Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents.

PURPOSE: To determine the treatment outcome and clinical factors that are of prognostic significance for children and adolescents with relapsed or refractory Hodgkin's disease (HD) who received treatment with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Fifty-three consecutive children and adolescents 21 years of age or younger with relapsed or refractory HD underwent HSCT. RESULTS: At day 100 after transplantation, 29 patients (55%) were in a complete remission or maintained a continuous complete response, six (11%) had a partial response, and 11 (21%) failed to respond or had progressive disease. The failure-free survival (FFS) at 5 years was 31%, and overall survival was 43%. Twenty-one patients died of progressive HD, and nine died secondary to transplantation-related complications, including two secondary leukemias. Prognostic factors important for FFS were normal pretransplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P < .001), and disease sensitivity at the time of HSCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06). There was no statistically significant difference in FFS or overall survival between age subgroups that were analyzed (< 13, 13 to 18, 19 to 21) or in comparison with an adult cohort. CONCLUSION: HSCT is an effective treatment modality that can result in long-term cures and should be considered for children and adolescents with relapsed HD.

Acute lymphoblastic leukemia of NK-cell lineage: responses to IL-2.

Acute lymphoblastic leukemias with phenotypic characteristics of natural killer cell derived lineage are extremely uncommon. We identified an ALL with a phenotype consistent with an NK-cell of origin. The blasts underwent a proliferative response to r-IL2 in culture but showed no spontaneous or r-IL2 or gamma-INF induced cytotoxicity. With r-IL2 stimulation however, the tumor cells demonstrated a dramatic acquisition of low density CD8 surface positivity and a loss of CD11b expression after short term culture. By comparison to ALL of B or T lineage, NK ALL likely represents an early stage of bone marrow derived NK-cell precursor.

Protein C deficiency following hematopoietic stem cell transplantation: optimization of intravenous vitamin K dose.

Patients undergoing hematopoietic stem cell transplantation (HSCT) are dependent on i.v. vitamin K supplementation to prevent deficiency. Vitamin K deficiency may contribute to the development of a hypercoagulable state by limiting hepatic synthesis of fully functional carboxylated anticoagulant protein C (PC). The ratio of PC antigen (CAg) to PC measured in a clot-based functional assay (CFx) reflects the degree to which PC is carboxylated. The 133 patients undergoing HSCT received vitamin K 10 mg per week (low dose, 101 patients) or 5 mg per day (high dose, 32 patients) i.v. as their sole exogenous source of vitamin K. CAg and CFx were assayed before HSCT preparative regimen and again 14 days later. CAg and CFx fell significantly in both groups from day 0 to day 14 but there were no differences between the low-dose and high-dose vitamin K groups. For both groups, CAg correlated strongly with CFx at day 14 (p = 0.0001). At day 14, the CAg/CFx ratio for the low-dose group was significantly greater than for the high-dose group (1.26 +/- 0.4 vs 1.09 +/- 0.1, p < 0.0002), suggesting that low-dose patients had a higher proportion of incompletely carboxylated PC. The CAg/CFx ratio at day 14 correlated with serum albumin for the high-dose group (p = 0.05), but not the low-dose group (p = 0.09), suggesting that the change in ratio in the low-dose group was not simply due to a lack of protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombotic complications of BMT: association with protein C deficiency.

A decrease in levels of circulating anticoagulant protein C has been shown to occur following autologous BMT, and this deficiency may contribute to a hypercoagulable state placing patients at risk for thromboembolic events. We report four patients who suffered a variety of thrombotic complications following BMT (non-bacterial thrombotic endocarditis, superior vena cava thrombosis, thrombotic stroke, purpura fulminans, small bowel infarction secondary to diffuse microvascular thrombosis), which were preceded by or temporally related to decreased levels of protein C. Treatment with fresh frozen plasma (FFP) led to slight, temporary increases in protein C levels but infusions of FFP did not prevent either death or extension of the thrombus in these four cases, suggesting the need for higher protein C doses and/or concomitant anticoagulation. Though no direct causal relationship between these thrombotic complications and the protein C deficiency can be proved, a generalized hypercoagulable state caused by protein C deficiency may have contributed to the development, severity or progression of these complications.

Pharmacokinetics of antithrombin concentrate during autologous hematopoietic stem cell transplantation.

