The treatment of children suffering from chronic myelogenous leukemia: A comparison of the result of treatment with imatinib mesylate and allogeneic hematopoietic stem cell transplantation

HSCT is the only proven treatment option for CML, a rare disease in children. Recently, there are promising reports on the advantageous effect of imatinib mesylate for pediatric patients with CML. We conducted a retrospective study on 33 pediatric patients suffering from CML. Fourteen underwent HSCT and the rest were treated with imatinib. With a median follow‐up of 24 months, the two‐yr OS in the HSCT group and the imatinib group was 84% and 87%, respectively (p = 0.714). The probabilities of two‐yr DFS were 59% in the HSCT group and 82% in the imatinib group, either (p = 0.880). Relapse occurred in 5 (35.7%) patients of the HSCT group, and 8 (42.1%) patients showed relapse in the imatinib group. Among nine patients who died, five were in the HSCT group and the rest were in the imatinib group. The probability of relapse in the patients of the imatinib group followed up for several consecutive years may be higher than observed in the HSCT group, so we cannot easily conclude which way is more reliable.     

Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic‐phase chronic myeloid leukemia treated with imatinib

Bone marrow samples of newly diagnosed children with chronic‐phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti‐human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic‐phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.     

IKZF1 deletion and co‐occurrence with other aberrations in a child with chronic myeloid leukemia progressing to acute lymphoblastic leukemia

Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR‐ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6‐year‐old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis. It remains to be addressed whether distinct mechanisms might account for CML pathogenesis in early childhood.     

NOTCH1 mutation in a female with myeloid/NK cell precursor acute leukemia

A 6‐year‐old Japanese female was diagnosed as having myeloid/NK cell precursor acute leukemia (MNKL) using immunocytochemical analysis. The patient was treated by cord blood transplantation from an HLA 1‐locus mismatched unrelated donor after chemotherapy comprising cytosine arabinoside, idarubicin, etoposide, and L ‐asparaginase. We detected a nonsense mutation, C7412A, resulting in S2471X, where X is a terminal codon, in the PEST domain of NOTCH1 in this patient. The presence of the NOTCH1 activating mutation in MNKL might suggest a possible role in the leukemogenesis of MNKL. Pediatr Blood Cancer. 2010;55:1406–1409. © 2010 Wiley‐Liss, Inc.     

Interferon-α potentiates priming-dependent FMLP-induced neutrophil superoxide generation in a patient with chronic myeloid leukemia

13 year old girl diagnosed as having chronic myeloid leukemia (CML) was treated with interferon-α (IFN-α) alone and 4 months later hematological remission was obtained. In the course of the IFN-α treatment there was neither infectious sign nor side effects. In this study we have examined the effect of IFN-α on superoxide O₂^? generation by polymorphonuclear neutrophils (PMN). The PMN of the patient generated less O₂^? than PMN from normal controls. When patient PMN were cultured in the presence of 1000 U/mL IFN-α, enhancement of the formyl-methionyl-leucyl-phenylalanine induced O₂^?generation following priming with tissue necrosis factor-α was observed. Over the course of the IFN-α therapy, such O₂^? generation was gradually restored. It is suggested that CML PMN are in the resting condition in terms of their ability to generate O₂^? and that IFN-α is effective in inducing O₂^? generation by CML PMN.     

Successful treatment of primary refractory acute myeloid leukemia with megadose stem cell transplantation, bone marrow boost and reduced intensity conditioning avoiding chronic graft vs. host disease and severe late toxicity

We report on a 9-yr-old boy suffering from primary refractory AML. Remission was not achieved after two courses of induction therapy, leading to prolonged aplasia for more than 3 months and severe infection. Therefore, the boy was treated with a reduced intensity conditioning regimen consisting of fludarabine, cyclophosphamide and OKT3. Megadose transplantation of highly enriched CD34+ peripheral stem cells from his HLA-identical brother, followed on day +11 by a boost of unmanipulated bone marrow, was performed. Regeneration of donor hematopoiesis was rapid and led to resolution of infection. No additional donor lymphocyte infusions were necessary. More than 4 1/2 yr after the transplant the boy remains in complete continuous remission with no evidence for chronic GvHD or other late effects. Therefore, we conclude that reduced intensity conditioning in combination with allogeneic megadose stem cell transplantation and bone marrow boost may have helped to achieve cure from primary refractory AML as well as a good quality of life for this boy.     

Very long survival in complete cytogenetic remission in an adolescent with lymphoid blast crisis of chronic myeloid leukemia after treatment with intensive ALL‐directed chemotherapy combined with continuous imatinib

An 11‐year‐old male was diagnosed with chronic‐phase chronic myeloid leukemia (CML) in 1998 and received therapy with interferon‐α2b and low‐dose cytarabine. In 6 years, he progressed to lymphoid blast crisis and received induction chemotherapy with prednisolone, vincristine, daunorubicin, and l ‐asparaginase concomitantly with imatinib 400 mg/day, and continuation with vincristine + prednisolone, cytarabine + etoposide, vincristine + l ‐asparaginase, cyclophosphamide + etoposide, and 6‐mercaptopurine + methotrexate. Complete molecular response (MR) was achieved and therapy was continued with imatinib 800 mg/day. He relapsed to chronic‐phase CML after interruption of imatinib and regained MR after its restart. The patient is alive 17.5 years after CML diagnosis and 11.5 years after lymphoid blast crisis.     

Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.     

A variant c‐KIT mutation,D816H,fundamental to the sequential development of an ovarian mixed germ cell tumor and systemic mastocytosis with chronic myelomonocytic leukemia

An activating point mutation of the c‐KIT tyrosine kinase receptor gene, D816H, has been described in germ cell tumors (GCTs). We report an adolescent diagnosed with an ovarian mixed GCT and systemic mastocytosis with chronic myelomonocytic leukemia (SM‐CMML). The teratoma and dysgerminoma differed by copy number aberrations via single nucleotide polymorphism (SNP) microarray, but were inclusive of the same c‐KIT D816H point mutation (c.2446G>C) also identified in blood and bone marrow mast cells. These findings indicate not only a clonal origin of the GCT and hematologic malignancy, but also suggest a rare KIT mutation may be playing a fundamental role in malignancy development.     

Proven Epstein–Barr encephalitis with negative EBV‐DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia

We report a case of EBV encephalitis in a seven‐yr‐old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis. Blood and CSF PCR analyses were negative for the most common viruses involved in immunocompromised patients including EBV. A cerebral biopsy was performed, which showed intense gliosis and perivascular lymphocytic cuffing. PCR analysis performed on brain tissue was positive only for the EBV genome, while extensive investigations for other viral infections were negative. The patient's neurological symptoms rapidly worsened and he died two months later. This case report suggests that in patients presenting neurological and radiological signs of encephalitis after an HSCT, an EBV involvement should be considered, even in the absence of CSF and blood PCR virus detection.     

Favorable four‐yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation‐associated HUS

aHUS is a clinical challenge for successful renal transplantation. Case report: A 14‐yr‐old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH‐related protein (CFHR1/CFHR3) homozygous deletion‐associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation “under cover” of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post‐transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow‐up after transplantation. Conclusion: Specific pre‐ and post‐transplant management allowed successful renal transplantation in a CFH antibody‐positive patient.