Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

Results of a randomized phase III trial in children and adolescents with advanced stage diffuse large cell non Hodgkin's lymphoma: a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) adopted a histology-based approach to the management of pediatric non-Hodgkin's lymphomas (NHL) utilizing the National Cancer Institute Working Formulation for Clinical Usage. Patients with diffuse large cell lymphoma (DLCL) were treated on a separate protocol from small cell diffuse undifferentiated or lymphoblastic lymphomas. This study assessed the overall and event free survival of children with DLCL and determined the effects of cyclophosphamide upon these end-points in a prospective randomized trial. One hundred and twenty eligible stage III or IV NHL patients with the confirmed diagnosis of diffuse large cell or immunoblastic histology were enrolled on study between October 1986 and November 1991. Patients were randomized to receive or not receive cyclophosphamide; 58 received cyclophosphamide, doxorubicin, vincristine, 6-mercaptopurine (6-MP), and prednisone (ACOP+) and 62 were treated with doxorubicin, vincristine, 6-MP, and prednisone (APO). In both treatment programs methotrexate was substituted when the doxorubicin cumulative dose reached 450 mg/m2. Radiation was administered to bulky disease if progression or no response were observed after induction therapy. Planned duration of therapy was 12 months. The 5-year event free survival (EFS) rates of patients treated with ACOP+ versus APO were 62% +/- 7% and 72% +/- 6%, respectively. While there was no statistically significant difference between the two treatment arms (p = 0.28), we can only say that we are 95% confident that the difference in 5-year EFS falls in the wide range from 28% in favor of APO to 8% favoring ACOP+. Marrow suppression was the main toxicity with one fatal infection. There were three other deaths on study due to respiratory failure in patients with mediastinal masses. Only one patient experienced cardiotoxicity requiring discontinuation of doxorubicin. Ten patients received radiation therapy to achieve. In conclusion the efficacy of elimination of cyclophosphamide from the treatment program of children and adolescents with advanced stage diffuse large cell lymphoma was inconclusive as to its effect on EFS. Furthermore, the majority of the patients (92%) did not require any radiation therapy to bulky disease indicating that the chemotherapy regimens are quite efficient for achievement of complete remission.

A phase II study of Homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study.

BACKGROUND: Homoharringtonine (HHT) is a plant alkaloid that is derived from a Chinese evergreen tree. Its mechanism of action is thought to be by inhibition of protein, DNA, and RNA synthesis by inhibition of chain initiation. The treatment of acute myelogenous leukemia (AML) in children, has been hampered by few new effective agents developed in the past 30 years. Significant numbers of children still die of this disease. The purpose of this study is to evaluate the efficacy and toxicity of HHT for the therapy of refractory AML in children. PROCEDURE: Patients entered the study and were treated with HHT 7mg/m(2)/day for 10 days. The cycles could be repeated every 21 days depending on recovery from myelosuppression. RESULTS: Thirty-seven patients entered the study, with twenty-eight evaluable for response. Complete response was obtained in four and a partial response in one (response rate 5/28 = 18%). Significant toxicities included prolonged severe myelosuppression in all responsive patients and neuropathogenic pain in two patients. The median duration of response was 62 days with a range of 28-126 days. CONCLUSIONS: HHT has activity against chemotherapy resistant AML in children, with tolerable toxicity. This agent warrants further clinical evaluation in combination with other agents or perhaps biologic response modifiers which will hopefully lead to useful therapeutic options. Med Pediatr Oncol 2001;37:103-107.

The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and is among the most curable of the pediatric malignancies. Many clinical, biological, genetic, and molecular features have been identified as having prognostic significance in the outcome of patients with ALL. The standard features are age and WBC at diagnosis, with infants (less than one year), adolescents (greater than nine years), and children with WBC above 50,000/microl being at higher risk. Certain chromosomal abnormalities are also strong predictors; in particular, the Philadelphia chromosome and MLL gene rearrangements (especially in infants) are adverse features, while TEL-AML1 is favorable. It is important to note, however, that even the most important known predictors explain only a small proportion of the variability in outcome. These features are currently used to tailor the intensity of treatment so that the toxicity of treatment can be minimized and cure rates can continue to improve. This article reviews time-honored prognostic features, recent advances, and future directions in this field.

Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma.

PURPOSE: Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. PATIENTS AND METHODS: Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. RESULTS: Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. CONCLUSION: A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.

Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia.

PURPOSE: To determine the remission rate and toxicity of mitoxantrone, etoposide, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/or refractory acute myeloid leukemia. PATIENTS AND METHODS: MEC therapy consisted of mitoxantrone 6 mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2 hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of pharmacokinetic interactions, drug doses were decreased to 60% of those found to be effective without coadministration of CSA. MDR1 expression was evaluated by reverse transcriptase polymerase chain reaction, flow cytometry, and the ability of CSA at 2.5 micromol/L to increase intracellular accumulation of (3)H-daunomycin in blasts from bone marrow specimens. RESULTS: The remission rate was 35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n = 6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59). Toxicities included infection, cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum creatinine and bilirubin. In most who had relapsed while receiving therapy or whose induction therapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients. CONCLUSION: Serum levels of CSA capable of reversing multidrug resistance are achievable in children with acceptable toxicity. The CR rate of 35% achieved in this study is comparable to previously reported results using standard doses of mitoxantrone and etoposide. The use of CSA may have improved the response rate for the MDR1-positive patients so that it was not different from that for the MDR1-negative patients.

Late events in pediatric patients with Ewing sarcoma/primitive neuroectodermal tumor of bone: the Dana-Farber Cancer Institute/Children's Hospital experience.

The outcome for 82 pediatric patients with Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone is reported; the patients were treated at the Dana-Farber Cancer Institute (DFCI) and Children's Hospital (CH) in Boston, MA (USA) from 1971-1988. The charts of all patients with ES/PNET of bone treated during this period were reviewed for disease status, therapy, sites of relapse, information on second malignancies, and survival status. Eighty-two patients with ES/PNET of bone treated at DFCI/CH were identified. The 10-year event-free survival (EFS) rates were 12% (95% confidence interval [CI] 0, 27%) and 38% (95% CI 26, 51%) for patients with and without metastases, respectively (P = 0.002); the overall survival (OS) rates were 17% (95% CI 1, 33%) and 48% (95% CI 35, 61%) for patients with and without metastases (P = 0.001). Median follow-up for surviving patients is 10.2 years. Primary site in the pelvis also was associated with a poor outcome for patients with no metastatic disease (P = 0.006 OS, P = 0.03 EFS). Thirty-one patients survived in first remission at least 5 years from diagnosis, and of these, five experienced relapse of original disease, and five experienced secondary malignancies. Pediatric patients treated for ES/PNET of bone remain at risk for life-threatening events into the second decade of follow-up. After 5 years, the risk of second malignant neoplasm is at least as high as the risk of late relapse. Prolonged follow-up of patients with ES and PNET of bone is indicated.

Quality-adjusted survival after treatment for acute myeloid leukemia in childhood: A Q-TWiST analysis of the Pediatric Oncology Group Study 8821.

PURPOSE: To describe quality-of-life considerations in post-remission therapies for children with acute myelogenous leukemia. PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle. RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P <.001), more time in TWiST (P =.06), and had more relapse-free time (P =.03) and time alive (P =.07). Allo BMT was superior to ABMT with greater time in TWiST (P =.02), relapse-free time (P =.01), and time alive P =.002). CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.

Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821.

