The impact of isolated central nervous system relapse following initial complete remission in childhood acute lymphocytic leukemia

Volume 97 Number 3

Brief clinical and laboratory observations

bitors of coagulation in nonhemophiliac children, J PEDIATR 96:439, 1980. 6. Green D: Spontaneous inhibitors of factor VIII, Br J Haematol 15:57, 1978. 7. Klein KG, Parkin JD, and Madaras F: Studies on acquired inhibitors of factor VIII induced by penicillin allergy, Clin Exp Immunol 26:155, 1976. 8. Schleider MA, Nachman RL, Jaffe EA, and Coleman M: A clinical study of the lupus anticoagulant, Blood 48:499, 1976.

4 29

9. Feinstein DI, and Rappaport SI: Acquired inhibitors of blood coagulation, Prog Hemost Thromb 1:75, 1972. 10. Kirk PJ, McLellan DS, and Aronstram A: Acquired circulating anticoagulant in a four year old child, Br Med J 2:1296, 1976. 11. BeckDW, Strauss RG, Kisker CT, and Henriksen RA: An intrinsic coagulation pathway inhibitor in a three year old child, Am J Clin Pathol, 71:470, 1979.

The impact of isolated central nervous system relapse following initial complete remission in childhood acute lymphocytic leukemia Robert J. Wells, M.D.,* Robert M. Weetman, M.D., and Robert L. Baehner, M.D., Indianapolis, Ind,

CENTRAL NERVOUS SYSTEM involvement has long been recognized as a complication of acute lymphocytic leukemia? This complication occurs in up to 50% of patients with ALL who do not receive effective CNS prophylaxis. 2' :' Once a CNS relapse develops, further CNS or bone marrow relapses and death rapidly ensue. 4 In the past two decades the incidence of CNS relapse has been reduced, to less than 10% by employing a combination of cranial radiation and intrathecal methotrexate immediately after initial remission has been attained) Patients who received CNS prophylaxis without irradiat i o n and who later have a CNS relapse can be effectively treated with cranial-spinal radiation and intrathecal methotrexate with minimal complications.6 At the present time, however, both the outcome and ideal therapy are uncertain for those patLents initially treated with cranial radiation and intrathecal methotrexate but who later have an isolated CNS relapse. This report will documeni the course of ten such patients. MATERIALS AND METHODS Patients. All patients in this study were treated by the Division of Hematology/Oncology of the James W. Riley From the Department of Pediatrics, Section of Hematology/ Oncology, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine. Supported by grants PHS T32-AM 719303 from the National Institutes of Health and by a grant from the Riley Memorial Association. *Reprint address: Section of Hematology/ Oncology, Riley Hosflital Room P 132, Indiana University School of Medicine, 1100 W. Michigan, Indianapolis, 1N 46223.

0022-3476/80/090429+04500.40/0 9 1980 The C. V. Mosby Co.

Hospital for Children between April, 1974, and December, 1979. The diagnosis of ALL was confirmed in all cases by examination of bone marrow aspirates. All patients also had their cerebrospinal fluid examined at the time of diagnosis and no patient in this study wa s found to have evidence of CNS leukemia. A total of 196 patients presented with newly diagnosed ALL during this time. All patients were initially treated in accordance with the Abbreviations used: ALL: acutelymphocytic leukemia CNS: central nervous system CSF: cerebrospinal fluid Children's Cancer Study Group protocol for ALL being used at the tim e of their diagnosis. Generally this involved induction therapy with vincristine, prednisone, and Lasparaginase, CNS intensification with six doses of intrathecal methotrexate plus 1,800 to 2,400 rads cranial radiation given in the second month of therapy, and maintenance with 6-mercaptopurine and methotrexate (with the possible addition of other drugs depending on protocol randomization, including vincristine, prednisone, cytosine arabinoside, cyclophosphamide, and adriamycin). Relapse of the central nervous system was documented by the demonstration of lymphoblasts in the CSF using the cytocentrifugation method. CSF blast cell counts ranged from 24 tO 3,800 cells/mm 3. The number of blasts did not correlate with the outcome. When a CNS relapse was discovered, a bone marrow aspirate was performed. Only those patients with continued bone marrow remis-

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The Journal of Pediatrics September 1980

Table. S u m m a r y of clinical a n d laboratory data

Patient

Age at diagnosis of A L L

WBC at diagnos&

Interval to CNS relapse(mo)

