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Meningeal leukemia in the blastic phase of chronic granulocytic leukemia
Meningeal Leukemia in the Blastic Phase of Chronic Granulocytic Leukemia
JOEL H. SCHWARTZ, M.D.’ GEORGE P. CANELLOS, M.D.+ ROBERT C. YOUNG, M.D. VINCENT T. DeVITA, Jr., M.D.
Bethescb,Maryland
From the Medicine Branch, National Cancer Institute, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Robert C. Young, Medicine Branch, Bldg. IO, Room 12N226, Natlonal Cancer Instiiute, Bethesda, Maryland 20014. Manuscript accepted June 23, 1975. l Present address: Division of HematologyOncology, Department of Medicine, St. Vincent’s Hospital, Worcester, Massachusetts. + Present address: Children’s Cancer Research Foundation, Sidney Farker Center, Boston, Massachusetts.
One hundred one patients were treated for Ph’ posttlve chronic granulocytlc leukemia (CGL) In ths blastk phaw. In seven of these (6.9 per cent), menlngeal leukemla devetoped. Of the 90 patients who died of their disease, a complete remWon was achieved In 12 with a median survival of 12 months (three to 28 months). Incomplete responders had a median survival of only 2.5 months (one to 14 months). In five of the 12 complete responders (42 per cent), but In only two of the lncomolete responders (2.3 per cent), menlngeal leukemla devebped. The principal neurologk signs were cranlal nerve pslstes and papllledema. AH patlents had pteocytosfs with myekrblasts In the cerebrosplnal fluid. As In patlents with acute leukemla and diffuse hktlocytlc lymphoma, Increased survival of patients In whom hematologic remisslon from the blastlc phase of CGL k achieved may allow sufficient time for the development of menlngeal leukemia. lntrathecal methotrexate Is extremely successful In treating this complkatlon. Cerebrosplnal flukl pleocytosls was eradicated In all seven of our patients, and neurolagic symptoms and signs were completely etlmfnated In five patients. No evktence of meningeal leukemia was found in three of the five patients In whom an autopsy was performed. Effective therapy for acute leukemia of childhood with increase in survival has resulted in an increased incidence of meningeal leukemia [i-6]. Presumably, chemotherapeutic agents given systemically fail to diffuse into the meninges in adequate levels, thus providing a “pharmacologic refuge” for leukemic cells [7]. Meningeal and central nervous system complications have also been recently reported in adults with acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) [8,9], and in patients with diffuse histiocytic and undifferentiated lymphoma [lo]. In each of these instances, higher remission rates and longer survival times have been noted, which may account for the increased frequency of involvement of the central nervous system. Meningeal leukemia is almost unknown in the chronic phase of chronic granulocytic leukemia (CGL) and even during blastic transformation, only a few cases have been reported in the English literature [9,1 l-131. This may be explained by the fact that this phase of CGL is usually refractory to therapy, and patients have a median survival of approximately two months. In recent years, programs for the chemotherapy of patients with blastic transformation of CGL
December1875
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MENINGEAL LEUKEMIA IN CHRONK:GRANULOCYTK: LEUKEMIA-SCHWARTZ ET AL.
at the National Cancer institute (NCI) have resulted in
ly) and ARA-C (20 mg/m*, given intravenously) every four days for eight doses. The peripheral counts returned to normal after the first dose. The marrow was consistent with a hematoiogic remission, and repeat cytogenetics revealed ail metaphases to have 46 chromosomes, Ph’+. Two months later the patient had the sudden onset of left seventh nerve palsy. Lumbar puncture revealed 46 white blood cells/mm3 with 80 per cent myeiobiasts. The patient was treated with 16 mg of IT MTX followed by 8 mg 11 days later; both doses were followed by leucovorin rescue, 36 mg given intramuscularly in three divided doses. Thereafter, the patient received 12 mg IT MTX with 48 mg ieucovorin rescue given intramuscularly every one to two weeks for six weeks and then monthly. The cerebrospinai fluid was clear of abnormal ceils by four weeks after the onset of therapy. Blastic transformation recurred in November 1967 despite systemic maintenance therapy. Abscesses of the left nostril and rectum developed complii cated by Staphylococcal and Pseudomonas septicemia. Despite antibiotic therapy, the patient died on January 17, 1968. Postmortem examination revealed no evidence of meningeal leukemia.
some complete remissions with consequent improved survival of those patients. This has resulted in a unique series of cases in which meningeal leukemia complicated
the course of the blastic phase of of seven such patients are the subject of this report.
CGL. The characteristics
PATIENTS AND METHODS Since January 1, 1965, 101 patients with Philadelphia chromosome-positive CGL in the biastic phase have been treated with a series of protocols of either single agents or combination chemotherapy. The clinical and hematologic criteria for the diagnosis of the blastic phase of CGL have been previously described [14] as have the details of some of these chemotherapy trials [ 14,151. A complete remission is defined as (1) return of marrow morphology to nOrmOCeiiUhrityor granulocytic hyperplasia with less than 5 per cent blast forms, characteristic of CGL in the chronic phase; (2) normal peripheral blood counts with a hemoglobin level >I2 g/100 ml, a white blood cell count of 5 to 15,000/mrn3 with no peripheral blast forms or promyelocytes, and a platelet count > 150,000/mm3; (3) disappearance of aneupioid blast cell lines, if present, with return to the cytogenetic constitution of the chronic phase (46 chromosomes, Ph’ positive); (4) regression of splenomegaly, if present; and (5) disappearance of blastic phase-related symptoms. The diagnosis of meningeal leukemia entails the demonstration of blast cells in the spinal fluid, regardless of neurologic symptoms or signs. Peripheral or bone marrow cytogenetics were performed on all patients by Dr. J. Whang Peng, NCI. Four of seven patients in this study also had cytogenetic studies performed on c ells isolated from the spinal fluid. Therapy of the patient’s meningeal leukemia varied in dose and schedule of administration, but included combinations of intrathecal methotrexate (IT MTX, 12 to 20 mg/m*) usually with calcium leucovorin rescue (12 to 20 mg/m* given either as a single intramuscular injection or given orally or intramuscularly in four divided doses per day for one to two days beginning 24 hours after the instiiiation of IT MTX) or intrathecai cytosine arabinoside (IT ARA-C, 30 to 75 mg/m*) and cranial irradiation.
Case 2.
This 30 year old white man presented in October 1972, with spienomegaly and splenic infarction. The blood counts revealed a white blood cell count of 10,300/mm3 with 33 per cent blast forms, a platelet count of 48,OOOl mm3 and a hemoglobin level of 11.5 g/100 ml. The bone marrow revealed a double Ph’ chromosome in 8 per cent of metaphases, 84 per cent hypodipioidy (43 to 45 chromosomes) and morphology consistent with CGL. in blastic transformation. Vincristine (VCR) (2 mg/m* given intravenously on days 1 and 8) and prednisone (PRED) (60 mg/m* given orally daily for five days) were administered intermittently until complete remission was obtained. The patient was then maintained on intravenous VCR (2 mg/m*) given twice monthly and oral MTX (20 mg/m*) given twice weekly.
CASE REPORTS Case 1. A 14 year old white boy was referred to the NCI with splenomegaiy, a white blood ceil count of 205,000/ mm3, a hemoglobin level of 9.4 g/100 ml and a platelet count of 1,250,000/mm3. Bone marrow was consistent with CGL and contained the Ph’ chromosome. Therapy was initiated with busuifan, 4 mg daily. Three years later, biastic transformation supervened with a white blood ceil count of 60.000/mm3, composed of 60 per cent myeloblasts. Bone marrow examination confirmed the diagnosis, and cytogenetics revealed 80 per cent hypodiploidy (45 chromosomes). Physical examination revealed massive splenomegaiy. Therapy for blastic transformation consisted of bis-chloroethyl nitrosourea (BCNU) (40 mg/m*, given intravenous-
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In August 1973, while there was still some marrow remission, frontal headaches and diplopia developed. Lumbar puncture revealed an initial pressure of 260 mm water and a white blood cell count of 415 cells/mm3 with 90 per cent myeloblasts. Cerebrospinal fluid protein and glucose levels were both 41 mg/lOO ml. The patient was treated with IT ARA-C (100 mg); four days later a repeat lumbar puncture revealed 80 ceils/mm3 with 90 per cent myeloblasts. Diplopia had completely disappeared. IT MTX was administered (25 mg) with leucovorin rescue in equivalent dosage 24 hours later. The lumbar puncture was repeated four days later and revealed an initial pressure of 185 mm water with a cell count of 25 cells/mm3 containing 92 per cent blast forms. One week after this therapy, bilateral papiiiedema and bilateral Babinski reflexes developed. Lumbar puncture revealed an initial pressure of 320 mm water with 21 cells/ mm3 and 19 per cent blast forms. A radioiodinated serum albumin scan revealed no evidence of hydrocephaius, and the oral administration of 8 mg/day of dexamethasone was begun and tapered to 1.5 mglday. The patient was continued on IT MTX (25 mg) initially twice weekly the first
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MENINGEAL LEUKEMIA IN CHRONICGRANULOCYTIC LEUKEMIA-SCHWARTZ ET AL.
