Acute lymphoblastic leukemia

Study objectives: To evaluate lung function in patients cured from childhood acute lymphoblastic leukemia (ALL) with chemotherapy alone or plus bone marrow transplantation (BMT). Pulmonary toxicity is a well-recognized side effect of many ALL treatments.

Design: Cross-sectional study conducted at least 3 years after cessation of therapy.

Setting: Outpatient pneumology department of the University Hospital.

Patients: Forty-four subjects (age range at observation, 6 to 23 years): 21 treated only with intensive Berlin-Frankfurt-Munster (BFM)-type chemotherapy for newly diagnosed ALL (group A), and 23 treated with chemotherapy plus BMT (group B).

Measurements: A detailed history of smoking habit, respiratory symptoms, and diseass was recorded directly from the patients with the aid of their parents. A complete physical examination and lung function testing (lung volumes and diffusion capacity for carbon monoxide [DLCO]) were performed in all subjects.

Results: No patient reported acute or chronic respiratory symptoms or diseases. In group A patients, lung function was in the normal range, except for three subjects in whom there was an isolated impairment of DLCO. In group B patients, lung function was markedly impaired, with more than half the patients having an abnormal DLCO. A statistically significant difference was found between the two groups for FVC (p = 0.022) and DLCO (p = 0.004).

Conclusions: Intensive, BFM-type frontline chemotherapy is not associated with late pulmonary dysfunction; however, retreatment including BMT can frequently injure the lung. Thus, in patients who undergo BMT and whose life expectancy is long, careful monitoring of lung function and counseling about avoiding additional lung risk factors is recommended. (CHEST 1999; 116:1163-1167)

Key words: acute lymphoblastic leukemia; long-term lung function

Abbreviations: AIEOP = Associazione Italiana di Ematologia ed Oncologia Pediatrica; ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; BMT = bone marrow transplantation; DLCO = diffusion capacity for carbon monoxide

Advances in treatment have dramatically improved the survival rate of children affected by acute lymphoblastic leukemia (ALL).[1] These treatments are, however, potentially associated with vital organ system damage, which may become clinically evident many years later and may adversely affect long-term survival and the quality of life of cured patients.

Pulmonary toxicity is a well-recognized side effect of radiotherapy and some cytostatic drugs, such as busulphan,[2] used in conditioning regimens for bone marrow transplantation (BMT). However, several other chemotherapeutic agents used in the frontline treatment of childhood ALL, eg, methotrexate and several alkylating agents, such as cyclophosphamide, may also affect pulmonary function.[3-5] Moreover, in most series, upper and lower respiratory tract infections are very common during therapy, and some of these infections can have long-term respiratory sequelae.[6]

Available data on pulmonary function in long-term survivors of childhood ALL, treated with chemotherapy alone or followed by BMT, are poor and conflicting, probably because of the different criteria used to select and treat the patients.[7-12] The aim of our study was to evaluate long-term lung function in patients cured from childhood ALL by either chemotherapy alone or chemotherapy plus BMT.

MATERIALS AND METHODS

Patient Selection and Study Protocol

In this cross-sectional examination of lung function, we included the survivors of childhood ALL treated in our pediatric department according to the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL 88 protocol[13] between 1988 and 1990 (group A) and all of those who received BMT between 1987 and 1994 (group B). Group A comprised 28 patients from an initial 35 (6 died of relapse and 1 of infection), and group B, 27 from an initial 63 (17 died of relapse, 3 of interstitial pneumonia, 8 of graft-vs-host-disease, 5 of multiorgan failure, 1 of encephalitis, and 2 of cerebral hemorrhage). Seven patients from group A and four from group B were lost to follow-up because they lived abroad or far from our department. All but 1 of the 21 group A patients had been in first continuous remission until the cross-sectional observation. The exception was one patient in second remission after a testicular relapse; he had not undergone BMT because of the lack of a related or unrelated donor. All 23 group B patients were treated with chemotherapy plus BMT. The characteristics of the population studied are reported in Table 1.

Table 1--Characteristics of the Patient Included in the Study(*)

(*) Values given as median (range) unless otherwise indicated.

All patients were examined at least 3 years after stopping therapy. All information about stage of disease and treatment were obtained from clinical records. During the examination, a detailed history of smoking habit, respiratory symptoms, and diseases was recorded directly from the patients with the aid of their parents. A complete physical examination and lung function tests were then performed in all patients.