Systemic reinduction

CNS maintenance

Time from first to second relapse

1

15 mo

88,000

14

Yes

Yes

2

3 yr 6 mo

29,000

17

Yes

Yes

3

14 yr

136,000

5

Yes

No

4

5 yr

12,000

24

Yes

Yes

5

25 mo

3,000

12

Yes

Yes

6

34 mo

19,000

39

Yes

Yes

7

5 yr 8 mo

3,000

36; testicular also

Yes

Yes

7 mo BM

8

8 yr

12,000

10

No

No

7 mo BM

9

4 yr 10 mo

3,000

17

Yes

Yes

5 mo BM

10

5 yr 8 mo

14,000

22

Yes

No

6 mo CNS, l 1 mo CNS

Current status CR 33 mo after relapse CR 37 mo after relapse; off therapy 1 mo Dead 7 mo after relapse CR 27 mo after relapse CR 13 mo after relapse CR 25 mo after relapse Dead 17 mo after first relapse Dead 13 mo after first relapse Dead 19 mo after first relapse CR 16 mo after first relapse

CNS complications

Fatal leukoencephalopathy Guillian- Barr6

Abnormal EEG and CT scan; increased CSF protein

Abbreviations used: ALL = Acute lymphocytic leukemia; WBC = white blood count; EEG = electroencephalogram; CSF = cerebrospinal fluid; CR = complete remission; CT scan = computerized tornography scan; CNS = central nervous system; BM ~ bone marrow. System Reinduction and CNS maintenance, see text.

sion (less t h a n 5% blasts) at that time are i n c l u d e d in this study. T h e C N S relapses were treated with intrathecal m e t h o trexate biweekly until the C S F was clear o f blasts, a n d then weekly until a total of six doses h a d b e e n given. T h e patients were t h e n treated with cranial (2,400 rads)-spinal (1,200 rads) radiation. Most patients (eight of ten) then received a p r o g r a m which consisted o f intrathecal a d m i n istration o f m e t h o t r e x a t e m o n t h l y for six m o n t h s a n d then every o t h e r m o n t h for a year (a total o f 12 additional intrathecal doses of m e t h o t r e x a t e after i n d u c t i o n o f C N S remission over the next 18 months). Nine o f the ten patients also received a systemic r e i n d u c t i o n course of vincristine weekly, p r e d n i s o n e daily, a n d n i n e doses of n-asparaginase for one m o n t h after their C N S relapse. All patients were evaluated at m a x i m u m intervals o f one m o n t h with a history, physical examination, a n d complete blood count. L u m b a r p u n c t u r e a n d b o n e marrow aspiration were p e r f o r m e d every one to three months. F u r t h e r evaluations such as computerized t o m o g r a p h y ,

electroencephalogram, a n d psychologic evaluation were reqtiested w h e n clinically indicated. RESULTS The clinical courses o f the ten patients w h o qualified for this study are listed in the Table. All patients developed a C N S relapse while receiving systemic m a i n t e n a n c e c h e m o t h e r a p y . N i n e o f these patients h a d only a CNS relapse a n d were otherwise in complete remission. One patient (7) h a d a s i m u l t a n e o u s testicular a n d C N S relapse with b o n e m a r r o w showing a remission; this patient is included in the study. T h r e e a d d i t i o n a l patients were f o u n d w h o h a d a simultaneous b o n e m a r r o w a n d CNS relapse as their first relapse event; these three patients were excluded from the study. Five o f the ten patients are alive a n d in c o n t i n u o u s remission while receiving t h e r a p y 13 to 37 m o n t h s (median 27 m o n t h s ) after their C N S relapse. T h r e e patients developed b o n e m a r r o w relapses five to seven m o n t h s after their CNS relapse. All a r e n o w dead, with d e a t h

