Search

PURPOSE To determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only. PATIENTS AND METHODS At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI. RESULTS Of 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality therapy (CMT). Nine of 80 patients randomized at the time of diagnosis to receive CMT did not receive radiation (RT) because of a protocol violation, but were monitored for EFS and OS and included in all analyses. The estimated EFS and OS rates at 5 years for the 179 eligible patients are 79% and 92%, respectively. The actuarial EFS at 5 years was 80% for patients who received CMT and 79% for patients who received MOPP-ABVD only. The OS for the former group is estimated to be 87% and for the latter patients 96%. Age < or = 13 years of age at diagnosis and the attainment of a clinical CR after three cycles of chemotherapy were associated with a statistically significant improved EFS. CONCLUSION Our results indicate that after the delivery of eight cycles of MOPP-ABVD, the addition of low-dose RT does not improve the estimated EFS or OS in pediatric patients with advanced-stage Hodgkin's disease.

AIMS: The MLL gene on chromosome 11q23 is frequently disrupted by chromosomal translocations in association with haematological malignancies. Recently, a specific site within the 8.3 kb MLL break-point cluster region that is cleaved during the early stages of apoptosis has been identified. Because MLL gene rearrangements are used to identify patients with high risk leukaemia, it was the aim of this study to determine whether this DNA cleavage event could be triggered in diagnostic bone marrow samples solely through ex vivo incubation at room temperature. METHODS: Pretreatment bone marrow samples were collected from six paediatric leukaemia patients. Genomic DNA for Southern blot analysis of MLL gene rearrangements was isolated immediately after samples were obtained and compared to genomic DNA isolated after incubation of specimens for 24-60 hours at room temperature, simulating delays in processing that might occur when samples are delivered to reference laboratories. In addition, cryopreserved samples from 70 paediatric leukaemia patients were screened for evidence of site specific MLL cleavage. RESULTS: After ex vivo incubation of bone marrow samples, site specific MLL cleavage resulting in a pseudo-rearrangement of the MLL gene was detected in two of six patients. In addition, a third patient with a similar MLL pseudo-rearrangement in cryopreserved cells was identified. CONCLUSIONS: Pseudo-rearrangement of the MLL gene at chromosome 11q23 was caused by ex vivo incubation of bone marrow samples. This novel phenomenon, which could lead to misclassification of leukaemia patients, might also be of importance for genotype analysis by Southern blotting at other loci.

Although previous research has delineated medical, cognitive, and neuropsychologic late effects of central nervous system (CNS) prophylaxis for childhood acute lymphoblastic leukemia (ALL), it has been difficult to draw conclusions about the long term psychosocial sequelae of these treatments due to methodologic problems that led to inconclusive results in past studies. In the current study, the authors examined the long term psychosocial functioning of childhood ALL survivors who had been treated on a Phase III clinical protocol (Cancer and Leukemia Group B [CALGB] 7611) between 1976 and 1979, in which they were randomized to receive either 2400 centigray of cranial radiation (CRT) with intrathecal methotrexate (IT-MTX) or intermediate dose systemic methotrexate (IV-MTX) with IT-MTX.One hundred ten survivors of childhood ALL (mean age, 20.8 years) treated on CALGB 7611 who were age 14 years or older and disease free for at least 1 year were studied a mean of 14.7 years after their entry on CALGB 7611. In a telephone interview, a psychosocial assessment battery was administered to the patients, consisting of measures that assessed psychologic, sexual, social, and vocational functioning as well as any delayed physical effects.Survivors who had received CRT + IT-MTX had significantly poorer academic achievement (P = 0.0001), poorer self-images with regard to their bodies (P = 0.001), and greater psychologic distress (P = 0.005).Cranial radiation used to treat children with ALL has significant long term sequelae in terms of poorer academic achievement and psychosocial functioning. These data add weight to the conclusion that CRT prophylaxis should only be used to treat children who are at high risk of CNS relapse.

