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Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline–based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients

Background Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith‐Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large‐scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Methods Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Results Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low‐level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Conclusions Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low‐level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing‐based approaches and detecting a cancer predisposition may modify treatment., In the current study, all patients presenting with Wilms tumor or hepatoblastoma undergo 11p15.5 methylation analysis. Approximately one‐third are found to have an epimutation at this locus that is detectable in peripheral blood.

Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P.99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD

Mixed phenotype acute leukemia (MPAL) represents a poorly characterized group of acute leukemias that lack an accepted therapeutic approach and are typically associated with poor outcomes. We present our experience of genomic profiling, pretransplantation therapy, and transplantation outcomes for 36 well-characterized pediatric and adult patients with MPAL, defined according to the 2016 World Health Organization leukemia update. A predominance of acute lymphoid leukemia (ALL)-associated mutations and cytogenetic abnormalities was noted. Remission rates after induction appeared comparable among adults (20 of 23) and children (11 of 13) and among those who received ALL (10 of 11) or acute myeloid leukemia-type (21 of 25) induction. Adults underwent transplantation in first remission while children underwent transplantation in the setting of relapse or MLL rearrangement. The median follow-up among the 25 patients who underwent transplantation was 39.6 months and median overall survival was not reached. Relapse after transplantation was associated with MLL rearrangement (P = .022), reduced-intensity conditioning (P .001), and higher WBC at diagnosis (P = .034). These data highlight differing therapeutic approaches between adult and pediatric MPAL and demonstrate favorable survival of adult MPAL patients consolidated with allogeneic hematopoietic cell transplantation.

Children’s Cancer Group CCG-1882 improved outcome for 1–21-year old with high risk acute lymphoblastic leukemia and Induction Day 8 marrow blasts ≥25% (slow early responders, SER) with longer and stronger post induction intensification (PII). This CCG-1961 explored alternative PII strategies. We report 10-year follow-up for patients with rapid early response (RER) and for the first time details our experience for SER patients. A total of 2057 patients were enrolled, and 1299 RER patients were randomized to 1 of 4 PII regimens: standard vs. augmented intensity and standard vs. increased length. At the end of interim maintenance, 447 SER patients were randomized to idarubicin/cyclophosphamide or weekly doxorubicin in the delayed intensification phases. The 10-year EFS for RER were 79.4 ± 2.4% and 70.9 ± 2.6% (hazard ratio = 0.65, 95% CI 0.52–0.82, p

From 2009 to 2018, 10 consecutive patients with Wilms tumors and bilateral nephroblastomatosis, who had completed standard therapy, were provided a maintenance chemotherapy regimen consisting of vincristine and dactinomycin every 3 months for 12 months in order to prevent an early metachronous Wilms tumor. One patient (10%) with Beckwith-Wiedemann syndrome developed a new tumor, without anaplasia. There were no significant toxicities reported during maintenance. All patients are currently alive with no evidence of disease. Further investigations are recommended to determine the utility of this approach.

Introduction Children with Down syndrome (DS) carry a 20-fold higher risk of developing acute lymphoblastic leukemia (ALL) than other children and have increased rates of treatment-related mortality (TRM) and relapse. The prognosis for relapsed DS-ALL patients is grim with long-term survival rates of 20%. Blinatumomab, a CD19/CD3 bispecific antibody, is FDA approved for relapsed pediatric pre-B ALL, and recently approved for patients with minimal residual disease (MRD). However there are few reports of the use of blinatumomab in DS-ALL patients, and no reports of blinatumomab as a bridge to stem cell transplant (SCT) in this population. Case Description A 19 year old male with DS presented with thrombocytopenia and was diagnosed with pre-B ALL. Upfront therapy included fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, pegaspargase, and rituximab for 8 cycles, and he achieved complete remission (CR). Maintenance therapy included 26 months of 6-mercaptopurine, vincristine, methotrexate, and prednisone. He relapsed 5 months after completion of therapy and was found to have a P2RY8-CRLF2 fusion. IgH gene rearrangement analysis by next generation sequencing (LymphoTrack assay) demonstrated clonal rearrangement. Re-induction therapy included vincristine, pegaspargase, and prednisone. He completed 2 additional courses of chemotherapy but continued to have MRD both by flow cytometry and LymphoTrack. Given persistent MRD with CD19+ lymphoblasts, he was treated with blinatumomab at the FDA recommended dosing; he had no signs of toxicity. He achieved negative MRD by flow cytometry and LymphoTrack after 1 cycle. He then proceeded to a T-cell depleted peripheral blood SCT from a 10/10 matched sibling after conditioning with total body irradiation, thiotepa, and cyclophosphamide. Post-SCT course was uncomplicated and he is now 1 year post-SCT with no evidence of leukemia and 100% donor chimerism. Conclusion Blinatumomab is clinically effective and safe for patients with relapsed/refractory pre-B ALL, yet there is limited information on its use in DS-ALL patients. These patients have been largely excluded from blinatumomab trials given their altered immune system and unknown level of innate T cell dysfunction, potentially altering the efficacy of blinatumomab. We present here the case of a 22 year old male with relapsed DS-ALL who remained MRD positive after several cycles of re-induction chemotherapy, but achieved a CR following 1 cycle of blinatumomab with no toxicities, and safely proceeded to SCT. Although this is a single case, it demonstrates clinical efficacy of blinatumomab in relapsed DS-ALL, suggesting that these patients' T cells can be engaged to recognized CD19-positive leukemic blasts. Furthermore, blinatumomab represents a particularly attractive bridging therapy to SCT for DS-ALL patients who experience high rates of TRM with traditional agents.