Volume 97 Number 3

occurring 13 to 19 months after the initial CNS relapse. One patient has had two further CNS relapses 6 and 11 months after the initial CNS relapse. This patient is again in complete remission 16 months after the first relapse. One patient died seven months after his initial CNS relapse while in complete remission; this patient was felt to have leukoencephalopathy on the basis of physical findings, increased CSF protein concentration, abnormal electroencelphalogram, and abnormal computerized tomography. Unforttinately an autopsy was not performed so this diagnosis could not be further confirmed. This was the only patient in the group to receive 42-hour methotrexate infusions as part of his maintenance chemotherapy and th e only patient to receive cranial-spinal radiation as part of his initial CNS intensification therapy. One other patient (4) developed a significant complication referable to the nervous system. Two months after his CNS relapse he developed a Guillian-Barr6-1ike syndrome consisting of muscle weakness, depressed tendon reflexes, and increased CSF protein concentration. These signs and symptoms cleared spontaneously over the next five months and the patient is now asymptomatic. Finally Patient 10, who has had three CNS relapses, now has an elevated CSF protein concentration and encephalopathic changes on both electroencephalogram and computerized tomography scan. DISCUSSION The patients in the report can best be compared to those of Willoughby,~ who received no initial cranial radiation for CNS prophylaxis and then had an isolated CNS relapse. Nine of these patients were treated with intrathecal methotrexate and cranial spinal irradiation. Seven of these nine patients developed subsequent relapses in the CNS or bone marrow at 7, 9, 17, 18, 22, 47, and 53 months after the initial relapse. Two patients remain disease-free off therapy for more than one year, at 56 and 57 months after the initial relapse. 7 No major complications of therapy were reported in this group of patients. Hustu et aP. 8 have reported a series of similar patients with comparable results. Relapses were reported from five to 52 months after the initial relapse, with the follow-up ranging from 33 to 67 months. Hustu and Aur 8 have reported a series of 16 patients who relapsed initially in the CNS after receiving cranial radiation as part of their initial therapy. These patients were treated with intrathecal methotrexate weekly or biweekly until their CSF cleared and then with monthly intrathecal medication as maintenance. It was planned to treat all patients with cranial spinal radiation at the conclusion of systemic chemotherapy, but only four patients remained relapsefree until that time; the remainder relapsed in the bone

Brief cfinical and laboratory observations

43 1

marrow (8) and CNS (4). The CNS relapses were treated with cranial spinal radiation. Of the total of eight who received radiation, four are still in remission and off therapy at 31 to 74 months. The CNS relapse therapy for the patients in our report consisted of four parts: initial intrathecal methotrexate, cranial-spinal radiation, systemic reinduction therapy, and finally CNS maintenance therapy with more intrathecal methotrexate. It is not possible to determine if all or only some of these are necessary to achieve these results. It is also difficult to determine if this method of therapy is better than that described by Hustu and Aur" for patients receiving previous cranial radiation, since the number of patients in both series is small. Another variable which could account for survival differences is improved systemic maintenance chemotherapy, from which our patients conceivably benefited, i n addition, the follow-up time for our patients is obviously shorter than for those of Hustu, so that a definite statement about the beneficial aspects of our therapy must await longer follow-up. Finally, of those patients in our series who had only an isolated CNS relapse, and who were started on the full therapy described including CNS maintenance and systemic reinduction, five of six remain in complete remission. The patients in this report have experienced at least two significant complications, one a fatal leukoencephalopathy and the other a Guillian-Barr6-1ike illness. In addition, a third patient has encephalopathic changes, which could be caused either by our failure to control his CNS leukemia or by the therapy itself. In summary, an isolated CNS relapse as the first relapse from initial complete remission in ALL can be treated with intrathecal methotrexate and cranial-spinal radiation in patients who received cranial irradiation as part of their initial CNS prophylaxis. One-haft of our patients had a bone marrow relapse, a CNS relapse, or other neurologic sequelae within seven months of the initial relapse. The remainder of the patients have all continued in maintained complete remission for 13 to 37 months after their initial relapse. REFERENCES

1. Price RA: Histopathology of CNS leukemia and complications of therapy, Am J Pediatr Hematol/Oncol 1:21, 1979. 2. Aur RJA, Simone J, Hustu HO, Waiters T, Borella L, Pratt C, and Pinkel D: Central nervous system therapy and combined chemotherapy of childhood lymphocytic leukemia, Blood 37:272, 1971. 3. Evans AE, D'Angio GJ, and Mitus A: Central nervous system complications of children with acute leukemia, J Pediatr 64:94, 1964. 4. Sullivan MP, Vietti TJ, Fernbach DJ, Gr~ffith KM, Hardy TB, and Watkins WL: Clinical investigations in the treat-

432

Brief cfinical and laboratory Observations

ment of meningeal leukemia: radiation therapy vs. conventional intrathecal methotrexate, Blood 34:301, 1969. Hustu HO, Aur RJA, Verzosa MS, Simone JV, and Pinkel D: Prevention of central nervous system leukemia by irradiation, Cancer 32:585, 1973. Willoughby MLN: Treatment of overt meningeal leukemia in children: Results of second MRC meningeal leukemia trial, Br Med J 1:864, 1976.

The Journal of Pediatrics September 1980

7.

