infectious complications and immunodeficiency in patients with human t-cell lymphotropic virus...

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Infectious Complications and Immunodeficiency in Patients with Human T-cell Lymphotropic Virus I-Associated Adult T-cell Leukemia/ Lymphoma Jeffrey D. White, M.D.,* Sara L. Zaknoen, M.D.,*,t Claude Kasten-Sport&, M.D.,*,$ Lois E. Top, M.N.Ed.,* Lydia Navarro-Roman, M.D.,@II David L. Nelson, M.D.," and Thomas A. Waldmann, M.D.*

Background. Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T-cells occurring in patients infected with the human T-cell lymphotropic virus-I. These patients frequently develop a variety of infections throughout their disease course.

Methods. Charts and autopsy reports were reviewed for 41 patients with ATL with follow-up varying from 2 to 120 months. Infectious episodes were identified and documented. Analyses of humoral and cell-mediated immunity were performed. Cell-mediated immunity was assessed in vivo with the Merieux multitest skin test panel. Humoral immunity was assessed by quantitative immunoglobulin levels, by determining human antimouse antibody after murine monoclonal antibody infusion and by

From the *Metabolism Branch, National Cancer Institute, and the 11 Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

t Current affiliation: Department of Hematology/Medical On- cology, University of Cincinnati, Cincinnati, Ohio.

+ Current affiliation: Bone Marrow Transplantation Program, Division of Hematology-Oncology, Harper Hospital, Detroit, Michi- gan.

5 Current affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.

The authors thank Dr. Seth Steinberg for assistance with the statistical analyses; Mane Saunders-Rice for data retrieval; Carole C. Kurman and Carolyn K. Goldman for technical assistance; the De- partment of Transfusion Medicine; and the nurses on 38 south of the National Institutes of Health Clinical Center. They also thank Dr. Hir- oyuki Ishii for the translation of some of the Japanese literature on ATL and the refemng physicians for supplying the information on their patients' infections.

Address for reprints: Jeffrey D. White, M.D., Metabolism Branch, National Cancer Institute, Building 10, Room 4N115, Bethesda, MD 20892.

Received October 24, 1994; revision received December 16, 1994; accepted December 16, 1994.

an in vitro immunoglobulin biosynthesis coculture sys- tem.

Results. A total of 112 infectious episodes were documented. Fifty-seven serious infections were identified. The incidence of total infections was 1.40/patient-year and for serious infections was 0.7l/patient-year. The mean serum IgG and IgA levels were within normal range, the mean IgM level was at the lower limit of normal. Peripheral blood mononuclear cells from all patients studied failed to make meaningful amounts of IgG, M, or A when activated. Peripheral blood mononuclear cells of all of the 13 patients studied suppressed production of immunoglobulin by cocultured normal PBMC. Twenty- three of the 27 patients tested were anergic.

Conclusions. ATL is a profoundly immunosuppress- ing malignancy. This is manifested by an extremely high incidence of infectious episodes/patient-year. The incidence of infection appears to be greater than for mycosis fungoides, Hodgkin's lymphoma and non-Hodgkin's lymphoma. Cancer 1995; 75:1598-607.

Key words: leukemia, T cell, immunocompromised host, human T-cell lymphotropic virus type I (HTLV-I) infections, antibodies, monoclonal, receptors, interleukin-2.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T cells that is associated with the human T-cell lymphotropic virus type I (HTLV-I). Various opportunistic infections have been reported in patients with ATL,' and some of the specifics of an immunodeficiency state associated with HTLV-I infection and ATL have been delineated.2r3

The geographic distribution of ATL parallels that of the incidence of HTLV-I in the population. The largest number of patients have been reported from the south-

Infections and Immunodeficiency in ATLIWhite e t al . 1599

ern Japanese district of K y ~ s h u . ~ Consequently, most of the literature regarding this disease and its infectious complications derives from patients in that region. Data on the incidence of HTLV-I infection and ATL in the United States, the Caribbean, and Central and South America are just beginning to be acc~mula t ed .~ ,~

We report our experience of infections occurring in patients with ATL seen at the Clinical Center of the Na- tional Institutes of Health. The spectrum and incidence of infections are discussed and compared with those of other hematologic malignancies. The clinical manifestations of the serious infections are described. Clinical and laboratory features of the immunodeficiency in these patients are discussed, and recommendations are made for the prophylaxis of infections in patients with ATL.