week, once weekly for two weeks, then once at three weeks and finally monthly for two months (all with leucovorin rescue), with gradual clearing of cerebrospinal blast forms. In September 1973, blastic crisis recurred; therapy was unsuccessful. Gram-positive septicemia developed with a resistant diphtheroid and, finally, acute progressive renal failure. The patient died on January 19, 1974, 14.5 months after the onset of blastic transformation. At postmortem, multiple petechiae of the leptomeninges and cerebellum were found, but there was no evidence of meningeal leukemia. Case 3. In May 1969, this 40 year ok! woman presented with a white blood cell count of 104,000/mm3 and a hemoglobin level of 12.2 g/100 ml. Additional findings included a palpable spleen tip and granulocytic hyperplasia of the bone marrow. Cytogenetics revealed 46 chromosomes, Ph’+. Dibromomannitol (DBM) was administered, 150 mg/day, with satisfactory control of the disease. In March 1971, the patient underwent elective splenectomy. In November 1971, while still receiving DBM, a slight increase in the white blood cell count (20,000/mm3) was noted with a bone marrow morphology consistent with acceleration of disease. In December 1971, a further increase in the white blood cell count and intermittent bone pain prompted a change in therapy to busulfan, 4 to 6 mg/day. In February 1972, the white blood cell count was 24,000/mm3 with 7 per cent myeloblasts but with 30 per cent blast forms in the marrow. Cytogenetics now revealed 60 per cent hyperdiploidy (47 to 46 chromosomes) and 2 per cent hypodiploidy (44 to 45 chromosomes), including the Ph’. Lumbar puncture on this admission was entirely within normal limits. Therapy with VCR and PRED was begun, and the bone marrow in April 1972 was consistent with remission; cytogenetics reverted back to 46 chromosomes, Ph’i-. In April 1972, nausea, vomiting, fever, severe frontal headaches, confusion and polydipsia developed. Lumbar puncture revealed an initial pressure of 250 mm water, a protein level of 109 mg/lOO ml, a glucose level of 34 mg/lOO ml and 204 cells, 96 per cent myeloblasts. Two doses of 100 mg IT ARA-C were administered without altering the cell count. Four doses of 25 mg IT MTX were administered and intermittent intramuscular leucovorin was given for two days. The cerebrospinal fluid was cleared of malignant cells within four weeks of the onset of IT theraPY. At this time the systemic disease was poorly controlled and the marrow cytogenetics again revealed a return of hyperdiploidy (see Table I). Treatment with ARA-C/G-TG resulted in leukopenia but no remission. Septicemia supervened and the patient died shortly thereafter. Permission for autopsy was not granted. Case 4. In this 45 year old man, headache and sore throat developed in March 1968. Blood studies revealed a white blood cell count of 133,000/mm3, a hemoglobin level of 6.6 g/100 ml and a platelet count of 6,000/mm3. A diagnosis of acute undifferentiated leukemia was made
and treatment was begun with VCR (1.2 mg intravenously), MTX (2.5 mg orally every day) and 6-mercaptopurine (6MP) (100 mg orally every day). The bone marrow was compatible with remission, and the patient underwent consolidation with these three drugs plus prednisolone (POMP). In June 1968, marrow examination revealed granule cytic hyperplasia and positive Ph’ chromosome. The patient appeared to have CGL which had presented with the characteristics of blastic transformation. One month later the white blood cell count increased to 95,000/mm3 with 80 to 90 per cent myeloblasts. Cytogenetics revealed 90 per cent hypodiploidy (45 chromosomes). A hematologic remission was induced with VCR and PRED with reversion of the cytogenetics to 100 per cent 46 Ph’. The patient was maintained on twice weekly oral MTX (27.5 to 55 mg) for the next six months. Because of some nausea and headache during the induction of remission, a lumbar puncture was performed which revealed 12 cells, all myeloblasts. Two doses of IT MTX (15 mg/m*) without leucovorin were given three days apart with clearing of the cerebrospinal fluid. Weekly IT MTX therapy was continued for two weeks followed by two monthly doses and a final bimonthly dose. Although asymptomatic, 1,360 blast cells were found in the cerebrospinal fluid on repeat lumbar puncture, eight weeks after a dose of IT MTX was given, and the monthly administration of IT MTX was reinstituted for four months. The patient remained in peripheral hematologic remission but, despite this, continued to demonstrate small numbers of abnormal cells in the cerebrospinal fluid. Thus, intermittent weekly IT courses of ARA-C were administered (50 mg/m*) beginning in May 1969, nine months after the initial diagnosis of meningeal leukemia. A cytogenetic study (August 1969) of the meningeal blast cells revealed a normal chromosomal number, with the Ph’ chromosome. In November 1969, diplopia secondary to a left sixth nerve palsy appeared. Radiation therapy, up to 1,800 rads was given to the base of the brain. Complete resolution was attained by alternating IT MTX (15 to 25 mg/m2) and intramuscular leucovorin rescue with IT ARA-C (75 mg/ m*) every third day for three doses. In November 1969, and again in March 1970, systemic relapse of blastic leukemia occurred, coincident with a return of the 45 chromosome Ph’ positive cell line in the marrow. Reinduction of remission was attained with VCR therapy (3 to 4 mg intravenously) on both occasions. Maintenance therapy with 6-MP (1,.5 mg/kg/day orally) was instituted. Despite weekly therapy with IT ARA-C (40 to 50 mg/m*) for five doses and monthly therapy for two months, the patient demonstrated central nervous system relapse in March 1970, and was treated with twice weekly IT MTX with leucovorin rescue or IT ARA-C. The weekly administration of IT ARA-C was then continued but meningeal leukemia persisted. In July 1970, the patient again demonstrated blastic transformation. Intravenous VCR was administered at a dose of 4 mg for three successive weekly doses. During this admission, because of continued central nervous system leukemia, manifested by headache, nausea and vomiting, the patient was treated with 18 mg/m*
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MENINQEAL LEUKEMlbi IN CHRONH: GRANULOCYTK: LEUKEMIA-SCl-tWARTZ
IT MTX followed by a course of leucovorin, 18 mg/m* given intramuscularly in one dose for five weekly courses. In September 1970, the patient was admitted with a left third nerve palsy, and 3 blast cells were noted in the cerebrospinal fluid. Radiotherapy with 2,200 rads to the base of the brain was instituted. Simultaneously, he was found to be in peripheral blastic transformation, with marrow cytogenetics demonstrating return of the hypodiploid cell line. Intravenous VCR (4 mg) was administered for three successive weekly doses. Three weeks after discharge, the patient presented with a white blood cell count of 12,000/mm3, with 39 per cent blast forms, 36,000 platelets/mm3 and 98 per cent blast forms in the marrow. The patient’s third nerve palsy was continuing to improve. Antileukemic therapy, first with VCR and then with ARA-C/8-TG, was unsuccessful. Urinary incontinence, stammering speech and a left hemiparesis developed. Cerebrospinal fluid examination revealed 58 blast forms/mm3. Despite IT MTX and supportive measures, he became progressively obtunded and died. Postmortem examination revealed encephalomalacia of the left temporal lobe and right cerebellar hemisphere. Mild leukemic infiltration of the dura and left optic nerve was noted as well as moderate infiltration of both third nerves. On examination of the cerebrum, the leptomeninges and Virchow-Robin spaces were infiltrated with blast forms. Finally, examination of the spinal cord revealed leptomeningeal and peripheral nerve root infiltration. Case 5. This 26 year old man with CGL remained untreated for two years until an increase in white blood cells (to 100,000 mm3) prompted therapy with DBM (100 to 400 mg/day). A year and a half later the patient underwent elective splenectomy. In February 1972, blastic transformation developed with a white blood cell count of 81,000/mm3 and 38 per cent blast forms. Cytogenetlcs showed that 4 per cent of the cells had a long submetacentric marker. The patient was treated wlth intravenous ARA-C/6-TG (200 mg/m2/day for five days). A left ptosis and bilaterally weak iliopsoas here noted at this time. Lumbar puncture revealed an initial pressure of 260 mm of water, normal protein and glucose levels, and 2 white blood cells/mm3. These clinical signs gradually cleared over the next two weeks without IT therapy. The patient responded poorly to systemic therapy, and one month later became confused and disoriented. A repeat lumbar puncture revealed an initial pressure of 100 mm water, a sugar level of 78 mg/lOO ml, a protein level of 49 mg/iOO ml and 17 myeloblastslmm3. IT MTX was administered (20 mg/m2) with divided intramuscular leucovorin rescue, and a three day course of intravenous ARAC/6-TG was also given. No abnormal cells were found on a repeat lumbar puncture three days later, but therapy with the same dose of IT MTX was continued twice weekly. The systemic therapy resulted in leukopenia, and the patient died of disseminated candidiasis, nine weeks after the onset of blastic transformation. Case 6.
822
This 48 year old white woman was well until July
December 1975
The American Journal of Medicine
ET AL.
1968 when she presented with a white blood cell count of 100,000/mm3. Marrow cytogenetics revealed the Ph’ chromosome and therapy with daily oral busulfan (4 mg) was begun. The patient underwent elective splenectomy in October 1972, and continued to do well until October 1973, when the white blood cell count again increased to 55,000/mm3 with 20 to 40 per cent myeloblasts. Bone marrow now revealed extensive myelofibrosis and hyperdiploidy (see Table I). The patient was treated with hydroxyurea with good control until January 1974, when a nodular skin infiltration over the breasts and abdomen appeared. Biopsy was positive for myeloblasts. The administration of VCR (2.0 mg/m2 intravenously on days 1 and 8) and PRED (100 mg/m2 orally every day for five days) was begun. In May 1974, the patient began to complain of intermittent headache without other neurologic symptoms. Neurologic examination was entirely negative, but a lumbar puncture revealed an initial pressure of 150 mm water, a protein content of 64 mg/iOO ml, a sugar level of 56 mg/ 100 ml and 23 cells, 95 per cent of which were immature myeloid cells. Therapy was begun with twice weekly IT MTX (12 mg/m2) without leucovorin, the protein level returned to normal after one dose and the cerebrospinal fluid pleocytosis cleared completely by the fourth dose. Only five total doses were given since the patient had severe leukopenia and severe headache developed after each dose. The patient failed to respond to either VCR and PRED or ARA-C/6-TG therapy. Severe leukopenia and bilateral pulmonary infiltrates developed. The patient was treated for a presumed fungal infection but she died on June 24, 1974, 8.5 months after the onset of blastic crisis. Permission for autopsy was not granted. Case 7. This 21 year old man was referred to the NCI with splenomegaly and a tentative diagnosis of CGL. Laboratory data on admission showed a white blood cell count of 137.000/mm3, a platelet count of 927,000/mm3 and a hemoglobin level of 12.7 g/l00 ml. Bone marrow examination revealed hypercellularity. Cytogenetics revealed that 20 per cent of the cells had 45 chromosomes and 80 per cent had 46 chromosomes, all Ph’ positive. The patient was treated with DBM and did well until June 1970 when bone marrow examination revealed hypercellularity and 90 per cent myeloblasts. VCR was administered and a complete remission, including disappearance of the hypodiploid cell line, was induced with three courses. The patient was given oral MTX for maintenance. Two weeks later the patient began to complain of headache, stiff neck, nausea and vomiting. There were no focal neurologic signs, but papilledema was present. Lumbar puncture showed an initial pressure of 600 mm water. The cerebrospinal fluid was cloudy with 2,100 white blood cells/mm3 (all myeloblasts), a glucose level of 54 mg/lOO ml and a protein level of 75 mg/lOO ml. All cultures were negative. Therapy with IT ARA-C, 100 mg every four days for three doses, was begun. However, bilateral sixth nerve palsies developed and the patient was given IT MTX (15
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MENINGEAL LEUKEMIA
,,$m2) with intermittent intramuscular leucovorin rescue twice weekly for the next two weeks, plus 2,000 rads of irradiation to the base of the brain. After one week, lumbar punctures revealed only 2 to 7 white blood cells with no blast forms, although the elevated cerebrospinal fluid protein level persisted. The patient’s neurologic symptoms and signs completely disappeared, and the patient was maintained on once weekly and then twice monthly IT MTX (15 mg/m*) with leucovorin. The systemic disease remained in remission during this hospitalization. The patient did relatively well over the next six months, receiving four weekly doses of VCR (3 mg intravenously) for reappearance of blast cells in the marrow in November 1970. In January 197 1, a generalized seizure precipitated another admission. Lumbar puncture revealed an initial pressure of 250 mm water and a protein level of 72 mg/ 100 ml with 4 white blood cells (2 myeloblasts), when the marrow was in remission. The patient received 15 mg/m* of IT MTX with rescue. The cerebrospinal fluid cleared within one week and for the remainder of his life, the patient had no further difficulties with meningeal leukemia, but he was maintained intermittently on IT MTX with leucovorin every one to four weeks. Over the next seven months, blastic transformation became more difficult to control and in April 1971 the patient was switched to ARA-C/6-TG therapy. He died in July 197 1 15 months after the onset of blastic transformation. Postmortem examination revealed leukemic involvement in every organ system including peripheral nerves and all cranial nerves. Focal infiltration of cells was seen in the arachnoid and dura of almost all sections. The infiltrates extended into the brain substance along VirchowRobin spaces to give foci around vessels. In addition, there were micro hemorrhages in the brain substance. Small arteries were packed with blast forms; leukemic nodules were present within and around vessels. RESULTS Of the 10 1 consecutive patients treated for Ph’ positive CGL in the blastic phase, meningeal leukemia developed in seven (6.9 per cent). The clihical characteristics of these seven patients are summarized in Table I. The median peripheral white blood count of the seven patients with meningeal leukemia at the onset of blastic transformation was 55,000/mm3 (10,300 to 133,000/mm3) with a median blast count of 40 per cent (7 to 80 per cent). The median peripheral white blood cell count at the onset of meningeal leukemia was only 12,000/mm3 (3,200 to 63,000/mm3) with no blast forms in six of seven cases, as each of these patients was under treatment at the time. Neurologic symptoms included headache (five patients), mental aberrations (two patients), diplopia (two patients) and seizures (one patient). Neurologic signs included cranial nerve deficits of either nerves Ill, VI or VII in five patients with two nerve deficits in
IN CHRONIC GRANULOCYTIC
LEUKEMIA--
SCHWARTZ
E.T AL.