Antithrombin is a naturally-occurring anticoagulant protein. Congenital deficiency of this protein predisposes to thrombotic complications. Acquired deficiency of antithrombin occurs in a variety of clinical circumstances, including hematopoietic stem cell transplantation (HSCT), and is associated with multiorgan failure and death in these situations. Normalization of antithrombin levels by infusion of concentrates of this protein has been found to be beneficial in many of these situations, but has not been routinely used in HSCT. Before antithrombin concentrates can be widely recommended in HSCT, its pharmacokinetics at various phases of the transplant process must be defined to allow estimation of the proper dose and dosing interval. To this end, the recovery and half-life of antithrombin concentrate was determined prior to and 7, 14 and 28 days after beginning the preparative regimen in nine patients with lymphoma undergoing HSCT. The recovery of the infused material was constant during the transplant hospitalization, averaging 2.0% per unit/kg. The half-life, however, dropped significantly during the latter half of the transplant procedure. The half-lives pre-chemotherapy and on day 7 were similar and averaged 20.4 h. On days 14 and 21 the the half-lives were significantly lower at 12.2 and 15.5 h, respectively. The drop in half-life during the transplant process will require antithrombin concentrate to be given more frequently during this time to maintain constant antithrombin levels.

Allogeneic bone marrow transplantation for children with acute leukemia: long-term follow-up of patients prepared with high-dose cytosine arabinoside and fractionated total body irradiation.

High-dose therapy and allogeneic matched sibling bone marrow transplantation (BMT) is considered to be the treatment of choice for children with relapsed acute lymphoblastic leukemia (ALL), or for children with acute myeloid leukemia (AML) in first remission. However, the rate of bone marrow relapse after transplant for either of these diseases remains high. In this study, we assessed the efficacy and toxicity of high-dose cytosine arabinoside and total body irradiation (TBI) followed by allogeneic BMT, for children with acute leukemia or myelodysplastic syndrome (MDS). Sixty-five pediatric patients underwent allogeneic related (n = 57) or unrelated (n = 8) BMT. Twenty-seven were transplanted for ALL in second remission (CR2), and 16 for AML in first remission (CR1). The other 22 were high risk patients: six were transplanted for ALL in third remission (CR3), two for AML in CR2, two for myelodysplastic syndrome (MDS) and 12 for acute leukemia in relapse. Patients were prepared with cytosine arabinoside 3000 mg/m2 per dose twice daily for 6 days followed by 12000 cGy TBI as 200 cGy fractions twice daily for 3 days. Minimum follow-up is 21 months. Five-year event-free survival (EFS) and the actuarial relapse rate is 59 and 14% for patients with ALL in second remission, and 38 and 14+% for patients with AML in first remission. Twelve patients have relapsed (three are alive in remission after testicular or marrow relapse) and 28 have died of other causes. Acute GVHD with or without infection was the cause of death in 11 patients. Ten of the 11 patients who died of acute GVHD were considered at 'high risk' for GVHD (inadequate GVHD prophylaxis, or mismatched family donor or a matched unrelated donor). Toxicities in the immediate post-BMT period included diarrhea, oropharyngeal mucositis and conjunctivitis. Significant late toxicities included short stature, avascular necrosis of bone, and poor school performance (most often in patients who had received prior cranial irradiation). Our conclusions are that high-dose Ara-C and TBI followed by allogeneic bone marrow transplantation is effective therapy for children in second complete remission of their acute leukemia. However, significant late toxicities occur, and it is clear that more effective, less toxic therapies are necessary for these patients.

Treatment of veno-occlusive disease of the liver with bolus tissue plasminogen activator and continuous infusion antithrombin III concentrate.

Veno-occlusive disease (VOD) of the liver is a common complication of BMT and is accompanied by reduced levels of natural anticoagulants and by multi-organ dysfunction. We describe two cases of clinical VOD developing after autologous BMT and accompanied by ultrasonographic features of reversed portal venous flow. In both cases the patients had decreased levels of antithrombin (AT). Once the diagnosis of VOD was made, these patients were treated with tissue plasminogen activator (tPA) and continuous infusion AT. Each patient had radiographic and clinical resolution of VOD with the therapy. This novel treatment appears to have reversed the course of VOD without the increased risk of bleeding seen in the use of heparin therapy.

Cerebral infarction associated with protein C deficiency following allogeneic bone marrow transplantation.

Hypercoagulable states associated with deficiencies in circulating anticoagulant protein C occur after chemotherapy for a variety of malignant diseases. Protein C deficiency also occurs following bone marrow transplantation (BMT) and may be responsible for a variety of transplantation-associated complications. We report the case of a child who suffered a stroke associated with low protein C antigen and activity occurring 11 months after allogeneic BMT. Protein C levels recovered spontaneously by 18 months after BMT. We speculate that the protein C deficiency and and resultant hypercoagulable state led to the stroke, and the deficiency of this anticoagulant was a sequela of the transplant.

Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy.

Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).

Peripheral T-cell lymphoma in children and adolescents: role of bone marrow transplantation.

Although PTCL in children, as in adults, has a spectrum of clinical, morphologic, cytogenetic and immunologic features, there are several significant differences in these features between children and adults. Our data show that CD30 expression is much more common in pediatric PTCL than is reported in adult PTCL. Furthermore, the majority of children with CD30-positive PTCL do not have tumors with anaplastic large cell histology. Our data also suggest that the t(2;5) is not a specific marker of anaplastic large cell lymphoma in childhood. The likelihood of cure for children with PTCL is unclear, predominantly because of the lack of large numbers of pediatric patients with this less common entity. As with other NHL, we expect that treatment with conventional dose chemotherapy following relapse will be unsuccessful in most cases. Although the data are preliminary, it appears that high dose chemoradiotherapy followed by hematopoietic stem cell transplantation is an effective therapy in these patients. We have been particularly successful with a regimen based on thioTEPA, VP-16 and total body irradiation, but other regimens may also be efficacious. Further studies of this interesting group of tumors are clearly needed.

Effect of 6-hydroxydopamine on murine hematopoietic stem cells: enhanced cytotoxicity on megakaryocyte colony forming units.

We examined the effect of catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on murine committed megakaryocyte progenitor cells, the megakaryocyte-colony forming unit (CFU-Meg). More mature cells of the megakaryocyte series have the capacity for active uptake of catecholamines, and we speculated that the CFU-Meg would also take up 6-OHDA and be selectively killed. CFU-Meg were much more sensitive to the effects of this agent than were granulocyte-macrophage colony forming units (CFU-GM) or spleen-colony forming units. Co-incubation with catalase, which would destroy hydrogen peroxide generated extracellularly by the autoxidation of 6-OHDA, ablated 6-OHDA toxicity towards CFU-GM, but also significantly reduced the effect on CFU-Meg. Mazindol, a selective dopamine uptake inhibitor did not alter 6-OHDA effect on either CFU-Meg or CFU-GM. Finally, CFU-Meg were no more sensitive to incubation with hydrogen peroxide than were CFU-GM. These data suggest that CFU-Meg, unlike their more mature progeny, do not actively concentrate 6-OHDA, and the excess toxicity of this agent towards CFU-Meg is probably due to increased sensitivity to autoxidation products of 6-OHDA, other than hydrogen peroxide, generated extracellularly.

Determining when a clinical activity should be classified as research requiring Institutional Review Board Review.

The boundary between therapy and research may at times be difficult to distinguish, and it is, therefore, important for health care professionals to recognize when a clinical activity should be properly classified as research. Research may be subject to federal regulations which require advance review and approval by an Institutional Review Board (IRB) in order to protect the rights and welfare of patients who serve as human subjects. This paper will discuss the criteria health care professionals can use to distinguish between therapy, innovative therapy, and therapeutic or clinical research.

Autoimmune neutropenia and Hodgkin's disease: successful treatment with intravenous gammaglobulin.

We describe a child with Hodgkin's disease (HD) who presented with profound neutropenia, secondary to an antineutrophil antibody. The patient responded to intravenous immunoglobulin (IVIG), with prompt and sustained improvement in total white blood cell count (WBC) and absolute neutrophil count (ANC). The literature pertaining to autoimmune cytopenias complicating HD is reviewed, as well as the role of IVIG in management of these disorders.

Acute megakaryoblastic leukemia following transient myeloproliferative disorder in a patient without Down syndrome.

Transient myeloproliferative disorder (TMD) and subsequent acute myeloid leukemia (AML) occur with increased frequency in infants and children with Down syndrome. TMD can also occur in phenotypically normal newborns. We describe the second case of a non-Down syndrome child with TMD who subsequently developed AML. Trisomy 21 karyotypic was restricted to hematopoietic cells in the blood and bone marrow. No other karyotypic abnormalities were found. Leukemic blasts showed megakaryoblastic features with immunophenotyping. This case shows that TMD in a child without Down syndrome may not be entirely benign. Close follow-up is warranted.

Successful treatment of severe aplastic anemia by bone marrow transplantation from HLA nonidentical family members: preliminary results utilizing cyclophosphamide and 600 cGY fractionated total body irradiation.