Patients and Methods

Patients

The hospital charts and available autopsy reports were reviewed for all 41 patients evaluated for entry to three interleukin-2 (IL-2) receptor directed therapeutic trials for the treatment of ATL at the Metabolism Branch of the National Cancer Institute between November 1982 and March 1993. Diagnostic pathologic materials were reviewed by the Hematopathology Section of the Lab- oratory of Pathology of the National Cancer Institute. All patients had a diagnosis of ATL determined by (1) the presence of a clonal T-cell leukemia or lymphoma, by morphologic and immunophenotypic analysis of peripheral blood lymphocytes and lesions of skin or lymph nodes, and ( 2 ) the presence in the serum of antibodies against HTLV-I. The clinical subtype of ATL was designated using the criteria of the Japanese Lymphoma Study Group.7 Informed consent was obtained from all patients.

Definitions

Efforts were made to obtain information regarding the entire period from initial diagnosis of ATL through death or last follow-up for each patient. Records from referring physicians and hospitals were requested for infections that were diagnosed outside of the Clinical Center. We have excluded self-limited, undiagnosed ill- nesses (e.g., upper respiratory tract infections).

A diagnosis of infection was termed microbiologically documented if a pathogenic organism was cultured or identified by cytology or histopathology from the indicated site and the patient had clinical signs or symptoms consistent with an infectious disease. A clin-

ical infection was one in which the patient had signs or symptoms consistent with an infection but no specific organism was identified or for which the microbiologic data were not available. A serious infection was any infection that resulted in hospital admittance or required intravenous antibiotic therapy. Also included in this definition is any infection that presented in an unchar- acteristic manner, was attributable to the patient’s immunosuppression, and had significant potential for greater morbidity if not treated (e.g., disseminated strongyloidiasis or primary varicella infection). An infection was considered to have contributed to death if signs or symptoms of a confirmed, serious infection were present in the terminal phase of the patient’s illness and were not relieved by treatment. An infectious episode is defined as the occurrence of an infection by a single organism affecting one or more organs concur- rently or an illness clinically indicated to be an infection. Our definitions of infectious episode, serious infection, and clinically documented infection are similar to those used in large, published studies of infectious episodes in Hodgkin’s disease’ and non-Hodgkin’s lymphoma.’ The term “opportunistic” refers to the following infections: pneumocystis pneumonia, cytomegalovirus infections, Candida albicans or tropicalis infections, C y p - tococcus neoforrnans infections and aspergillosis.

The period of patient observation was divided into four phases:

1. pretreatment, which was before any treatment for ATL;

2 . during treatment, which was from the initiation of treatment of ATL to 60 days after the last cycle of treatment (includes the initial and salvage treatment periods); and

3 . posttreatment, which was divided into remission (more than 60 days after the last cycle of a treatment course that had resulted in a partial or complete remission) and relapse (the period from diagnosis of relapse or progression of disease until treatment was reinstituted).

The incidence of total and serious infectious episodes was calculated by dividing the total number of infectious episodes of either type by the product of the number of patients in the group and the mean follow- up of that group expressed in years.

Antibody Testing

Sera from patients were examined for antibodies to HTLV-I and human immunodeficiency virus using en- zyme-linked immunosorbent assays (ELISA, Abbott

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Laboratories, Chicago, IL, or Cellular Products, Inc., Buffalo, NY) performed in the Department of Transfu- sion Medicine of the Clinical Center or by Hazelton Laboratories (Vienna, VA). All positive ELISA results were confirmed by Western blot.

Immunoglobulin Biosynthesis

In vitro immunoglobulin biosynthesis was assessed using patient peripheral blood mononuclear cells (PBMC) stimulated with pokeweed mitogen as described pre- viously,'" with the exception that immunoglobulin levels were determined by ELISA (Hazeiton Laboratories, Vienna, VA), rather than by radioimmunoassay.

Cell Mediated Immunity Testing

For each patient, the skin of the forearm was wiped with alcohol, and the Merieux skin test panel was ap- plied with pressure and a rocking motion to keep the prongs in contact with the skin for at least 10 seconds. The sites of inoculation were examined at 24 and 48 hours after application, and the largest diameter of the areas of induration were measured. If any site had a diameter that was greater than or equal to 2 mm, the panel was considered positive, if the control (glycerin) site was negative. A patient was considered anergic only if none of the seven antigen inoculation sites had an induration that was greater than or equal to 2 mm in diameter. One of the patients had individual intrader- ma1 skin tests with the antigens Candida, diphtheria, and streptokinase-streptodornase, instead of the Me- rieux panel.

