Recurrent Acute Lymphoblastic Leukemia Research Articles

Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients

20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18).In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.

Central nervous system relapse in adults with acute lymphoblastic leukemia.

7080 Background: Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) in adults is associated with poor outcome. Few reports have analyzed the impact of contemporary...

Current approach to relapsed acute lymphoblastic leukemia in children

Recurrent acute lymphoblastic leukaemia(ALL) is a common disease for pediatric oncologists and accounts for more deaths from cancer in children than any other malignancy. Although most patients achieve a second remission, about 50% of relapsed ALL patients do not respond to salvage therapy or suffer a second relapse and most children with relapse die. Treatment must be tailored after relapse of ALL, since outcome will be influenced by well-established prognostic features, including the timing and site of disease recurrence, the disease immunophenotype, and early response to retrieval therapy in terms of minimal residual disease(MRD). After reinduction chemotherapy, high risk(HR) patients are clear candidates for allogeneic stem cell transplantation(SCT) while standard risk patients do better with conventional chemotherapy and local therapy. Early MRD response assessment is currently applied to identify those patients within the more heterogeneous intermediate risk group who should undergo SCT as consolidation therapy. Recent evidence suggests distinct biological mechanisms for early vs late relapse and the recognition of the involvement of certain treatment resistance related genes as well cell cycle regulation and B-cell development genes at relapse, all providing the opportunity to search for novel target therapies.

Repair of Tracheal Aspergillosis Perforation Causing Tension Pneumothorax

Tracheobronchial aspergillosis is a rare entity mainly observed in immune-compromised patients or those who have undergone transplantation. It may cause airway ulcerations or bleeding. We report the case ofa 17-year-old patient receiving chemotherapy foracute lymphoblastic leukemia who presented withright-sided tension pneumothorax. Chest tube drainage revealed a massive air leak without reexpansion of the lung, and bronchoscopy showed a15-× 15-mm defect of the distal trachea related to aspergillosis infection. The defect was closed by an intrathoracic transposition of a pedicled latissimus dorsi muscle flap, which was sutured into the debrided defect followed by temporary endotracheal stenting and antifungal medication.

Chromothripsis-Mediated Structural Variations and Clonal Evolution In Recurrent Childhood High Hyperdiploid Acute Lymphoblastic Leukemia