We have performed bone marrow transplants on four children with severe aplastic anemia who lacked an human leukocyte antigen (HLA)-identical sibling donor. Patients were prepared with cyclophosphamide and 600 cGy fractionated total body irradiation, and then received marrow from a parent donor mismatched for one (two patients), two (one patient), or three (one patient) HLA antigens. All four patients engrafted. One died early of acute graft-versus-host disease. The three others showed sustained complete hematopoietic reconstitution. Two are alive and hematologically normal 43-87 months after transplant. Both have had acute and chronic graft-versus-host disease (CGVHD), and one of the two remains on immunosuppressive drugs. The fourth died at 48 months after transplant of CGVHD. The previous experience with HLA-incompatible marrow transplants is reviewed, and the rationale for this preparative regimen is discussed. Cyclophosphamide and 600 cGy fractionated total body irradiation is an effective preparative regimen for children with severe aplastic anemia receiving transplants from HLA-nonidentical parental donors, allowing engraftment and full hematologic reconstitution.

Assay for etoposide in human serum using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

An HPLC assay for etoposide in human serum was developed. Serum, spiked with podophyllotoxin (internal standard), was treated with sodium dodecyl sulphate prior to solid phase extraction. Analysis was performed on a 300x3.9 mm Bondclone 10 C18 column coupled with a fluorometric detector (lambda(ex) 230 nm, lambda(em) 330 nm). The retention times for etoposide and podophyllotoxin were 14 and 28 min respectively. The range of assay was 0.5 to 20 microg/ml with a detection limit of 0.2 microg/ml. This assay is suitable for use in clinical studies with etoposide.

The impact of escalating regulatory requirements on the conduct of clinical research.

A discussion of the impact of escalating regulatory requirements is provided, from the point of view of the administration of the institutional review board of an academic institution, and from clinical investigators who conduct studies at that same institution. Current and anticipated future issues are discussed.

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma.

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.

Full hematopoietic engraftment after allogeneic bone marrow transplantation without cytoreduction in a child with severe combined immunodeficiency.

Bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) with human leukocyte antigen (HLA)-identical sibling donors but no pretransplantation cytoreduction results in T-lymphocyte engraftment and correction of immune dysfunction but not in full hematopoietic engraftment. A case of a 17-month-old girl with adenosine deaminase (ADA) deficiency SCID in whom full hematopoietic engraftment developed after BMT from her HLA-identical sister is reported. No myeloablative or immunosuppressive therapy or graft-versus-host disease (GVHD) prophylaxis was given. Mild acute and chronic GVHD developed, her B- and T-cell functions became reconstituted, and she is well almost 11 years after BMT. After BMT, repeated studies demonstrated: (1) Loss of a recipient-specific chromosomal marker in peripheral blood leukocytes (PBLs) and bone marrow, (2) conversion of recipient red blood cell antigens to donor type, (3) conversion of recipient T-cell, B-cell, and granulocyte lineages to donor origin by DNA analysis, and (4) increased ADA activity and metabolic correction in red blood cells and PBLs.

Peripheral T-cell lymphoma in childhood and adolescence. A clinicopathologic study of 22 patients.

BACKGROUND: Peripheral T-cell lymphoma (PTCL), although the most common T-cell lymphoma in adults, is relatively rare in childhood, and only small series have been reported. METHODS/RESULTS: Twenty-two cases of PTCL were studied that occurred in patients 18 months to 20 years of age. Nine were seen when the condition was diagnosed, and the other 13 were referred after they had relapses. The stage at diagnosis was I or II (45%), III (41%), and IV (14%). Patients with Stage IV disease were younger than those with Stage I or II disease (2.5 versus 14.8 years, P = 0.04). Twelve patients had extranodal disease when the diagnosis was made; the skin was the most common site. Ten tumors were classified as diffuse large cell type; five, as diffuse anaplastic large cell type; and seven, as diffuse mixed cell type. Twenty of the 21 tumors tested were CD30 (Ki-1 or Ber-H2) antigen positive. Of the nine patients seen when the diagnosis was made and treated by the authors, three had a relapse (median, 12 months), a 2-year relapse-free survival (RFS) rate of 61%. For the total group, the RFS was longer for patients older than 12 years of age compared with those who were younger (20 versus 12 months, P = 0.05). Overall, six patients remained in their first complete remission. Sixteen patients had a relapse, and 13 of these underwent bone marrow transplantation (BMT). Six of these remained in complete remission (median, 18 months after BMT). Overall, only 6 of 22 patients died (median survival, > 60 months). CONCLUSION: It was concluded that aggressive therapy, including BMT for relapses, can provide prolonged disease control in most children with PTCL.