Hyperdiploid Precursor B-acute Lymphoblastic Leukemia Presenting as a Cavernous Sinus Mass in a 4-Year-old Male.

Risk stratification and appropriate treatment selection for children with precursor B-acute lymphoblastic leukemia (B-ALL) have improved outcomes. We report the case of a 4-year-old male with a lymphomatous cavernous sinus mass, a previously undescribed presentation of newly diagnosed hyperdiploid B-ALL. Few case reports in the literature describe lymphomatous involvement in this region, but none are associated with pediatric B-ALL. This case presented unique treatment and risk assignment challenges given the intracranial location of this tumor and proximity to the central nervous system.

Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study.

BACKGROUND: The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5-year overall survival (OS). This study aimed to improve outcome in patients with ITR of B-cell ALL (B-ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long-term sequelae by limiting use of testicular radiation. PROCEDURE: Forty patients in first ITR of B-ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high-dose methotrexate (MTX, 5 g/m2 ). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy-proven disease and received bilateral testicular radiation (24 Gy), whereas twenty-nine did not. RESULTS: Overall 5-year event-free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5-year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5-year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85). CONCLUSIONS: A 5-year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B-ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.

Long-term Results of the Risk-adapted Treatment for Childhood B-Cell Acute Lymphoblastic Leukemia: Report From the Japan Association of Childhood Leukemia Study ALL-97 Trial.

PURPOSE: This study was conducted as the first clinical trial by Japan Association of Childhood Leukemia Study to improve the outcome of B-cell acute lymphoblastic leukemia and explore a less toxic reinduction block. PATIENTS AND METHODS: From 1997 to 2002, 563 patients with B-cell acute lymphoblastic leukemia aged 1 to 15 years were enrolled. The patients were assigned into 4 risk groups (standard, intermediate, high, or extremely high risk) and treated with regimens intensified according to the risk. Two randomized trials were conducted to compare 2 regimens with and without a 3-week reinduction therapy in the standard-risk group, and to compare the efficacy of pirarubicin with daunorubicin in the intermediate-risk and high-risk groups. Prophylactic cranial irradiation was restricted in patients with high or extremely high risk. RESULTS: The event-free survival (EFS) rate at 10 years for all patients was 77.0%. Those in the standard-risk to extremely high-risk groups were 79.3%, 72.5%, 71.7%, and 66.3%, respectively. The 15-week induction/consolidation not followed by reinduction produced 76.4% of the EFS at 10 years comparable with the regimen with reinduction therapy. Pirarubicin at 25 mg/m administered 11 times throughout the treatment produced the EFS comparable with daunorubicin at 30 mg/m. CONCLUSION: The trial produced high survival rates in NCI-HR patients, although the outcomes in NCI-SR patients were not satisfactory possibly due to less intensive central nervous system-directed therapy.

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

BACKGROUND: Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. METHODS: Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. FINDINGS: Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). INTERPRETATION: (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. FUNDING: Immunomedics and Direction de la Recherche Clinique of Nantes.

Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis.

Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodies were conspicuous on biopsy and may serve as a morphologic clue to lymphocytic differentiation while molecular and immunophenotypic studies are pending. The patient was successfully treated with local radiation therapy and oral ponatinib.

BCR-ABL1 molecular remission after 90Y-epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B-ALL: proof of principle.

Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with (90) yttrium ((90) Y)-labeled anti-CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. (90) Y-Epratuzumab tetraxetan may be a promising therapeutic option for CD22(+) B-ALL patients.

Precursor B-acute lymphoblastic leukemia occurring in patients with a history of prior malignancies: is it therapy-related?

BACKGROUND: Precursor B-acute lymphoblastic leukemia occurring in patients with a history of malignancies is uncommon, and this condition is not well understood. DESIGN AND METHODS: A retrospective review of 457 adults with precursor B-acute lymphoblastic leukemia treated at our hospital identified 44 (9.6%) patients with prior malignancies. The clinical and genetic characteristics of this group of patients was compared with those of their counterparts with de novo disease and the relationship with prior chemoradiation therapy was assessed. RESULTS: Thirty of 44(6.2%) patients received cytotoxic therapies, whereas 14 patients did not. The former group showed a significantly shorter interval from prior malignancy to onset of precursor B-acute lymphoblastic leukemia (36 versus 144 months; P = 0.002). Compared with 413 de novo cases, the frequencies of t(4;11)(q21;q23) (P<0.001) and hypodiploidy (P = 0.009) with loss of chromosome 5, 7 or 17 were significantly higher in patients who received topoisomerase II inhibitor and/or alkylating agents. By contrast, Philadelphia-positive and normal karyotype were more frequent in patients who either did not receive chemotherapy or received only local radiation or nucleoside analogs. Patients with precursor B-acute lymphoblastic leukemia following prior malignancies and chemoradiation were older, had a lower complete remission rate and showed an inferior survival in univariate, but not multivariate analysis. CONCLUSIONS: The data support the interpretation that therapy-related precursor B-acute lymphoblastic leukemia does occur. In particular, cases associated with t(4;11)(q21;q23) or hypodiploidy with -5, -7, -17 are likely to be therapy-related and have a poor prognosis. The inferior outcome of these patients may be attributable to the high-risk cytogenetic abnormalities that are found in this group of patients.