High hyperdiploid acute lymphoblastic leukemia (HeH-ALL) is characterized by 51-67 chromosomes and nonrandom gains of specific chromosomes (X, 4, 6, 10, 14, 17, 18, and 21). It presents the most frequent numerical cytogenetic alteration in childhood pre B-cell ALL occurring in 25-30% of cases. Recurrent disease will affect 15-20%. Pre-leukemic HeH clones are generated in utero, but cooperating oncogenic lesions are necessary for overt leukemia and remain to be determined. Recently, a phenomenon termed chromothripsis has been described in which massive structural variations occur in a single aberrant mitosis. Whole or partial chromosomes are shattered and some fragments are lost in the process of rejoining. Thus, characteristically, chromosomal copy numbers oscillate between two copy number states. Chromothripsis has been suggested to be a tumor-driving alteration that may be present in 2-3% of all human cancers. Its role as a potential cooperating or initiating lesion in HeH-ALL has not been determined.We applied state-of-the-art whole-genome next-generation-sequencing to analyze structural variations in six pediatric patients with recurrent HeH-ALL. Matched sample sets taken at diagnosis, remission and/or relapse were compared. Paired end sequencing was carried out on a Genome Analyzer IIx or a HiSeq 2000 (Illumina), respectively. Reads were aligned against the human reference genome (GRCh37) using BWA. Translocations were detected by GASV. Copy number variations were analyzed by FREEC. Structural variations were validated by PCR/Sanger sequencing and FISH.Of the six patients analyzed, five harbored on average one interchromosomal translocation or intrachromosomal inversion, but one patient presented with massive genomic rearrangements (Figure). These affected chromosome 3, 11, 12 and 20. Ten copy number shifts on chromosome 3 oscillating between two copy number states (2 and 3) indicated that these rearrangements were caused by chromothripsis. Breakpoint sequencing revealed that one of the identified translocations (t(12;20)(p13.1;p12.3)), was indeed a three-loci-rearrangement composed of small fragments derived from chromosomes 3, 12 and 20. Characteristically for chromothripsis, the breakpoints clustered closely. Three breakpoints separated by 224 bp and 64 kb were located in the transducin (beta)-like X-linked receptor 1 (TBL1XR1) gene. Other genes repeatedly targeted included the MACRO domain-containing protein 2 (MACROD2) gene (a deacetylase involved in deacetylation of lysine residues in histones and other proteins), the KIAA1467 gene (a transmembrane protein of the integrin alpha FG-GAP repeat containing 3 (ITFG3) family), and a novel regulatory lincRNA (ENSG00000243276). MACROD2 was previously observed as a target of chromothripsis in a colorectal carcinoma. Thus, the characterized breakpoints may identify fragile genomic sites prone to chromothriptic rearrangement. DNA repair was effectuated by non-homologous-end-joining as typical addition of non-template nucleotides with microhomologies of two to four nucleotides at the breakpoints demonstrated. Copy number profiles of this patient showed that at least two distinct leukemic clones could be identified at diagnosis. One had acquired chromothriptic alterations and presented the dominant clone at relapse indicating chemotherapy resistance and tumor-driving potential. Prior whole-exome sequencing did not reveal mutations in known oncogenes or tumor suppressor genes. Therefore, loss of function or expression of genes affected by chromosomal rearrangements, such as TBL1XR1 that is recurrently mutated in childhood ALL with ETV6-RUNX1 translocation, may account for the tumor-driving effect. All leukemic cells at diagnosis showed conformity concerning number and pattern of whole chromosome gains demonstrating that chromothripsis was not an initiating oncogenic event, but occurred secondary to high hyperdiploidy. Further aberrations (t(4;7), loss of 4q) were gained by the chromothriptic clone and could be detected by FISH in minor subclones pointing at ongoing clonal evolution. Taken together, our study reveals chromothripsis as a novel assisting and tumor-driving lesion in HeH ALL.Chromothripsis in HeH-ALL. Copy number variations and translocations at diagnosis (left) and relapse (right). (magenta: chromothriptic translocations; green: other translocations) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Haemophilus influenzae Type b in an Immunocompetent, Fully Vaccinated ALL Survivor

A 7-year-old boy with a history of recurrent acute lymphoblastic leukemia (ALL), in remission, presented to primary care clinic after 2 days of progressive right hip pain with weight-bearing activities. He was otherwise asymptomatic at the time of presentation. Blood cultures revealed Gram-negative diplococci, which prompted an MRI that was significant for a hip joint effusion and femoral head bone marrow edema. The patient had no sick contacts and no significant past medical history other than ALL. The patient had been given all recommended childhood vaccinations. Arthrocentesis and needle biopsy of the femoral neck were not diagnostic for malignancy and revealed only mild hip joint inflammation, leading to a diagnosis of osteomyelitis. The organism in the original blood culture was identified as Haemophilus influenzae type b, β-lactamase negative. Review of the patient's medical records showed a history of complete immunization to Haemophilus influenzae type b. An immunologic evaluation was made to determine if the patient retained immunity from his other vaccinations. Pathogen-specific antibody testing revealed detectable antibodies to polio but not measles, mumps, rubella, varicella-zoster virus, tetanus, diphtheria, pertussis, or hepatitis B. This loss of immunologic memory appears to be a rarely described side effect of ALL chemotherapy. There is currently no protocol to evaluate the immunologic memory of patients who underwent chemotherapy for ALL or to revaccinate them after their treatment. It is unclear whether the loss of immunologic memory is genuinely rare or is underdiagnosed because affected patients are protected by herd immunity.