each of two patients, papilledema in three patients and hemiplegia in one patient. Cerebrospinal fluid cytology was positive for malignant cells in all seven patients with a median cerebrospinal fluid white cell count of 46/mm3 (2 to 2,i 00/mm3) and a median cerebrospinal fluid blast form count of 90 per cent (17 to 100 per cent). Increased intracranial pressure was demonstrated in the three patients with papilledema, elevated cerebrospinal fluid protein levels in four patients and hypoglycorrhachia in two patients. In five of these seven patients, meningeal leukemia developed 0.5 to nine months after the induction of complete remission of blastic transformation. In three of the five, the central nervous system was the first site of relapse, preceding bone marrow relapse by three months in two patients and by 16 months in the third patient. In the remaining two with complete remissions, there was a relapse in the central nervous system simultaneously or within a few weeks of the relapse in bone marrow. Of the original 101 patients, 99 died of their disease: a complete hematologic remission with a median survival of 12 months (three to 28 months) was achieved in 12; 87 with incomplete remissions had a median survival of 2.5 months (one to 14 months). In five of the 12 in complete remission (42 per cent), but only two of these in incomplete remission (2.3 per cent), meningeal leukemia developed. Initial cytogenetics performed on either peripheral blood or bone marrow samples revealed the following abnormalities: hypodiploidy in four patients with a predominant cell line of either 44 or 45 chromosomes (a complete remission was achieved in all), hyperdiploidy in two patients with predominance of 47 or 48 chromosomes (a complete remission was achieved in one), and euploidy in one patient with a long submetacentric marker. A double Ph’ chromosome was demonstrated in two patients. Cerebrospinal fluid cytogenetics was attempted in four cases; in two no metaphases were seen. The cerebrospinal fluid in one patient revealed 46 chromosomes containing the Ph’ chromosome with similar findings on cytogenetic studies of the bone marrow: this patient was in complete bone marrow remission at the time of central nervous system relapse. The second evaluable cerebrospinal fluid revealed hyperdiploidy (47 to 48 chromosomes) with similar findings in the bone marrow; this patient had a relapse simultaneously in the cerebrospinal fluid and bone marrow. The therapy of meningeal leukemia reported in this study is illustrated in Table II. Therapy consisted of IT MTX alone in three patients, IT MTX and IT ARA-C at different times in two patients and both intrathecal agents plus cranial irradiation in two patients. In nine
December 1975
The American Journal of Medlclne
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923
80
33
60.0
10.3
24.0
14, M
30, M
40, F
38
40
81.0
55.0
26, M
43, F
45, M
7
(%I
mm3
Patient
of Patients
In Whom ----___-
x2
VCR-PRED x3 m+ A RA-C/6-TG
AR A-C/6-TG
(CR) -t oral MTX
7
1
4
2
VCR-PRED (CR) + ARA-C/6-TG
POMP--f VCR-PRED
10
4
VCR-PRED with VCR-MTX maint. + ARA-C/6-TG --f HU, 6-MP, Dex (CR)
(CR)
BCNU-ARA-C
Duration: Blast Crisis to Blastic Crisis Meningeal Therapy Leukemia (remission status) (mo)
Characteristics
Age (yr) and Sex
Clinical
Periphera1 WBC/
I
Range of Blast Forms at Onset of Blastic Crisik
TABLE
Leukemia
ptosis; weak
Headache
psoas bilaterally, confusion, disorientation
Left
ilio-
Headache, nausea, diplopia tinnitus; left III and VI nerve palsies, urinary incontinence; stammering speech; left hemiparesis, tentorial herniation
Frontal headache, hyperemic discs, nausea and vomiting, confusion; polydipsia
Frontal headache, diplopia; bilateral papilledema, bilaterally + Babinski sign
Left VI I nerve palsy
Neurologic Symptoms and Signs
Meningeal
150
100
160
250
260
120
(mm H,O)
Initial Pressure
64
49
40
109
41
41
(mg/ 100 ml)
Protein Content
56
78
102
. . .
41
58
Sugar Level (mgl 100 ml)
23-95
2-17
32-80
204-96
415-90
46-80
Cell Count/mm3 % Blast Forms
_I_
in the Blastic Phase of CGL --____--_-_--___---_-_-_-_---------
Cerebrospinal Fluid*
Developed _
(45)
-
75% hyper (47.48, 49) double Ph’
80% 46 chromosomes with long submetacentric market
90% hypo
2% hypo (45), 60% hyper (47.48)
(88,92)
80% hypo (44,45), 8% double Ph’, later, hyperdiploid
(45)T
80% hypodiploid
Bone Marrow or Peripheral Cytogenetics
No mitoses seen
ND
46 chromosomes, Ph’+
8% hypo (45), 60% hyper (47, 48) Ph’+
Many cells, no mitoses seen
ND
Cerebrospinal Fluid Cytogenetics
MENINGEAL LEUKEMIA IN CHRONIC GRANULOCYTIC
LEUKEMIA-SCHWARTZ
ET AL.
episodes occurring in the seven patients, therapy was completely successful in eradicating cerebrospinal fluid pleocytosis in a median duration of two weeks (0.5 to five weeks). Three patients were given IT ARA-C for one to three doses as initial therapy; this was ineffective in all three, although in each of these patients complete cerebrospinal fluid remission was subsequently achieved, with IT MTX in two and with IT MTX plus cranial irradiation in one. Five patients treated with IT MTX, three of whom received maintenance therapy with IT MTX, never had a relapse following initial successful eradication of cerebrospinal fluid leukemia. Postmortem examination performed on the latter three patients revealed no evidence of meningeal leukemia. In one patient a complete cerebrospinal fluid remission was achieved with IT MTX and cranial irradiation, but relapse occurred three months later despite a short course of maintenance therapy. The cerebrospinal fluid pleocytosis was again successfully eradicated with IT MTX. In the seventh patient a complete cerebrospinal fluid remission was achieved initially with IT MTX, but a relapse occurred approximately five months later, two months after the last maintenance dose was given. In this patient a second complete cerebrospinal fluid remission was later achieved which lasted four months, after therapy with IT MTX alternating with IT ARA-C plus cranial irradiation; thereafter, only partial remissions were obtained. Both of these latter patients had evidence of meningeal leukemia at autopsy, and in both, infiltration along Virchow-Robin (perivascular) spaces in continuity with infiltrated leptomeninges was noted. The median time from the onset of blastic transformation to the onset of meningeal leukemia was four months (one to 10 months) and the median time from the onset of meningeal leukemia to death was 4.5 months (1.25 to 24 months). The median time from the onset of blastic transformation to death was nine months (2.25 to 28 months). COMMENTS Meningeal leukemia almost never occurs during the chronic phase of CGL. Moreover, this complication has rarely been noted in the course of chronic leukemias in the blastic phase [9,1 l- 131. In contradistinction to this, the postmortem incidence of leukemic infiltration in patients with CGL has been estimated at 40 to 50 per cent [9,16,17]. In a recent study, clinical meningeal leukemia was found in only one of 28 patients with CGL in blastic crisis (3.5 per cent) although pathologic involvement was found in 39 per cent [9]. A case of meningeal involvement as the initial manifestation of blastic transformation in CGL has
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MENINGEAL LEUKEMIA IN CHRONIC GRANLILOCYTIC LEUKEMIA-SCHWARTZ
TABLE
II
Therapy
of Meningeal
Leukemia
ET AL.
in the Blastic Phase of CGL --___ __-__
-_____ Duration to
Successful in Eradicating Neurologic Symptoms and
Age (yr) and
Sex
SignsandCerebrospinal g Meningeal Leukemia Therapy
Fluid Pleocytosis
Time from 0 nset of Blastic Crisis
Clear Cerebro-
Meningeal
spinal Fluid ef
Leukemia
Cells (wk)
at Autopsy
to Death (mo)
-
14, M
IT MTX + leucovorin; maintenance
Yes-pleocytosis only, VII nerve palsy persisted until time of death; no relapse
4
No
9
30, M
IT ARA-C xl + IT MTX + leucovorin; oral dexamethasone; maintenance
Yes; no relapse
5
No
14.5
40, F
IT ARA-C IT MTX
Yes; no relapse
4
ND
4
45, M
IT MTX with maintenance --* IT ARA-C -+ IT MTX + leucovorin alternating with IT ARA-C + radiotherapy (RT) to base of brain -+ IT ARA-C --f IT ARA-C or IT MTX + leucovorin -+ RT to base of brain -+ IT MTX + leucovorin
Yes, but only partially and intermittently (I I I nerve palsy persisted) multiple relapses of pleocytosis
Yes
28
26, M
IT MTX + leucovorin; maintenance
Yes.; no relapse
0.5
No
2.25
43, F
IT MTX
Yes; no relapse
2
ND
8.5
21, M
IT ARA-C x3 -+ IT MTX + leucovorin + RT to base of brain + IT MTX + leucovorin maintenance; oral dilantin
Yes; one relapse, retreated successfully
3 1
Yes
x2 + + leucovorin
also been reported. Headaches and nuchal rigidity were prominent. IT MTX induced a central nervous system remission but relapse, characterized by increasing pleocytosis with Ph’ positive myeloblasts and the development of a left lower facial paralysis, occurred two months after the last dose was given. Leukemic infiltration of the brain, spinal cord and meninges was found at postmortem [ 111. More recently, two cases of meningeal leukemia have been reported, occurring seven and four months, respectively, after complete remission from blastic crisis had been achieved. Therapy with IT MTX was essentially ineffective in the first patient who died one week after the onset of meningeal leukemia; autopsy revealed leukemic infiltration of the meninges. Therapy with IT MTX and then with IT ARA-C and cranial irradiation was apparently effective intermittently in the second patient [ 131.