Despite an almost 80% overall survival rate in pediatric T-cell acute lymphoblastic leukemia (T-ALL), there is a subset of patients who are refractory to standard chemotherapy regimens and could benefit from novel treatment approaches. Over a 2-year period, we treated 5 pediatric patients with refractory T-ALL, aged 3 to 15 years, with high-dose cyclophosphamide (CY) at a dose of 2100 mg/m for 2 consecutive days either alone (n=1) or in combination with other chemotherapy agents (n=4). Four of these 5 patients had a 1.5 log decrease in disease burden. Three of the 5 patients had no evidence of minimal residual disease (MRD) after high-dose CY. One patient developed transient grade 4 transaminitis and 1 patient developed grade 3 typhlitis. All 5 patients ultimately proceeded to hematopoietic stem cell transplant when MRD levels were

Background Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study. Procedure Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m2/day IV × 5 days, topotecan 1 mg/m2/day IV continuous infusion × 5 days, vinorelbine 20 mg/m2/week IV × 3 weeks, thiotepa 15 mg/m2/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). Results The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%). Conclusions TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia. Pediatr Blood Cancer 2014;61:431–435. © 2013 Wiley Periodicals, Inc.

Background Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. Procedure To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). Results Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019). Conclusions Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease. Pediatr Blood Cancer 2013;60:2018–2024. © 2013 Wiley Periodicals, Inc.

Summary Background Acute lymphoblastic leukaemia (ALL) is curable in more than 80% of children and adolescents who exhibit high-risk features. However, treatments are associated with symptomatic osteonecrosis that disproportionately affects adolescents. Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether dexamethasone dose modification would reduce the risk of osteonecrosis. We therefore compared use of continuous versus alternate-week dexamethasone within standard and intensified post-induction treatments. Methods In the CCG-1961 trial, a multicohort cooperative group trial, 2056 patients (aged 1–21 years) with newly diagnosed high-risk ALL (age ≥10 years, white blood cell count ≥50×10 9 per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m 2 per day on days 0–6 and 14–20) was compared with standard continuous dexamethasone (10 mg/m 2 per day on days 0–20) in computer-generated randomised regimens with permuted blocks within double or single delayed intensification phases, respectively. Masking was not possible because of the differences in the treatments. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002812. Findings Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. In patients aged 1–21 years, the overall cumulative incidence of osteonecrosis at 5 years was 7·7% (SE 0·9), correlating with age at ALL diagnosis (1–9 years, 1·0% [0·5]; 10–15 years, 9·9% [1·5], hazard ratio 10·4 [4·8–22·5]; 16–21 years, 20·0% [4·3], 22·2 [10·0–49·3]; p vs boys 9·3% [1·7], 1·7 [1·2–2·4]; p=0·001). For patients aged 10 years and older with a rapid response to induction treatment, the use of alternate-week dexamethasone during phases of delayed intensification significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7% [2·1] vs 17·0% [2·9], 2·1 [1·4–3·1]; p=0·0005), especially in those aged 16 years and older (11·3% [5·3] vs 37·5% [11·0], p=0·0003; girls 17·2% [8·1] vs 43·9% [14·1], p=0·05; boys 7·7% [5·9] vs 34·6% [11·6], p=0·0014). Interpretation Alternate-week dexamethasone during delayed intensification phases, a simple dose modification, reduces the risk of osteonecrosis in children and adolescents given intensified treatment for high-risk ALL. Its use is being evaluated in children with standard risk ALL. Funding US National Cancer Institute at the National Institutes of Health.

Purpose Lymph node metastasis and anaplasia predict relapse-free survival in Wilms tumor. We performed a multivariate analysis of our institutional database to identify factors independently associated with relapse-free and overall survival. Methods We retrospectively reviewed cases of confirmed Wilms tumor diagnosed between 1990 and 2010 and treated at our institution. The log-rank test was used to screen variables for consideration in the proportional hazards model. Results A total of 95 patients were treated at our institution during the study period, with a median follow-up of 3.3 years. Factors correlated with overall survival in the univariate analysis were local disease, metastasis, tumor size, anaplasia, renal vein tumor thrombus, inferior vena cava tumor thrombus, lymph node positivity, and tumor rupture. On multivariate analysis, factors associated with increased risk of death were lymph node positivity and anaplasia. Factors correlated with probability of relapse in the univariate analysis were lymph node positivity, anaplasia, and female sex. All 3 of these factors were also independently significant on multivariate analysis. Conclusion Lymph node involvement and anaplasia are significantly correlated with probability of relapse and overall survival, reemphasizing the strong recommendation to sample regional lymph nodes during Wilms tumor resection.

