High-dose cyclophosphamide treatment for refractory severe aplastic anemia in children.

OBJECTIVE: To determine if high-dose cyclophosphamide is an effective therapy for children with refractory severe aplastic anemia (SAA). BACKGROUND: SAA is an illness characterized by the depletion of hematopoietic precursors associated with life-threatening complications. Hematopoietic stem cell transplant (HSCT) is the treatment of choice if a human leukocyte antigen (HLA)-related donor is available. Immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine A (CSA) is an option for patients who are not HSCT candidates. Unrelated donor HSCT has been used with limited success. High-dose cyclophosphamide has been used successfully in the treatment of adults with SAA, but experience in children is limited. PROCEDURE: Five pediatric patients who had failed previous immunosuppressive therapy for SAA were treated with high-dose cyclophosphamide (45 mg/kg/day x 4 days). RESULTS: After 12 months of treatment, two of five patients experienced a complete response with high-dose cyclophosphamide therapy. The two complete responders achieved red cell recovery with a hematocrit of >36% at days 212 and 112 and platelet recovery with a platelet count of >100 x 10(9)/L at days 126 and 324. Of the remaining patients, one patient failed to respond, and two patients expired from infectious complications. CONCLUSIONS: High-dose cyclophosphamide can lead to complete responses in children with SAA who have failed to respond to traditional immunosuppressive therapy.

Analysis of infectious complications in infants with acute lymphoblastic leukemia treated on the Children's Cancer Group Protocol 1953: a report from the Children's Oncology Group.

Infants with acute lymphoblastic leukemia have a poor prognosis. The Children's Cancer Group (CCG) 1953 protocol tested the hypothesis that intensification of therapy would improve outcome for these patients. This intensified therapy resulted in better disease control, but resulted in greater toxicity. In this paper, we report the infectious complications associated with this intensified therapy. We retrospectively analyzed the infectious complications reported on the case report forms of all 115 patients enrolled on CCG 1953. Overall 495 infectious complications were identified in 115 patients. Bacterial infections occurred most frequently (74%), followed by viral (13%), fungal (11%), and protozoan (1%). Infection related mortality disproportionately occurred with viral (31%) and fungal (19%) infections. Twenty-three percent (n=26) of patients died of infectious complications, with the majority occurring during induction/intensification. Lower respiratory infections contributed to death in 12 patients and were most commonly viral (n=6) and fungal (n=3). Intensification of therapy resulted in increased infectious complications and deaths compared with previous studies. Future studies will need to focus on: (1) decreasing intensification during the first month of therapy, (2) developing targeted therapies, and (3) improving measures designed to prevent, quickly diagnose, and appropriately treat infections.

Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease.

Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.

Pilot study of idarubicin-based intensive-timing induction therapy for children with previously untreated acute myeloid leukemia: Children's Cancer Group Study 2941.

PURPOSE: Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. PATIENTS AND METHODS: On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. RESULTS: Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P <.001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P =.007), mean duration of course 1 by a week (P =.002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P =.02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P =.004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. CONCLUSION: In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.

Second neoplasms in survivors of childhood and adolescent cancer are often treatable.

PURPOSE: To estimate the incidence and types of second neoplasms in survivors of childhood and adolescent cancer, as well as the characteristics of those who developed second neoplasms. METHODS: Survivors who were under age 21 years at initial diagnosis, off therapy, and in remission for 2 years are referred to the Long Term Survivors' Clinic (LTSC) at Children's National Medical Center (CNMC). This review includes patients entered in the clinic database from January 1, 1997 to August 30, 2002. RESULTS: Twenty-three (2.3%) of 987 childhood cancer survivors followed in the LTSC had 26 (2.6%) second and third neoplasms. The mean age was 6.7 years at initial diagnosis, 20.3 years at diagnosis of the second neoplasm, and 20.5 years at diagnosis of the third neoplasm. Of 10 female and 13 male patients, 15 were white, six black, one Hispanic, and one Asian. All but two of the patients received radiation. Nineteen neoplasms, including seven thyroid carcinomas, six central nervous system tumors (three meningiomas), three basal cell carcinomas, two breast cancers, and one soft tissue sarcoma, occurred at sites within or contiguous to radiation sites. Five patients died, but the majority of neoplasms were treatable and most patients had good outcomes. CONCLUSION: Indefinite follow-up in a long-term survivors' clinic is indicated for adolescent and adult survivors of childhood cancer, with routine examination and screening for recurrence of the initial cancer as well as late effects, including second neoplasms.

Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group.

PURPOSE: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Children's Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients. PATIENTS AND METHODS: One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT. RESULTS: The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source. CONCLUSION: Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.

Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group.

CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensification. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P = .005), and treatment-related mortality declined from 19% to 12% (P = .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P = .021); respective survival was 68% and 62% (P = .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 x 10(9)/L, -7/7q-, -5/5q-, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.

FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL).

On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect. Following induction and DI treatment there was complete (0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant. Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years. The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Disclosure of potential conflicts of interest is found at the end of this article.

Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group.

Infant acute lymphoblastic leukemia (ALL) has a poor therapeutic outcome despite attempts to treat it based on prognostic factor-guided therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/11q23 rearrangement. All infants enrolled on Children's Cancer Group (CCG) 1953 were tested for MLL rearrangement by Southern blot and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or "other") by reverse-transcriptase polymerase chain reaction (PCR). One hundred fifteen infants were enrolled; overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL-rearranged cases was 33.6% and for MLL-nonrearranged cases was 60.3%. The difference in EFS between the 3 major MLL rearrangements did not reach statistical significance. Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis of CD10 negativity, age younger than 6 months, and MLL rearrangement, in that order. Toxicity was the most frequent cause of death. Relapse as a first event in CCG 1953 was later (median, 295 days) compared with CCG 1883 historic control (median, 207 days). MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but molecular 11q23 translocation partners do not predict outcome.

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that describes the extent and severity of chronic GVHD for each organ or site at any given time, taking functional impact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity that are based on the number of organs or sites involved and the degree of involvement in affected organs (mild, moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond 100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of moderate to severe global severity.

Successful treatment of invasive aspergillosis in two patients with acute myelogenous leukemia.

Invasive aspergillosis is a severe, devastating fungal infection that is seen in patients with hematologic malignancies and profound neutropenia. Despite aggressive treatment, the outcome is poor without neutrophil recovery. The authors describe two children with acute myelogenous leukemia (AML) with extensive invasive aspergillosis who were successfully treated both for their infection and the underlying malignancy. These patients were treated aggressively for their infections and simultaneously were able to complete treatment of their AML. Currently both patients are alive without evidence of fungal infection or AML. Patients with hematologic malignancies can survive severe, invasive aspergillosis during prolonged periods of neutropenia with a combination of antifungal and growth factor therapies, donor granulocyte infusions, and surgical debridement.