828
December 1975
The American Journal of Medklne
---__
____
1.5 (on 2 separate occasions)
__--
13
__-
Meningeal leukemia has become a common complication of the treatment of acute leukemia. Clinical neurologic involvement has been estimated to occur in 25 to 50 per cent of cases [l-3], with no demonstrable relationship to agents used to treat the leukemia [2] or to the height of the absolute blast form count at the time of diagnosis [9]. When patients are divided according to cell type of acute leukemia, an incidence of 40 per cent or higher is recorded for ALL and 6 to 17 per cent for AML [4,8,9]. Development of meningeal leukemia commonly occurs during complete remission and thus in long survivors [2,4,6,8,9,18]. When major symptoms and signs occur, they include, in order of frequency, symptoms of increased intracranial pressure (headache, vomiting, papilledema, lethargy, seizures), ocular disturbances (diplopia and blurred vision), cranial and peripheral nerve defi-
Volume 59
MENINGEAL LEUKEMIA IN CHRONIC GRANULOCYTIC
(facial nerve deficits, ptosis, foot drop) and psychic disturbances [ 21. Increased intracranial pressure and cranial nerve palsies occur more frequently in ALL, but root infiltration and cord compression are more characteristic of AML [8]. Cerebrospinal fluid abnormalities have included increased pressure, pleocytosis, hypoglycorrhachia and elevated protein levels [2,5]. lntrathecal therapy with MTX [4,5,19] or tits
ARA-C [20] and cranial irradiation [7,21,22] have been extremely successful in treating and preventing meningeal leukemia. Postmortem examinations have revealed a high incidence of meningeal involvement [2], often higher than the clinical evidence of involvement [ 231. Recently, a 27 per cent incidence of meningeal involvement in 52 patients with diffuse histiocytic and diffuse undifferentiated lymphoma has been reported. Cerebral symptoms, usually characterized by changes in mental status were most common, as were cranial nerve palsies (Ill, IV, VI, VII and XII). Seizures, nausea, vomiting and papilledema were not noted. Increased cerebrospinal fluid pressure was rare but pleocytosis, hypoglycorrhachia and elevated cerebrospinal fluid protein levels were common. Clinical improvement usually occurred within two to three weeks of the institution of intrathecal therapy and radiotherapy, although cranial and peripheral nerve palsies often persisted. At postmortem, cerebral lymphoma followed a conspicuous pattern of infiltration along Virchow-Robin spaces in continuity with densely infiltrated leptomeninges. There was a correlation between the increased disease-free survival and the propensity for the development of meningeal leukemia [IO]. An over-all incidence of meningeal leukemia in blastic transformation of CGL of 6.9 per cent is higher than that previously reported. Much like patients with ALL, AML and diffuse or undifferentiated lymphoma, development of meningeal leukemia is associated with drug-induced remission and longer survival. The white blood cell count and blast form counts at the onset of blastic transformation appear unrelat-
LEUKEMIA---SCHWARTZ
ET AL.
ed to the subsequent development of meningeal leukemia. Neurologic findings resemble those occurring in patients with acute leukemia and are somewhat dissimilar from patients with lymphomatous meningitis in whom papilledema, seizures and increased intracranial pressure were rarely seen [ lo]. From this series of patients the most effective therapy appears to be twice weekly intrathecal injections of MTX (12 to 15 mg/m*) with calcium leucovorin rescue (12 to 15 mg/m*/day) given in single or divided doses orally or intramuscularly beginning 24 hours after the instillation of MTX and continuing for 48 hours. The drug is administered until clearing of cerebrospinal
fluid
pleocytosis
occurs.
This
is fol-
lowed by weekly, then twice monthly, and finally, monthly maintenance therapy. Cranial irradiation may be added in patients with cranial nerve deficits who are at high risk for disease along the nerve sheaths. Specific treatment applied to these patients is very successful in eradicating the neurologic complications, akin to the situation in acute leukemia and diffuse lymphoma. Infiltration at postmortem, when present, is similar in distribution to that in patients with acute leukemia and diffuse lymphoma. Meningeal leukemia is a serious extramedullary manifestation of the blastic transformation of CGL. It appears to be particularly likely to develop in those patients in whom a complete remission is achieved with chemotherapy. This complication was previously unappreciated since the median survival of those without a remission in the blastic phase of CGL is two to two and a half months whereas the median time to onset of meningeal leukemia appears to be four months. Recently, with the introduction of more effective treatment, especially the VCR and PRED regimen, the incidence of meningeal leukemia appears to equal that seen in AML. Because this is only now an emerging problem, it is difficult to comment on the role of prophylactic central nervous system therapy although our data suggest that meningeal leukemia may complicate the course of patients who are otherwise in good systemic remission.
REFERENCES 1. 2.
3.
4.
Haghbin M, Zuelzer WW: A long-term study of cerebrospinal leukemia. J Pediatr 67: 23. 1965. Hyman CB, Bogle JM, Brubaker CA, Williams K, Hammond D: Central nervous system involvement by leukemia in children. I. Relationship to systemic leukemia and description of clinical and laboratory manifestations. Blood 25: 1. 1965. West RJ, Graham-Pole J, Hardisty RM, Pike MC: Factors in pathogenesis of central-nervous-system leukemia. Br Med J 3: 311. 1972. Nies BA, Thomas LB, Freireich EJ: Meningeal leukemia. A follow-up study. Cancer 18: 546, 1965.
5.
6.
7.
8.
December 1075
Nieri RL, Burger? EO, Groover RV: Central-nervous-system complications of leukemia: a review. Mayo Clin Proc 43: 70, 1968. Evans AE, Gilbert ES, Zaudstra R: The increasing incidence of central nervous system leukemia in children. Cancer 33: 427, 1974. Hustu HO, Aur RJA, Verzosa MS, Simone JV, Pinkel D: Prevention of central nervous system leukemia by irradiation. Cancer 32: 585, 1973. Dawson DM, Moloney WC: Neurologic complications of acute leukemia in adults: changing rate. Ann Intern Med 79: 541, 1973.
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MENINGEAL LEUKEMIA IN CHRONIC ORANULOCYTIC LEUKEMIA-SCHWARTZ
9.
10.
11.
12.
13.
14.
Wolk RW. Masse SR. Conklin R. Freireich EJ: The incidence of central nervous system leukemia in adults with acute leukemia. Cancer 33: 883, 1974. Bunn PA, Schein PS. Banks PM. DeVita VT: CNS complications in patients with diffuse histiocytic and undifferentiited lymphoma: leukemia revisited. Blood (in press). Kwaan HC, Pierre RV, Long DL: Meningeal involvement as first manifestation of acute myeloblastic transformation in chronic granulocytic leukemia. Blood 33: 348, 1989. Mastrangelo R, Zuelrer WW, Thompson RL: The significance of the Ph’ chromosome in acute myeloblastic leukemia-serial cytogenetic studies in a critical case. Pediatrics 40: 834. 1987. Atkinson K, Kay HEM, Lawler SD, Well DG, McElwain TJ: Meningeal leukemia after b&tic transformation of chronic myeloii leukemia. Cancer 35: 529. 1975. Canellos GP, DeVita VT, Whang-Peng J, Carbone PP: Hematologic and cytogenetic remission of b&tic transformation in chronic granulocytic leukemia. Blood 38: 87 1,
ET AL.
17.
18.
19.
20. 21.
1971.
15.
18.
828
Carbone PP. Canellos GP, DeVii VT: Blastic leukemias secondary to chronic leukemias and lymphomas. Chapter Ill. Therapy of the blastic phase of chronic granulecytic leukemia. Recent Results in Cancer Research 30 (Mathe G, ed), Berlin-Heidelberg, Springer-Verlag, 1970. Jensen KB, de Fine Oliverius B, Reske-Nielsen E, Sgaard l-k
December 1075
The Am&can
Journal of Medklna
22.
23.
Vohmw 59
Lesions in the central nervous system in leukaemia: a clinical and pathological analysis of 50 patients. Acta Neurol Stand 48(Suppl. 43): 285, 1970. Reske-Nielsen E. Petersen JH, Sgaard H, Jensen KB: Leukemia of the central nervous system. Lancet 1: 211, 1974. Shaw RK, Moore EW, Freieich EJ, Thomas LB Meningeal leukemia: a syndrome resulting from increased intracranial pressure in patients with acute leukemia. Neurolw 10: 823, 1980. Hyman CB, Bogle JM, Brubaker CA, Willllms K. Hammond D: Central nervous system involvement by leukemia in children. II. Therapy with intrathecal methotrexate. Blood 25: 13, 1985. Wang JJ, Pratt CB: lntrathecal arabinosyl cytosine in meningeal leukemia. Cancer 25: 531, 1970. Sullivan MP, Vietti TJ, Fernbach DJ, Griffith KM, Haddy TB, Watkins WL: Clinical investigations in the treatment of meningeal leukemia: radiation therapy regimens vs. conventional intrathecal rnethotrexate. Blood 34: 304, 1989. Aur RJA, Simone J, Hustu HO, Walters T. Borella L. Pratt C. Pinkel D: Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 37: 272, 1971. Phair JP, Anderson RE, Namiki H: The central nervous system in leukemia. Ann Intern Med 81: 883, 1984.