The development of treatment-related myelodysplastic syndrome (tMDS) or treatment-related acute myelogenous leukemia (tAML) is a complication that can occur after chemotherapy or radiation therapy. Eighteen patients with a previous malignancy treated at our institution and three patients with a nonmalignant primary tumor received an allogeneic hematopoietic stem cell transplant (HSCT) on the pediatric bone marrow (BM) transplantation service for the treatment of tMDS/tAML over a 15-year period. Five patients proceeded to HSCT without induction chemotherapy. Fourteen patients received high-dose cytarabine according to the Capizzi II regimen as first-line induction therapy with 13 of them achieving complete remission (CR) or refractory anemia (RA) with persistent cytogenetic abnormalities after this treatment. Two patients received an anthracycline-based induction therapy. Conditioning regimens were selected according to previous therapies: 11 patients received busulfan-melphalan-fludarabine (BU-MEL-FLU), which consisted of busulfan (0.8 mg/kg/dose every 6 hours ×10 doses), melphalan (70 mg/m(2)/dose × two doses), and fludarabine (25 mg/m(2)/dose × five doses) for cytoreduction; three patients received a total body irradiation (TBI)-containing regimen; seven patients received myeloablative regimens containing busulfan and/or melphalan and/or thiotepa with doses modified for organ toxicity. Sixteen patients received T cell-depleted (TCD) grafts; four patients received unmodified grafts; one patient received a double-unit cord blood transplantation (DUCBT). Donors included HLA-matched (n = 9), or mismatched (n = 3) related donors, or HLA-matched (n = 4), or mismatched (n = 4) unrelated donors, or DUCBT (n = 1). Disease status at the time of HSCT was: morphologic and cytogenetic CR (n = 12); RA with positive cytogenetics (n = 6); and refractory disease (n = 3). With a median follow-up of 5.9 years (2.2-15.7 years), the 5-year overall survival (OS) and disease-free survival (DFS) rates for the entire group were 61.1% with 12 patients alive without evidence of either primary disease or tMDS/tAML. The OS and DFS rate for the 11 patients who received the BU-MEL-FLU cytoreduction with TCD grafts was 54.5%. DFS was 65.7% for patients in RA or CR at HSCT compared with 0% for patients with5% residual marrow blasts (P = .015). Nine patients died; the cause of death was relapse of MDS/AML (n = 4) or primary disease (n = 2), graft-versus-host disease (GVHD; n = 2), and infection (n = 1). Four patients developed grade II to IV acute GVHD. One patient developed localized chronic GVHD. Our results suggest that the strategy of induction with high-dose cytarabine therapy followed by allogeneic stem cell transplantation improves the overall outcome for patients with tMDS/tAML. In addition, the use of a TCD transplantation with BU-MEL-FLU as cytoreduction may decrease the toxicity of transplantation in heavily pretreated patients without an increase in relapse rate.

BACKGROUND: Histiocytic sarcoma (HS) is an exceedingly rare tumor and carries a dismal prognosis when patients present with advanced-stage disease. Because of the poor response rates to conventional chemotherapy and the rarity of the disease, no standard of care exists for patients with HS. The authors report the single-agent use of the anti-CD52 antibody alemtuzumab in 2 patients who had advanced-stage HS. METHODS: Two patients with chemotherapy-refractory, metastatic HS with tumors that expressed the CD52 antigen received a prolonged course of treatment with the anti-CD52 monoclonal antibody alemtuzumab. RESULTS: Resected tumor samples from both patients demonstrated CD52 expression. Both patients had marked responses to single-agent alemtuzumab. One patient had a complete response with no evidence of disease for >5 years. The second patient had a major response to alemtuzumab and also remained alive with no evidence of disease for >4 years. CONCLUSIONS: Further studies need to be performed to examine CD52 expression and function in HS as well as the role of alemtuzumab in a larger cohort of patients. However, the clinical impact of single-agent alemtuzumab in the 2 patients described in this report was very encouraging. Given the toxicity and frequent inefficacy of conventional chemotherapy, patients with incompletely resected HS should be strongly considered for alemtuzumab therapy. Cancer 2012. © 2011 American Cancer Society.