Statistics

For each patient the difference in incidence was calculated by determining the number of infections per unit time for an interval and subtracting the same ratio for the interval to which it was being compared. The null hypothesis was that there was no difference in incidence between the intervals. These differences were evaluated for statistical significance using the Wilcoxon signed rank test. To test for a difference in incidence per unit time among the three subtypes, a comparison of the two Poison counts was performed. The P values reported are two tailed.

Results

Incidence and Timing of Infections

The records of 41 patients with ATL (Table 1) were reviewed, representing 2-120 months of observation

Table 1. Patient Characteristics

Characteristic No.

Gender Female 23 Male 18

Age (yr) Range 23-63 Mean 41

Black 37 Asian 2

Race

Hispanic 2 Geographic origin

Caribbean 20 United States 19 Japan 2

Clinical subtypes Acute/crisis 26 Chronic 9 Lymphoma 6

HTLV-I positive 41

Chemotherapy* 32 Antibodv theraovt 41

HIV-1 positive 0

CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; COP: cyclophosphamide, vincristine, prednisone; CVP: cyclophosphamide, vinblastine, prednisone; MACOP-B: methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; ProMACE: prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide; ProMACE-MOPP: prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine; ProMACE-CytaBOM: prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate; BAM-M: bleomycin, doxorubicin, methotrexate, and topical mechlorethamine. * CHOP, COP, or CVP, 11 patients; MACOP-8, 2 patients; ProMACE or Pro- MACE-MOW, 5 patients; ProMACE-CytaBOM, 4 patients; deoxycoformycin, 3 patients; other (includes BAM-M, etoposide, and high-dose dexamethasone, suramin, and some multiagent experimental protocol regimens), 17 patients. Most patients received more than one chemotherapy regimen. t Unmodified anti-Tac, 20 patients; 9%trium-labeled anti-Tac, 17 patients; Pseudomonas exotoxin conjugated anti-Tac, 5 patients; 13110dine-labeled T101, 1 patient. Two patients received more than one form of antibody therapy.

(mean, 23 months; median, 13 months) during each patient's illness. The patient group was predominantly black and virtually equally distributed between African American and African Caribbean patients. All patients had antibodies to HTLV-I and tested negative for antibodies to human immunodeficiency virus. Thirty-two (78%) patients had received chemotherapy at some point in their disease courses. Within this group, the patients received an average of 1.5 chemotherapy regimens per patient. The spectrum of chemotherapeutic regimens received by these patients is shown in Ta- ble 1.

Thirty-two patients had at least one episode of infection during the review period. There were 92 microbiologically documented and 20 clinical infectious epi-

Infections and Immunodeficiency in ATL/White et al. 1601

Table 2. Timing of Infections No. of infectionst

Patients with infections* Bacterial Opportunistic Other Total Incidencet

Pretreatment 17 ( 6 ) 2 (0) 6 (4) 16 (5) 24 (9) 0.91 (0.34) During treatment 31 (22) 28 (22) 30 (18) 26 (6) 84 (46) 2.92 (1.60)s Posttreatment

Remission 1(1) 0 0 1 0 ) 1(1) 0.06 (0.06) Relapse 3 (1) 1 0 2 (1) 3 (1) 0.37 (0.12)

All periods 32 (23) 31 (22) 36 (22) 45 (13) 112 (57) 1.40 (0.71)

* In parentheses is the number of patients with a serious infection. t In parentheses is the number of serious infections. $ Total infections per patient-year (see Methods). In parentheses is the incidence of serious infections. 5 Incidence of serious infections is statistically significantly greater in the during treatment period compared with the pretreatment period ( P = 0.029).

sodes that resulted in 112 total infectious episodes. Of these, 5 7 episodes were serious infections, occurring in 23 patients.

