Antibiotic therapy. Many of the infections which occur in cancer patients are caused by impairment of host defense mechanisms resulting from the malignancy or its therapy. Cancer chemotherapy frequently is administered in short courses at several week intervals. Recovery from the immunosuppressive effects of intensive short courses of chemotherapy usually is quite prompt, whereas the onset of myelosuppressive toxicity usually is more gradual and recovery requires a longer period of time.“” For chemotherapeutic agents and combinations with myelosuppressive toxicity, the interval between treatment courses is often dictated by the time required for recovery from this toxicity. Most of the infectious complications associated with chemotherapy occur during this period of myelosuppression. A study in patients with acute leukemia demonstrated the important relationship between the frequency of infection and the level of circulating neutrophils.3 The per cent of days spent with infection was determined in 54 patients who were followed from the onset of their disease until death; this was related to the neutrophil count (Fig. 1). Not only was the frequency of infection much higher at low neutrophil levels, but the propoi-tion of severe infection (major organ or disseminated infection) was higher. Patients with neutropenia are unable to produce an adequate inflammatory response at sites of infection.13 Consequently, infection disseminates widely and rapidly in these tThis work was supported in part by Grants CA 10042 and CA 05831 from the National Cancer
100
1
Fig. 1. Relation between neutrophil count and infection in patients with acute leukemia. From, Bodey, G.P., Rodriguez, V., Whitecar, J.P.:9 Courtesy of Excerpta Medica Foundation. patients. An autopsy study of pneumonia in 40 children who died of cancer illustrates this problem.5 None of the 18 children with neutrophil counts above lOOO/mm’developed septicemia in association with pneumonia, whereas, 64% of the 22 children with neutrophil counts less than 1000/mm3 developed septicemia. A majority of the episodes of septicemia at our institution occur in patients with neutropenia. In a study of 67 episodes of Pseudomonas septicemia, the neutrophil counts were less than 1000/mm3in 81% of the Institute, National Institutes of Health, U.S.P.H.S., Bethesda, MD 20014, U.S.A.
301
Radiation Oncology 0 Biology ??Physics
302
patients; neutrophil counts were less than 100/mm3 in 36% of patients.16 Similarly, in a study of 152 episodes of Klebsiella septicemia, neutrophil counts were less than lOO/mm” in 50% of the patients.15 Recovery from most severe infections is related to the patients’ ability to respond with an increased production of neutrophils (Fig. 2).
0 lnitld
omnucocrn CaJw-‘loo Chnage-
Nme
400 MI
‘looo Rix
‘loo0
mu
Fig. 2. Fatality rate from severe infection related to neutrophil count in patients with acute leukemia. From, Bodey, G.P., Rodriguez, V., Whitecar, J.P.? Courtesy of Excerpta Me&a Foundation. The effectiveness of some antibiotics in neutropenic patients is related to the patient’s ability to respond to infection with an increased production of neutrophils. The broad spectrum aminoglycoside antibiotic, gentamitin sulfate, is an example. In a study of cancer patients, 63 patients with infections which were caused by a single species of aerobic gram negative bacillus received gentamicin sulfate.’ During 32 episodes, the patients had persistent neutropenia or their neutrophil count decreased. The response rate for this group of patients was only 31%. During 31 episodes, the patients maintained an adequate neutrophil count. The response rate among this group of patients was 74%: Adequate serum activity has been demonstrated in neutropenic patients who failed to respond to gentamicin sulfate therapy. Serum specimens have been obtained from patients before and during infusions of the antibiotic, and two-fold serial dilutions have been tested in vitro against the patients’ organisms. These
Vol. 1. No. 3-4
organisms have been inhibited by 1:4 or greater dilutions of the serum. In vitro sensitivity tests indicated that the organisms did not develop resistance to gentamicin sulfate during therapy. None of these neutropenic patients had localized abscesses where poor perfusion might have been responsible for failure. Furthermore, a’ S&150% increase in the dose of drug did not improve the results. Unlike the’ aminoglycosides, penicillins have been very effective even in neutropenic patients. Methicillm caused a prompt reduction in the number of fatal staphylococcal infections in these patients.’ A recent important addition to this family of antibiotics is carbenicihin. Thus drug has extended the spectrum of the penicillins to include Pseudomonas aeruginosa, indole positive Proteus sp., and some Enterobacter sp.” The drug has been used in the treatment of Pseudomonas infections in cancer patients.” The cure rate was 76% among the 29 patients whose neutrophil count fell during the fhst week of infection. It was 8% among the 22 patients whose neutrophil count increased in response to their infection. Hence, the activity of this drug does not depend upon the patient’s neutrophil level. Fungal infections are common in cancer patients. Systemic candidiasis is the most frequent serious fungal infection in these patients. Although multiple factors play a role in predisposing the cancer patient to candidiasis, neutropenia is one of the major contributing factors. Amphotericin B is seldom effective in neutropenic patients. In a series of 71 systemic Candida infections in patients with acute leukemia, only 5 were cured.’ Of 16 patients who received amphoteritin B, 4 recovered; however, all four patients simultaneously achieved remission of their leukemia and had recovery of their neutrophil counts. Amphotericin B did not prolong the survival of patients with systemic candidiasis who did not achieve remission and who had persistent neutropenia when compared to untreated patients. Prompt therapy of infection in the cancer patient with neutropenia is important to prevent dissemination and death. Further-
Neutropenia and infection following cancer chemotherapy 0 G. P. BODEY et al.
