INTENSITY OF IMMUNOSUPPRESSIVE THERAPY AND T H E INCIDENCE OF PNEUMOCYSTIS C A R I N I I PNEUMONITIS WALTER T. HUGHES, MD, SANDOR FELDMAN, MD, RHOMES J. A. AUR,MD, MANUEL S. VERZOSA, MD, H. OMAR HUSTU, MD, A N D JOSEPH V. SIMONE, MD

O n e h u n d r e d and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of remission a n d central nervous system (CNS) irradiation to receive maintenance chemotherapy with 1, 2, 3, or 4 chemotherapy agents. The incidence of P. carinii pneumonitis (PCP) was 5.0, 2.3, 2.2, and 22.496, respectively, d u r i n g the period of maintenance therapy. A n additional 31 patients enrolled i n t h e same study were placed in special categories t o receive three drugs for maintenance plus supplemental chemotherapy or irradiation because of CNS leukemia o n admission, remission failure, mediastinal mass, or generalized lymphosarcoma without bone marrow involvement. The incidences of PCP i n these groups were 16.7, 30.0, 35.7, a n d 096, respectively, d u r i n g t h e period of maintenance therapy. Cancer 36:2004-2009, 1975.

P

(PCP) IS rarely encountered in normal healthy people. However, patients receiving immunosuppressive therapy for cancer or organ transplantation are at high risk for this serious and often fatal infection. T h e incidence of PCP is reported t o vary with the type of cancer,3 age: nutritional status,4 and between institutions.6 T h e suggestion has been made that the intensity of immunosuppression may be a provocative factor.5 Within recent years significant advances have been made in the treatment of acute lymphocytic leukemia (ALL) by the use of combination chemotherapy and irradiation.7-1 Despite the success in achieving a 5-year cure rate in a high percentage of patients, maximum survival rates are impeded to some extent by fatalities from infectious diseases. I n children with ALL in continuous complete NEUMOCYSTIS CARINII PNEUMONITIS

From the Divisions of Infectious Diseases, Hematology-Oncology, and Radiation Therapy Services, St. Jude Children’s Research Hospital, Memphis, TN. Supported by Giant AI-11277 from the National Institute of Allergy and Infectious Diseases; Cancer Research Center Grant CA-08480 and Grant CA-13050, National Cancer Institute and General Research Support Grant RR-05584, National Institute of Health, and by ALSAC. Address for reprints: Walter T. Hughes, MD, 332 North Lauderdale, Memphis, T N 38101. Received for publication January 22, 1975.

remission, PCP is a major cause of death.8 To date there is no effective method for the prevention of this infection. Knowledge of a positive relationship between the type and extent of anticancer therapy might provide a basis for identifying high-risk categories of patients for PCP and for the modification of anticancer regimens to lower the mortality rates from infectious complications. Careful surveillance for 2.5 years of a group of children with ALL randomized in a prospective study to receive gradations of chemotherapy agents provided a solid basis for determining the effects of the intensity of chemotherapy on the incidence of PCP.

MATERIALS AND METHODS I n January 1972, a prospective study (Total Therapy: Study VHI) was begun to compare the efficacy and toxicity of combinations of 4, 3, 2, and 1 drugs to treat ALL during remission. Only previously untreated cases were enrolled and all qualified ALL patients admitted to St. Jude Children’s Research Hospital (S.J.C.R.H.) were admitted sequentially to the study. Chemotherapy Protocol All patients were treated initially (Phase I) with prednisone, 40 mg/m2 per day orally; vincristine, 1.5 mg/m2 per week intravenously;

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and asparaginase, 10,000 units/m2 per week intravenously for two injections. When clinical and hematologic remission was attained within 1 month, all patients received cobalt60 irradiation (1500 to 2400 rads) to cranium over a period of 2.5 weeks, and methotrexate, 12.0 mg/m2 twice a week for five doses intrathecally (Phase 11). One week after termination of cranial irradiation the patient was randomized by the sealed envelope method to receive one of four regimens for maintenance therapy for a period of 2 to 3 years (Phase 111) (Table 1). Patients randomized to group A were maintained on one drug-methotrexate 40 mg/m* per week intravenously. Group B received two drugs: methotrexate, 20 mg/mz per week intravenously and 6-mercaptopurine, 50 mg/m2 per day orally. Group C patients were maintained on three drugs: methotrexate and 6-mercaptopurine, as in group B, plus cyclophosphamide, 200 mg/ mz per week intravenously. Group D patients were given the three drugs as in group C plus arabinosyl cytosine (ARAC), 50.0 mg/mz per week intravenously. T h e drug dosages described-were initial dosages and were modified if necessary to meet the biologic tolerance of each patient. Certain patients presented extensive or complicated forms of malignancy with central nervous system leukemia, mediastinal mass, or a generalized form of lymphosarcoma without bone marrow involvement at the time of diag-

TABIX1.

