Vita J. Land

Secondary Leukemia or Myelodysplastic Syndrome After Treatment With Epipodophyllotoxins

PURPOSE The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. METHODS Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. RESULTS The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.

Toxicity of L‐asparaginase in children with advanced leukemia

A total of 105 patients with advanced acute leukemia in relapse received 123 trials of L‐asparaginase. Three different schedules were used, two of which involved simultaneous administration of vincristine and prednisone. Treatment was temporarily interrupted because of toxicity in 14 patients, and permanently discontinued in an additional 31. In 13 patients, this occurred before 10 doses of L‐asparaginase were given, while in the remaining 18 patients, therapy was stopped after remission was attained. The major toxicities were pancreatitis (fatal in four patients), hypersensitivity reactions, disturbances of liver function (fatal in two patients), and clinical and laboratory manifestations of central nervous system (CNS) dysfunction. Diabetic keto‐acidosis was encountered in two patients and was fatal in one. Severe leukopenia ascribed to L‐asparaginase occurred in two patients, in one of whom it was the contributory cause of death. Toxicity was not clearly different with any of the three treatment schedules. Most of the patients with only laboratory evidence of toxicity had no associated clinical manifestations, and this did not appear to decrease the likelihood of obtaining a remission.

Combination chemotherapy (vincristine, adriamycin, cyclophosphamide, and 5‐fluorouracil) in the treatment of children with malignant hepatoma

Members of Childrens Cancer Study Group and the Pediatric Division of the Southwest Oncology Group conducted a study of chemotherapy for children with malignant liver tumors. All patients received vincristine, cyclophosphamide, Adriamycin and 5‐fluorouracil in 6 weekly cycles for one year. Surgical resection and irradiation were employed when indicated. Between January 1976 and August 1978, 62 patients were entered on study; one was rejected for a protocol error, and ten had inadequate trials of chemotherapy, dying within one month of entry. The median time on study for all patients was 12 months. Twenty‐four patients had no measurable disease following surgical treatment and chemotherapy was employed as adjuvant treatment; 20/24 (83%) remain relapse‐free from 8–42+ months, (median, 30 months). In 27 patients, residual measurable disease was available to determine the response to chemotherapy. The response rate was 12/27 (44%), lasting 3–45 months (median, 18 months). The median follow‐up of all survivors is 30 months. Hematologic toxicity was significant, particularly during the initial courses of chemotherapy; 28/57 patients developed severe toxicity which was fatal in three. The results from the current study were compared to those from a previous one initiated in 1972, in which actinomycin D, vincristine, and cyclophosphamide were given in sequence, one during each month for one year. Although the population of the two studies was not identical, there was a difference in the response rates (P = 0.02), relapse‐free interval (P = 0.008), and survival (P = 0.003), The most striking improvement was seen in the patients with Group I disease, there were 7/11 relapses in the first study and 1/16 in the current one.

Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.

Metastatic chondroblastoma. Report of a fatal case with a review of the literature on atypical, aggressive, and malignant chondroblastoma.

A boy with metastatic and fatal chondroblastoma is presented. Unlike previously published examples of metastatic chondroblastoma, these metastases developed before any operative manipulation of the primary tumor. The histologic characteristics of the primary, metastatic, and locally recurrent tumors were those of a conventional chondroblastoma. A review of published cases of atypical, aggressive, and malignant chondroblastoma is presented with current follow‐up information. Although some metastatic chondroblastomas may result from operative manipulation of the primary tumor and are clinically benign, other histologically benign chondroblastomas exist that are capable of pursuing a malignant course. The authors designate these as malignant chondroblastomas. No histologic criteria exist for the separation of these tumors.

Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Occult testicular leukemia: Testicular biopsy at three years continuous complete remission of childhood leukemia: A Southwest Oncology Group study

Between June 1977 and December 1978, occult testicular leukemia (OTL) was discovered at three years of continual complete remission (CCR) from the time of diagnosis of acute lymphoblastic leukemia (ALL) in 5 of 59 (8.5%) of males undergoing bilateral wedge testicular biopsy at 1 of 15 participating Southwest Oncology Group (SWOG) institutions. Forty‐six of the 54 males with normal biopsies (78% of the total group of 59) have remained free of recurrent ALL at a median of 18 months (range 13 to 23 months) since the biopsy procedure, whereas eight have relapsed for the first time—five bone marrow (BM), one sclera, one simultaneous BM and testes, and one testes—at a median of 12.5 months (range 4 to 22 months) after the normal testicular biopsy. With aggressive therapy after biopsy in the five boys with OTL, one has died 19 months after biopsy (after two BM relapses), one is alive 21 months after biopsy (after two BM relapses), and three are alive and free of recurrent ALL 13, 16, and 19 months, respectively, since the diagnosis of OTL.