more, neutropenia induced by chemotherapy is reversible if the patient can survive long enough for the bone marrow to recover. The safest approach is to assume that all febrile episodes (temperature of 101°F or greater, without obvious other cause) in the neutropenic patient result from infection; over 80% of febrile episodes in these patients are eventually proved to be caused by infection. Often no clinical signs and symptoms are present other than fever because these patients have an inadequate inflammatory response. For example, in a series of patients with acute leukemia, only 40% of major pulmonary infections found at autopsy were recognized antermortem.* The initial evaluation of fever in neutropenic patients should include a careful physical examination, urinalysis, chest X-ray film and cultures of blood, urine, throat, and other appropriate sites. Blood cultures should be obtained at least once each day as long as fever persists, since the infecting organism may not be isolated from the initial specimen. Even when the etiologic agent has been identified, persistent or recurrent fever may indicate super-infection. Culture specimens from other sites should be obtained twice weekly as long as fever persists. Since most infections occurring in neutropenic patients are caused by gram negative bacilli, broad spectrum antibiotics should be utilized as initial therapy. No antibiotic combination has been uniformly effective in these patients. Probably the best regimen for initial therapy is the combination of carbenicillin and cephalothin; this can be revised when the etiologic agent is identified. A major concern is the management of the neutropenic patient in whom antibiotic therapy has‘been initiated but the cause of the fever c¬ be ascertained. We recently completed a study which suggests that if the patient responds to this antibiotic regimen, it should be continued for 7-10 days.14 Although infection can be proved in only 20% of these patients, some of them will die if the antibiotic therapy is discontinued prematurely. Patients with fever which persists for three to four days despite therapy tManufactured
303
with carbenicillin and cephalothin should have the carbenicillin replaced with gentamicin sulfate. Nearly 50% of these febrile episodes are eventually proved to result from infection. Most of these infections are resistant to both carbenicillin and cephalothin but respond when gentamicin sulfate is administered. Since many antibiotics are only minimally effective for the treatment of infections in neutropenic patients, white blood cell transfusions have been utilized in an attempt to control infection. Unfortunately, the half life of leukocytes in the blood is only about 6 hr; in order to achieve an increment of 1500 neutrophils per mm3 blood, 10” cells must be transfused. Chronic myelogenous leukemia patients with high peripheral white blood counts have been used as donors for white blood cell transfusions. The leukocytes are collected by leukapheresis, returning the plasma and erythrocytes to the donor. The transfusion of 10” leukocytes results in the defervesence of fever in over 50% of neutrophenic recipients.‘* Among patients with gram negative bacilli bacteremia, over 60% become afebrile and 40% are cured of their infection when leukocyte transfusions are administered along with antibiotics. Over 100 transfusions of leukocytes collected from normal donors have been given to cancer patients with neutropenia; 75% of the recipients responded to leukocyte transfusion with reduction of fever and clearing of infection. Since the management of infectious complications in cancer patients with neutropenia is often difficult, a prophylactic program, utilizing patient isolation units (Life Islandst, laminar air flow rooms) and antibiotic regimens has been under investigation in recent years.6 The proportion of days spent with infection was related to the neutrophil count for 33 patients with acute leukemia who were undergoing chemotherapy while on this prophylactic program.4 A control group of same patients receiving the similar chemotherapy was selected for comparison. At every level of circulating neutrophils, the former patients spent less time with infection
by T. M. Matthews Research, Inc., Alexandria, Virginia.