Infections occurred predominantly in two of the four phases of the observation periods (Table 2). Only three infections occurred in the relapse period and one in the remission period. The incidence of total infectious episodes in the pretreatment period was 0.9l/patient year, and during therapy the incidence was 2.92/patient year; this difference is not statistically significant. However, the incidence of serious infectious episodes in the during treatment period (l.bO/patient year) was significantly greater than in the pretreatment period (0.34/patient year) ( P = 0.029). Most bacterial and opportunistic infections occurred during treatment for ATL. Total and serious infections occurred at a lower incidence when patients received antibody therapy than when they received chemotherapy. Considering only the patients who received both chemotherapy and antibody therapy, the incidence of serious infectious episodes during chemotherapy (1,85/patient year) was significantly greater than the incidence during the pretreatment period (0.34/patient year) ( P < 0.01). How- ever, for this group, the incidence during antibody therapy (0.50/patient year) did not differ significantly from that of the pretreatment incidence ( P > 0.7). Overall, there were 1.40 total infectious episodes and 0.71 serious infectious episodes per patient year.

Of the serious infections, nine occurred before the patient received any treatment for ATL. One patient with cryptococcal meningitis had symptoms develop after a short course of oral prednisone for the skin manifestations of what was then considered mycosis fungoides and was later diagnosed as ATL. Another patient, included in the during treatment group, first had symptoms of what was eventually diagnosed as crypto-

coccal meningitis 2 days after starting a regimen of chemotherapy.

Among the 24 patients with a known cause of death, 8 had an infection as the primary or a contributory cause of death. Two patients who went to autopsy had at least one serious infection that was not diagnosed or anticipated before death (pulmonary aspergillosis and cytomegalovirus pneumonia in one patient and Pneumocystis carinii pneumonia in the other).

Types of Infection

The range of infections seen in these patients is shown in Tables 3 and 4. Among the 57 serious infections were 20 episodes of bacterial sepsis, 8 serious candidal infections, 5 Pneumocystis pneumonias, 4 cytomegalovirus infections, 4 clinical pneumonias, 3 Cryptococcus neofor- man5 infections, 3 episodes of disseminated cutaneous varicella, 2 pulmonary Aspergillus infections, 2 episodes of Herpes simplex esophagitis, 1 Influenza A pneumonitis, 1 disseminated strongyloidiasis, 1 clinically indicated cytomegalovirus retinitis, 1 maxillary sinusitis, 1 Clostridiurn di f ic i le colitis, and 1 Pseudomonas urinary tract infection.

Of the 36 episodes of opportunistic infection identified, candidal infections were the most common, with 16 documented infectious episodes and 4 episodes of thrush seen in 39% of the patients. Pneumocystis pneumonia was the next most common opportunistic infection, with six episodes in six (15%) patients. Cytomega- lovirus, C. neoformans, and Aspergillus species also were seen in 1070, 7%, and 5% of patients, respectively.

A total of 14 infections by members of the Herpes- virus family were seen in 12 (30%) patients. Gastroin- testinal parasitic infections occurred in 15% of patients. One patient had a disseminated Strongyloides infection

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Table 3. Microbiologically Documented Infections: Organisms and Sites*

Fungal Caiidida albicaiis

Oral cavity Blood Urinary tract Esophagus Vagina Skin Lung Myocardium Stomach

C r y tococcus

Meninges Blood

Lung

Lung and blood

iieoforniaiis

Aspergillus species

Caiidida tropicalis

Viral Cytoniegalovirus

Blood Lung Adrenal medulla Skin

Herpes simplex Oral cavity Esophagus Nasal Vaginal

Lo c a 1 i z e d Disseminated skin

Varicella/zoster

Influenza A; lung Hepatitis B Molluscuni

coiitagiosuni

Parasitic Piieuniocystis caririii

Stroiigyloides Lung

stercoralis Stool Sputum

Giardia laniblia; stool

Isospora belli Trichonioiias

vagiiialis Scabies Blastocystis honiiiiis;

stool 1

Bacterial Staphylococcus aureus

Blood Skin Urine Pleural fluid

Staphylococcus epidermidis

Blood

Sinus Blood Urine

Pseudonionas aerugiiiosa

Staphylococcus heniolyticus

Blood Urine

Blood Urine

Blood Urine Wound

Enterococcus Blood Urine Wound

Blood

Blood Ascites Pleural fluid

Citrobacter Blood

Corynabacterium (JK) Blood

Enterobacter Blood

Acinetobacter

Escherichia coli

Klebsiella pneunionia

Streptococcus fecalis

Streptococcus heniolyticus

calcoaceticuus

Aerococcus viridans Blood

Blood

5 2 2 1

3

2 1 1

1 1

2 2

1 1 2

1 1 1

2

1 1 1

1

1

1

1

1

* An infectious episode may involve the same organisms affecting multiple sites. t Numbers in parentheses denotes the number of infections diagnosed at post- mortem examination.