The Pediatric Oncology Group (POG) conducted a two-arm, randomized study for the treatment of children and adolescents with stage III small, non-cleaved cell lymphoma (SNCCL). Regimen A, based on the group's previous best treatment for this group of patients, included cyclophosphamide (CTX) and high-dose methotrexate (MTX), as well as vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemoprophylaxis. Regimen B, based on a single institution pilot study (Total B therapy), consisted of two rapidly alternating chemotherapy combinations (CTX, VCR, doxorubicin; MTX, and cytarabine (Ara-C) plus coordinated IT chemotherapy.One hundred thirty-four consecutive patients were entered on this study. Seventy patients were randomized to Regimen A, and 64 patients to Regimen B. One hundred and twenty-two patients are eligible for response.Complete remission (CR) was achieved by 81% (52/64) of patients on Regimen A, and 95% (55/58) of patients on Regimen B (p=0.014 one-sided). The two-year event-free survival (EFS) is 64% (SE=6%) on Regimen A, and 79% (SE=6%) on Regimen B (p=0.027 by one-sided logrank test). No patient has relapsed on either regimen after a year from diagnosis, although one patient had a second malignancy at day 371. Severe, but manageable, hematologic toxicity was seen in the majority of patients on both regimens, but was more frequent on Regimen B.We conclude that the cure rate in stage III SNCCL is significantly improved with the use of a short, six-month chemotherapy regimen of fractionated CTX alternated with coordinated MTX and Ara-C. Results suggest that drug schedule, not simple drug selection, influences outcome.

The cure rate of childhood acute lymphoblastic leukemia (ALL) has improved dramatically. Still there is a paucity of long-term data. With the improving cure rate, the quality of life and avoidance of second cancers have become important concerns. We evaluated 596 children and adolescents with ALL on Cancer and Leukemia Group B 7611 (CALGB 7611) who were randomized between 1976 and 1979 to receive intermediate-dose methotrexate (IDM) plus intrathecal methotrexate (IT MTX) or cranial radiation (CRT) plus IT MTX. After 10 additional years of follow-up, the pattern and significance of the results reported in 1983 are confirmed. IDM offered better hematologic protection (P0.0006), better testicular protection (P = 0.002), but CRT offered better central nervous system (CNS) protection (P0.0001). The retrieval rate for the 231 patients who relapsed while on therapy or within 6 months of elective cessation of therapy is 20 +/- 5%. For the 33 patients who relapsed more than 6 months after cessation of therapy, the retrieval rate is 49 +/- 10%. For all patients, the 12-year event-free survival was 37 +/- 3.6% and the overall survival was 49 +/- 3.5%. There were two cases of second malignancies reported in 3,502 person-years of survival. Both occurred following salvage therapy. There was no evidence of an excessive number of second primaries over the general population of children. There were no reported instances of clinical cardiopathy. After a median follow-up of 11 years, there have been no reports of cardiopathy and no evidence of an increased risk of second cancers in children treated on CALGB 7611. While the overall outcome is not what would be expected with modern therapy, one can conclude that CRT offered better CNS protection, but IDM offered better systemic and testicular protection. A small risk of second cancers or cardiac dys-function may be acceptable with therapies which produce long-term documented survival benefits.

B-cell acute lymphoblastic leukemia (B-ALL), more frequently than any other B-lineage neoplasm, exhibits oligoclonal Ig heavy chain (IgH) gene rearrangement in 15% to 43% of all cases studied. To study the molecular processes that promote multiple IgH rearrangements, a comprehensive sequence analysis of a B-ALL case was performed in which seven clonal IgH gene rearrangements were identified. The genetic profiles suggested that a single leukemic progenitor clone evolved into several subclones through dual processes of variable (VH) to preexisting diversity-joining (DJH) gene segment rearrangement and VH to VH gene replacement. Predominant IgH-V usage and the uniquely rearranged clonotype-specific VHDJH region gene sequences were identified using a novel DNA-based gene amplification strategy. Polymerase chain reaction (PCR) was directed by an IgH-J generic primer and a complement of family-specific IgH-V primers that defined the major B-cell IgH-V gene usage. Clonality of rearranged VHDJH bands was substantiated by high resolution denaturant gel electrophoretic analysis. Sequence patterns of the amplified VHDJH fragments segregated into two groups defined by common DJH sequences. Partial N region homology at the VHD junction as well as shared DJH sequences firmly established VH to VHDJH gene replacement as a mechanism generating clonal evolution in one group. In the second subset, oligoclonality was propagated by independent VH gene rearrangements to a common DJH precursor. The contributions of all clonal Ig-VHDJH repertoires for each group was approximately 50% and reflected a symmetric distribution of leukemic subclones generated by either process. Thus, oligoclonal rearrangements evolved by two independent, yet seemingly contemporaneous molecular genetic mechanisms. All seven clones displayed nonfunctional Ig-VHDJH recombinations. These observations may have relevance to the recombinatorial opportunities available during normal B-cell maturation.