We determined the type and frequency of chromosomal aberrations in leukemic cells of 478 children diagnosed with acute myeloid leukemia and enrolled in the Pediatric Oncology Group study 8821. Of the 478 cases, 109 (22.8%) had normal karyotypes. Chromosomal abnormalities of 280 patients (58.6%) were classified into subgroups: 11q23 abnormalities (n = 88, 18.4%), t(8;21) (n = 56, 11.7%), t(15;17) (n = 55, 11.5%), inv(16)/t(16;16) (n = 28, 5.9%), trisomy 8 alone (n = 10, 2.1%), monosomy 7 (n = 9, 1.9%), non-Down-associated trisomy 21 alone (n = 7, 1.5%), and rare recurrent chromosomal translocations (n = 27, 5.6%). The remaining 89 patients (18.6%) had miscellaneous clonal abnormalities. Overall, 84.9% of the children achieved a complete remission; the 4-year event-free survival (EFS) estimate was 33.8% +/- 2.4%. Remission rates were significantly higher (96.4%, P =.011) for patients with t(8;21) and inv(16)/t(16;16) but significantly lower (74.5%, P =.022) for those with t(15;17). The 4-year survival rate for all patients was 43.5% +/- 2.4%; for those with an inv(16)/t(16;16), 75.0% +/- 8.6%; a normal karyotype, 53.8% +/- 4.9%; a t(8;21), 51.6% +/- 7.3%; a t(15;17), 39.8% +/- 6.9%; and an 11q23 abnormality, 32.9% +/- 5.1%. Four-year EFS estimates for patients with inv(16)/t(16;16) (58.2% +/- 10.9%, P =.007), t(8;21) (45.1% +/- 7.7%, P =.014), or normal karyotypes (43.1% +/- 5.0%, P =. 012) were higher than the 4-year EFS estimate for all patients, but EFS estimates for patients with t(15;17) (19.6% +/- 8.0%, P =.033) or 11q23 abnormalities (23.8% +/- 4.8%, P =.0013) were lower. EFS estimates did not differ significantly among 11q23 subgroups. Limited analysis suggested that patients with inv(16) can be salvaged better following relapse than those with t(8;21). Thus, patients with an inv(16)/t(16;16) may have high survival rates when treated with chemotherapy alone.

Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin.

The high event-free survival rates of Down syndrome (DS) children with acute myeloid leukemia (AML) are due, in part, to increased in vitro sensitivity of DS myeloblasts to cytosine arabinoside (ara-C) and daunorubicin and the greater generation of ara-C triphosphate (ara-CTP) from ara-C compared with myeloblasts from non-DS patients (Taub et al, Blood 87:3395, 1996). This study further explores the molecular basis of chemotherapy sensitivity of DS AML patients by examining the expression of chromosome 21-localized genes in myeloblasts from newly diagnosed AML patients. Transcript levels of two chromosome 21-localized genes, cystathionine-beta-synthase (CBS) and superoxide dismutase (SOD), measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), were 12.0- and 3. 8-fold higher in DS compared with non-DS myeloblasts (P <.0001 and P <.0001, respectively). Conversely, there were no significant increases in transcripts for 2 other chromosome 21-localized genes, carbonyl reductase and the reduced folate carrier. CBS transcript levels correlated with both in vitro ara-C sensitivity measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium-bro mid e (MTT) assay (P =.003) and the generation of (3)H-ara-C triphosphate (ara-CTP) after in vitro incubations with 5 micromol/L (3)H-ara-C (P =.0003). Transcripts of deoxycytidine kinase were 2.6-fold higher in DS compared with non-DS cells and may be a factor in the enhanced metabolism of ara-C in DS cells. There was no significant correlation of SOD transcripts with in vitro ara-C and daunorubicin sensitivities. Increased CBS transcripts could result in elevated CBS activity, which modulates ara-C metabolism by altering reduced folate pools, deoxycytidine triphosphate pools, S-adenosylmethionine levels, and/or methylation of the deoxycytidine kinase gene. The further identification of the molecular mechanisms of chemotherapy sensitivity of DS AML patients may lead to significant improvements in the treatment and cure of AML.

Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines.

In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7. 1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-alpha (TNF-alpha) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-alpha (GM-, IL-4-, TNF-alpha-AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell-dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4-, or TNF-alpha-AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.

Controlling conditioning-related emesis in children undergoing bone marrow transplantation.

PURPOSE/OBJECTIVES: To compare the efficacy of two antiemetic regimens, ondansetron alone versus perphenazine with diphenhydramine, on emesis control in children undergoing conditioning therapy for bone marrow transplantation (BMT). DESIGN: Single-center, prospective, open, randomized, crossover study. SETTING: Pediatric BMT unit in an urban area in the northeastern United States. SAMPLE: 28 children, ages 4-17, undergoing BMT for a variety of underlying diseases. METHODS: After randomization to one of the two antiemetic regimens, emesis control was evaluated during conditioning therapy. If a participant experienced more than five episodes of emesis during any 12-hour period, he or she was crossed over to the other antiemetic regimen. If emesis control still was not achieved, the participant was removed from the study and other medications were administered to control vomiting. MAIN RESEARCH VARIABLES: Number of emetic episodes and incidence of side effects. FINDINGS: 10 of 15 patients (67%) who received ondansetron experienced major emesis control (no more than two episodes) compared with 0 of 13 patients (0%) who received perphenazine with diphenhydramine (p = 0.044, Fisher exact test). Of those who crossed over to ondansetron after failure with perphenazine and diphenhydramine, 38% were able to achieve major emesis control. CONCLUSIONS: Ondansetron offers superior antiemetic control over the combination of perphenazine and diphenhydramine for children undergoing high-dose chemotherapy with or without total body irradiation for BMT. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must develop an understanding of the etiology of therapy-induced emesis and the mechanisms of action of the various classes of antiemetic agents designed to control it. Implementing documentation to describe events of emesis will help to tailor antiemetic therapy to a patient's specific situation. Further research is necessary to determine alternate strategies, including different combinations or sequences of antiemetics to provide optimum emetic control during acute and delayed phases of emesis. The higher cost of ondansetron therapy must be considered within the context of superior efficacy.

Diagnosis and treatment of childhood acute myelogenous leukemia.

Acute myelogenous leukemia (AML) accounts for about 20% of the acute leukemias seen in children. In contrast to childhood acute lymphoblastic leukemia (ALL), there has only been a modest improvement in the cure rate of children with AML during the past two decades. Approximately 40% of children treated with chemotherapy alone are long-term survivors. The outcome is somewhat better for those children who are given bone marrow transplants from histocompatible sibling donors early in the first remission. During the last decade, however, new insights into the molecular basis of AML has increased our understanding of the pathogenesis and biology of this group of leukemias and are beginning to provide us with new therapeutic strategies.

A pilot study of continuous infusion Ara-C in combination with rhG-CSF in relapsed childhood acute myeloid leukemia.

Relapse in acute myeloid leukemia (AML) following intensive chemotherapy bears a bad prognosis. We treated 18 children with relapsed AML on two separate protocols that included continuous infusion (CI) of cytosine arabinoside (ara-C) (total dose 4gr-6gr/m2) over 96-120 hours. In an attempt to increase the fraction of blasts in S-phase and render them more sensitive to cell-cycle specific agents such as ara-C, 10 patients received 5mcg/kg rhG-CSF twice daily beginning 48 hours before and continuing through the duration of the CI ara-C (POG #9192 study). The percentage of cells is S phase before and after G-CSF administration was determined. In a second group of patients (n = 8) who received ara-C alone, endogenous concentrations of G-CSF and serial blood counts were measured (St Jude's R4 study). The rationale of the St Jude's R4 was to optimize the schedule of the second course of ara-C at a time when the patient's endogenous G-CSF concentration was increased and thus maximize the percent of cells captured in S phase. Four out of 8 patients receiving CI ara-C alone and 4 out of 10 patients receiving CI ara-C with rhG-CSF achieved a complete remission (CR) after 1 cycle of therapy. Four patients in CR underwent marrow transplantation (2 allogeneic and 2 autologous). Cell cycle analysis of blast cells cultured in vitro with or without G-CSF showed a two fold increase in the percentage of cells in S phase (P = 0.03) whereas cells obtained from patients before and after G-CSF administration showed no difference in cell cycling. Correlation between G-CSF concentrations and ANC showed a negative association indicating that the regulatory mechanisms for G-CSF production remained intact. In our relatively small series, CI ara-C achieved a CR rate of 44% with rhG-CSF having no effect on the remission rate. Although in vitro rhG-CSF increased the percentage of blasts in S phase significantly, in vivo effects were not observed. Larger studies with combinations of different hematopoietic growth factors and cell-cycle active drugs are needed to evaluate the role of these cytokines in the therapy of recurrent AML.