Table 4. Clinical Infections

No. of episodes

Lobar pneumonia 4 Sinusitis 5 Otitis media 1

Foot infection 2 Urethritis 1 Thrush* 4

Pharyngi tis 1

Conjunctivitis 1 Cytomegalovirus retinitis 1

* Represents oral lesions consistent with candida infection but not microbiologically confirmed. Lesions responded to empiric antifungal therapy.

with larvae present in her stool and sputum. Staphylo- COCCUS aureus sepsis was the most common serious bacterial infection and occurred exclusively during treatment for ATL. Of the seven patients who had s. epidermidis or aureus sepsis, three had a central line and were neutropenic, one was neutropenic only, one had a central line only, one did not have an obvious source of infection, and for one the information regarding central line and neutrophil count was not available.

Clinical Course of Serious Infections

Five of the six P. carinii pneumonias occurred during treatment for ATL. None of the patients was receiving prophylaxis at the time of infection. Three of the six patients died of uncontrolled infections despite administration of intravenous trimethoprim/sulfamethoxazole. A fourth patient died of sepsis and respiratory fail- ure during treatment for a documented P. carinii pneumonia and at autopsy had bilateral interstitial pneumonitis with interstitial fibrosis, although no Pneumocystis organisms were found. Of the three patients who survived their infection, none have experienced a recurrence in 20 months, 11 months, and 2+ months of follow-up. The third patient is continuing a regimen of trimethoprim/sulfamethoxazole prophylaxis at this writing.

Three patients had cytomegalovirus pneumonia. The diagnosis was made within a month of the patient’s death in two instances and at autopsy in the third. The infection was a contributory cause of death in at least two of these patients. The only patient who was treated early enough to assess response started to improve with ganciclovir before dying of disseminated aspergillosis. The two patients with cryptococcal meningitis had chronic ATL, and in each the infection presented early in the disease course. They both responded well to am-

Infections and Immunodeficiency in ATL/White e t al. 1603

Table 5. Infectious Episodes and ATL Subtypes

No. of patients No. of infections Incidence ATL subtype With infection Total Serious Other Total Total* Serioust

Acute/crisis 22 26 37 38 75 2.32$ 1.156 Chronic 6 9 18 9 27 0.68 0.46 Lymphoma 4 6 2 8 10 1.20 0.24

ATL: adult T-cell leukemia/lymphoma. * Total number of infections divided by the number of patient-years (see Methods). t Number of serious infections divided by the number of patient-years (see Methods). $ The incidence for acute/crisis is significantly greater than for chronic (P < 0.0001) or lymphoma (P < 0.002). 5 The incidence for acute/crisis is significantly greater than for chronic ( P < 0.0001) or lymphoma ( P < 0.0001).

photericin therapy, with or without flucytosine. Neither patient experienced a recurrence of meningitis. Ten patients in our study had two or more concurrent serious infections. Four of these patients died because of the inability to control one of these infections.

Incidence of Infections and ATL Subtypes

Episodes of infection occurred in patients with each of the three subtypes of ATL represented (Table 5). The incidence of total infections was significantly greater in the patients with the acute subtype (2.32/patient year) than in those with the chronic subtype (0.68/patient year) ( P < 0.0001) or the lymphoma subtype (1.20/patient year) ( P < 0.002). This also was true for serious infections in these patient groups: acute (l.l5/patient year) versus chronic (0.46/patient year) (P < 0.0001) or lymphoma (0.24/patient year) ( P < 0.0001).

Immune Function Abnormalities

Indicators of immune function were analyzed before the patient received monoclonal antibody therapy. Hu- moral immune function in 13 patients was studied in vitro by a pokeweed mitogen stimulated immunoglobulin biosynthesis assay. None of the patients’ PBMC populations made meaningful amounts (i.e., >lo0 ng/ lo6 cells in culture) of immunoglobulin M (IgM), IgG, or IgA. In addition, immunoglobulin biosynthesis of normal PBMC was suppressed when co-cultured with equal numbers of patient PBMC in all of the 13 patients examined. Only one of these patients produced a humoral immune response to the infused murine monoclonal antibody, anti-Tac.