Recurrent Precursor-B Acute Lymphoblastic Leukemia Presenting as a Cervical Malignancy

A 59 year old woman with a history of acute lymphoblastic leukemia in remission presented with right flank pain. An abdominal ultrasound showed mild to moderate right hydronephrosis due to obstruction, and computed tomography scan showed a bulky mass near the cervix, concerning for cervical or uterine malignancy. A Papanicolaou smear was suspicious for malignancy, and immunocytochemical stains were positive for terminal deoxynucleotidyl transferase (TdT) and cluster of differentiation (CD)-10, focally positive for CD34 and CD79a, and negative for CD3, CD20, and paired box protein-5 (PAX-5). Cervical biopsies showed an infiltrating population of cells with immunophenotype similar to the cells on cervical cytology. The cytologic and histologic workup was compatible with infiltration of the uterine cervix by recurrent precursor-B acute lymphoblastic leukemia. A bone marrow biopsy showed normocellular marrow without evidence of tumor or infiltrative disease. Complete blood count and peripheral blood smear showed no evidence of leukemic involvement. Acute lymphoblastic leukemia diagnosed on cervical Pap smear has been very rarely reported. The majority of cases of hematologic malignancy involving the uterine cervix present with vaginal bleeding. To our knowledge, only three cases of recurrent precursor-B acute lymphoblastic leukemia in the uterine cervix have been reported, two of which occurred in pediatric patients. One pediatric patient presented with vomiting and abdominal pain, and was found to have hydronephrosis on imaging. This is perhaps the first case of precursor-B acute lymphoblastic leukemia diagnosed on cervical cytology in an adult patient with hydronephrosis and without vaginal bleeding.

Recurrent Precursor-B Acute Lymphoblastic Leukemia Presenting as Cervical Malignancy

Recurrent Precursor-B Acute Lymphoblastic Leukemia Presenting as Cervical Malignancy

Osteosarcoma Following Growth Hormone Therapy in Recurrent Acute Lymphoblastic Leukemia and Rapadilino Syndrome

A 16-year old Caucasian girl was evaluated for scoliosis 9 years after bone marrow transplant (BMT) and 13 years after her initial ALL diagnosis. A chest radiograph showed a lesion of the right third rib. Histopathology was consistent with a high-grade OS. She died 5 months after OS diagnosis. There is no family history of cancer. Prior therapy comprised BFM standard risk for de novo ALL, St. Jude Children’s Research Hospital regimen and cranial-spinal radiation for central nervous system (CNS) recurrence, Children’s Cancer Group (CCG) 1941, and matched unrelated allo-transplant (conditioned with TBI and thiotepa, cyclophosphamide, and ATG) for bone marrow recurrence. Two years after transplant GH therapy commenced. A 15-year-old Hispanic girl with RAPADILINO syndrome experienced left lower extremity pain. Magnetic resonance imaging (MRI) showed a destructive lesion and biopsy was consistent with OS. At 11 years of age short stature was diagnosed. Growth hormone therapy was started and discontinued once OS was diagnosed. There is no family history of cancer. The Childhood Cancer Survivor Study reported the 25-year follow-up among survivors of childhood ALL. The cumulative incidence of SMN of 5.2% (6.2% for those receiving radiation therapy) at 25 years from diagnosis [2]. St. Jude Children’s Research Hospital (SJCRH) investigators reported the incidence of SMN as a first event in 2169 patients treated between 1962 and 1998 [3]. The cumulative incidence of SMN was 4.17% at 15 years and 10.85% at 30 years. Two cases of OS constituting 1.2% of SMN were observed.

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical-translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.