Immunophenotypes and karyotypes of leukemic cells in children with Down syndrome and acute lymphoblastic leukemia.

PURPOSE Immunophenotypes and karyotypes of leukemic cells were analyzed in a large series of Down syndrome patients with acute lymphoblastic leukemia (ALL) to examine the frequency of adverse prognostic features in comparison with other patients with ALL. PATIENTS AND METHODS Presenting features and leukemic cell characteristics were compared for 76 patients with Down syndrome and 4,733 other patients with newly diagnosed ALL treated on protocols of the Pediatric Oncology Group (POG) and St Jude Childrens Research Hospital (SJCRH). Treatment outcome was analyzed for the patients with non-T-cell disease enrolled on a single trial, for whom adequate follow-up data were available. RESULTS Down syndrome patients had lower platelet counts (P < .01) and were less likely to have an anterior mediastinal mass (P < .01) or CNS leukemia (P = .01). They were significantly more likely to have the pre-B immunophenotype (49% v 25.5%, P < .01) and less likely to have T-cell ALL (5.5% v 16%, P = .01). There was a notable absence among patients with Down syndrome of the t(4;11), t(1;19), and t(9;22), which are chromosomal translocations associated with an adverse prognosis in ALL. Treatment outcome did not differ significantly between patients with Down syndrome and the other children with non-T-cell ALL (P = .21); a third of the treatment failures in the former group resulted from treatment-related toxicities. CONCLUSION Children with Down syndrome and ALL had a low frequency of adverse clinicobiologic features at diagnosis. However, these findings did not translate into a superior outcome, apparently because of treatment-related toxicity in this group. Future trials should focus on pharmacokinetics and other strategies to reduce toxicity in these compromised patients.

Treatment of CNS relapse in children with acute lymphoblastic leukemia : a pediatric oncology group study

PURPOSE To assess the efficacy and toxicity of chemotherapy and cranial radiation for the treatment of children with acute lymphoblastic leukemia (ALL) following first isolated CNS relapse. PATIENTS AND METHODS One hundred twenty children were treated on Pediatric Oncology Group (POG) protocol 8304. All children had received prophylactic CNS therapy during their initial treatment. The treatment protocol included a four-drug reinduction and six weekly doses of triple intrathecal therapy (TIT). Cranial radiation, 24 Gy, was followed by monthly TIT. Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks. RESULTS All 120 patients achieved a second complete remission. There have been 61 protocol failures. Thirty-five patients had a bone marrow relapse, four with simultaneous CNS involvement and one with concurrent testicular leukemia. Thirteen patients had a second isolated CNS relapse, 10 a testicular relapse, and two relapsed in other sites. One patient died in remission. Overall event-free survival (EFS) at 4 years was 46% +/- 7%. The toxicity associated with this protocol was minimal except for leukoencephalopathy, which occurred in 20 (17%) patients. The treatment comparison between VM26/Ara-C or PDN/DOX pulses showed a trend toward superior EFS (P = .12) in favor of VM-26/Ara-C. CONCLUSION To date, this represents the largest series of patients with ALL treated uniformly for an isolated CNS relapse. Since marrow relapse remains the primary site of failure, future protocols must intensify systemic therapy.

Favorable prognosis associated with hyperdiploidy in children with acute lymphocytic leukemia correlates with extra chromosome 6 : a pediatric oncology group study

Pretreatment bone marrow cytogenetic studies were included for 1664 patients with acute lymphoblastic leukemia (ALL) accrued to Pediatric Oncology Group (POG) 8035 laboratory classification study from May 1981 through January 1986. There was a significant difference (P = 0.0001) in distribution of stem‐line karyotype (normal, hypodiploid, pseudodiploid, or hyperdiploid) among children with early pre‐B, pre‐B, or T‐cell ALL, with early pre‐B patients demonstrating a higher proportion of hyperdiploid karyotypes with modal chromosome numbers>51. Cytogenetic classification of 1216 patients with early pre‐B or pre‐B ALL evaluable for duration of event‐free survival (EFS), with median follow‐up of 42 months, showed a significant prolongation of five‐year EFS associated with hyperdiploidy>51 (75%; standard error [SE] = 5%) compared with hyperdiploidy 47 to 51 (46%; SE = 7%), hypodiploidy (55%; SE = 11%), and pseudodiploidy (45%; SE = 7%) (P = 0.0001). Five‐year EFS was intermediate for patients with normal (58%), constitutionally abnormal (66%), or unsuccessful analyses (66%). The breakpoint defining hyperdiploidy associated with better prognosis was best defined as>51 (P = 0.0002). Of 239 children with hyperdiploid karyotypes, analysis of the contribution of each chromosome to EFS duration showed a significant association between improved EFS and additional chromosome(s) six (P = 0.02). Chromosome translocation was associated with shorter EFS (P = 0.0001).