Background: Relapsed or refractory pediatric acute myeloid leukemia (AML) is an unfortunate reality in approximately 40% of children and young adults diagnosed with AML. Therapeutic options are limited in this heavily pre-treated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. Non-anthracycline based salvage regimens are crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC) in a cohort of patients with AML. Herein, we report on an expanded cohort of AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2007. We report our center's experience using a Clofarabine-based regimen with Topotecan, Vinorelbine, and Thiotepa (TVTC), its overall response rate defined as complete remission (CR) and its use as a bridge to hematopoietic stem cell transplant (HSCT). Patients and Methods: All patients 10% bone marrow involvement, who were treated with the phase 2 recommended schedule of TVTC were included in this analysis. Patients received the TVTC regimen with Topotecan 1 mg/m2/day (120 hour continuous infusion, Days 0-4), Vinorelbine 20 mg/m2/dose (Days 0, 7, 14), Thiotepa 15 mg/m2/dose (Day 2), and Clofarabine 40 mg/m2/day (Days 3-7). The regimen could be administered without hospitalization in patients who did not require hospitalization for other reasons. Most patients received antimicrobial prophylaxis starting on Day 8 with Levofloxacin and fungal prophylaxis with either Posaconazole or Voriconazole. GCSF 5mcg/kg/day was initiated on Day 8. Bone marrow evaluation was performed at the point of hematologic recovery to assess response. Overall response rate (ORR) was defined as complete remission (CR) plus complete remission without platelet recovery (CRp). Results: A total of 29 patients with relapsed (n=19) or refractory (n=10) AML were treated since 2007. Eight patients (28%) had prior hematopoietic stem cell transplantation (HSCT). The ORR of the entire cohort was 59% (17/29). The ORR of patients with relapsed vs. refractory disease was 74% (14/19) and 30% (3/10), respectively. Seventeen of 29 patients (59%) received TVTC as a 1st re-induction regimen with 59% (10/17) of those patients achieving a CR/CRp. The remaining 12 patients had TVTC as 2nd or greater regimen with 58% (7/12) of those patients achieving a CR/CRp. Among the 17 total responders in the cohort, 13 (76%) proceeded to HSCT. Of those who proceeded to HSCT, 8 of 13 are alive today (62%). Median time since HSCT is 66 months (range 14 to 107 months). The most common adverse effects were febrile neutropenia in 20 out of 29 patients (69%) which was Grade 3 or less, 3 of 29 patients (10%) with Grade 4 or greater febrile neutropenia requiring ICU admission. One patient developed an abdominal mucormycosis infection. One patient developed bone marrow aplasia and died due to sepsis 45 days after receiving TVTC. Conclusions: TVTC is an active regimen for children and young adults with relapsed/refractory AML, with an acceptable toxicity profile . Non-anthracycline containing salvage regimens are especially important as patients usually receive >400mg/m2 daunorubicin equivalents during frontline therapy. The majority of responders were successfully bridged to HSCT without exposure to additional anthracycline, with approximately half of these patients demonstrating long-term survival. TVTC warrants further exploration as a re-induction regimen in a larger cohort of patients with relapsed/refractory AML. Disclosures Kobos: Janssen Research & Development: Employment.

Acute megakaryoblastic leukemia (AMKL) constitutes ∼5%–15% of cases of non–Down syndrome AML in children, and in the majority of cases, chimeric oncogenes resulting from recurrent gene rearrangements are identified. Based on these rearrangements, several molecular subsets have been characterized providing important prognostic information. One such subset includes a group of patients with translocations involving the KMT2A gene, which has been associated with various fusion partners in patients with AMKL. Here we report the molecular findings of a 2-yr-old girl with AMKL and t(11;17)(q23;25) found to have a KMT2A–SEPT9 fusion identified through targeted RNA sequencing. A KMT2A–SEPT9 fusion in this subset of patients has not previously been reported.

Meningiomas are among the most common brain tumors in adults. They are most commonly located over the cerebral convexities and are infrequently found in an intraventricular location. Ionizing cranial radiation is a risk factor for late occurrence of meningiomas within the radiation field. While pathologic grading of meningiomas is straightforward, significant variability often exists between pathologists in applying standard grading criteria. This has implications for prognosis. Radiation-induced meningiomas may also have predilection to recur. The authors describe a case of an intraventricular meningioma occurring 23 years after cranial irradiation for childhood acute lymphoblastic leukemia.

Background We determined the maximum tolerated dose (MTD) of clofarabine when administered with topotecan, vinorelbine, thiotepa, and dexamethasone (TVTC) for children with relapsed or refractory acute leukemia, and observed the efficacy and toxicities of this therapy. Procedure Twelve patients with acute lymphoblastic or myeloblastic leukemia were given a 14-day remission induction therapy. Clofarabine was administered at a dose of 30 or 40 mg/m2/day over 2 hr for five consecutive days in six patients each. Patients who achieved a remission proceeded to a stem cell transplant (HSCT). A second cycle could be administered prior to HSCT. Results Of the six patients at the 30 mg/m2 clofarabine dose, two achieved a complete response (CR) and one a PR and proceeded to BMT. Three patients had progressive disease. Five of the six patients at the 40 mg/m2 achieved a CR. Four proceeded to HSCT, and one relapsed prior to HSCT. One patient died on day 45 with marrow hypoplasia without evidence of leukemia. Hematologic and infectious adverse events were universal. The one dose limiting non-infectious toxicity observed was prolonged marrow hypoplasia. Conclusion TVTC has significant anti-leukemic activity in both acute lymphoblastic and myeloblastic leukemia. The MTD of clofarabine is 40 mg/m2/day in this combination. This is the recommended dose for the phase II study in patients with refractory or relapsed leukemia, a population which has limited therapeutic options. Pediatr Blood Cancer 2010;54:687–693. © 2010 Wiley-Liss, Inc.