Humphrey GB, Krous HF, Filler J, Maxwell JD, and Van Houtte JJ: Treatment of overt CNS leukemia, Am J Pediatr Hematol/Oncol 1:37, 1979. 8. Hustu HO, and Aur RJA: Extramedullary leukemia, Clin Haematol 7:313, 1978.

Diffuse fasciitis with eosinophilia: A steroid-responsive variant of scleroderma William J. Britt, M.D., Paul H. Duray, M.D., Mark V. Dahl, M.D.,* and Robert W. Goltz, M.Do, Minneapolis, Minn.

SHULMAN 1 first described two adult patients with diffuse fasciitis, h y p e r g a m m a g l o b u l i n e m i a , a n d periPheral b l o o d eosinophilia in 1974. R o d n a n et al 2 a n d C a p e r t o n a n d H a t h a w a y 3 each reported five similar patients, including a 4-year-old girl. C o m m o n findings included: (1) a b r u p t onset o f sleroderma-like i n d u r a t i o n o f skin over o n e or more distal extremities (rarely involving the trunk, sparing the face a n d hands), (2) absence of the R a y n a u d p h e n o m e n o n a n d visceral involvement, (3) peripheral blood eosinophilia, (4) h y p e r g a m m a g l o b u l i n e m i a (pred o m i n a n t l y IgG), (5) sclerotic a n d inflamed superficial fascia underlying cutaneous lesions, a n d (6) a favorable clinical a n d laboratory response to systemically administered corticosteroids. Since these initial reports, m a n y additional patients with similar findings have been described. 4-~ In this report we describe the clinical a n d pathologic findings o f diffuse fasciitis with eosinophilia in an 8year-old girl. Since this entity frequently responds favorably to corticosteroid therapy, this d i s o r d e r should be i n c l u d e d in the differential diagnosis o f acute scleroderm a - m o r p h e a - l i k e disorders o f the child. CASE REPORT An 8-year-old, previously healthy, white girl developed painful, tightened areas of the skin on her anterior legs. The affected areas were initially treated with topical corticosteroid cream, which gave some subjective improvement. Subsequently, new similarly involved areas developed on the skin of both anterior thighs and the flexor aspects of both upper arms. She was referred to the University of Minnesota for evaluation.

From the Departments of Pediatrics, Pathology, an~ Dermatology, University of Minnesota. *Reprint address': University of Minnesota, 420 Delaware St. S.E., Box 98--Mayo, Minneapolis, MN 5,5455.

The patient had no history of dysphagia, shortness of breath, musculoskeletal complaints, recent infections, allergies, exposure to toxins, or recent live-virus vaccination. A topical corticosteroid cream was the only medication the patient had received in the past year. Abnormal physical findings were limited to the skin and joints. A continuous band of taut, nontender, indurated skin with a somewhat atrophic epidermis extended from the dorsum of the foot to the lateral aspect .of the thigh on both legs, with circumferential involvement of the upper legs. A continuous band of similarly involved skin extended from the lateral upper arm to the wrist bilaterally. Similar patchy skin lesions were present on the posterior thorax. The face and hands were uninvolved. The cutaneous lesions contained areas of hyper- and hypopigmentation but no telangiectasia or calcinosis. There was no evidence of muscle weakness or atrophy. Although synovial involvement was not clinically apparent, there were flexion contractures of both knees and elbows. Laboratory studies disclosed the following values: hemoglobin, 13.9 mg/dl; WBC, 6,700/ram 3, with 47% polymorphonuclear leukocytes, 7% immature forms, 30% lymphocytes, 4% monocytes, and 10% eosinophils; platelet count, 373,000/mm3; absolute eosinophil count, 302/mm~; erythrocyte sedimentation rate (Westergren), 52 mm/hour. Serum IgG was elevated at 1,910 mg/ml, but levels of IgM, IgA, and IgE'were normal. No rheumatoid factor or IgG antinuclear antibody was detected. Other normal findings included total hemolytic complement, serum creatinine, serum creatine phosphokinase, blood urea nitrogen, serum electrolytes, urinalysis, and creatinine clearance. Normal radiologic studies included an esophogram and chest and lumbosacral spine films. The results of the electrocardiogram was also normal. A deep surgical biopsy specimen was examined by routine and immunofluorescence microscopy. The epidermis was slightly hyperplastic and overlaid a normal papillary dermis. The collagen bundles of the reticular dermis were coarsely thickened, and extended into the subcutaneous tissue well below the eccrine

0022-3476/80/090432 + 03500.30/0 9 1980 The C. V. Mosby Co.