2005

nosis, or failed to attain remission at the end of 4 weeks of Phase I of induction therapy. T h e therapy protocol for these categories is summarized in Table 2. Diagnosis of PCP Patients with febrile episodes and signs and symptoms of respiratory infection were investigated with chest roentgenograms and cultures of the blood, pharynx, urine, and stool. Those with diffuse alveolar disease and others with pneumonitis unresponsive to antibiotics were subjected to percutaneous transthoracic needle aspiration of the lung. T h e aspirated specimen was applied to microscope slides and stained with toluidine blue 0, polychrome methylene blue, and Gomori’s methenamine silver nitrate stains. Aliquots were also cultured for bacteria and fungi. T h e diagnosis of PCP was made when diffuse pulmonary infiltrates were apparent by chest roentgenogram and P. carinii was identified in the lung aspirate. Serum immunoglobulin G, A, and M values were determined for patients with PCP. I n all patients who died autopsy studies included examination of the lungs for P. carinii using Gomori’s stain. Comparison to Other Infections To determine if the intensity of anticancer therapy might influence the incidence of infections other than PCP, we selected the varicella and zoster infections for comparison.

Incidence of P. carinii fneumonitis in Relation to Phase and Types of Anti-Leukemic Therapy Therapy protocol Phase I : Pred, VCR, ASP (4 wk) Phase 11: C N S RAD, M T X (I.T.) (2.5 wk) Phase I11 (randomized) (2-3 yr) Gronp A = M T X Group €3 = M T X , 6 M P Group C = M T X , 6 M P , Cyclo Group D = M T X , 6 M P , Cyclo, ARA-C

No. patients

No. (yo)with P C P

149

0 (0%)

149

6 (4.0%)

20 43 45 41

1 (5.0%)* 1 (2.3%) 1 (2.2%)* 10 (22.4%)

* Ibxiuired additional chemotherapy because of relapses. Statistical analysis: T h e differences between group A, B or C and group D are highly significant b y t h e Chi sqnare test ( p = < 0.001). VCR = Vincristine I’red = Prednisone I U D = Irradiation I.T. = Intrathecally Cyclo = Cyclophosphamide

ASP = L-asparaginase C N S = Central nervous system M T X = Methotrexate 6 - MP = 6-Mercaptopurine ARA-C = Arabinosyl cytosine

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I

Ph.ise

Remission Failure

C N S Leukernid

of

Thcrdpy

on

Admis5ion

at

4

Leukernid with Mediastinal

wk.

Mass

Gen. lymphoSdrCOmd with

Normdl Marrow

Phdw I 4 wk

Phdw 1 1 4 wk

Ph.i\c

CNS

Irrddidtion +

Methotrexate ( I . T . )

I

II I

Methotrexdte. 6-Mercaptopurine, Cyclophosphdmide Ara-C I

1-

6 No. with

PCP

I 16 . 7 %

I

I

10

3

30.0%

Varicella and zoster were chosen because these infections have characteristic clinical features not easily confused with other infections and because concomitant clinical investigations were being done which provided careful surveillance of the study group for the occurrence and identification of these infections. Varicella and zoster infections were identified by the typical clinical manifestations and in almost all cases the demonstration of herpesvirus-like particles by electron microscopy, cultivation of varicella-zoster virus, or both, from vesicle fluid. Bacterial and fungal infections were not analyzed since identification of the causative agents of febrile episodes was not always accomplished and recognition of these infections might have been masked many times by antibiotic therapy.