JOEL H. SCHWARTZ, M.D.’ GEORGE P. CANELLOS, M.D.+ ROBERT C. YOUNG, M.D. VINCENT T. DeVITA, Jr., M.D.
Bethescb,Maryland
From the Medicine Branch, National Cancer Institute, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Robert C. Young, Medicine Branch, Bldg. IO, Room 12N226, Natlonal Cancer Instiiute, Bethesda, Maryland 20014. Manuscript accepted June 23, 1975. l Present address: Division of HematologyOncology, Department of Medicine, St. Vincent’s Hospital, Worcester, Massachusetts. + Present address: Children’s Cancer Research Foundation, Sidney Farker Center, Boston, Massachusetts.
One hundred one patients were treated for Ph’ posttlve chronic granulocytlc leukemia (CGL) In ths blastk phaw. In seven of these (6.9 per cent), menlngeal leukemla devetoped. Of the 90 patients who died of their disease, a complete remWon was achieved In 12 with a median survival of 12 months (three to 28 months). Incomplete responders had a median survival of only 2.5 months (one to 14 months). In five of the 12 complete responders (42 per cent), but In only two of the lncomolete responders (2.3 per cent), menlngeal leukemla devebped. The principal neurologk signs were cranlal nerve pslstes and papllledema. AH patlents had pteocytosfs with myekrblasts In the cerebrosplnal fluid. As In patlents with acute leukemla and diffuse hktlocytlc lymphoma, Increased survival of patients In whom hematologic remisslon from the blastlc phase of CGL k achieved may allow sufficient time for the development of menlngeal leukemia. lntrathecal methotrexate Is extremely successful In treating this complkatlon. Cerebrosplnal flukl pleocytosls was eradicated In all seven of our patients, and neurolagic symptoms and signs were completely etlmfnated In five patients. No evktence of meningeal leukemia was found in three of the five patients In whom an autopsy was performed. Effective therapy for acute leukemia of childhood with increase in survival has resulted in an increased incidence of meningeal leukemia [i-6]. Presumably, chemotherapeutic agents given systemically fail to diffuse into the meninges in adequate levels, thus providing a “pharmacologic refuge” for leukemic cells [7]. Meningeal and central nervous system complications have also been recently reported in adults with acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) [8,9], and in patients with diffuse histiocytic and undifferentiated lymphoma [lo]. In each of these instances, higher remission rates and longer survival times have been noted, which may account for the increased frequency of involvement of the central nervous system. Meningeal leukemia is almost unknown in the chronic phase of chronic granulocytic leukemia (CGL) and even during blastic transformation, only a few cases have been reported in the English literature [9,1 l-131. This may be explained by the fact that this phase of CGL is usually refractory to therapy, and patients have a median survival of approximately two months. In recent years, programs for the chemotherapy of patients with blastic transformation of CGL
December1875
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MENINGEAL LEUKEMIA IN CHRONK:GRANULOCYTK: LEUKEMIA-SCHWARTZ ET AL.
at the National Cancer institute (NCI) have resulted in
ly) and ARA-C (20 mg/m*, given intravenously) every four days for eight doses. The peripheral counts returned to normal after the first dose. The marrow was consistent with a hematoiogic remission, and repeat cytogenetics revealed ail metaphases to have 46 chromosomes, Ph’+. Two months later the patient had the sudden onset of left seventh nerve palsy. Lumbar puncture revealed 46 white blood cells/mm3 with 80 per cent myeiobiasts. The patient was treated with 16 mg of IT MTX followed by 8 mg 11 days later; both doses were followed by leucovorin rescue, 36 mg given intramuscularly in three divided doses. Thereafter, the patient received 12 mg IT MTX with 48 mg ieucovorin rescue given intramuscularly every one to two weeks for six weeks and then monthly. The cerebrospinai fluid was clear of abnormal ceils by four weeks after the onset of therapy. Blastic transformation recurred in November 1967 despite systemic maintenance therapy. Abscesses of the left nostril and rectum developed complii cated by Staphylococcal and Pseudomonas septicemia. Despite antibiotic therapy, the patient died on January 17, 1968. Postmortem examination revealed no evidence of meningeal leukemia.
some complete remissions with consequent improved survival of those patients. This has resulted in a unique series of cases in which meningeal leukemia complicated
the course of the blastic phase of of seven such patients are the subject of this report.
CGL. The characteristics
PATIENTS AND METHODS Since January 1, 1965, 101 patients with Philadelphia chromosome-positive CGL in the biastic phase have been treated with a series of protocols of either single agents or combination chemotherapy. The clinical and hematologic criteria for the diagnosis of the blastic phase of CGL have been previously described [14] as have the details of some of these chemotherapy trials [ 14,151. A complete remission is defined as (1) return of marrow morphology to nOrmOCeiiUhrityor granulocytic hyperplasia with less than 5 per cent blast forms, characteristic of CGL in the chronic phase; (2) normal peripheral blood counts with a hemoglobin level >I2 g/100 ml, a white blood cell count of 5 to 15,000/mrn3 with no peripheral blast forms or promyelocytes, and a platelet count > 150,000/mm3; (3) disappearance of aneupioid blast cell lines, if present, with return to the cytogenetic constitution of the chronic phase (46 chromosomes, Ph’ positive); (4) regression of splenomegaly, if present; and (5) disappearance of blastic phase-related symptoms. The diagnosis of meningeal leukemia entails the demonstration of blast cells in the spinal fluid, regardless of neurologic symptoms or signs. Peripheral or bone marrow cytogenetics were performed on all patients by Dr. J. Whang Peng, NCI. Four of seven patients in this study also had cytogenetic studies performed on c ells isolated from the spinal fluid. Therapy of the patient’s meningeal leukemia varied in dose and schedule of administration, but included combinations of intrathecal methotrexate (IT MTX, 12 to 20 mg/m*) usually with calcium leucovorin rescue (12 to 20 mg/m* given either as a single intramuscular injection or given orally or intramuscularly in four divided doses per day for one to two days beginning 24 hours after the instiiiation of IT MTX) or intrathecai cytosine arabinoside (IT ARA-C, 30 to 75 mg/m*) and cranial irradiation.
Case 2.
This 30 year old white man presented in October 1972, with spienomegaly and splenic infarction. The blood counts revealed a white blood cell count of 10,300/mm3 with 33 per cent blast forms, a platelet count of 48,OOOl mm3 and a hemoglobin level of 11.5 g/100 ml. The bone marrow revealed a double Ph’ chromosome in 8 per cent of metaphases, 84 per cent hypodipioidy (43 to 45 chromosomes) and morphology consistent with CGL. in blastic transformation. Vincristine (VCR) (2 mg/m* given intravenously on days 1 and 8) and prednisone (PRED) (60 mg/m* given orally daily for five days) were administered intermittently until complete remission was obtained. The patient was then maintained on intravenous VCR (2 mg/m*) given twice monthly and oral MTX (20 mg/m*) given twice weekly.
CASE REPORTS Case 1. A 14 year old white boy was referred to the NCI with splenomegaiy, a white blood ceil count of 205,000/ mm3, a hemoglobin level of 9.4 g/100 ml and a platelet count of 1,250,000/mm3. Bone marrow was consistent with CGL and contained the Ph’ chromosome. Therapy was initiated with busuifan, 4 mg daily. Three years later, biastic transformation supervened with a white blood ceil count of 60.000/mm3, composed of 60 per cent myeloblasts. Bone marrow examination confirmed the diagnosis, and cytogenetics revealed 80 per cent hypodiploidy (45 chromosomes). Physical examination revealed massive splenomegaiy. Therapy for blastic transformation consisted of bis-chloroethyl nitrosourea (BCNU) (40 mg/m*, given intravenous-
820
December 1975
The Am&can
Journal of Medklno
In August 1973, while there was still some marrow remission, frontal headaches and diplopia developed. Lumbar puncture revealed an initial pressure of 260 mm water and a white blood cell count of 415 cells/mm3 with 90 per cent myeloblasts. Cerebrospinal fluid protein and glucose levels were both 41 mg/lOO ml. The patient was treated with IT ARA-C (100 mg); four days later a repeat lumbar puncture revealed 80 ceils/mm3 with 90 per cent myeloblasts. Diplopia had completely disappeared. IT MTX was administered (25 mg) with leucovorin rescue in equivalent dosage 24 hours later. The lumbar puncture was repeated four days later and revealed an initial pressure of 185 mm water with a cell count of 25 cells/mm3 containing 92 per cent blast forms. One week after this therapy, bilateral papiiiedema and bilateral Babinski reflexes developed. Lumbar puncture revealed an initial pressure of 320 mm water with 21 cells/ mm3 and 19 per cent blast forms. A radioiodinated serum albumin scan revealed no evidence of hydrocephaius, and the oral administration of 8 mg/day of dexamethasone was begun and tapered to 1.5 mglday. The patient was continued on IT MTX (25 mg) initially twice weekly the first
Volume 59
MENINGEAL LEUKEMIA IN CHRONICGRANULOCYTIC LEUKEMIA-SCHWARTZ ET AL.