Serum immunoglobulin levels were obtained in 33 of the 41 patients. Mean serum IgG was 1,200 f 578 mg/dl (normal range, 650-1,590 mg/dl), mean IgM was 75 k 62 mg/dl (normal range, 75-408 mg/dl), and mean IgA was 179 f 122 mg/dl (normal range, 93-393

mg/dl). Among the eight patients with low IgG, IgA, or IgM levels there did not appear to be a detectable in- crease in the incidence of infection when compared with the group of patients with normal immunoglobulin levels. Two patients had IgG levels below 100 mg/ dl. There was only one bacterial infection during the combined 12 months of follow-up for these patients. None of these patients had a tumor response to therapy, so we are unable to determine if the deficiencies were reversible with effective antitumor therapy.

Twenty-three of the 27 (85%) patients skin tested for delayed type hypersensitivity were anergic. Four (15%) patients had skin test reactivity to one or more antigens before IL-2 receptor directed therapy. Seven of the 19 patients experiencing a remission with these antibody therapies had skin test reactivity to recall antigens after having a response to therapy (5 partial responses, 2 complete responses). All seven patients were anergic before treatment. Although most patients were anergic to skin tests, opportunistic infections (pneumocystis, cytomegalovirus pneumonia, Aspergillosis, cryptococcal meningitis, Candida sepsis) occurred even in patients who showed skin test reactivity.

Overall, 9 of the 34 evaluable patients who received murine anti-Tac (unmodified or yttrium labeled) had human anti-mouse antibody (HAMA) develop after monoclonal antibody therapy. All of these patients had HAMA develop only after they had a partial or complete response to therapy. Two of these patients had reactions to recall antigens before antibody administration, and of the seven who were anergic before treatment, all of the six who were retested had skin test reactivity develop after treatment. The median time to development of HAMA was 116 days after the first dose of antibody (range, 11-812 days).

Discussion

In 1973, Yodoi et al.”,12 encountered a patient with chronic T-cell leukemia, which was later identified as

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the first documented case of a new disease entity, ATL. The geographic clustering of ATL in southern Japan, the Caribbean islands, and the southeastern United States coincides with areas endemic for HTLV-L6?l3 Most patients with ATL have a clonal pattern of HTLV-I provi- rus integrated in the DNA of the leukemic cells. The clinical manifestations of this disease are variable and include lymphadenopathy, leukemia, liver and spleen enlargement, skin rash, lytic bone lesions, severe infections, and manifestations of hyper~alcemia.~, '~ The leukemic cells are small to medium size lymphocytes with basophilic cytoplasm and indented or deeply cleft nu- clei with clumped chromatin. The flower cell with a multilobulated nucleus is a characteristic finding. Anal- ysis of their immunophenotype by fluorescence activated cell sorting reveals a characteristic pattern of

Four clinicopathologic subtypes have been defined that encompass the diverse clinical presentations: smoldering, chronic, lymphoma, and the acute type. The smoldering and chronic subtypes can enter a crisis phase during which they behave like the aggressive, rapidly progressive acute subtype. This classification has significant prognostic value, with the acute and lymphomatous forms being associated with a much poorer prognosis than are the smoldering or chronic forms7

CD2+, CD3+, CD4+, CD7-, CD25+.

Clinical and Laboratory Evidence of Immunodeficiency in ATL

Modest immune suppression is evident in otherwise healthy carriers of HTLV-I. Yamaguchi et al.I5 examined the T cell subsets in 15 HTLV-I carriers with normal leukocyte counts. Twelve had atypical cells present on examination of peripheral blood smears. Absolute numbers of cells staining with CD3, CD4, CD8, and CD2 were normal. The CD4/CD8 ratios were normal. Despite apparently normal numbers of T cells and no evidence of malignancy, 11 of the 12 patients had infections. Hyperinfection with Strongyloides stercoralis attributable to a selective defect in the humoral response to the organism has been reported frequently in HTLV-I carriers. l6-I8

Despite the many reports of opportunistic infections in HTLV-I carriers, there is no comparison in the literature of the infection incidence of carriers and patients with ATL. In our study, 39% of all patients had a pretreatment infection, and 15% had a serious infection during that period. In data compiled by the Japanese Lymphoma Study Group on 818 patients with ATL, 26% had infections on pre~entation.~ The pretreatment incidence of opportunistic infections in our study (6 in-

fections in 26.48 patient years = 0.227/patient year) is so high that if it were uniformly seen among HTLV-I carriers, there would be large numbers of opportunistic infections in this population, and at least some of our patients would have been expected to have these infections develop before their diagnosis of ATL. The revers- ibility of anergy in some patients with ATL who respond to therapy supports the presence of a superim- posed worsening of immune function of ATL over the HTLV-I carrier state.