Clinical Data Collection

The children in group A had been stratified and treated according to the then current AIEOP-ALL 88 study: Five of 21 patients were eligible for the standard risk protocol (8801), 11 of 21 for the intermediate one (8802), and 5 of 21 were in the high-risk group (8803). Treatment included Berlin-Frankfurt-Munster (BFM)-type intensive polychemotherapy with prednisone (60 mg/[m.sup.2] qd for 4 weeks), dexamethasone (10 mg/[m.sup.2] qd for 3 weeks) vincristine (1.5 mg/[m.sup.2] for 8 doses), alkylating agents (cyclophosphamide, 1 g/[m.sup.2] for 3 doses), anthracyclines (daunorubicin, doxorubicin, 30 mg/[m.sup.2] for 3 doses), methotrexate (5 g/[m.sup.2] given IV over 24 h, 4 courses IM weekly for 18 months), cytarabine (75 mg/[m.sup.2] for 24 doses), L-asparaginase (10,000U/[m.sup.2] for 12 doses), and antimetabolites (6-mercaptopurine, 6-thioguanine, 25 to 50 mg/[m.sup.2]. The various treatment regimens for each patient are summarized in Table 2. Treatment directed at the CNS included extended intrathecal chemotherapy, which was associated with cranial irradiation only in high-risk patient (12 Gy if [is less than or equal to] 2 years of age, or 18 Gy if [is greater than or equal to] 2 years. The child who experienced testicular relapsed received gonadal and cranial irradiation and a second course of chemotherapy according to protocol BFM-REZ 90.[13]

(*) IDR = idarubicin; DNM = daunorubicin; DXR = doxorubicin; VP16 = etoposide; ARA-C = cytarabine; VCR = vincristine; VDN = vindesine; VM26 = teniposide; L-ASP = L-asparaginase; 6MP = 6-mercaptopurine; IFO = ifosfamide; EDX = cyclophosphamide; DEX = dexamethasone; PDN = prednisone; MTX = methotrexate; 6TG = 6-thioguanine; X = received treatment.

The children in group B received diffrent AIEOP first-line protocols for high-risk patients, namely protocols 85 to 87, which were based on the experience of the Children Cancer Group-like studies, and 88 and 91, which were based on BFM startification and treatment criteria.[13-15] These protocols included multiple cytotoxic drugs such as prednisone, vincristine, daunorubicin, methotrexate, cytosine, arabinoside, L-asparaginase, 6-mercaptopurine, idarubicin, etoposide, vindesine, teniposide, and ifosfamide (Table 2). Because many of these patients had been treated before BMT in other centers, it is not possible to give more precise data on the specific drugs received; indeed, no information at all was available in 1 patient. Details of the above 2-year frontline treatments are reported elsewhere.[13-15] Twenty-two patients had fractionated total body irradiation in their conditioning regimen, and only 1 received busulphan. BMT was performed in five patients in first complete hematologic remission and in the other patients, who had experienced medullary relapses, in second or third remission. Seven patients were given autologous BMT, and 16 were given allogeneic BMT. Seven patients had acute graft-vs-host disease, and five had chronic graft-vs-host disease.

Respiratory Symptoms

The presence of cough and/or phlegm, dyspnea, and wheezing both at rest and during exercise was recorded at follow-up appointments, the details coming directly from the patients or from their parents. Information on the entire period from when therapy was stopped was obtained from clinical records; routinely, patients had been examined about 2 months after cessation of treatment.

Pulmonary Function Testing

Measurements of lung volumes were obtained by a water-sealed spirometer (Pulmonet III; SensorMedics; Anaheim, CA). Measurements were performed according to the European Community for Coal and Steel statements[16] and the American Thoracic Society recommendations.[17] The best of three FVC measurements was recorded, as well as [FEV.sub.1] and [FEV.sub.1]/FVC ratio.

Diffusion capacity for carbon monoxide (DLCO) was determined using the single-breath method (Transferscreen-II; Jaeger; Wuerzburg, Germany) and corrected for hemoglobin content. Because the correction of DLCO for alveolar volume did not influence the results of our analysis, only uncorrected DLCO values are reported. Measurements were performed according to the European Community for Coal and Steel[16] and American Thoracic Society[18] guidelines. Because this test is more difficult and requires greater cooperation to perform than FVC, DLCO data are unavailable for six patients.