Over the last 40 years, cryptosporidium has increasingly been recognized as a cause of acute self-limiting diarrhea in normal hosts. In the immunocompromised patient, cryptosporidium may cause severe illness with prolonged diarrhea and malabsorption. Pharmacologic therapy of cryptosporidium relies on adequate delivery of drug metabolites to the colon. Here we describe a patient who developed toxic megacolon during induction therapy for leukemia, requiring ileostomy formation to proceed with leukemia treatment. Although the megacolon resolved promptly, the resulting isolation of the colon from the fecal stream prevented luminal delivery of active metabolites of anti-protozoal drugs, resulting in persistent cryptosporidiosis. Refeeding of the ileostomy output into the colon effectively eradicated cryptosporidium from the colon and permitted closure of the ileostomy.

Purpose Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002. Patients and Methods CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count ≥ 50,000/μL and/or age ≥ 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL. Results Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/μL was an adverse prognostic factor. Conclusion Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

Primary cutaneous lymphomas are rare in the pediatric population and most often represent mycosis fungoides or CD30+ lymphoproliferative disorders. Primary cutaneous B-cell lymphoma has rarely been reported in children, and in the past may have been mistaken for disseminated nodal disease or benign cutaneous lymphoid hyperplasias. We describe two cases of marginal zone primary cutaneous B-cell lymphoma in young males. Thus far both have been managed with local therapy. We review the literature of this rare malignancy.

Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.

Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition., Author Summary Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia. Here we report two unrelated kindreds with inherited mutations in ETV6, the gene encoding the transcription factor ETS variant 6. These families were characterized by a low platelet count (thrombocytopenia) and acute lymphoblastic leukemia (ALL). Sequencing a panel of genes identified germline ETV6 mutations associated with leukemia and thrombocytopenia in multiple individuals tested. In one family, there was a substitution within the DNA binding domain of ETV6, termed L349P, and in the second there were five base pairs missing in ETV6 (N385fs), causing an abnormally truncated protein. We overexpressed the ETV6 mutants in the HeLa cell line and measured protein levels and localization within the cells. Instead of localizing to the nucleus, as expected for a transcription factor, the mutant proteins were found in the cytoplasm. The mutant proteins also showed decreased ability to regulate the expression of other genes typically suppressed by ETV6. These findings suggest that germline ETV6 mutations cause a new type of heritable leukemia. This discovery makes possible the pre-symptomatic diagnosis of leukemia susceptibility in families with germline ETV6 mutations, and also provides new information on the causes of leukemia.

We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early r

BACKGROUND Initial treatment for adult patients with Philadelphia chromosome-positive (Ph[+]) chronic myelogenous leukemia (CML) now includes imatinib mesylate. However, to our knowledge, there are few data regarding imatinib safety, efficacy, and response monitoring in patients age < 18 years. METHODS In the current series, the authors report 5 consecutive patients ages 20 months to 12 years with Ph(+) leukemia who were treated with imatinib and evaluated for a response using cytogenetics, fluorescent in situ hybridization (FISH), and real-time quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) on serial bone marrow aspirations. Doses of imatinib were escalated as tolerated from a starting dose of 400 mg/m2 (patients with a body surface area [BSA] 1 m2). RESULTS After the initiation of imatinib therapy, all 4 patients with CML were found to have no detectable Ph chromosome by cytogenetics (median of 198 days of imatinib therapy; range, 138–346 days), FISH (median of 285 days of imatinib therapy; range, 138–366 days), and real-time RT-PCR (median of 287 days of imatinib therapy; range, 224–366 days). One patient with Ph(+) acute mixed lineage leukemia achieved a morphologic disease remission with standard chemotherapy, but within 10 months had increasing Ph positivity in consecutive bone marrow aspirations. Imatinib was added to the intensive leukemia therapy, and within 26 days there were no detectable Ph(+) cells in the bone marrow. Mild thrombocytopenia was noted in two patients and transient mild hepatic toxicity was noted in one patient. CONCLUSIONS Imatinib mesylate was found to be effective in inducing undetectable residual disease in a small cohort of pediatric patients with Ph(+) leukemia. Further studies of the use of imatinib in childhood Ph(+) malignancies are needed. Cancer 2003;98:2643–50. © 2003 American Cancer Society.