We have previously developed a homoharringtonine (HHT) resistant murine C1300 neuroblastoma cell line with increased p-glycoprotein expression and cross resistance to Adriamycin. Drug resistance in this cell line was reversed using cyclosporin-A, dipyridamole and cremophor-EL (CRE). Because of the high CRE content of parenteral taxol, we examined the ability of this solvent to reverse taxol cross-resistance in this cell line. Comparative ID-50s using clonogenic assays in agar indicate a 214-fold resistance to HHT. CRE reverses taxol cross-resistance in a dose-dependent manner from 0.003 to 0.1%, and is maximally effective at a subtoxic concentration of 0.03%. High pressure liquid chromatography (HPLC) analysis of taxol treated C1300/HHT cells reveal that CRE causes changes in intracellular drug levels that are not related to drug efflux. Our work shows that clinical preparations of taxol, when diluted to effective doses, contain enough CRE to mitigate multi-drug resistance. Clinical successes of taxol in refractory tumors may be due in part to the ability of its CRE base to reverse multi-drug resistance.

Sixty-two patients with advanced-stage Hodgkin's disease and a median age of 12 years (range, 3 to 22 years) were treated with four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with four cycles of doxorubicin, vinblastine, bleomycin, and dacarbazine (ABVD) followed by low-dose radiotherapy (RT). We determined the feasibility, immediate safety, and rapidity of response of patients to this regimen, as well as the relationship between prognostic factors and the rate of complete remission (CR), event-free survival (EFS), and overall survival. Therapy was well tolerated, and the major toxicity was hematopoietic. At the end of chemotherapy, 54 of 62 patients (87%) were in CR by clinical restaging, with a biopsy of residual disease where necessary. The actuarial 3-year EFS is 77% (SE, 11%), with a median follow-up of 35 months, and the survival is 91% (SE, 7%). With respect to EFS, female patients and those with stage II or III disease fared statistically better than males and patients with stage IV disease, respectively. Six patients have died: three of progressive Hodgkin's disease, one of secondary acute myelocytic leukemia (AML), one of secondary non-Hodgkin's lymphoma (NHL), and one of overwhelming bacterial sepsis. The Pediatric Oncology Group (POG) is currently engaged in a randomized study of these eight cycles of chemotherapy with and without RT to assess the role of RT in achieving comparable results.

This study prospectively evaluated the endocrine function of 11 children treated with cranial irradiation (CRT) for brain tumors. All tumors were remote from the hypothalamic-pituitary axis. Children were studied before treatment and at 3, 6, and 12 months after the completion of CRT. T4, thyroid-stimulating hormone, prolactin, plasma cortisol, and urinary follicle-stimulating hormone and luteinizing hormone values were normal before and after treatment in all patients. Growth hormone (GH) deficiency was identified in 0 of 7 patients before treatment, in 2 of 7 patients 3 months post-CRT, in 9 of 11 patients 6 months post-CRT, and in 7 of 8 patients 12 months post-CRT. Growth deceleration was identified in five of seven prepubertal patients. GH deficiency is an extremely common sequelae of CRT, beginning as early as 3 months after the completion of CRT. The deficit is progressive over time.

