Joseph H. Laver

Cytomegalovirus Pneumonia after Bone Marrow Transplantation Successfully Treated with the Combination of Ganciclovir and High-Dose Intravenous Immune Globulin

STUDY OBJECTIVE To assess the efficacy of the combination of the antiviral agent ganciclovir (9-1,3 dihydroxy-2-propoxymethylguanine) and high-dose intravenous immune globulin for treating cytomegalovirus interstitial pneumonitis after allogeneic bone marrow transplantation. DESIGN Nonrandomized prospective trial of combined treatment with two drugs; findings in these patients were compared with those in control patients treated with either of the two drugs alone. SETTING Medical, pediatric, and intensive care units of a tertiary-care cancer treatment center. PATIENTS Consecutive cases of 10 patients in the study group and of 11 patients in a historical control group with evidence of cytomegalovirus pneumonia after bone marrow transplantation for treatment of leukemia or congenital immune deficiency. INTERVENTIONS Study Group (10 patients): ganciclovir, 2.5 mg/kg body weight, three times daily for 20 days, plus intravenous immune globulin, 500 mg/kg every other day for ten doses. Patients were then given ganciclovir, 5 mg/kg.d three to five times a week for 20 more doses, and intravenous immune globulin, 500 mg/kg twice a week for 8 more doses. Control Group (11 patients): ganciclovir alone (2 patients), 5 mg/kg twice a day for 14 to 21 days; cytomegalovirus hyperimmune globulin (5 patients), 400 mg/kg.d for 10 days; and intravenous immune globulin (4 patients), 400 mg/kg.d for 10 days. MEASUREMENTS AND MAIN RESULTS Responses were observed in all patients treated with combination therapy; 7 of 10 patients were alive and well, and had no recurrence of disease at a median of 10 months after therapy. No therapeutic benefit was observed, and none of the 11 patients treated with either ganciclovir or intravenous immune globulin alone survived (P = 0.001 by Fisher exact test). CONCLUSIONS Ganciclovir, when combined with high-dose intravenous immune globulin, appears to have significantly altered the outcome of patients with cytomegalovirus pneumonia after allogeneic bone marrow transplantation.

Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25 000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50 000/μor patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.

Allogeneic Bone Marrow Transplantation after Hyperfractionated Total-Body Irradiation and Cyclophosphamide in Children with Acute Leukemia

Ninety-seven children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) received HLA-identical bone marrow transplants from sibling donors, after preparation with 1320 cGy of hyperfractionated total-body irradiation and high-dose cyclophosphamide. Kaplan-Meier product-limit estimates (means +/- SE) of disease-free survival at five years among patients with ALL in second remission, third remission, and fourth remission or relapse were 64 +/- 9, 42 +/- 14, and 23 +/- 11 percent, respectively, with probabilities of relapse of 13 +/- 7, 25 +/- 13, and 64 +/- 16 percent. Among patients with AML in first remission, second remission, and third remission or relapse, five-year disease-free survival estimates were 66 +/- 10, 75 +/- 15, and 33 +/- 19 percent, with respective relapse probabilities of 0, 13 +/- 12, and 67 +/- 19 percent. The most frequent cause of death in patients in early remission (ALL in second or third remission or AML in first or second remission) was bacterial sepsis, fungal sepsis, or both, most often in the presence of acute or chronic graft-versus-host disease. Among patients with ALL who received transplants while in second remission, the duration of the initial remission had no effect on the probability of relapse after transplantation. The only pretransplantation factor that significantly affected outcome was the disease status at the time of transplantation; patients in early remission had better disease-free survival. We conclude that transplantation after preparation with hyperfractionated total-body irradiation and cyclophosphamide is an effective mode of therapy in children with refractory forms of acute leukemia.

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia

We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability.

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

Advanced-Stage Large-Cell Lymphoma in Children and Adolescents: Results of a Randomized Trial Incorporating Intermediate-Dose Methotrexate and High-Dose Cytarabine in the Maintenance Phase of the APO Regimen: A Pediatric Oncology Group Phase III Trial

PURPOSE The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkins lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates. PATIENTS AND METHODS From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months. RESULTS The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity. CONCLUSION The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.