BACKGROUND Recurring breakpoints in chromosome bands 15q13-15 occur infrequently in leukemia. To the authors' knowledge, the clinical significance of these breakpoints in childhood acute lymphoblastic leukemia (ALL) has not been previously investigated. METHODS Centrally reviewed karyotypes of children with newly diagnosed ALL enrolled on Children's Cancer Group protocols from 1988 to 1995 formed the basis of the current report. Statistical analyses used chi-square tests for homogeneity of proportions, and outcome was analyzed using life table methods and associated statistics. RESULTS Of 1946 cases with centrally reviewed and accepted cytogenetic analyses, 23 cases (1%) had breakpoints in chromosome bands 15q13-15. Most patients with 15q13-15 breakpoints had standard risk ALL, although breakpoints in 15q13-15 occurred more frequently in infants than in older children. The majority of these patients (16 patients; 70%) had balanced 15q13-15 rearrangements. Additional chromosomal abnormalities not involving 15q included abnormal 12p, abnormal 9p, Philadelphia chromosome, deletion 6q, and an 11q23 breakpoint. Thirteen (57%) 15q13-15 breakpoints occurred in pseudodiploid karyotypes; five (22%) were in hyperdiploid karyotypes with 47-50 chromosomes; two (9%) were in hyperdiploid karyotypes with > 50 chromosomes; and three (13%) were in hypodiploid karyotypes. Of the 23 patients with 15q13-15 breakpoints, 21 were survivors, 18 survived event-free for 2.2-9.3 years, and 3 were alive 1 to 3 years after a relapse at time of writing. CONCLUSIONS The current study suggests that genes at 15q13-15 may be involved in the leukemogenesis of some cases of childhood ALL, but that with current intensive therapy such aberrations do not confer increased risk of treatment failure. Cancer 2002;94:1102–10. © 2002 American Cancer Society. DOI 10.1002/cncr.10325

To determine the maximum tolerated dose (MTD) and assess the toxicity profile and pharmacokinetics of weekly gemcitabine infusions in pediatric patients with refractory hematologic malignancies. Fourteen patients under 21 years old were given infusions of gemcitabine for escalating durations at 10 mg/m2/min weekly for three consecutive weeks. Two males and two females were studied at each dose level. Pharmacokinetics of the drug's metabolism were measured by high pressure-liquid chromatography (HPLC) for 24 h after the first dose. Intracellular difluorodeoxycytidine triphosphate formation in leukemic blasts was measured in selected patients. The MTD of gemcitabine in these patients was 3600 mg/m2/week for three consecutive weeks (10 mg/m2/min for 360 min). Hepatotoxicity was the dose limiting toxicity. Thirty to fifty percent of patients exhibited fever, rash, or myalgia. Rare instances of hypotension and pulmonary toxicity were observed. Two of six patients [one acute lymphoblastic leukemia (ALL) and one acute myelogenous leukemia (AML)] treated at the MTD had at least M2 marrows, although peripheral blood counts did not recover sufficiently for the patients to be considered in complete response. Pharmacokinetics of gemcitabine fit a two-compartment open model with terminal half-life and plasma clearance value of 62 min and 2.2 l/min/m2, respectively. No gender differences were observed. In conclusion, the MTD of gemcitabine was 10 mg/m2/min for 360 min every week for 3 weeks. This is the recommended phase II dose schedule for children with leukemia. The activity of the drug at this schedule in heavily pretreated, refractory patients warrants a phase II trial in hematologic malignancies.

PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children’s Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.

Clofarabine, a nucleoside analogue for treatment of relapsed leukemia, is 50–60% excreted in urine. Clofarabine has not been studied in patients on hemodialysis. We measured levels in one patient in acute renal failure. Prior to dialysis, 43 hr after a 40 mg/m2 infusion, plasma concentration was 139 ng/ml. One hour after begining hemodialysis, a 20 mg/m2 infusion began. Plasma concentrations were 84.2, 81.1, and 88.0 ng/ml while the dialysis and clofarabine infusion occurred simultaneously. Post-dialysis, while the clofarabine was still infusing, the level was 95.8 ng/ml. Hemodialysis does decrease clofarabine levels, but given its large volume distribution, hemodialysis may not be effective for clofarabine overdose. Pediatr Blood Cancer 2010;55:196–198. © 2010 Wiley-Liss, Inc.

PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12–14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12–14 in children with newly diagnosed ALL treated on Children’s Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12–14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12–14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12–14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12–14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P = .04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P = .25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P = .72). CONCLUSION: Aberrations of 13q12–14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.

BACKGROUND The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31–0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10–1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18–1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78–4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG. Cancer 2000;88:1945–54. © 2000 American Cancer Society.

Nasopharynx cancer is a rare malignancy in childhood. This study aims to determine the role of chemotherapy, the optimal dose of radiation, and the long-term outcome for children with locoregional disease.Thirty-three patients [median age 14 (range: 12-20) years] were treated for Stage I-IVB nasopharynx cancer. Thirteen patients (39%) received radiotherapy alone and 20 patients (61%) had chemotherapy and radiotherapy. The median radiation dose to the primary tumor was 66 Gy (range: 54-72 Gy). The median follow-up time for surviving patients was 8.4 years (range: 0.5-23.6 years). RESUL TS: The actuarial 10-year locoregional relapse-free survival, distant metastases-free survival, and overall survival rates were 77%, 68%, and 58% , respectively. Locoregional control was improved for patients treated with radiation doses60 Gy compared to those receivingor = 60 Gy (93% vs. 60%, p0.03). The addition of chemotherapy had no significant effect on locoregional control but did reduce the development of distant metastases (16% vs. 57%, p = 0.01). Combined modality therapy improved 10-year disease-free survival (84% vs. 35%, p0.01) and survival (78% vs. 33%, p0.05) over radiation alone. The 10-year actuarial rate of severe complications was 24%.60 Gy are used for gross disease. The addition of chemotherapy decreases the risk of distant metastases and increases survival.

We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.

Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.

Contemporary intensive therapies are effective for the majority of pediatric T-lineage acute lymphoblastic leukemia (ALL) patients, thus current challenge is to identify patients who may benefit from alternative treatment modalities. Previously, we demonstrated that human leukemic cell growth in the severe combined immunodeficiency (SCID) mouse was a significant prognostic factor for very high risk B-lineage ALL patients. In the current report we show that primary leukemic cells from 24 of 88 (27%) T-lineage ALL patients (SCID+) caused histopathologically detectable leukemia in SCID mice. These SCID+ patients were similar to SCID- (n = 64) patients with respect to virtually all presenting features, including age, sex, race, and leukocyte count. Growth of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of T-lineage ALL patients. Two-year event-free survival (EFS) outcomes for SCID+ patient and SCID- patients were 76.2% (SD = 5.6%) and a 64.0% (SD = 10.4%; p = 0.20). Overall survival also was similar between the two groups (p = 0.36). Among the subset of patients with M1 or M2 marrow status by day 7 of induction chemotherapy (rapid early responders), those who were SCID+ had poorer outcomes than those who were SCID-, with a 2-year EFS of 68.4% (SD = 11.9%) vs. 85.7% (SD = 6.0%) and relative hazard rate of 3.06 (p = 0.06). These data suggest that leukemic cell growth in SCID mice may identify a subset of T-lineage ALL patients who are at higher risk for relapse despite achieving a rapid early response to induction chemotherapy.

Current treatments for relapsed/refractory leukemias are unable to achieve extended remissions in most patients even with multiagent chemotherapy. Clofarabine is a new nucleoside analog that has demonstrated clinical benefit in phase I-II studies, and is currently being studied in children and adults with leukemias and has been approved for the treatment of children with relapsed or refractory acute lymphocytic leukemia. We report the experience of three adolescents, two with acute lymphocytic leukemia in 3rd relapse and one with relapsed/refractory acute myeloid leukemia, who achieved complete remission with clofarabine. The remissions were sustained with repeated cycles of monotherapy for 47, 59, and 64 weeks, respectively.

BACKGROUND Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). METHODS This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. RESULTS Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P = 0.008), age >10 years (P = 0.02), and have a leukocyte count ≥50,000/L (P < 0.0001). Nearly all Ph+ (96.7%) and Ph- (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD = 1.2%), respectively (P < 0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. CONCLUSIONS The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL. Cancer 1998;83:2030-2039. © 1998 American Cancer Society.

BACKGROUND Childhood acute lymphoblastic leukemia is the single most common childhood malignancy. Despite substantial improvements in therapy, cases in which relapse occurs are still more common than newly diagnosed cases of many other childhood cancers. The survival of patients who relapse despite improved therapy continues to be of interest. METHODS One thousand one hundred forty-four relapses and 28 second malignant neoplasms were identified among the 3712 eligible patients enrolled on Children's Cancer Group trials between 1983 and 1989. The details of treatment after relapse were not accessible. Subsequent secondary event free survival and overall survival were examined by the site of and time to initial relapse. A variety of potential prognostic factors were examined employing the log rank statistic and Wilcoxon regression model. RESULTS Rates of 6-year survival (± standard error) after isolated bone marrow, isolated central nervous system (CNS), and isolated testis relapse were 20% ± 2%, 48% ± 4%, and 70% ± 5%, respectively. Rates of survival after isolated bone marrow relapse at 0-17 months, 18-35 months, and after 36 months were 6% ± 2%, 11% ± 2%, and 43% ± 4%, respectively. Rates of survival after isolated CNS relapse at 0-17 months, 18-35 months, and after 36 months were 33% ± 4%, 59% ± 5%, and 72% ± 8%, respectively. Rates of survival after isolated testis relapse at 0-17 months, 18-35 months, and after 36 months were 52% ± 11%, 57% ± 10%, and 81% ± 5%, respectively. Rates of survival after combined bone marrow and CNS or testis relapse at 0-17 months, 18-35 months, and after 36 months were 9% ± 5%, 11% ± 6%, and 49% ± 7%, respectively. CONCLUSIONS Substantial survival at 6 years is evident among several subsets of this unselected group of heterogeneously treated children, namely, those with isolated or combined bone marrow relapse after 36 months and those with isolated extramedullary relapse at any time. Second malignant neoplasms are rare thus far. Cancer 1998;82:1387-95. © 1998 American Cancer Society.