304
Radiation Oncology 0 Biology 0 Physics
than the control patients, and most of these dilferences were statistically significant. Of the patients treated in the protected environ-
Vol. 1, No. 3-4
ment units, 45% never developed infection compared to 27% of the control patients.
REFERENCES 1. Bodey, G.P.: Infectious complications of acute leukemia. Med. Times 94: 1076-1085, 1966. 2. Bodey, G.P.: Fungal infections complicating acute leukemia. J. Chron. Dis. 19: 667-687, 1966. Buckley, M., Sathe, Y.S., 3. Bodey, G.P., Freireich, E.J.: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann. Intern Med. 64: 32%340,1966. 4. Bodey, G.P., Gehan, E.A., Freireich, E.J., Frei, E., III: Protected environment-prophylactic antibiotic program in the chemotherapy of acute leukemia. Am. J. Med. Sci. 262: 138-151, 1971. 5. Bodey, G.P., Hersh, E.M.: The problem of infection in children with malignant disease. In: Neoplasia in Childhood. Proceedings of the 12th AMWI Clinical Conference at the University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Texas. Chicago Year Book Publishers, 1969, pp. 135-154. 6. Bodey, G.P., Johnston, D.: Microbiological evaluation of protected environments during patient occupancy. AppL Microbial. 22: 828836, 1971. 7. Bodey, G.P., Middleman, E. Umsawasdi, T., Rodriguez, V.: Infections in cancer patients: results with gentamicin sulfate therapy. Cancer 29: 1697-1701, 1972. 8. Bodey, G.P., Powell, R.D., Jr., Hersh, E.M.,, Yeterian, A., Freireich, E.J.: Pulmonary complications of acute leukemia. Cancer 19: 781-793, 1%6. 9. Bodey, G.P., Rodriguez, V., Whitecar, J.P.: Severe infections in leukemic patients. An approach to antibiotic therapy. In: Advances and the Management of Pseudomonas and
10. 11.
12.
13.
14.
15.
16.
17.
Proteus Infections, ed. by Hoffman, F.: Proceedings of the Symposium, 12 July 1%9. New York, Excerpta Medica Foundation Publishers, 1970, pp. 65-78. Bodey, G.P., Terre& M.L.: In vitro activity of carbenicillin against gram negative bacilli. J. Bacreriol. 95: 1587-1590, 1968. Bodey, G-P., Whitecar, J.P., Middleman, E., therapy of Rodriguez, V.: Carbenicillin pseudomonas infections. J.A.M.A. 218: 62-66, 1971. Freireich, E.J., Morse, E.E., Bronson, W., Carbone, P.P.: Tranfusion of granulocytes from donors with chronic myelogenous leukemia to leukopenic recipients. In Proceed ings IX Congress Inremationai Sot. Hematology. Bethesda, National Cancer Institute, vol. 1, 1%2, pp_ 547-559. J&e, R.H.: Morphology of the inflammatory defense reactions in leukemia. Arch. Path. 14: 177-190, 1932. Rodriguez, V., Burgess, M.A., Bodey, G.P.: Management of fever of unknown origin in cancer patients with neutropenia. Cancer 32: 1007-1012, 1973. Umsawasdi, T., Middleman, E.A., Luna, M., Bodey, G.P.: Klebsiella bacteremia in cancer patients. Am. J. Med. Sci. 265: 473-487,1973. Whitecar, J.P., Bodey, G.P., Luna, M.: Pseudomonas bacteremia in cancer patients. Am. J. Med. Sci. 260: 216-223, 1970. Whitecar, J.P., Jr., Bodey, G.P., McCredie, K.B., Hart, J.S., Freireich, E.J.: Cyclophosphamide, Vincristine, Arabinosyl Cytosine and Prednisone (COAP) combination chemotherapy for adult acute leukemia. Cancer. Chemother. Rep. 56: 543-550, 1972.
