Successful treatment of relapsed anaplastic large cell lymphoma with vinblastine monotherapy and allo-HSCT with reduced intensity conditioning regimen.

Relapsed anaplastic large cell lymphoma (ALCL) is chemosensitive, but recurrence is common. Although vinblastine (VLB) monotherapy is an effective treatment for relapsed ALCL, the optimal treatment duration is unknown, and some patients experience further relapse after completing the treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is also an effective treatment for relapsed ALCL, although transplant-related toxicity is a problem. Here, we report an 11-year-old patient with relapsed ALCL who underwent induction therapy with VLB monotherapy and achieved complete remission (CR) after 12 courses. CR was confirmed on positron emission tomography-computed tomography. The patient then underwent allo-HSCT with reduced intensity conditioning (fludarabine, melphalan, and low-dose total body irradiation). He developed grade II acute graft-versus-host disease (GVHD), which was successfully treated with methylprednisolone. There was no evidence of chronic GVHD. He has remained in CR without any complications for 19 months after allo-HSCT.

Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation.

Noonan syndrome (NS) is a congenital genetic disorder characterized by certain facial features, short stature, and congenital heart disease. The disorder is caused by genetic alterations in the RAS/MAPK signal pathway. NS patients show a predisposition to malignancy; however, acute lymphoblastic leukemia (ALL) is rarely reported. Here, we describe a NS patient with B-cell precursor ALL (BCP-ALL) harboring a hyperdiploid karyotype and a PTPN11 germline mutation (c.922A>G; p.N308D). We also discuss the relationship between the hyperdiploid karyotype and genetic alterations in the RAS/MAPK pathway in BCP-ALL.

All-trans retinoic acid combined with 5-Aza-2'-deoxycitidine induces C/EBPα expression and growth inhibition in MLL-AF9-positive leukemic cells.

The present study tested whether all-trans retinoic acid (ATRA) and 5-Aza-2'-deoxycitidine (5-Aza) affect AML cell differentiation and growth in vitro by acting on the CCAAT/enhancer binding protein α (C/EBPα) and c-Myc axis. After exposure to a combination of these agents, cell differentiation and growth arrest were significantly higher in human and murine MLL-AF9-expressing cells than in MLL-AF4/AF5q31-expressing cells, which were partly associated with increased expression of C/EBPα, C/EBPε, and PU.1, and decreased expression of c-Myc. These findings indicate that MLL-AF9-expressing cells are more sensitive to ATRA and 5-Aza, indicating that different MLL fusion proteins possess different epigenetic properties associated with retinoic acid pathway inactivation.

Quantitative RT-PCR analysis of the MOZ-CBP fusion transcript in therapy-related acute myeloid leukemia with t(8;16)(p11;p13).

We developed a real time reverse transcriptase polymerase chain reaction (RT-PCR) assay system for detecting the MOZ-CBP fusion transcript and used it to monitor minimal residual disease (MRD) status in a patient with therapy related acute myeloid leukemia (t-AML) harboring t(8;16)(p11;p13). Expression of the MOZ-CBP fusion transcript was determined by RT-PCR analysis of the patient's bone marrow at the time of diagnosis. Thereafter, real time RT-PCR was used to evaluate MRD levels throughout the entire course of treatment. The sensitivity of quantitative RT-PCR for the MOZ-CBP fusion transcript was 10(-5). Below this level, MRD was classified as negative. Real time RT-PCR of the bone marrow after induction therapy showed the reduction of MOZ-CBP transcript to approximately 10(-3) level when compared to the diagnostic sample. MRD was classified as negative (< 10(-5) compared with that in the bone marrow at diagnosis) after 5 courses of chemotherapy, a level that was maintained post-allo-hematopoietic stem cell transplantation. Real time RT-PCR of the MOZ-CBP transcript is a useful tool for assessing MRD status for a patient with therapy related acute myeloid leukemia who was initially predicted to have a poor prognosis.

[Effective infliximab treatment for a recurrent type of acute intestinal graft-versus-host disease accompanied by steroid-induced depression].