BACKGROUND Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS Complete remission was induced in 97% of patients. The overall event free survival (EFS) ± the standard deviation was 60 ± 4% 6 years after diagnosis, in contrast to 36 ± 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 ± 7%. EFS was best on the NY (67 ± 7%) and the BFM (67 ± 6%) arms. These were significantly better than the EFS on the 2 LSA2-L2 regimens, with an EFS of 53 ± 8% (Regimen B) and 42 ± 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 ± 5% vs. 6 ± 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes. Cancer 1998;82:600-612. © 1998 American Cancer Society.

BACKGROUND Early response to therapy is defined as the initial response prior to Day 28 of treatment, the conventional time of marrow evaluation. The number of reports linking early response to therapy with the ultimate outcome of childhood acute lymphoblastic leukemia is substantial and growing. When this study began, these experiences had yet to be comprehensively reviewed. METHODS A comprehensive search of the published literature yielded contributory reports of 14 trials conducted in the United States and Europe. In addition, unpublished data from one Children's Cancer Group trial were made available. Outcome measures were standardized by conversion to ratios of the incidence of adverse events among poorer and better responders. RESULTS Early response to therapy was an independent prognostic factor in each of the 15 trials, which together included more than 10,000 patients. The incidence of slower early response ranged from 2-33%, with various measures and criteria used in different trials. Patients with a slower early response were 1.5-6.1 times (median, 2.7) more likely to have an adverse event than patients with a more rapid early response, however defined. Early response maintained prognostic significance after the exclusion of induction failure and within risk strata defined by age, white blood cell count, and/or immunophenotype. Its significance was also maintained in multivariate analyses where performed. CONCLUSIONS Early response to therapy, whether determined by evaluation of bone marrow or peripheral blood, is a consistent, independent prognostic factor in childhood acute lymphoblastic leukemia. Slower early response may serve as a useful surrogate for outcome, a more complex end point, in investigations of the cellular and molecular determinants of resistance to therapy. It may also allow early identification of a patient subpopulation for whom current therapy is less effective and alternative strategies may be justified. Cancer 1997; 80:1717-26. © 1997 American Cancer Society.

Acute myelocytic leukemia (AML) is a malignancy that is intrinsically resistant to methotrexate (MTX). AML blasts, when incubated with radiolabeled MTX, form lower amounts of long chain polyglutamates compared to acute lymphocytic leukemia (ALL) blasts, thus providing an explanation for their lack of responsiveness to MTX. Leukemic blasts obtained from two children with acute megakaryocytic leukemia (M7 subtype) when incubated with radiolabeled MTX showed increased accumulation of total as well as long chain MTX polyglutamates, comparable to levels previously demonstrated in another subtype of AML, acute monocytic leukemia (M5), as well as in blasts from patients with pre-B ALL. We suggest that M7-AML patients with blasts showing increased MTX polyglutamylation might benefit from treatment with MTX.

PURPOSE Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

We found a marked variation in BCL-2 oncoprotein expression levels of primary leukemic cells from 338 children with newly diagnosed acute lymphoblastic leukemia (ALL). None of the high-risk features predictive of poor treatment outcome in childhood ALL, such as older age, high white blood cell (WBC) count, organomegaly, T-lineage immunophenotype, ability of leukemic cells to cause overt leukemia in severe combined immunodeficient (SCID) mice, presence of MLL-AF4, and BCR-ABL fusion transcripts were associated with high levels of BCL-2 expression. Overall, high BCL-2 levels were not associated with slow early response, failure to achieve complete remission, or poor event-free survival. High BCL-2 levels in primary leukemic cells predicted slow early response only in T-lineage ALL patients, which comprised approximately 15% of the total patient population. Even for this small subset of patients, the level of BCL-2 expression did not have a significant impact on the short-term event-free survival.

Methotrexate (MTX) transport was examined in 27 patients with untreated acute lymphocytic leukemia (ALL) and 31 patients with relapsed ALL using a previously described fluorescent MTX analog (PT430) displacement assay (Blood 80:1158, 1992). Only 13% of untreated patients were considered to have impaired MTX transport, whereas more than 70% of relapsed patients had evidence of impaired MTX transport. To further characterize the basis for this defect, Northern analyses for the reduced folate carrier (RFC) were performed on the RNA available from the leukemic blasts of 24 patients in whom MTX transport had been measured. Six of nine samples with impaired MTX transport had decreased RFC expression (one had no detectable RFC expression), while three had no decrease in RFC expression. None of 15 samples with normal MTX transport had decreased RFC expression. A reverse-transcriptase polymerase chain reaction (RT-PCR) assay was developed to quantitate RFC mRNA expression more accurately. Decreased RFC expression was demonstrated in six of the nine samples with impaired MTX transport, confirming the results obtained by Northern blot. These data indicate decreased RFC expression associated with impaired MTX transport is observed in relapsed ALL following treatment with MTX-containing therapy.