Late Recurrence of Precursor B-cell Acute Lymphoblastic Leukemia 9 Years and 7 Months After Allogeneic Hematopoietic Stem Cell Transplantation

We present the case of a 15-year-old adolescent boy with recurrent precursor B-cell acute lymphoblastic leukemia, which appeared 9 years and 7 months after a first unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The patient received chemotherapy and a subsequent second unrelated allogeneic HSCT, and was free of the disease 3 years after the second HSCT. A molecular study revealed the same rearrangement pattern at IGK@ in both the first relapse and the later relapse, confirming the common origin of the leukemic blasts at different time points. However, a new Vδ2-Dδ3 rearrangement of TRD@ emerged at the later relapse. A subsequent, more sensitive examination revealed a minor subpopulation with rearrangements at both IGK@ and TRD@, even during the first relapse. This finding suggests that the minor clone, related to the major clone, was present at the first relapse, leading to the later recurrence, even though the major clone at the first relapse had been eradicated by the first allogeneic HSCT. Although a later relapse after allogeneic HSCT is a rare phenomenon, clinicians should keep in mind that later relapses can occur, even after allogeneic HSCT.

Augmentation of the Antileukemia Potency of Total-Body Irradiation (TBI) by a Novel P-site Inhibitor of Spleen Tyrosine Kinase (SYK)

A novel spleen tyrosine kinase (SYK) P-site inhibitor, 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C-61), (but not vehicle) markedly enhanced H(2)O(2)-induced apoptosis of primary leukemia cells from each of five relapsed B-lineage acute lymphoblastic leukemia (ALL) patients, as measured by in vitro TUNEL assays. A highly radiation-resistant subclone of the murine B-lineage leukemia cell line BCL-1 was next used to investigate the in vivo radiosensitizing effects of C-61. C-61 enhanced the antileukemia potency of 7 Gy total-body irradiation (TBI) in the context of syngeneic bone marrow transplantation (BMT) at 20% of its nonobservable adverse effect level (NOAEL) that does not exhibit detectable single-agent activity against BCL-1 leukemia in vivo. Based on this preclinical proof-of-principle study, we hypothesize that the incorporation of C-61 into the pretransplant TBI regimens of patients with recurrent or high-risk B-lineage acute lymphoblastic leukemia (ALL) will help overcome the radiochemotherapy resistance of their leukemia cells and thereby improve their treatment response and survival outcome after BMT.

Serial Analysis of BCR-ABL Kinase Domain Mutations Prior to and During Imatinib Treatment for Newly Diagnosed and Recurrent BCR-ABL Positive Acute Lymphoblastic Leukemia.

Abstract 2041Poster Board II-18 Background:Patients with newly diagnosed and recurrent Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) differ profoundly in their responsiveness to imatinib: whereas nearly all imatinib-naïve patients with de novo Ph+ALL initially achieve a complete remission (CR), eventually followed by secondary resistance, imatinib rarely induces a CR in patients with disease recurrence after chemotherapy. Mutations in the BCR-ABL tyrosine kinase domain (KD) are commonly associated with acquired imatinib resistance, but their role in primary resistance is not known. Recently, we determined that the same mutation found at relapse could already be detected prior to first imatinib exposure in 30% to 40% of patients with de novo Ph+ALL but surprisingly was not associated with an inferior response to imatinib monotherapy, which resulted in a CR rate exceeding 90%. Possible reasons for the inferior response of patients with recurrent Ph+ALL include a higher frequency of pre-existing mutations, a preponderance of mutations with greater transforming activity, a larger mutant clone or the contribution of non-mutational resistance mechanisms. To elucidate the potential role of these resistance mechanisms, we compared patients with de novo Ph+ALL and patients who had failed prior chemotherapy with respect to the frequency and pattern of pre-existing mutations, the level of mutant clones, the outgrowth kinetics of mutations during the first 4 weeks of imatinib monotherapy and the concordance between mutations detected prior to imatinib and at the time of relapse. Patients and methods:By denaturing high-performance liquid chromatography (D-HPLC; sensitivity 0.1-1%), ligation PCR (sensitivity 0.1-0.005%) and cDNA sequencing, we examined bone marrow and/or peripheral blood samples collected pre-treatment, during therapy and at relapse from 91 patients with Ph+ lymphoid leukemias who were enrolled in the initial phase II studies of imatinib for treatment of BCR-ABL positive leukemias after chemotherapy failure (n=65), or in a prospective, randomized clinical trial assessing front-line imatinib therapy in elderly patients with newly diagnosed Ph+ALL (n=26). Results:Prior to imatinib treatment, the frequency of TKD mutations did not differ significantly between patients with de novo and recurrent Ph+ ALL, respectively (30 % vs. 46%; p=n.s.) as detected by highly sensitive DHPLC and ligation PCR. P-loop mutations predominated in both patient groups (92% and 85% of detected mutations). The T315I gatekeeper mutation was identified in 4 patients, mutations in the activation loop were uncommon. Following only four weeks imatinib, the prevalence of detectable mutations increased substantially in patients with recurrent (to 75%) but not with de novo Ph+ALL (38%). Moreover, the median mutated bcr-abl transcript levels after 4 weeks of imatinib treatment were significantly higher in patients with recurrent than with de novo Ph+ALL (median 10%, [range 0-100] versus median 0%;range [0-7]). Conspicuously, we observed good concordance between the type of bcr-abl mutation detected prior to imatinib and at relapse. Conclusions:The incidence, pattern and levels of TKD mutations detected prior to imatinib and at relapse are similar in advanced and newly diagnosed Ph+ALL. In contrast, the outgrowth kinetics of cells with TKD mutations were far more rapid in patients with recurrent disease. These data provide clinical-translational evidence for a cooperative effect between mutational and non-mutational resistance mechanisms in Ph+ALL, and highlight the importance of early mutation monitoring using highly sensitive methodology. Disclosures:Hochhaus:Novartis : Research Funding. Ottmann:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.