Granulocytosis causing sickle-cell crisis

mgikg), or topiramate (25 mg/kg) or a combination of the two by intraperitoneal injection. A control group received vehicle (0.9% saline) alone. An hour later, each animal was given 85 mgkg pentylenetetrazol subcutaneously; the time taken to the first generalised seizure was rec~rded .~ A cut-off point of 15 min was set. Although neither topiramate or lamotrigine exerted an effect, none of the animals pre-treated with the combination experienced a seizure throughout the observation period. It is not possible to be certain that the combination (and not topiramate alone) was the effective strategy in these patients. Nevertheless, although lamotrigine was administered to the limit of tolerability, doses of topiramate remained quite small: add-on regulatory trials with topiramate reported maximum seizure reduction with 400-800 mg daily.’ The study in mice also supports particular efficacy for the combination. This may be a consequence of the drugs’ wide range of mechanisms of action affecting Na’ and Ca” channels, and GABA-mediated inhibition and excitatory aminoacid neurotransmission.

Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-ricin A chain immunotoxin.

Anti-CD7-dgA, DA7, consists of deglycosylated ricin A chain coupled to a mouse monoclonal anti-human CD7 antibody. This study determined the maximally tolerated dose (MTD) of this immunotoxin administered as a one hour infusion over five days to 11 patients with T-cell lymphoma (>30% CD7+ malignant cells). The MTD was 0.2 mg/kg/day or 1 mg/kg/120 hours (maximal toxicity grade 3) with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT). Predictors of severe VLS included age and absence of circulating lymphoma cells. Two partial responses and one minimal response were seen. Patients with minimal lymphoma burden or T-cell large granular lymphocyte (LGL) leukemia showed the best responses. The mean maximal serum concentration of immunotoxin at the MTD was 2.5 ug/ml. The mean alpha-phase half-life was 1.5 hours and the mean beta-phase half-life was 8 hours. Repeated dosing had minimal effects on either peak serum immunotoxin concentrations or serum half-lives. While human antimouse antibodies were observed, they were low in concentration (<55 ng/ml). Human anti-ricin antibody was elevated in one patient (190 ng/ml). VLS presented with hypoalbuminemia, dyspnea, pulmonary edema, aphasia, and peripheral edema and cleared over a two week period. Serum fibronectin levels were measured in three patients and were very low in one patient who developed VLS. No specific binding of DA7 immunotoxin was seen with vascular endothelium in various human tissues.

Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study.

PURPOSE Contemporary chemotherapy has significantly improved the event-free survival (EFS) among patients with T-cell disease. However, myelosuppression has been a significant adverse effect of this approach. In this study, we assessed the impact of r-metHu granulocyte colony-stimulating factor (G-CSF) on the period of neutropenia, number of days of hospitalization, and delays in subsequent administration of chemotherapy in a cohort of patients with T-cell leukemia (T-ALL) or advanced stage lymphoblastic lymphoma (ASLL). PATIENTS AND METHODS This open-label, randomized trial incorporated r-metHuG-CSF into the induction and two consecutive continuation-therapy cycles of our intensive program for T-cell malignancies. In the induction phase, r-metHuG-CSF was given after two different combinations of chemotherapy, one of which included vincristine, prednisone, cyclophosphamide, and adriamycin and the other a continuous infusion of high-dose ara-C and L-asparaginase. In the two continuation-therapy cycles, r-metHuG-CSF was given following the combination of vincristine, adriamycin, prednisone, and 6-mercaptopurine (MP) and after continuous infusion of high-dose cytarabine (ara-C). RESULTS Fifty-six patients with T-ALL and 33 with ASLL were enrolled onto study from April 1994 to December 1995. Our data show no significant difference in number of days of absolute neutrophil count (ANC) less than 500/microL, hospitalizations, or delays in therapy in the induction phase. However, in the continuation-therapy phase the number of days of ANC less than 500/microL was significantly shorter (P = .017) on the G-CSF-arm without significantly affecting the number of days of hospitalizations or delays in therapy. CONCLUSION r-metHuG-CSF did not significantly affect the period of neutropenia, hospitalization, or delays in therapy in the induction phase, whereas in the two cycles of continuation therapy, it significantly shortened the period of neutropenia.

High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.