week, once weekly for two weeks, then once at three weeks and finally monthly for two months (all with leucovorin rescue), with gradual clearing of cerebrospinal blast forms. In September 1973, blastic crisis recurred; therapy was unsuccessful. Gram-positive septicemia developed with a resistant diphtheroid and, finally, acute progressive renal failure. The patient died on January 19, 1974, 14.5 months after the onset of blastic transformation. At postmortem, multiple petechiae of the leptomeninges and cerebellum were found, but there was no evidence of meningeal leukemia. Case 3. In May 1969, this 40 year ok! woman presented with a white blood cell count of 104,000/mm3 and a hemoglobin level of 12.2 g/100 ml. Additional findings included a palpable spleen tip and granulocytic hyperplasia of the bone marrow. Cytogenetics revealed 46 chromosomes, Ph’+. Dibromomannitol (DBM) was administered, 150 mg/day, with satisfactory control of the disease. In March 1971, the patient underwent elective splenectomy. In November 1971, while still receiving DBM, a slight increase in the white blood cell count (20,000/mm3) was noted with a bone marrow morphology consistent with acceleration of disease. In December 1971, a further increase in the white blood cell count and intermittent bone pain prompted a change in therapy to busulfan, 4 to 6 mg/day. In February 1972, the white blood cell count was 24,000/mm3 with 7 per cent myeloblasts but with 30 per cent blast forms in the marrow. Cytogenetics now revealed 60 per cent hyperdiploidy (47 to 46 chromosomes) and 2 per cent hypodiploidy (44 to 45 chromosomes), including the Ph’. Lumbar puncture on this admission was entirely within normal limits. Therapy with VCR and PRED was begun, and the bone marrow in April 1972 was consistent with remission; cytogenetics reverted back to 46 chromosomes, Ph’i-. In April 1972, nausea, vomiting, fever, severe frontal headaches, confusion and polydipsia developed. Lumbar puncture revealed an initial pressure of 250 mm water, a protein level of 109 mg/lOO ml, a glucose level of 34 mg/lOO ml and 204 cells, 96 per cent myeloblasts. Two doses of 100 mg IT ARA-C were administered without altering the cell count. Four doses of 25 mg IT MTX were administered and intermittent intramuscular leucovorin was given for two days. The cerebrospinal fluid was cleared of malignant cells within four weeks of the onset of IT theraPY. At this time the systemic disease was poorly controlled and the marrow cytogenetics again revealed a return of hyperdiploidy (see Table I). Treatment with ARA-C/G-TG resulted in leukopenia but no remission. Septicemia supervened and the patient died shortly thereafter. Permission for autopsy was not granted. Case 4. In this 45 year old man, headache and sore throat developed in March 1968. Blood studies revealed a white blood cell count of 133,000/mm3, a hemoglobin level of 6.6 g/100 ml and a platelet count of 6,000/mm3. A diagnosis of acute undifferentiated leukemia was made
and treatment was begun with VCR (1.2 mg intravenously), MTX (2.5 mg orally every day) and 6-mercaptopurine (6MP) (100 mg orally every day). The bone marrow was compatible with remission, and the patient underwent consolidation with these three drugs plus prednisolone (POMP). In June 1968, marrow examination revealed granule cytic hyperplasia and positive Ph’ chromosome. The patient appeared to have CGL which had presented with the characteristics of blastic transformation. One month later the white blood cell count increased to 95,000/mm3 with 80 to 90 per cent myeloblasts. Cytogenetics revealed 90 per cent hypodiploidy (45 chromosomes). A hematologic remission was induced with VCR and PRED with reversion of the cytogenetics to 100 per cent 46 Ph’. The patient was maintained on twice weekly oral MTX (27.5 to 55 mg) for the next six months. Because of some nausea and headache during the induction of remission, a lumbar puncture was performed which revealed 12 cells, all myeloblasts. Two doses of IT MTX (15 mg/m*) without leucovorin were given three days apart with clearing of the cerebrospinal fluid. Weekly IT MTX therapy was continued for two weeks followed by two monthly doses and a final bimonthly dose. Although asymptomatic, 1,360 blast cells were found in the cerebrospinal fluid on repeat lumbar puncture, eight weeks after a dose of IT MTX was given, and the monthly administration of IT MTX was reinstituted for four months. The patient remained in peripheral hematologic remission but, despite this, continued to demonstrate small numbers of abnormal cells in the cerebrospinal fluid. Thus, intermittent weekly IT courses of ARA-C were administered (50 mg/m*) beginning in May 1969, nine months after the initial diagnosis of meningeal leukemia. A cytogenetic study (August 1969) of the meningeal blast cells revealed a normal chromosomal number, with the Ph’ chromosome. In November 1969, diplopia secondary to a left sixth nerve palsy appeared. Radiation therapy, up to 1,800 rads was given to the base of the brain. Complete resolution was attained by alternating IT MTX (15 to 25 mg/m2) and intramuscular leucovorin rescue with IT ARA-C (75 mg/ m*) every third day for three doses. In November 1969, and again in March 1970, systemic relapse of blastic leukemia occurred, coincident with a return of the 45 chromosome Ph’ positive cell line in the marrow. Reinduction of remission was attained with VCR therapy (3 to 4 mg intravenously) on both occasions. Maintenance therapy with 6-MP (1,.5 mg/kg/day orally) was instituted. Despite weekly therapy with IT ARA-C (40 to 50 mg/m*) for five doses and monthly therapy for two months, the patient demonstrated central nervous system relapse in March 1970, and was treated with twice weekly IT MTX with leucovorin rescue or IT ARA-C. The weekly administration of IT ARA-C was then continued but meningeal leukemia persisted. In July 1970, the patient again demonstrated blastic transformation. Intravenous VCR was administered at a dose of 4 mg for three successive weekly doses. During this admission, because of continued central nervous system leukemia, manifested by headache, nausea and vomiting, the patient was treated with 18 mg/m*
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MENINQEAL LEUKEMlbi IN CHRONH: GRANULOCYTK: LEUKEMIA-SCl-tWARTZ
IT MTX followed by a course of leucovorin, 18 mg/m* given intramuscularly in one dose for five weekly courses. In September 1970, the patient was admitted with a left third nerve palsy, and 3 blast cells were noted in the cerebrospinal fluid. Radiotherapy with 2,200 rads to the base of the brain was instituted. Simultaneously, he was found to be in peripheral blastic transformation, with marrow cytogenetics demonstrating return of the hypodiploid cell line. Intravenous VCR (4 mg) was administered for three successive weekly doses. Three weeks after discharge, the patient presented with a white blood cell count of 12,000/mm3, with 39 per cent blast forms, 36,000 platelets/mm3 and 98 per cent blast forms in the marrow. The patient’s third nerve palsy was continuing to improve. Antileukemic therapy, first with VCR and then with ARA-C/8-TG, was unsuccessful. Urinary incontinence, stammering speech and a left hemiparesis developed. Cerebrospinal fluid examination revealed 58 blast forms/mm3. Despite IT MTX and supportive measures, he became progressively obtunded and died. Postmortem examination revealed encephalomalacia of the left temporal lobe and right cerebellar hemisphere. Mild leukemic infiltration of the dura and left optic nerve was noted as well as moderate infiltration of both third nerves. On examination of the cerebrum, the leptomeninges and Virchow-Robin spaces were infiltrated with blast forms. Finally, examination of the spinal cord revealed leptomeningeal and peripheral nerve root infiltration. Case 5. This 26 year old man with CGL remained untreated for two years until an increase in white blood cells (to 100,000 mm3) prompted therapy with DBM (100 to 400 mg/day). A year and a half later the patient underwent elective splenectomy. In February 1972, blastic transformation developed with a white blood cell count of 81,000/mm3 and 38 per cent blast forms. Cytogenetlcs showed that 4 per cent of the cells had a long submetacentric marker. The patient was treated wlth intravenous ARA-C/6-TG (200 mg/m2/day for five days). A left ptosis and bilaterally weak iliopsoas here noted at this time. Lumbar puncture revealed an initial pressure of 260 mm of water, normal protein and glucose levels, and 2 white blood cells/mm3. These clinical signs gradually cleared over the next two weeks without IT therapy. The patient responded poorly to systemic therapy, and one month later became confused and disoriented. A repeat lumbar puncture revealed an initial pressure of 100 mm water, a sugar level of 78 mg/lOO ml, a protein level of 49 mg/iOO ml and 17 myeloblastslmm3. IT MTX was administered (20 mg/m2) with divided intramuscular leucovorin rescue, and a three day course of intravenous ARAC/6-TG was also given. No abnormal cells were found on a repeat lumbar puncture three days later, but therapy with the same dose of IT MTX was continued twice weekly. The systemic therapy resulted in leukopenia, and the patient died of disseminated candidiasis, nine weeks after the onset of blastic transformation. Case 6.
822
This 48 year old white woman was well until July
December 1975
The American Journal of Medicine
ET AL.
1968 when she presented with a white blood cell count of 100,000/mm3. Marrow cytogenetics revealed the Ph’ chromosome and therapy with daily oral busulfan (4 mg) was begun. The patient underwent elective splenectomy in October 1972, and continued to do well until October 1973, when the white blood cell count again increased to 55,000/mm3 with 20 to 40 per cent myeloblasts. Bone marrow now revealed extensive myelofibrosis and hyperdiploidy (see Table I). The patient was treated with hydroxyurea with good control until January 1974, when a nodular skin infiltration over the breasts and abdomen appeared. Biopsy was positive for myeloblasts. The administration of VCR (2.0 mg/m2 intravenously on days 1 and 8) and PRED (100 mg/m2 orally every day for five days) was begun. In May 1974, the patient began to complain of intermittent headache without other neurologic symptoms. Neurologic examination was entirely negative, but a lumbar puncture revealed an initial pressure of 150 mm water, a protein content of 64 mg/iOO ml, a sugar level of 56 mg/ 100 ml and 23 cells, 95 per cent of which were immature myeloid cells. Therapy was begun with twice weekly IT MTX (12 mg/m2) without leucovorin, the protein level returned to normal after one dose and the cerebrospinal fluid pleocytosis cleared completely by the fourth dose. Only five total doses were given since the patient had severe leukopenia and severe headache developed after each dose. The patient failed to respond to either VCR and PRED or ARA-C/6-TG therapy. Severe leukopenia and bilateral pulmonary infiltrates developed. The patient was treated for a presumed fungal infection but she died on June 24, 1974, 8.5 months after the onset of blastic crisis. Permission for autopsy was not granted. Case 7. This 21 year old man was referred to the NCI with splenomegaly and a tentative diagnosis of CGL. Laboratory data on admission showed a white blood cell count of 137.000/mm3, a platelet count of 927,000/mm3 and a hemoglobin level of 12.7 g/l00 ml. Bone marrow examination revealed hypercellularity. Cytogenetics revealed that 20 per cent of the cells had 45 chromosomes and 80 per cent had 46 chromosomes, all Ph’ positive. The patient was treated with DBM and did well until June 1970 when bone marrow examination revealed hypercellularity and 90 per cent myeloblasts. VCR was administered and a complete remission, including disappearance of the hypodiploid cell line, was induced with three courses. The patient was given oral MTX for maintenance. Two weeks later the patient began to complain of headache, stiff neck, nausea and vomiting. There were no focal neurologic signs, but papilledema was present. Lumbar puncture showed an initial pressure of 600 mm water. The cerebrospinal fluid was cloudy with 2,100 white blood cells/mm3 (all myeloblasts), a glucose level of 54 mg/lOO ml and a protein level of 75 mg/lOO ml. All cultures were negative. Therapy with IT ARA-C, 100 mg every four days for three doses, was begun. However, bilateral sixth nerve palsies developed and the patient was given IT MTX (15
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MENINGEAL LEUKEMIA
,,$m2) with intermittent intramuscular leucovorin rescue twice weekly for the next two weeks, plus 2,000 rads of irradiation to the base of the brain. After one week, lumbar punctures revealed only 2 to 7 white blood cells with no blast forms, although the elevated cerebrospinal fluid protein level persisted. The patient’s neurologic symptoms and signs completely disappeared, and the patient was maintained on once weekly and then twice monthly IT MTX (15 mg/m*) with leucovorin. The systemic disease remained in remission during this hospitalization. The patient did relatively well over the next six months, receiving four weekly doses of VCR (3 mg intravenously) for reappearance of blast cells in the marrow in November 1970. In January 197 1, a generalized seizure precipitated another admission. Lumbar puncture revealed an initial pressure of 250 mm water and a protein level of 72 mg/ 100 ml with 4 white blood cells (2 myeloblasts), when the marrow was in remission. The patient received 15 mg/m* of IT MTX with rescue. The cerebrospinal fluid cleared within one week and for the remainder of his life, the patient had no further difficulties with meningeal leukemia, but he was maintained intermittently on IT MTX with leucovorin every one to four weeks. Over the next seven months, blastic transformation became more difficult to control and in April 1971 the patient was switched to ARA-C/6-TG therapy. He died in July 197 1 15 months after the onset of blastic transformation. Postmortem examination revealed leukemic involvement in every organ system including peripheral nerves and all cranial nerves. Focal infiltration of cells was seen in the arachnoid and dura of almost all sections. The infiltrates extended into the brain substance along VirchowRobin spaces to give foci around vessels. In addition, there were micro hemorrhages in the brain substance. Small arteries were packed with blast forms; leukemic nodules were present within and around vessels. RESULTS Of the 10 1 consecutive patients treated for Ph’ positive CGL in the blastic phase, meningeal leukemia developed in seven (6.9 per cent). The clihical characteristics of these seven patients are summarized in Table I. The median peripheral white blood count of the seven patients with meningeal leukemia at the onset of blastic transformation was 55,000/mm3 (10,300 to 133,000/mm3) with a median blast count of 40 per cent (7 to 80 per cent). The median peripheral white blood cell count at the onset of meningeal leukemia was only 12,000/mm3 (3,200 to 63,000/mm3) with no blast forms in six of seven cases, as each of these patients was under treatment at the time. Neurologic symptoms included headache (five patients), mental aberrations (two patients), diplopia (two patients) and seizures (one patient). Neurologic signs included cranial nerve deficits of either nerves Ill, VI or VII in five patients with two nerve deficits in
IN CHRONIC GRANULOCYTIC
LEUKEMIA--
SCHWARTZ
E.T AL.