RESULTS From January 1972 through September 1974, 180 children with acute lymphocytic leukemia were admitted to the Total Therapy Study VIII; 149 were randomized into groups A, B, C and D and 31 were categorized in special groups. Six additional patients with ALL were

I4

1

6’

0

42.0% ( 3 5 . 7 % )

initially entered into the protocol but died within the ,first week from bacterial infections and hemorrhage and were excluded from this analysis. Of the 180 patients, 102 (57y0) were male; 161 were Caucausian, 18 Negro and 1 Oriental; and ages ranged from 4 months to 19 years (median, 5 years). PCP occurred in 29 (16.0%) of the 180 patients. This incidence is three times greater than the overall incidence of PCP in children with malignancies at S.J.C.R.H.3 The median age for the 29 patients with PCP was 5 years; 18 (62%) were male, and 27 were Caucausian. These features were similar to the distribution of the patients without PCP. The patients were residents of 18 states. There was no pattern of geographic endemicity. For example, the incidence of PCP was the same for Tennessee residents as residents of Michigan, Florida, Louisiana, Indiana, and Kentucky. Two cases of PCP occurred in 1972, nine in 1973 and 18 in 1974. This increase in prevalence was directly related to the size of the population at risk (Fig. 1). Although the prevalence rate increased rapidly from quarter to quarter the incidence of PCP ranged without

150

1

140

m=Ec-

Pneumonitis

'"i

r-

2007

#

;120 5

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PNEUMOCYSTIS CARINII PNEUMONITIS Hughes et al.

No. 6

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MONTHS OF CHEMOTHERAPY

..-c

II)

5 C

n GROUP

40

38

30

=

0

B

46 r 44 42 40

20

2

10

z

36 34 32 30 29 26

-

---

7,

--

0 YEARS

FIG. 1. The prevalence of PCP is related to the size of the population at risk. The number of pa-

tients with leukemia in the study and the numbers with PCP are plotted quarterly for each year. The incidence per quarter is printed above corresponding bars.

q\ 46

pattern from 1.1 to 7.5% of the population at risk. Table 1 depicts the chemotherapy regimens in relation to the incidence of PCP. In group D where four drugs were used for maintenance chemotherapy the incidence of PCP was 4.5 times that of group A where only methotrexate was given. The incidences of the infection in groups B and C were not significantly different from group A. This comparison suggests that the more extensive immunosuppression expected from the administration of more chemotherapy agents is a factor in the acquisition of PCP. An alternate possibility is that ARA-C is singly responsible. However, the patients with more extensive malignancy (Table 2) did not receive ARA-C, except for one patient who did not have PCP. T h e incidence of PCP was highest in the group receiving mediastinal irradiation in addition to maintenance with three chemotherapy agents which did not include ARA-C. Seven patients had the onset of PCP during or within 1 week after the completion of Phase 11, before randamization to Phase I11 maintenance chemotherapy. Three of the patients were later randomized to group C, three to group D and one to the category with mediastinal involvement (Figs. 2 and 3 ) . Incidence figures adjusted to indicate the occurrence of PCP during the various maintenance regimens

36

w

GROUP D

29 YI 26 24 g 22 t 20

5

--

L

6 C

MONTHS OF CHEMOTHERAPY

FIG.2. Temporal relationship of PCP to antileukemic therapy. A: Group A, one-drug maintenance. B: Group B, two-drug maintenance. C: Group C, three-drug maintenance. D: Group D, four-drug maintenance.

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ME D IAST I N A L IN VOLVE ME N T AN D I R R AD1AT ION 14

-

%

n 60

a =?i corinii Pneumonitis H MED.

RAD.

H C N S RAD., MTX

4-

IC-

z 2-

p71

0 I

MTX, 6MP, CYCLO

3

m m

I/A

FIG. 3. Temporal relationships of PCP to antileukemic therapy in patients with mediastinal involvement, three-drug maintep a w e and mediastinal irradiation.

2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20212223242526 MONTHS OF CHEMOTHERAPY

were 2.2% for group C, 22.474 for group D and 35.7% for the category with mediastinal irradiation. T h e difference in incidence for group D and the special categories groups is highly significant when compared to those of groups A, B, and C either with or without adjustment of incidence to exclude those patients who acquired PCP before randomization (p =

Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.

One hundred and forty-nine children with acute lymphocytic leukemia treated according to a prospective protocol were randomized after induction of rem...
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