A 22-year-old man with chronic active Epstein-Barr virus infection underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA two allele-mismatched unrelated donor. Ten months after allo-BMT, he developed protein-losing enteropathy following a respiratory syncytial virus infection. A diagnosis of a recurrent type of acute graft-versus-host disease (GVHD) was made based on the histopathological findings, such as the infiltration of T lymphocytes into the superficial epithelium and crypts, and apoptotic bodies in crypts. Although methylprednisolone (mPSL: 10 mg/kg) administration for two consecutive days improved gastrointestinal symptoms, acute pancreatitis and severe depression developed in association with corticosteroid treatment. Reduction of mPSL and administration of infliximab (5 mg/kg/dose, 3 times) resulted in rapid improvement of depression and pancreatitis without aggravating intestinal GVHD. Recent studies have demonstrated that tumor-necrosis-factor (TNF)-α is associated with not only GVHD but also depression and acute pancreatitis. In the present case, anti-TNF-α treatment enabled us to reduce corticosteroid dose without aggravating GVHD, which suggests that this approach might be effective for the treatment of depression and acute pancreatitis.

Late appearance of a Philadelphia chromosome in a patient with therapy-related acute myeloid leukemia and high expression of EVI1.

A 17-year-old boy developed therapy-related acute myeloid leukemia (t-AML) 3 years after the cessation of chemo- and radiotherapy for undifferentiated sarcoma of the liver. At the onset of the t-AML, his white blood cell count was 900/microL with a 46,XY,t(2;3)(p21;q26),del(5)(q?) karyotype. Despite intensive chemotherapy and two hematopoietic stem cell transplants, he died of the leukemia. At the terminal phase, his white blood cell count surpassed 30,000/microL and the Philadelphia (Ph) chromosome appeared. Expression of EVI1 in bone marrow cells was remarkably high at the onset of t-AML, although it was not detected at the end of therapy for the sarcoma. Polymerase chain reaction analysis of bone marrow cells revealed that mRNA for the bcr-abl chimera was negative at the onset of t-AML and positive at the terminal phase. These results suggest that EVI1 overexpression was the major factor contributing to leukemogenesis, and the late appearance of the Ph chromosome is closely associated with the progression to an aggressive form of leukemia.

Intestinal pseudo-obstruction in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with phenytoin therapy.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is most commonly associated with a mitochondrial DNA A to G point mutation at nucleotide 3243 (A3243G) and individuals with the disorder present a wide range of multisystemic symptoms. Seizures in MELAS patients are often intractable and require multiple antiepileptic drugs. Here we report a MELAS patient who presented with acute intestinal pseudo-obstruction following the administration of phenytoin (PHT) as an antiepileptic treatment. She presented with the first stroke-like episode at the age of 6 years and mitochondrial DNA analysis revealed A3243G with 94% mutation load in skeletal muscle. Despite treatment with phenobarbital and clobazam at the age of 16 years, she developed status epilepticus which ceased following PHT infusion. Thereafter, she was started on PHT treatment. One month later, however, she was readmitted because of remarkable abdominal distention. Although abdominal CT showed acute ileus with hepatic portal venous gas mimicking surgical emergency, the abdominal distention gradually recovered over several days following the discontinuation of PHT. Our clinical observations suggest the possibility that intestinal pseudo-obstruction in this patient related to PHT therapy. Careful clinical observation including gastrointestinal symptoms is required in the management of epilepsy in MELAS patients.

Swyer-James Syndrome in a 7-Year-Old Female.

Swyer-James syndrome is a rare syndrome that occurs as a result of repeated bronchiolitis and pneumonitis in childhood. Most cases are asymptomatic, and subsequent diagnosis may not occur until adulthood. We present the case of a 7-year-old female with Swyer-James syndrome, which was initially diagnosed and treated as asthma. The patient developed respiratory distress and atelectasis which were treated with biphasic cuirass ventilation. This case suggests that Swyer-James syndrome should be a concern in patients with chronic cough and wheezing, and highlights the importance of taking a careful history and appropriate radiological investigations for diagnosis. Once Swyer-James syndrome is diagnosed, prophylaxis and appropriate management of respiratory infections becomes important.

BCL2 Inhibitor (ABT-737): A Restorer of Prednisolone Sensitivity in Early T-Cell Precursor-Acute Lymphoblastic Leukemia with High MEF2C Expression?

Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as a high-risk subtype of pediatric T-cell acute lymphoblastic leukemia (T-ALL). Conventional chemotherapy is not fully effective for this subtype of leukemia; therefore, potential therapeutic targets need to be explored. Analysis of the gene expression patterns of the transcription factors in pediatric T-ALL revealed that MEF2C and FLT3 were expressed at higher levels in ETP-ALL than typical T-ALL. Using human T-ALL and BaF3 cell lines with high expression levels of MEF2C, the present study tested whether the BCL2 inhibitor (ABT-737) restores the sensitivity to prednisolone (PSL), because MEF2C causes PSL resistance, possibly by augmenting the anti-apoptotic activity of BCL2. Treatment with PSL and ABT-737 caused a significant reduction in the IC50 of PSL in the MEF2C-expressing LOUCY cells, in addition to the MEF2C-transduced BaF3 cells, but not in the non-MEF2C-expressing Jurkat cells. The combination treatment significantly accelerated the killing of primary leukemic blast cells of ETP-ALL with high expression levels of MEF2C, which were co-cultured with murine stromal cells. These findings suggest that BCL2 inhibitors may be a therapeutic candidate in vivo for patients with ETP-ALL with high expression levels of MEF2C.

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation.

After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.

Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient.

Investigation of genetic alterations associated with relapse in acute lymphoblastic leukemia (ALL) may help to identify druggable targets for specific therapies. Early T-cell precursor ALL (ETP-ALL) is a subtype of T-ALL with poor prognosis. Although the genetic landscape of ETP-ALL has been determined, genetic alterations related to the relapse of ETP-ALL have not been fully investigated. Here, we report the first patient with relapsed pediatric ETP-ALL to exhibit a homozygous JAK3 activating mutation, V674A, caused by acquired uniparental disomy (UPD). Single nucleotide polymorphism array analysis revealed acquired UPD (aUPD) at the 19p13.3-p12 locus only in leukemic cells at relapse. Sanger sequence of the JAK3 gene, which was located at 19p13.1 and frequently mutated in ETP-ALL, was performed in paired leukemic samples to determine homozygous JAK3 V674A mutation only in relapsed leukemic cells. In contrast, leukemic cells at initial diagnosis harbored hemizygous JAK3 V674A mutation. Further, whole-exome sequencing revealed mutations in 18 genes only in relapsed samples, although none of these was recurrent in T-ALL. These findings suggest that aUPD at 19p13.1 is partly associated with relapse in this patient. Pharmacological inhibition of JAK3 may be therapeutic in such cases.

Post-transcriptional modulation of C/EBPα prompts monocytic differentiation and apoptosis in acute myelomonocytic leukaemia cells.

CCAAT/enhancer binding protein alpha (C/EBPα) induction induces monocytic differentiation even in acute myeloid leukaemia (AML). In this study, the induction/activation of C/EBPα in myelomonocytic AML was investigated using a combination of all-trans retinoic acid (ATRA) and RAD001 (Everolimus), a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Combining these agents increased PU.1, C/EBPε and C/EBPα expression, increased the p42/p30 C/EBPα ratio, and decreased C/EBPα phosphorylation at serine 21, and was accompanied by growth inhibition, induction of CD11b expression and apoptosis in AML cell lines. Thus, agents that induce sufficient levels of C/EBPα expression might be useful in treating AML.

Successful non-T-cell-depleted HLA-haploidentical 3-loci mismatched bone marrow transplantation.

A 17-year-old boy with therapy-related acute myelocytic leukemia (FAB classification-M0) successfully received allogeneic non-T-cell depleted (non-TCD) bone marrow transplantation (BMT) from his 3-loci HLA-mismatch mother, although pre-BMT detection of feto-maternal microchimerism was negative. The BMT was performed with reduced intensity conditioning (total body irradiation; 4 Gy, fludarabine; 20 mg/m(2) x 6, and melphalan; 70 mg/m(2) x 2) and short-course methotrexate and tacrolimus for GVHD prophylaxis. Complete donor chimera was obtained on day 19, associated with Grade 3 acute GVHD (skin: Stage 1, liver: Stage 0, gut: Stage 3) that was well controlled with immunosuppressive therapies. At day 200 of transplantation, he was in complete remission with no signs of chronic GVHD. Our case suggests that non-TCD HLA-haploidentical 3-loci mismatched BMT can be safely performed from mother to offspring even when feto-maternal microchimerism is barely detectable with the current detection procedure.