each of two patients, papilledema in three patients and hemiplegia in one patient. Cerebrospinal fluid cytology was positive for malignant cells in all seven patients with a median cerebrospinal fluid white cell count of 46/mm3 (2 to 2,i 00/mm3) and a median cerebrospinal fluid blast form count of 90 per cent (17 to 100 per cent). Increased intracranial pressure was demonstrated in the three patients with papilledema, elevated cerebrospinal fluid protein levels in four patients and hypoglycorrhachia in two patients. In five of these seven patients, meningeal leukemia developed 0.5 to nine months after the induction of complete remission of blastic transformation. In three of the five, the central nervous system was the first site of relapse, preceding bone marrow relapse by three months in two patients and by 16 months in the third patient. In the remaining two with complete remissions, there was a relapse in the central nervous system simultaneously or within a few weeks of the relapse in bone marrow. Of the original 101 patients, 99 died of their disease: a complete hematologic remission with a median survival of 12 months (three to 28 months) was achieved in 12; 87 with incomplete remissions had a median survival of 2.5 months (one to 14 months). In five of the 12 in complete remission (42 per cent), but only two of these in incomplete remission (2.3 per cent), meningeal leukemia developed. Initial cytogenetics performed on either peripheral blood or bone marrow samples revealed the following abnormalities: hypodiploidy in four patients with a predominant cell line of either 44 or 45 chromosomes (a complete remission was achieved in all), hyperdiploidy in two patients with predominance of 47 or 48 chromosomes (a complete remission was achieved in one), and euploidy in one patient with a long submetacentric marker. A double Ph’ chromosome was demonstrated in two patients. Cerebrospinal fluid cytogenetics was attempted in four cases; in two no metaphases were seen. The cerebrospinal fluid in one patient revealed 46 chromosomes containing the Ph’ chromosome with similar findings on cytogenetic studies of the bone marrow: this patient was in complete bone marrow remission at the time of central nervous system relapse. The second evaluable cerebrospinal fluid revealed hyperdiploidy (47 to 48 chromosomes) with similar findings in the bone marrow; this patient had a relapse simultaneously in the cerebrospinal fluid and bone marrow. The therapy of meningeal leukemia reported in this study is illustrated in Table II. Therapy consisted of IT MTX alone in three patients, IT MTX and IT ARA-C at different times in two patients and both intrathecal agents plus cranial irradiation in two patients. In nine
December 1975
The American Journal of Medlclne
Volume 50
923
80
33
60.0
10.3
24.0
14, M
30, M
40, F
38
40
81.0
55.0
26, M
43, F
45, M
7
(%I
mm3
Patient
of Patients
In Whom ----___-
x2
VCR-PRED x3 m+ A RA-C/6-TG
AR A-C/6-TG
(CR) -t oral MTX
7
1
4
2
VCR-PRED (CR) + ARA-C/6-TG
POMP--f VCR-PRED
10
4
VCR-PRED with VCR-MTX maint. + ARA-C/6-TG --f HU, 6-MP, Dex (CR)
(CR)
BCNU-ARA-C
Duration: Blast Crisis to Blastic Crisis Meningeal Therapy Leukemia (remission status) (mo)
Characteristics
Age (yr) and Sex
Clinical
Periphera1 WBC/
I
Range of Blast Forms at Onset of Blastic Crisik
TABLE
Leukemia
ptosis; weak
Headache
psoas bilaterally, confusion, disorientation
Left
ilio-
Headache, nausea, diplopia tinnitus; left III and VI nerve palsies, urinary incontinence; stammering speech; left hemiparesis, tentorial herniation
Frontal headache, hyperemic discs, nausea and vomiting, confusion; polydipsia
Frontal headache, diplopia; bilateral papilledema, bilaterally + Babinski sign
Left VI I nerve palsy
Neurologic Symptoms and Signs
Meningeal
150
100
160
250
260
120
(mm H,O)
Initial Pressure
64
49
40
109
41
41
(mg/ 100 ml)
Protein Content
56
78
102
. . .
41
58
Sugar Level (mgl 100 ml)
23-95
2-17
32-80
204-96
415-90
46-80
Cell Count/mm3 % Blast Forms
_I_
in the Blastic Phase of CGL --____--_-_--___---_-_-_-_---------
Cerebrospinal Fluid*
Developed _
(45)
-
75% hyper (47.48, 49) double Ph’
80% 46 chromosomes with long submetacentric market
90% hypo
2% hypo (45), 60% hyper (47.48)
(88,92)
80% hypo (44,45), 8% double Ph’, later, hyperdiploid
(45)T
80% hypodiploid
Bone Marrow or Peripheral Cytogenetics
No mitoses seen
ND
46 chromosomes, Ph’+
8% hypo (45), 60% hyper (47, 48) Ph’+
Many cells, no mitoses seen
ND
Cerebrospinal Fluid Cytogenetics
MENINGEAL LEUKEMIA IN CHRONIC GRANULOCYTIC
LEUKEMIA-SCHWARTZ
ET AL.
episodes occurring in the seven patients, therapy was completely successful in eradicating cerebrospinal fluid pleocytosis in a median duration of two weeks (0.5 to five weeks). Three patients were given IT ARA-C for one to three doses as initial therapy; this was ineffective in all three, although in each of these patients complete cerebrospinal fluid remission was subsequently achieved, with IT MTX in two and with IT MTX plus cranial irradiation in one. Five patients treated with IT MTX, three of whom received maintenance therapy with IT MTX, never had a relapse following initial successful eradication of cerebrospinal fluid leukemia. Postmortem examination performed on the latter three patients revealed no evidence of meningeal leukemia. In one patient a complete cerebrospinal fluid remission was achieved with IT MTX and cranial irradiation, but relapse occurred three months later despite a short course of maintenance therapy. The cerebrospinal fluid pleocytosis was again successfully eradicated with IT MTX. In the seventh patient a complete cerebrospinal fluid remission was achieved initially with IT MTX, but a relapse occurred approximately five months later, two months after the last maintenance dose was given. In this patient a second complete cerebrospinal fluid remission was later achieved which lasted four months, after therapy with IT MTX alternating with IT ARA-C plus cranial irradiation; thereafter, only partial remissions were obtained. Both of these latter patients had evidence of meningeal leukemia at autopsy, and in both, infiltration along Virchow-Robin (perivascular) spaces in continuity with infiltrated leptomeninges was noted. The median time from the onset of blastic transformation to the onset of meningeal leukemia was four months (one to 10 months) and the median time from the onset of meningeal leukemia to death was 4.5 months (1.25 to 24 months). The median time from the onset of blastic transformation to death was nine months (2.25 to 28 months). COMMENTS Meningeal leukemia almost never occurs during the chronic phase of CGL. Moreover, this complication has rarely been noted in the course of chronic leukemias in the blastic phase [9,1 l- 131. In contradistinction to this, the postmortem incidence of leukemic infiltration in patients with CGL has been estimated at 40 to 50 per cent [9,16,17]. In a recent study, clinical meningeal leukemia was found in only one of 28 patients with CGL in blastic crisis (3.5 per cent) although pathologic involvement was found in 39 per cent [9]. A case of meningeal involvement as the initial manifestation of blastic transformation in CGL has
December 1975
The American Journal of Mediclne
Volume 59
925
MENINGEAL LEUKEMIA IN CHRONIC GRANLILOCYTIC LEUKEMIA-SCHWARTZ
TABLE
II
Therapy
of Meningeal
Leukemia
ET AL.