Antibody responses to tetanus toxoid and Haemophilus influenzae type b conjugate vaccines following autologous peripheral blood stem cell transplantation (PBSCT).

Accelerated granulocyte and platelet recovery following peripheral blood stem cell transplantation (PBSCT) are well documented. We hypothesize that functional immunity may also be enhanced in PBSCT and performed a phase II trial of immunizations in patients with lymphoma undergoing autologous transplantation with peripheral blood stem cells or bone marrow. Seventeen BMT and 10 PBSCT recipients were immunized at 3, 6, 12, and 24-months post-transplantation with Haemophilus influenzae type b (HIB)-conjugate and tetanus toxoid (TT) vaccines. IgG anti-HIB and anti-TT antibody concentrations were measured and compared between the two groups. Geometric mean IgG anti-HIB antibody concentrations were significantly higher for PBSCT recipients compared to BMT recipients at 24 months post-transplantation (11.3 micrograms/ml vs 0.93 microgram/ml, P = 0.051) and following the 24 month immunization (66.2 micrograms/ml vs 1.30 micrograms/ml, P = 0.006). Similar results were noted for IgG anti-TT antibody with significantly higher geometric mean antibody concentrations in the PBSCT group at 24 months post-transplantation (182 micrograms/ml vs 21.6 micrograms/ml, P = 0.039). Protective levels of total anti-HIB antibody were achieved earlier in PBSCT recipients compared with those of BMT recipients. PBSCT recipients had higher antigen-specific antibody concentrations following HIB and TT immunizations. These results suggest enhanced recovery of humoral immunity in PBSCT recipients and earlier protection against HIB with immunization.

CD8+ T cells activated during the course of murine acute myelogenous leukemia elicit therapeutic responses to late B7 vaccines after cytoreductive treatment.

We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-gamma. Cytotoxic T lymphocyte (CTL) assays demonstrate that cells from week-2 vaccinated mice (which succumb to their leukemia), surprisingly develop a stronger CTL activity than cells from week-1 vaccinated mice (which reject their leukemia). Finally, the combination of late chemotherapy and late B7 vaccine administration can cure only 20% of leukemic mice, whereas early chemotherapy and the same late B7 vaccine administration cure 100% of leukemic mice. These results demonstrate that in murine AML tumor growth does not induce T-cell anergy or a Th2 cytokine profile and suggest that tumor growth is most likely to be the limiting factor in the curative potential of late B7 vaccines.

Treatment of childhood leukemia.

The development of successful therapy for most children with acute lymphoblastic leukemia can be attributed to sequential clinical studies that show the importance of combination chemotherapy, sanctuary-specific treatment, and supportive care measures. The relative resistance of acute myelogenous leukemia to chemotherapy led to strategies that include dose-intensified chemotherapy and bone marrow transplantation. The improvement in long-term survival for children with acute leukemia has been gratifying but also has been associated with late effects that underscore the need for careful follow-up and for designing risk-adapted therapies.