Ten consecutive patients were entered on a pilot study--for the treatment of children with far-advanced Burkitt's lymphoma--which was conducted at the Roswell Park Memorial Institute (R.P.M.I.) and the University of Rochester Medical Center (U. of R.). With the use of high-dose cyclophosphamide (HDC), intermediate-dose methotrexate (IDM), vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemotherapy, nine of these 10 children achieved a complete remission (CR), and six of these nine children have remained in CR for more than 3 years and are likely cured of their disease. This regimen had significant, but generally manageable, toxicity. A single patient with ataxia-telangiectasia died during induction therapy of pneumonia and a gastrointestinal hemorrhage. A single patient with severe hemorrhagic cystitis required the substitution of cytosine arabinoside for cyclophosphamide (Cytoxan) in the regimen. One of five children presenting with bone marrow involvement survives. Such involvement appears to place patients at greater risk for developing meningeal disease. Attempts at more aggressive methods of central nervous system (CNS) prophylaxis should be employed in this group of patients.

The hypothalamic-pituitary function of 93 children, who had received central nervous system (CNS) prophylaxis as part of their therapy for acute lymphocytic leukemia (ALL), and who remained in continuous complete remission, was evaluated retrospectively. Treatment regimens included--Group I: 31 subjects, intrathecal methotrexate (IT MTX); Group II: 31 subjects, IT MTX plus 2400 rad cranial irradiation; and Group III: 31 subjects, IT MTX and intravenous intermediate-dose methotrexate. Serum thyroid-stimulating hormone (TSH) and T4 levels were normal. All participants had normal adrenocorticotropic hormone (ACTH) secretion as assessed by plasma cortisol responses to insulin hypoglycemia. Urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) excretion of pubertal and postpubertal patients (N = 37) was appropriate, except for one subject from Group I who had an abnormally high output of gonadotropins, and one from Group II who had abnormally low levels. Growth hormone (GH) responses were subnormal after sequential arginine-insulin stimulation as follows--Group 1: 3 of 31 patients; Group II: 6 of 25 patients; and Group III: 2 of 29 patients. Nevertheless, all children had normal linear growth. It was concluded that the three forms of CNS prophylaxis evaluated had no long-term adverse effect on TSH and ACTH secretion. FSH-LH production appears to be normal, but final judgment must await follow-up studies because 60% of the patients were prepuberteral or still receiving chemotherapy. Eleven patients had subnormal GH responses after pharmacologic stimulation of the pituitary, but long-term linear growth was unaffected.

Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.

There have been several reports of the association between Down's Syndrome and acute megakaryoblastic (M7) leukemia (AMKL). The diagnosis of this rare form of leukemia has been better delineated by the use of the platelet peroxidase reaction and the antifactor VIII antibody immunoperoxidase test. In the past, the prognosis of patients with a combination of Down's Syndrome and AMKL has been extremely poor, with a median survival of 6.9 months for 11 reported cases in the literature. The present report reviews the previously reported cases and describes a unique patient with mosaic Down's syndrome and AMKL with favorable response to therapy.

The toxicity of high dose cytosine arabinoside (Ara-C) in 23 leukemic children aged 1.5 years to 16 years 11 months was evaluated. The group included 11 children with acute lymphoblastic leukemia (ALL), nine with acute nonlymphoblastic leukemia (ANLL), two with chronic myelocytic leukemia (CML) in blastic crisis, and one with Burkitt's lymphoma. Toxicity consisted of bone marrow suppression in all patients, with a mean nadir time of 11 days for platelets and granulocytes. All patients experienced nausea and vomiting; 12 of 23 had drug induced fever; seven of 23 conjunctivitis; five of 23 mucositis; four of 23 diarrhea, and one of 23 elevated transaminase with hyperbilirubinemia. Adverse reactions were mild and reversible in all patients. No serious neurologic toxicity was seen. The toxicity observed in four patients with prior cranial irradiation was not any different from nonirradiated patients. The only life-threatening effect was neutropenia, the consequences of which were generally well controlled with antibiotic therapy. While this agent was effective in induction of remission in AML patients resistant to standard doses of Ara-C, it had no significant effect in a very small number of patients with relapsed ALL and CML in blast crisis. Side effects of high dose Ara-C though relatively substantial are manageable enough to warrant wider scale efficacy trials of this agent in childhood leukemias and solid tumors.

cis-Dichlorodiammineplatinum(II) (cis-platinum) was evaluated in three separate studies at Roswell Park Memorial Institute in children and adolescents with cancer. In the first study, 16 patients with a variety of solid tumors were treated. Objective responses were seen in patients with neuroblastoma, osteogenic sarcoma, seminoma, and medullary carcinoma of the thyroid. In the second study, five of eight patients with far-advanced osteogenic sarcoma showed objective responses to cis-platinum. In the third study, cis-platinum and Adriamycin were employed as primary adjuvant chemotherapy along with surgery in osteogenic sarcoma. Nine of ten patients have remained disease-free from 8 to 31 months (mean, 19 months). cis-Platinum is an active agent in pediatric tumors.

Ovarian function was evaluated in eight adolescent women 1-90 months after completion of treatment for non-Hodgkin's lymphoma, which included a cyclophosphamide-containing combination chemotherapy protocol and radiation therapy. Two women received whole abdomen irradiation and both had ovarian failure. In contrast, none of six women who received combination chemotherapy and radiation therapy which did not include the abdomen had evidence of ovarian failure. These findings suggest that both the prepubertal and postpubertal ovary are relatively unaffected by this combination chemotherapy program which included cyclophosphamide and methotrexate.

Until recently the prognosis of childhood non-Hodgkin's lymphoma has been poor. A program of combination chemotherapy and involved area radiotherapy was instituted in the Department of Pediatrics at Roswell Park Memorial Institute in 1971. Thirty-one biopsy proven untreated children entered this study. There were 4 Stage I, 9 Stage II, 6 Stage III, and 12 Stage IV. Initial site of presentation was neck and mediastinum in 16, abdomen in 12, and other sites in three. Nineteen were lymphocytic, seven histiocytic, three undifferentiated, and one was mixed. None had well differentiated or nodular histology. Chemotherapy consisted of vincristine and steroid induction along with intrathecal methotrexate followed by a maintenance phase consisting of daily oral 6-mercaptopurine, weekly oral methotrexate and monthly pulses of vincristine, cyclophosphamide and steroid. Because of initially poor results in Stage IV disease, the protocol was altered midway and high dose methotrexate on three occasions following induction was added. Twelve of 13 Stage I and II patients remain disease free. Four of 6 Stage III patients and 4 of 12 Stage IV patients remain disease free. Only 1/7 of the Stage IV patients prior to high dose methotrexate is disease free, whereas, 3/5 patients with high dose methotrexate are disease free. In total, 19/30 (63%) are disease free for a period ranging from 15+ to 63+ months with 19 patients being disease free for over one year and 12 for over two years.

Subcutaneous cerebrospinal fluid reservoirs (Ommaya) were placed in 27 children and adolescents with acute lymphoblastic leukemia. Eleven of the reservoirs were used for administration of preventive central nervous system therapy and the remaining 16 reservoirs were used in the management of overt meningeal leukemia. Seven of the 11 patients treated prophylactically had recurrence of leukemia. The first site of recurrence was the central nervous system in three (42%) cases. Four of the 16 patients with reservoirs placed for the treatment of overt meningeal leukemia have not had recurrent disease. Of the 12 patients who relapsed, the site of first recurrence was the central nervous system in five cases. The incidence of major complications was 26%.