in the Blastic Phase of CGL --___ __-__
-_____ Duration to
Successful in Eradicating Neurologic Symptoms and
Age (yr) and
Sex
SignsandCerebrospinal g Meningeal Leukemia Therapy
Fluid Pleocytosis
Time from 0 nset of Blastic Crisis
Clear Cerebro-
Meningeal
spinal Fluid ef
Leukemia
Cells (wk)
at Autopsy
to Death (mo)
-
14, M
IT MTX + leucovorin; maintenance
Yes-pleocytosis only, VII nerve palsy persisted until time of death; no relapse
4
No
9
30, M
IT ARA-C xl + IT MTX + leucovorin; oral dexamethasone; maintenance
Yes; no relapse
5
No
14.5
40, F
IT ARA-C IT MTX
Yes; no relapse
4
ND
4
45, M
IT MTX with maintenance --* IT ARA-C -+ IT MTX + leucovorin alternating with IT ARA-C + radiotherapy (RT) to base of brain -+ IT ARA-C --f IT ARA-C or IT MTX + leucovorin -+ RT to base of brain -+ IT MTX + leucovorin
Yes, but only partially and intermittently (I I I nerve palsy persisted) multiple relapses of pleocytosis
Yes
28
26, M
IT MTX + leucovorin; maintenance
Yes.; no relapse
0.5
No
2.25
43, F
IT MTX
Yes; no relapse
2
ND
8.5
21, M
IT ARA-C x3 -+ IT MTX + leucovorin + RT to base of brain + IT MTX + leucovorin maintenance; oral dilantin
Yes; one relapse, retreated successfully
3 1
Yes
x2 + + leucovorin
also been reported. Headaches and nuchal rigidity were prominent. IT MTX induced a central nervous system remission but relapse, characterized by increasing pleocytosis with Ph’ positive myeloblasts and the development of a left lower facial paralysis, occurred two months after the last dose was given. Leukemic infiltration of the brain, spinal cord and meninges was found at postmortem [ 111. More recently, two cases of meningeal leukemia have been reported, occurring seven and four months, respectively, after complete remission from blastic crisis had been achieved. Therapy with IT MTX was essentially ineffective in the first patient who died one week after the onset of meningeal leukemia; autopsy revealed leukemic infiltration of the meninges. Therapy with IT MTX and then with IT ARA-C and cranial irradiation was apparently effective intermittently in the second patient [ 131.
828
December 1975
The American Journal of Medklne
---__
____
1.5 (on 2 separate occasions)
__--
13
__-
Meningeal leukemia has become a common complication of the treatment of acute leukemia. Clinical neurologic involvement has been estimated to occur in 25 to 50 per cent of cases [l-3], with no demonstrable relationship to agents used to treat the leukemia [2] or to the height of the absolute blast form count at the time of diagnosis [9]. When patients are divided according to cell type of acute leukemia, an incidence of 40 per cent or higher is recorded for ALL and 6 to 17 per cent for AML [4,8,9]. Development of meningeal leukemia commonly occurs during complete remission and thus in long survivors [2,4,6,8,9,18]. When major symptoms and signs occur, they include, in order of frequency, symptoms of increased intracranial pressure (headache, vomiting, papilledema, lethargy, seizures), ocular disturbances (diplopia and blurred vision), cranial and peripheral nerve defi-
Volume 59
MENINGEAL LEUKEMIA IN CHRONIC GRANULOCYTIC
(facial nerve deficits, ptosis, foot drop) and psychic disturbances [ 21. Increased intracranial pressure and cranial nerve palsies occur more frequently in ALL, but root infiltration and cord compression are more characteristic of AML [8]. Cerebrospinal fluid abnormalities have included increased pressure, pleocytosis, hypoglycorrhachia and elevated protein levels [2,5]. lntrathecal therapy with MTX [4,5,19] or tits
ARA-C [20] and cranial irradiation [7,21,22] have been extremely successful in treating and preventing meningeal leukemia. Postmortem examinations have revealed a high incidence of meningeal involvement [2], often higher than the clinical evidence of involvement [ 231. Recently, a 27 per cent incidence of meningeal involvement in 52 patients with diffuse histiocytic and diffuse undifferentiated lymphoma has been reported. Cerebral symptoms, usually characterized by changes in mental status were most common, as were cranial nerve palsies (Ill, IV, VI, VII and XII). Seizures, nausea, vomiting and papilledema were not noted. Increased cerebrospinal fluid pressure was rare but pleocytosis, hypoglycorrhachia and elevated cerebrospinal fluid protein levels were common. Clinical improvement usually occurred within two to three weeks of the institution of intrathecal therapy and radiotherapy, although cranial and peripheral nerve palsies often persisted. At postmortem, cerebral lymphoma followed a conspicuous pattern of infiltration along Virchow-Robin spaces in continuity with densely infiltrated leptomeninges. There was a correlation between the increased disease-free survival and the propensity for the development of meningeal leukemia [IO]. An over-all incidence of meningeal leukemia in blastic transformation of CGL of 6.9 per cent is higher than that previously reported. Much like patients with ALL, AML and diffuse or undifferentiated lymphoma, development of meningeal leukemia is associated with drug-induced remission and longer survival. The white blood cell count and blast form counts at the onset of blastic transformation appear unrelat-
LEUKEMIA---SCHWARTZ
ET AL.
ed to the subsequent development of meningeal leukemia. Neurologic findings resemble those occurring in patients with acute leukemia and are somewhat dissimilar from patients with lymphomatous meningitis in whom papilledema, seizures and increased intracranial pressure were rarely seen [ lo]. From this series of patients the most effective therapy appears to be twice weekly intrathecal injections of MTX (12 to 15 mg/m*) with calcium leucovorin rescue (12 to 15 mg/m*/day) given in single or divided doses orally or intramuscularly beginning 24 hours after the instillation of MTX and continuing for 48 hours. The drug is administered until clearing of cerebrospinal
fluid
pleocytosis
occurs.
This
is fol-
lowed by weekly, then twice monthly, and finally, monthly maintenance therapy. Cranial irradiation may be added in patients with cranial nerve deficits who are at high risk for disease along the nerve sheaths. Specific treatment applied to these patients is very successful in eradicating the neurologic complications, akin to the situation in acute leukemia and diffuse lymphoma. Infiltration at postmortem, when present, is similar in distribution to that in patients with acute leukemia and diffuse lymphoma. Meningeal leukemia is a serious extramedullary manifestation of the blastic transformation of CGL. It appears to be particularly likely to develop in those patients in whom a complete remission is achieved with chemotherapy. This complication was previously unappreciated since the median survival of those without a remission in the blastic phase of CGL is two to two and a half months whereas the median time to onset of meningeal leukemia appears to be four months. Recently, with the introduction of more effective treatment, especially the VCR and PRED regimen, the incidence of meningeal leukemia appears to equal that seen in AML. Because this is only now an emerging problem, it is difficult to comment on the role of prophylactic central nervous system therapy although our data suggest that meningeal leukemia may complicate the course of patients who are otherwise in good systemic remission.
REFERENCES 1. 2.
3.
4.
Haghbin M, Zuelzer WW: A long-term study of cerebrospinal leukemia. J Pediatr 67: 23. 1965. Hyman CB, Bogle JM, Brubaker CA, Williams K, Hammond D: Central nervous system involvement by leukemia in children. I. Relationship to systemic leukemia and description of clinical and laboratory manifestations. Blood 25: 1. 1965. West RJ, Graham-Pole J, Hardisty RM, Pike MC: Factors in pathogenesis of central-nervous-system leukemia. Br Med J 3: 311. 1972. Nies BA, Thomas LB, Freireich EJ: Meningeal leukemia. A follow-up study. Cancer 18: 546, 1965.
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Nieri RL, Burger? EO, Groover RV: Central-nervous-system complications of leukemia: a review. Mayo Clin Proc 43: 70, 1968. Evans AE, Gilbert ES, Zaudstra R: The increasing incidence of central nervous system leukemia in children. Cancer 33: 427, 1974. Hustu HO, Aur RJA, Verzosa MS, Simone JV, Pinkel D: Prevention of central nervous system leukemia by irradiation. Cancer 32: 585, 1973. Dawson DM, Moloney WC: Neurologic complications of acute leukemia in adults: changing rate. Ann Intern Med 79: 541, 1973.
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MENINGEAL LEUKEMIA IN CHRONIC ORANULOCYTIC LEUKEMIA-SCHWARTZ
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Wolk RW. Masse SR. Conklin R. Freireich EJ: The incidence of central nervous system leukemia in adults with acute leukemia. Cancer 33: 883, 1974. Bunn PA, Schein PS. Banks PM. DeVita VT: CNS complications in patients with diffuse histiocytic and undifferentiited lymphoma: leukemia revisited. Blood (in press). Kwaan HC, Pierre RV, Long DL: Meningeal involvement as first manifestation of acute myeloblastic transformation in chronic granulocytic leukemia. Blood 33: 348, 1989. Mastrangelo R, Zuelrer WW, Thompson RL: The significance of the Ph’ chromosome in acute myeloblastic leukemia-serial cytogenetic studies in a critical case. Pediatrics 40: 834. 1987. Atkinson K, Kay HEM, Lawler SD, Well DG, McElwain TJ: Meningeal leukemia after b&tic transformation of chronic myeloii leukemia. Cancer 35: 529. 1975. Canellos GP, DeVita VT, Whang-Peng J, Carbone PP: Hematologic and cytogenetic remission of b&tic transformation in chronic granulocytic leukemia. Blood 38: 87 1,
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Carbone PP. Canellos GP, DeVii VT: Blastic leukemias secondary to chronic leukemias and lymphomas. Chapter Ill. Therapy of the blastic phase of chronic granulecytic leukemia. Recent Results in Cancer Research 30 (Mathe G, ed), Berlin-Heidelberg, Springer-Verlag, 1970. Jensen KB, de Fine Oliverius B, Reske-Nielsen E, Sgaard l-k
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Lesions in the central nervous system in leukaemia: a clinical and pathological analysis of 50 patients. Acta Neurol Stand 48(Suppl. 43): 285, 1970. Reske-Nielsen E. Petersen JH, Sgaard H, Jensen KB: Leukemia of the central nervous system. Lancet 1: 211, 1974. Shaw RK, Moore EW, Freieich EJ, Thomas LB Meningeal leukemia: a syndrome resulting from increased intracranial pressure in patients with acute leukemia. Neurolw 10: 823, 1980. Hyman CB, Bogle JM, Brubaker CA, Willllms K. Hammond D: Central nervous system involvement by leukemia in children. II. Therapy with intrathecal methotrexate. Blood 25: 13, 1985. Wang JJ, Pratt CB: lntrathecal arabinosyl cytosine in meningeal leukemia. Cancer 25: 531, 1970. Sullivan MP, Vietti TJ, Fernbach DJ, Griffith KM, Haddy TB, Watkins WL: Clinical investigations in the treatment of meningeal leukemia: radiation therapy regimens vs. conventional intrathecal rnethotrexate. Blood 34: 304, 1989. Aur RJA, Simone J, Hustu HO, Walters T. Borella L. Pratt C. Pinkel D: Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 37: 272, 1971. Phair JP, Anderson RE, Namiki H: The central nervous system in leukemia. Ann Intern Med 81: 883, 1984.