Adipocytes Impair Leukemia Treatment in Mice

Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P < 0.05). Interestingly, this protection was independent of cell-cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment.

Anterior complications in case of recurrent acute lymphoblastic leukaemia diagnosed by biopsy of aqueous humour

Anterior complications in case of recurrent acute lymphoblastic leukaemia diagnosed by biopsy of aqueous humour

Myeloablative Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: Analysis of Graft Sources and Long-Term Outcome

Analysis of hematopoietic cell transplantation (HCT) for high-risk or recurrent acute lymphoblastic leukemia (ALL) using different donor sources is confounded by variable conditioning and supportive care. We studied 623 consecutive ALL myeloablative HCT (1980 to 2005). Donors were autologous (n = 209), related (RD; n = 245), unrelated (URD; n = 100), and umbilical cord blood (UCB; n = 69). After median of 8.3 years of follow-up, 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 29% (95% CI, 26% to 32%), 26% (95% CI, 23% to 29%), and 43% (95% CI, 39% to 47%), respectively. Treatment-related mortality (TRM) at 2 years was 28% (95% CI, 25% to 31%). Mismatched URD sources yielded higher TRM (relative risk [RR], 2.2; P < .01) and lower OS (RR, 1.5; P = .05) than RD or UCB HCT. Autografting yielded significantly more relapse (68%; 95% CI, 59% to 77%; P < .01) and poorer LFS (14%; 95% CI, 10% to 18%; P = .01). HCT in first complete remission (CR1) yielded significantly better outcomes than later HCT. In a 1990 to 2005 allogeneic CR1/second complete response cohort, 5-year OS, LFS, and relapse rates were 41% (95% CI, 35% to 47%), 38% (95% CI, 32% to 44%), and 25% (95% CI, 19% to 31%), respectively; 2-year TRM was 34% (95% CI, 28% to 40%). With RD, well-matched URD and UCB sources, 5-year LFS was 40% (95% CI, 31% to 49%), 42% (95% CI, 14% to 70%), and 49% (95% CI, 34% to 64%), respectively, while relapse was 31% (95% CI, 22% to 40%), 17% (95% CI, 0% to 37%), and 27% (95% CI, 13% to 41%). Acute graft-versus-host disease was associated with fewer relapses. Since 1995, we noted progressive improvements in OS, LFS, and TRM. Allogeneic, but not autologous, HCT for ALL results in durable LFS. Importantly, HCT using UCB led to similar outcomes as either RD or well-matched URD. HCT in early remission can best exploit the potent antileukemic efficacy of allografting from UCB, RD, or URD sources.