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

Between January 1974 and November 1978, 41 consecutive increased risk (age less than 24 months or less than 120 months, or leukocyte count greater than 30,000/mm3) patients with acute lymphoblastic leukemia (ALL) were entered on two consecutive treatment protocols which employed intermediate dose methotrexate (IDM). IDM was employed for central nervous system prophylaxis and systemic intensification. It was anticipated that the avoidance of prophylactic cranial irradiation would result in a lower incidence of longterm central nervous system sequelae. Twenty-two children and adolescents were entered on the first study (IDM X 3) which employed three courses of IDM (500 mg/m2) and six doses of intrathecal (IT) methotrexate (MTX). Nineteen children and adolescents were entered on the second study (IDM X 6) which employed six courses of IDM (3-500 mg/m2 and 3-1500 mg/m2), six doses of IT MTX and three additional doses of triple IT chemotherapy (MTX, cytosine arabinoside, and hydrocortisone or dexamethasone). The cumulative percentage of patients who remained in continuous complete remission was 30% for IDM X 3 and 57% for IDM X 6. This difference was statistically significant (P = 0.046; and BM + CNS, I-using IDM X 6. The cumulative incidence of primary CNS relapse was 36.4% for IDM X 3 and 29.9% for IDM X 6. This difference was not statistically significant (P = 0.44). The use of more intensive therapy with IDM and triple IT chemotherapy did improve the duration of continuous, complete remission but did not decrease the incidence of primary CNS relapse in increased risk patients.

During a 2-year prospective study of 28 leukemic children (24, acute lymphocytic leukemia [ALL]; 4, non-ALL) unselected for musculoskeletal symptoms, objective joint findings were present in 14 cases (p = 0.001 vs normal controls). These findings varied in severity, were most frequently present in the knee (12 of 14 children), and were found most frequently only at disease onset (7 of 14). The group with joint abnormalities had a higher frequency of functionally significant joint complaints prior to diagnosis of leukemia (p = less than 0.01) and radiographic abnormalities of periarticular bone of the knees and ankles (p = less than 0.10). Four of the 5 children with ALL who died had joint findings, a trend whose significance is uncertain because of unequal followup periods.

The experience with the treatment of malignant histiocytosis has been disappointing. Despite modest treatment success with a combination of cyclophosphamide, Adriamycin (doxorubicin), vincristine and prednisone, the overall prognosis remains poor. There are only a few reports of prolonged complete remissions in pediatric patients. The following report describes two children who have had long-term remission with an aggressive combination chemotherapy program that included intrathecal prophylaxis. The chemotherapeutic regimen described merits further evaluation in a larger number of patients.

We employed three courses of intermediate dose Methotrexate (IDM) added onto a standard induction and maintenance program with the concept of both central nervous system (CNS) prophylaxis and simultaneous systemic intensification. Cranial radiation (RT) was not employed as CNS prophylaxis. Fifty of 52 patients (to age 18) achieved complete remission. Time on study now ranges from 22-68 months with a median time of 33 months. We separated the children into standard risk and increased risk. We defined increased risk as a WBC over 30 000/mm3 at presentation and an age of less than two years or greater than 10 years at presentation. There have been 15 relapses on these 50 patients; 11 occurred in increased risk patients (of 22 increased risk patients) and four occurred in standard risk patients (of 28 standard risk patients). There were seven CNS relapses, six systemic relapses, one simultaneous systemic and CNS relapse and one testicular relapse. Toxicity to the IDM was small with the worst problem being mucositis. No leukoencephalopathy occurred. The control of hematological relapse is excellent and the avoidance of potential long-term complications notes is even of greater importance.

Computerized tomography (CT) scans of the head were done on 93 children with acute lymphocytic leukemia in continuous complete remission who had been randomly assigned to three different methods. of central nervous system (CNS) prophylaxis. Twenty-nine children had received six doses of intrathecal methotrexate, 30 had received six doses of intrathecal methotrexate plus 2400 rad of cranial irradiation, and 34 had received six doses of intrathecal methotrexate plus three courses of intermediate-dose intravenous methotrexate. The overall incidence of abnormal scans was 35%, of which 91% were felt to represent minimal abnormalities. CT scan abnormalities were noted in 30% of the children receiving intrathecal methotrexate only, in 40% of those receiving intrathecal methotrexate plus cranial irradiation, and in 35% of those receiving intrathecal methotrexate plus intermediate dose methotrexate. These differences were not statistically significant. None of the three methods of CNS prophylaxis resulted in significant CT scan abnormalities. However, the few moderately or markedly abnormal scans evaluated were restricted to patients who received intrathecal methotrexate plus cranial irradiation. The clinical significance of CT scan abnormalities in leukemic children receiving these treatments remains unclear.