Functional data are expressed as an SD score [defined as (actual result - predicted values)/population SD] and are defined as pathologic when [is less than] - 1.64, corresponding to less than the fifth percentile.[19] Taking into account the pubertal stage of each subject evaluated using Tanner's Method,[20] the SD score was corrected according to the tables reported by Rosenthal et al.[21, 22] Reference values were those from a recent cross-sectional study on lung function in healthy school children, 4 to 19 years of age.[21, 22]

Statistical Analysis

Student's t test was used for comparing the functional variables of the two groups of subjects. Values of p [is less than] 0.05 were considered statistically significant.

Ethics

All participants and the parents of the children [is less than] 18 years old gave their written informed consent. The study was in accordance with the Helsinki II declaration and was approved by the local medical ethics committee of our hospital.

RESULTS

The patients of the two groups were approximately the same age at diagnosis of ALL and by examination had passed a similar interval between cessation of therapy and cross-sectional observation (Table 1).

At examination, all patients were found to be free from any acute disease and, in particular, acute respiratory disease. No patient reported chronic respiratory symptoms. None of the patients was a smoker.

The mean and SD of the functional variables expressed as a raw percent of predicted and as SD score are reported in Table 3; percentage of patients with SD scores still in the normal range but negative (between 0 and -1.64) and of those with clearly pathologic SD scores ([is less than] -1.64) for groups A and B are also reported. In group A, the mean values of all the functional variables were in the normal range; only three patients had an isolated impairment of DLCO. In group B, on the other hand, the mean values of FVC, [FEV.sub.1] and [FEV.sub.1]/FVC ratio were still in the normal range, although mean values of the SD scores for FVC and [FEV.sub.1] were negative; in fact, there was a significant proportion of patients with negative values of SD scores for FVC and [FEV.sub.1] (74% and 65%, respectively) and a few subjects with clearly pathologic values (9% and 9%, respectively). The mean value of SD score for DLCO in this group was clearly pathologic; indeed, 58% of subjects had an impairment of DLCO. A statistically significant difference was found between the two groups for FVC (p = 0.022) and for DLCO (p = 0.004).

(*) Values given as a mean [+ or -] SD unless otherwise indicated.

DISCUSSION

In our experience, none of our long-term survivors of childhood ALL have chronic respiratory symptoms. Subjects treated with chemotherapy alone have well-preserved lung function, whereas a portion of those who had been treated with chemotherapy plus BMT have notably impaired lung function, with decreased lung volumes and/or transfer factor.

The results found in group A are in agreement with those of Turner-Gomes et al[12] but not with the more recently published study of Nysom et al.[11] The characteristics of our patients are similar to those of the patients included in both these studies. However, there is a large difference in the interval between stopping therapy and cross-sectional observation; in the study by Nysom et al,[11] the patients received diagnoses between 1970 and 1990, whereas our patients received diagnoses between 1987 and 1994. The conflicting results can consequently be attributed to changes of therapeutic strategies over time. The authors themselves found that age at follow-up was significantly correlated with doses of the drugs and with lung function abnormalities, suggesting that they reflect changes in treatment protocols.

In the group of survivors treated with chemotherapy plus BMT, the frequent occurrence of lung function abnormalities and the absence of respiratory symptoms, even in the presence of marked reduction in lung volumes and in DLCO, is in substantial agreement with the results reported by Nysom et al[7] and Jenney et al.[10]

The comparison between our two groups shows a completely different outcome in the long-term effects on lung function. In as much as survivors who had undergone BMT were in second or third remission, having experienced medullary relapses, they had received a greater amount of chemotherapy than survivors without BMT; we cannot, therefore, disentangle the effect of chemotherapeutic drug toxicity from lung injury caused by BMT itself and its related treatments and complications.

Our study has some strengths over those published thus far: our patients had the same disease, the recruitment period was brief, the therapeutic protocols were homogeneous and up-to-date, the sample size was sufficiently large, and the two groups could be well separated. The weaknesses are that the study is cross-sectional and lacks baseline respiratory function data. We believe, however, that given the young age of our patients at diagnosis, it is unlikely that they already had abnormal respiratory function.

We can, therefore, conclude that first-line treatment of ALL with chemotherapy alone is safe insofar as its effect on pulmonary function are concerned; more aggressive treatment, including higher amounts of chemotherapy and BMT, can frequently damage the lungs. Thus, in patients who undergo BMT and whose life expectancy is now excellent, careful monitoring of lung function and counseling about avoiding additional risk factors (smoke, pollution, work exposure) is recommended, even in the absence of respiratory symptoms. New regimens devised to minimize long-term toxicity without compromising survival rates may be necessary for patients undergoing BMT.

ACKNOWLEDGMENT: The authors thank Dr. Rachel Stenner for her assistance in the preparation of the manuscript.

REFERENCES

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[2] Beinert T, Dull T, Wolf K, et al. Late pulmonary impairment following allogeneic bone marrow transplantation. Eur J Med Res 1996; 1:342-348

[3] Limper AH, Rosenow EC III. Drug-induced interstitial lung disease. Curr Opin Pulm Med 1996; 2:396-404

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[7] Nysom K, Holm K, Hesse B, et al. Lung function after allogeneic bone marrow transplantation for leukemia or lymphoma. Arch Dis Child 1996; 74:432-436

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[9] Shaw NJ, Tweeddale PM, Eden OB. Pulmonary function in childhood leukemia survivors. Med Pediatr Oncol 1989; 17:149-154

[10] Jenney ME, Faragher EB, Jones PH, et al. Lung function and exercise capacity in survivors of childhood leukemia. Med Pediatr Oncol 1995; 24:222-230

[11] Nysom K, Holm K, Olsen JH, et al. Pulmonary function after treatment for acute lymphoblastic leukemia in childhood. Br J Cancer 1988; 78:21-27

[12] Turner-Gomes SO, Lands LC, Halton J, et al. Cardiorespiratory status after treatment for acute Lymphoblastic leukemia. Med Pediatr Oncol 1996; 26:160-165

[13] Conter V, Arico M, Valsecchi MG, et al, for the "Associazione Italiana Ematologica Oncologia Pediatrica" (AIEOP). Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Munster based intensive chemotherapy. J Clin Oncol 1995; 13:2497-2502

[14] Reiter A, Schrappe M, Wolf-Dieter L, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994; 84:3122-3133

[15] Paolucci G, Masera G, Vecchi V, et al. Treating childhood acute lymphoblastic leukemia (ALL): summary of ten years experience in Italy; ALL Steering Committee of the Associazione Italiana Ematologica Oncologica Pediatrica (AIEOP). Med Pediatr Oncol 1989; 17:83-91

[16] Report Working Part. Standardization of lung function tests. Eur Respir J 1993; 6(Suppl 16):3-52

[17] American Thoracic Society. Standardization of spirometry. Am J Respir Crit Care Med 1995; 152:1107-1136

[18] American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Am J Respir Crit Care Med 1995; 152:2185-2198

[19] Quanjer PH, Tammeling GJ, Cotes JE, et al. Lung volumes and forced ventilatory flows: standardized lung function testing. Eur Respir J 1993; 6(suppl 16):5-40

[20] Tanner JM. In: Growth at adolescence. 2nd ed. Oxford: Blackwell, 1962

[21] Rosenthal M, Bain SH, Cramer D, et al. Lung functions in white children aged 4 to 19 years: I. Spirometry. Thorax 1993; 48:794-802

[22] Rosenthal M, Cramer D, Bain SH, et al. Lung function in white children aged 4 to 19 years: single breath analysis and plethysmography. Thorax 1993; 48:803-808

(*) From the Institute of Respiratory Diseases (Drs. Fulgoni, Zoia, Corsico, Beccaria, and Cerveri), and Department of Pediatrics (Drs. Georgiani and Bossi), IRCCS Policlinico "S. Matteo," University of Pavia, Italy.

Supported by research project, IRCCS-Policlinico S. Matteo, Pavia N.681RCR96/02.

Manuscript received December 15, 1998; revision accepted April 28, 1999.

Correspondence to: Isa Cerveri, MD, Instituto Forlanini, IRCCS, Policlinico "S. Matteo," Universita' di Pavia, via Taramelli 5, 27100 Pavia, Italy; e-mail: isa@mbox.systemy.it3

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