There is extensive in vitro evidence for ATL cells having an immunosuppressor a c t i ~ i t y ~ * ' ~ - ~ ' that corre- lates with the clinical state of profound immunosuppression of these patients. In a previous study we reported suppression by freshly isolated ATL cells in a pokeweed mitogen driven immunoglobulin biosynthesis assay.3 We found that five of nine ATL cell populations functioned as suppressors in co-culture with normal B cells and irradiated helper T cells. In contrast, the malignant cells of patients with the HTLV-I negative S&zary syndrome, a CD4 positive T-cell leukemia, were able to provide help to normal B cells in this assay. None of the patients in the current study produced immunoglobulin in the pokeweed mitogen assay, and they were not able to offer T-cell help to isolated normal B cells.

Despite having generally normal total immunoglobulin levels, our patients had a defect in the ability to mount an antibody response to a new antigen chal- lenge. Most patients did not have an antiglobulin response to the infused murine monoclonal anti-Tac, and in the nine patients who had HAMA develop, the onset was quite late. For comparison, 7 of 10 patients who were tested after receiving monoclonal murine anti-Tac, cyclosporin A, prednisone, and azathioprine after renal transplant had HAMA develop, all within 1 month."

Shirakawa et al.23 found that fresh lymphocytes and cell lines from patients with ATL produced a soluble factor that suppressed concanavalin A mediated proliferation of normal PBMC in co-culture. This group isolated a 50-70 KD factor that suppressed production of IL-2 by T cells and responsiveness of T cells to IL-2 but not the expression of the IL-2 receptor. ATL cells in vitro constitutively produce a number of cytokines that can suppress immune function, including transforming growth factor p.24

In vivo evidence of depressed cell mediated immunity was manifested in our patients by an inability to respond to intradermal antigen inoculation. These defects frequently were corrected in patients who responded to antibody therapy. Despite the large numbers of CD4 positive cells in the peripheral blood of our patients, in in vitro assays these cells suppressed normal B-cell production of immunoglobulin. The studies per-

Infections and Immunodeficiency in ATLIWhite e t al. 1605

formed in our patients showed generalized deficiencies among patients but did not allow the identification of a subgroup at greater risk for infection.

Comparison of Infectious Propensity in ATL W i t h that in Other Hematologic Malignancies

Defects in cell mediated immunity in patients with Hodgkin’s disease have been clearly delineated,25-27 but infections in these patients are predominantly bacterial and viral (e.g., varicella and Herpes simplex). Two large studies have looked at the development of infections in patients with Hodgkin’s disease throughout the course of their illness. Notter et a1.’ reviewed the records of 300 patients from diagnosis to death or last follow-up. The mean patient age was 31.2 years, and the mean follow- up period was 5.7 years. A transformation of the authors’ results to determine incidence yields 0.104 infections/patient year and 0.066 serious infections/patient year. Another study’ of 210 patients with a mean patient age of 27 years and a mean follow-up of 62.6 months had an incidence of serious infections of 0.075/ patient year. The overall incidence of infection in our group of patients with ATL was 1.40/patient year and 0.71 serious infections/patient year, ten times higher than that observed in patients with Hodgkin’s disease.

Bishop et aLZ8 reviewed the infectious complications in a group of patients with non-Hodgkin’s lymphoma from lymphoma diagnosis to death or last follow-up. The median age of the 125 patients was 50 years, and the median follow-up period was 23 months. The article does not define which infections were serious, but the overall incidence of infection would be ap- proximately 0.56 infections/patient year, using the median follow-up as an approximation of the mean. There were only four opportunistic infections in this group, for an incidence of 0.017/patient year. The 36 opportunistic infections that occurred in our patients gives an incidence of 0.450/patient year.

Moriuchi et aLZ9 examined the records of patients with ATL and those with non-ATL non-Hodgkin’s lymphoma at their hospital and found a three times greater incidence of the overall number of infections and the pretreatment.infections in the ATL group. The dose intensity of chemotherapy was equivalent for patients with NHL and those with ATL (Y. Moriuchi, personal communication).