Outcome of recurrent or refractory acute lymphoblastic leukemia in infants with MLL gene rearrangements: A report from the Japan infant leukemia study group

Despite the poor outcome of recurrent or refractory acute lymphoblastic leukemia (ALL) in infants with MLL gene rearrangement, few studies have focused on this specific group. We conducted a retrospective analysis of infants with recurrent or refractory ALL from two previous consecutive Japanese studies to clarify the characteristics and prognostic factors among these patients All recurrent or refractory ALL infants with MLL gene rearrangement (MLL-R) who were registered in two consecutive Japanese nation-wide multicentric trials (MLL96 and MLL98; between 1995 and 2001) were eligible for the study. Among 80 MLL-R ALL infants, 34 cases of recurrence and 5 induction failures occurred. The median duration of first remission was 5 months (range, 0-28 months). All patients underwent various salvage chemotherapies; remission was achieved in 40.5% (15/37). A total of 23 patients received subsequent hematopoietic stem cell transplantations (HSCT): 9 in remission, 12 without remission, and 2 with unknown status. With median follow-up period of 5.5 years, the 5-year overall survival (OS) rate after the second-line treatment was 25.6% +/- 6.9%. Young age (<3 months) and central nervous system involvement at initial diagnosis were associated with poor outcome; however, failure to achieve remission after salvage therapy was the sole independent poor prognostic factor in multivariate analysis (P = 0.01). The prognosis of infants with recurrent or refractory MLL-R ALL is extremely poor despite alternative treatments including HSCT; therefore, it is necessary to develop novel treatment strategies.

Nonspecific Interstitial Pneumonia After Peripheral Blood Stem Cell Transplantation in an 11-year-old boy

Late-onset pulmonary complications after peripheral blood stem cell transplantation include various conditions such as opportunistic infections and interstitial pneumonias. It is sometimes difficult to diagnose interstitial pneumonias because there is substantial overlap in their computed tomography appearances. We present a case of an 11-year-old boy who consecutively developed pulmonary infection and cellular nonspecific interstitial pneumonia 9 months after peripheral blood stem cell transplantation for recurrent acute lymphocytic leukemia.

Ovarian and multiple lymph nodes recurrence of acute lymphoblastic leukemia: a case report and review of literature

Ovarian involvement of acute lymphoblastic leukemia (ALL) without relapse in the bone marrow or other extramedullary site is rare. We report a case of ovarian relapse in a 13-year-old girl who was diagnosed with ALL at the age of 11. A complete remission was induced with the Children Cancer Group 1882 protocol for high-risk-groups. After maintenance chemotherapy, the patient remained in relatively good health for the next 4 months. The patient presented with intermittent colicky right lower quadrant pain of 1-day duration. The pelvic ultrasound (US) showed a lobulated mixed echogenic mass in the right ovary, and an exploratory laparotomy was performed. Although uncommon, ovarian recurrence after treatment for ALL should be considered in patients with suggestive symptoms. Regular pelvic US is easy to perform and has no side effects and can help detect ovarian tumors early in ALL survivors.

Treatment of Bronchopleural Fistula With Small Intestinal Mucosa and Fibrin Glue Sealant

Bronchopleural fistula can be a devastating complication of pulmonary resections. Treatment options are often limited and carry significant morbidity or mortality, or both. We present a case of bronchopleural fistula occurring after pulmonary lobectomy for aspergilloma in a patient with recurrent acute lymphoblastic leukemia. The bronchopleural fistula was treated using bronchoscopic obliteration with Tisseel VH Fibrin Sealant (Baxter Healthcare Corp, Westlake Village, CA) and small intestinal submucosa with complete resolution and no morbidity. The relevant literature is reviewed.