The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia.

BACKGROUND: Despite incremental improvements in outcomes for patients with acute lymphoblastic leukemia, significant numbers of patients still die from this disease. Mammalian target of rapamycin inhibitors have shown potential in vitro and in vivo as therapeutic agents against a range of tumors including acute lymphoblastic leukemia. DESIGN AND METHODS: Flow cytometry was used to evaluate drug-induced cell death in acute lymphoblastic leukemia cell lines and patients' samples. Human xenografts in immunocompromised mice were used to assess the in vivo effects of selected combinations. Pharmacological inhibitors and lentiviral small interfering ribonucleic acid knock-down of p53 were used to investigate the mechanism of cell killing involved. RESULTS: Synergistic interactions between RAD001 and cytotoxic agents were demonstrated in vitro and in vivo, with increased caspase-dependent killing. RAD001 suppressed p53 and p21 responses, while suppression of p53 did not prevent killing, indicating p53 independence. RAD001 and cytotoxic agents activated the JUN N-terminal kinase pathway and the combination further increased JUN N-terminal kinase activation. JUN N-terminal kinase inhibition reduced synergistic cell killing by cytotoxic agents and RAD001 in pre-B acute lymphoblastic leukemia cell lines and patients' samples. Bortezomib and MG132, which activate the JUN N-terminal kinase pathway, also synergized with RAD001 in killing pre-B acute lymphoblastic leukemia cells. Killing was greater when RAD001 was combined with proteasome inhibitors than with cytotoxic drugs. CONCLUSIONS: These observations suggest that combining mammalian target of rapamycin inhibitors with conventional chemotherapy or selected novel agents has the potential to improve clinical responses in patients with pre-B acute lymphoblastic leukemia.

Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin.

Concordance of MLL-rearranged acute leukemia in infant monozygotic twins is thought to be 100% with a very short latency period, suggesting that either the MLL fusion itself is sufficient to cause leukemia or that it promotes the rapid acquisition of additional oncogenic events that result in overt disease. We report the first case of discordance in an infant monozygotic twin pair. Twin A presented at age 9 months with MLL-ENL(+) acute lymphoblastic leukemia and twin B remains healthy 3 years later. The presence and eventual clearance of a clonal population of MLL-ENL(+) cells was shown in the bone marrow and peripheral blood of twin B. Clearance of this clone was temporally associated with viral-induced cytopenias, suggesting an immune-mediated clearance of the clone before the development of leukemia. Thus, concordance of MLL-rearranged acute leukemia in infant monozygotic twins is not universal. The implications of this case for MLL-rearranged leukemogenesis are discussed.

Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

First isolated extramedullary relapse in children with B-cell precursor acute lymphoblastic leukaemia: results of the Cooprall-97 study.

We report on the efficiency of treatment of first isolated extramedullary relapse of B-cell precursor acute lymphoblastic leukaemia. Sixty-eight children and adolescents were included in the trial COPRALL-97. Stratification criteria were time to relapse: first complete remission duration of less than 24 months for group G3A (n=35), relapse beyond 24 months for group G3B (n=33). Treatment consisted of risk-adapted alternating short course multiagent systemic and intrathecal chemotherapy and irradiation (18Gy). Event free survival (EFS) and overall survival (OS) for all registered patients at 6 years were 43% and 55%, respectively. EFS at 4 years for patients of group G3A and G3B were, respectively, 31% and 61% (p=0.0071) while OS at 4 years were, respectively, 40% and 76% (p=0.065). Our analyses highlighted two independent risks factors predictive of decreased EFS: early relapse and age at the initial diagnosis above 6 years. Early central nervous system relapses have a bad prognosis, and new therapeutic strategies are needed.

[Primary cutane manifestation of a precursor-B-lymphoblastic lymphoma in the external ear]. / Primäre kutane Manifestation eines Vorläufer-B-lymphoblastischen Lymphoms im Bereich des äusseren Ohres.