At least one randomized, prospective study has reported that third generation non-Hodgkin’s lymphoma chemotherapy regimens induce more fatal events than do first generation regimen^.^' There may have been some differences in the intensity of chemotherapy received by patients with different subtypes of ATL in our

study that affected the infection incidences. Among patients with acute ATL, 19 of 26 (73%) had chemotherapy for a median of 5.5 months/patient. Of the nine patients with chronic ATL, six (67%) had chemotherapy for a median of 5.5 months. All of the six patients with lymphoma type ATL had chemotherapy for a median of 2.5 months. Nine of the patients with acute ATL were treated with third generation chemotherapy regimens or deoxycoformycin, whereas no patient with chronic and only one patient with lymphoma type ATL received such regimens. In addition, some of these patients received these regimens without antibiotic prophylaxis. This may be responsible for some of the difference in infection incidence among the acute, chronic, and lymphoma subtypes.

The chronic or cutaneous types of ATL may present similarly to mycosis fungoides or S6zary and be difficult to distinguish hist~logically.~~ Axelrod et al.33 reviewed the records of 356 patients with mycosis fungoides or S6zary syndrome. The median age at diagnosis was 58 years, and the median follow-up was 44 months. The overall incidence of infection was 0.279 infections/patient year. Most (60%) were bacterial skin infections, but several serious, systemic infections were identified. Using our definitions, this study found 0.090 serious infections/patient year. There were only five opportunistic infections that occurred during the study, yielding an incidence of 0.005/patient year. Thus, the development of an opportunistic infection in a patient with the diagnosis of mycosis fungoides or S6zary syndrome should stimulate a re-evaluation of the diagnosis, with consideration given to ATL.

Recommendations

In patients without antibodies to cytomegalovirus, we recommend the use of cytomegalovirus-negative blood products. We routinely use irradiated or leukocyte poor blood products to prevent cytomegalovirus infection and to guard against graft-versus-host reactions. We and others29z34 recommend prophylaxis against pneumocystis with trimethoprim/sulfamethoxazole. Most patients in our study did not receive antifungal prophylaxis during their treatment for ATL. However, because 14 of the 20 indicated or documented Candida infections occurred during chemotherapy, we recommend the consideration of antifungal prophylaxis in patients being treated with combination chemotherapy or high dose steroids. Patients with ATL should be examined for disseminated Strongyloides infection with stool and sputum direct examination, particularly, but not exclusively, in patients originating from endemic areas. Al- though surprisingly uncommon in patients with ac-

1606 CANCER April 2,1995, Volume 75, No. 7

quired immune deficiency syndrome, even in endemic areas,35 fatal infections with this organism have been reported in non-HTLV-I induced lymphoma^,^^ and such a possibility should be considered in ATL. Immu- nization with live virus vaccine is not recommended in these patients.

Summary

The care of patients infected with HTLV-I is challenging from the point of view of the malignancy and infections. The development of ATL in an HTLV-I carrier significantly worsens the preexisting immune deficiency and places patients with ATL among the most vulnerable immunocompromised patients.

We have looked at the incidence of infection in patients with three subtypes of ATL throughout the course of their disease. The presence of opportunistic infections during the pretreatment phase supports the role of a process of disease related immunosuppression, which is evidenced also by the in vitro tests of immune cell function and the high frequency of anergy among patients. We conclude that the opportunistic infections were the result of the immunosuppressive effects of HTLV-I and the worsened immunosuppression attend- ing the transformation to ATL. The systemic bacterial infections predominantly occurred during periods of chemotherapy and were more likely secondary to other factors (e.g., neutropenia and the presence of central ve- nous catheters).

When compared with reports of infections in other hematopoietic malignancies, the incidence of infections in patients with ATL, particularly opportunistic infections, is many times greater. We have been unable to identify a laboratory indicator of greater susceptibility to infection; however, it appears that patients with acute ATL may be at higher risk. In our patients, this may have been the result of these patients receiving more intensive chemotherapy. Interestingly, the incidence of infection in patients was not significantly increased during the administration of anti-IL-2 receptor based therapies, whereas it was increased during chemotherapy.

In conclusion, ATL is a profoundly immunosup- pressing malignancy manifesting an extremely high incidence of infectious episodes per patient year. The incidence of infection appears to be greater than for mycosis fungoides and Hodgkin’s and non-Hodgkin’s lymphomas.

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