A Non-Hodgkin Lymphoma (NHL) represents nearly three percent of all malignant tumors. Thirty to fourty percent of the lymphomas are located extra-nodal. Within the head and neck region they might occur in the tonsils, tongue base or the sinuses, the larynx and the pharynx. A cutaneous manifestation is rare. We report on an extranodal B-cell-lymphoma of the ear in a young woman. She reported on a piercing of the pinna months before with a subsequent infection. This infection led to the development of a massive ear tumor. Histologic examination resulted in the final diagnosis. In spite of the considerable extent of the lymphoma there was no systemic manifestation and a total remission was induced by chemotherapy before adjuvant radiation.

Longitudinal assessment of immunological status and rate of immune recovery following treatment in children with ALL.

BACKGROUND: We prospectively evaluated the immunological status, immune recovery and risk of infection in pediatric ALL patients treated on the BFM 95 protocol. PROCEDURE: Humoral and cellular immunity were evaluated in 72 children with ALL at the end of intensive therapy and values were compared to those at the completion of therapy and 6-monthly. Parameters investigated included lymphocyte subpopulation by flow cytometry, immunoglobulin levels by nephelometry, antibody titers to previous immunizations and delayed hypersensitivity with skin testing. Immune responses were correlated to duration of therapy, CNS radiotherapy, age and sex. RESULTS: Humoral immunity was severely depressed by the end of intensive therapy with low immunoglobulin levels and CD19, improved after therapy cessation. Cellular immune responses were normal at the end of intensive treatment but declined significantly by the end of therapy and both CD4 and CD8 remained low at later evaluation points whereas CD4/CD8 ratio was increasing. Duration of therapy and CNS radiotherapy did not affect the rate of immune recovery whereas female had higher CD19, CD45RO, and IgM and children >7 years had higher CD19 and lower CD16 and CD3DR. Among immunized children, 86.7% maintained protective antibodies to MMR and 63% to polio. Despite impairment of immunity, infections outside the neutropenic periods were common viral illnesses. CONCLUSION: Humoral immunity was depressed in children with ALL at the end of intensive therapy but began to recover after cessation of therapy. In contrast, cellular immunity declined significantly by the end of therapy and remained abnormal for at least 1 year post-therapy.

Pyridoxine and pyridostigmine treatment in vincristine-induced neuropathy.

Vincristine is a commonly used antineoplastic drug and frequently causes neurotoxicity. Here the authors report a 4-year-old boy with acute lymphoblastic leukemia in whom vincristine-induced peripheral and cranial neuropathy developed during remission induction therapy. The patient seemed to benefit from pyridoxine and pyridostigmine therapy greatly and this therapy is recommended in patients with severe vincristine-induced neuropathy.

Analysis of ETV6/RUNX1 fusions for evaluating the late effects of cancer therapy in ALL (acute lymphoblastic leukemia) cured patients.

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood. The improvements of therapies have increased the number of long-term survivors. However, an increased incidence of secondary neoplasias has been observed in this cohort. Our purpose was to evaluate the late effects of cancer therapy in cured patients previously treated for ALL, considering previous reports on the occurrence of gene fusions as putative markers of chromosomal instability. Twelve ALL patients (aged 5 to 16 years) and twelve healthy subjects (aged 18 to 22 years) were studied for the presence of ETV6/RUNX1 (TEL/AML1) translocations, which were detected by FISH (fluorescence in situ hybridization). The blood samples were collected months or years after completion of the therapy, and the frequencies of gene fusions in lymphocytes were compared with those obtained retrospectively for bone marrow samples at the time of diagnosis, and also for the control group. It was demonstrated that ETV6/RUNX1 gene fusion was a frequent event (0.59-1.84/100 cells) in peripheral blood lymphocytes from normal individuals and the ALL patients who underwent chemotherapy showed significantly (P = 0.0043) increased frequencies (0.62-3.96/100 cells) of the rearrangement when compared with the control groups (patients at diagnosis and healthy subjects). However, a significant difference was not found between the groups of patients at diagnosis and healthy subjects, when the two patients who were positive for the rearrangement were excluded. Therefore, increased frequencies of ETV6/RUNX1 fusions in ALL cured patients indicate the influence of previous exposure to anti-cancer drugs, and they may represent an important genetic marker for estimating the risk of relapse, or development of secondary neoplasias.

High-dose cytosine arabinoside and fractionated total body irradiation as a preparative regimen for the treatment of children with acute lymphoblastic leukemia and Down syndrome by allogeneic bone marrow transplantation.

The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.

Acute myelofibrosis terminating in acute lymphoblastic leukemia: case report and review of the literature.

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin.