Simultaneous occurrence of advanced neuroblastoma and acute myeloid leukemia

The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma (NB), who had been treated with 6 cycles of cyclophosphamide, doxorubicin, cisplatin, and etoposide for 12 months. The patient reached partial remission and presented a diagnosis of acute myelomonocytic leukemia (M4 AML), confirmed by immunophenotyping. After 2 months of therapy for leukemia, the child died with both malignancies in activity. A necropsy histologically confirmed the simultaneity of the two diseases. The authors review the possibilities of this association. The review leads to the conclusion that AML can occur as a secondary malignancy after the onset of the neuroblastoma, or be suggested by a misdiagnosis. The simultaneous occurrence of both as described here is not, however, found in the literature, to the best of the authors' knowledge.     

Immune reconstitution after autologous purged bone marrow transplantation in children

PURPOSE: Immune reconstitution was studied in 30 children who had received purged autologous bone marrow transplantation for neuroblastoma or acute myeloid leukemia (AML). METHODS: Patients with neuroblastoma received high-dose chemotherapy and total body irradiation, and patients with AML received chemotherapy alone. Marrows were purged ex vivo with either antineuroblastoma monoclonal antibodies (neuroblastoma) or 4-hydroperoxycyclophosphamide (AML). Lymphocyte subsets, mitogen stimulation studies, and immunoglobulin levels were studied every 4 months. RESULTS: There were no significant differences between the two groups of patients in lymphocyte number or subsets over time. In both groups, CD2+ and CD4+ cells were below normal in 33% of patients at 12 months. CD4+/CD8+ ratios were below normal for up to 8 months after transplantation and natural killer cells were elevated for up to 2 years in most patients. Median IgG and IgA levels were below the age mean even at 2 years after transplantation, although patients with AML had significantly higher IgG levels at 12 months compared with those with neuroblastoma. Lymphocyte proliferative responses to mitogens were markedly reduced at 4 months but returned to normal at 8 months. Despite the delay in immune reconstitution, there were no life-threatening infections. CONCLUSIONS: There appeared to be little difference in the overall kinetics of immune reconstitution between the children with neuroblastoma, who received total body irradiation and high-dose chemotherapy, and those with AML, who received high-dose chemotherapy alone as their pretransplant preparative regimen.     

p16 inactivation associated with aggressive clinical course and fatal outcome in TEL/AML1-positive acute lymphoblastic leukemia

The authors describe a 7-year-old boy with TEL/AML1-positive pre-B acute lymphoblastic leukemia, with hemizygous 9p21 deletion at presentation and no p16(INK4A) protein expression. Despite an initial response to a standard chemotherapy regimen, the patient suffered two hematologic relapses and died 34 months after diagnosis. The authors discuss the possibility that complete p16(INK4A) gene inactivation may adversely modify the prognostic significance of TEL/AML1 fusion in childhood acute lymphoblastic leukemia, and present evidence from clinical and in vitro observations in favor of this assumption.     

MUTATIONS OF RETINOBLASTOMA GENE (Rb-1) AS A PROGNOSTIC FACTOR IN CHILDREN WITH ACUTE LEUKEMIA AND NEUROBLASTOMA

Rb-1 is a tumor suppressor gene encoding for a nuclear phosphoprotein acting as a cell cycle regulator, normally expressed in hematopoietic cells and more often inactivated by point mutations with predominance for exons 20-24. The aim of this study is to correlate the retinoblastoma-1 (Rb-1) gene mutations with the prognosis and progression of childhood acute leukemia and neuroblastoma. Bone marrow slides from 26 children with leukemia (18 acute lymphoblastic leukemia [ALL] and 8 acute myeloid leukemia [AML]) and 4 children with neuroblastoma were studied. Exons 20, 21, and 22 were amplified using the polymerase chain reaction technique. Single strand conformational polymorphism (SSCP) and heterodoublex analysis were performed to detect mutations. In ALL cases, two samples in exon 20 (11.11%), one in exon 21 (5.56%), and four in exon 22 (22.22%) had altered conformation. All but one of these cases were classified as high-risk leukemia patients who either relapsed or never achieved remission. Two of the AML cases who did not achieve remission and one of the neuroblastoma cases with concomitant bone marrow infiltration had altered conformation as well. The SSCP and heterodoublex analysis showed that all but one who did not belong to the high-risk group had the same altered conformation. These data suggest that Rb-1 gene could possibly be used as an independent prognostic factor for the acute leukemia of childhood and result in the intensification of chemotherapy. In solid tumors with bone marrow involvement it could play a role as a marker of aggressive disease.     

Mutations of retinoblastoma gene (Rb-1) as a prognostic factor in children with acute leukemia and neuroblastoma

Rb-1 is a tumor suppressor gene encoding for a nuclear phosphoprotein acting as a cell cycle regulator, normally expressed in hematopoietic cells and more often inactivated by point mutations with predominance for exons 20-24. The aim of this study is to correlate the retinoblastoma-1 (Rb-1) gene mutations with the prognosis and progression of childhood acute leukemia and neuroblastoma. Bone marrow slides from 26 children with leukemia (18 acute lymphoblastic leukemia [ALL] and 8 acute myeloid leukemia [AML]) and 4 children with neuroblastoma were studied. Exons 20, 21, and 22 were amplified using the polymerase chain reaction technique. Single strand conformational polymorphism (SSCP) and heterodoublex analysis were performed to detect mutations. In ALL cases, two samples in exon 20 (11.11%), one in exon 21 (5.56%), and four in exon 22 (22.22%) had altered conformation. All but one of these cases were classified as high-risk leukemia patients who either relapsed or never achieved remission. Two of the AML cases who did not achieve remission and one of the neuroblastoma cases with concomitant bone marrow infiltration had altered conformation as well. The SSCP and heterodoublex analysis showed that all but one who did not belong to the high-risk group had the same altered conformation. These data suggest that Rb-1 gene could possibly be used as an independent prognostic factor for the acute leukemia of childhood and result in the intensification of chemotherapy. In solid tumors with bone marrow involvement it could play a role as a marker of aggressive disease.     

Pulmonary tuberculosis in a child receiving intensive chemotherapy for acute myeloblastic leukemia

The authors describe a 6-year-old boy who developed pulmonary tuberculosis during intensive chemotherapy for acute myeloblastic leukemia (AML). The diagnosis of tuberculosis was made by PCR from an open lung biopsy, while a bacterial culture was negative. The patient was treated with triple tuberculostatic drug therapy, followed by two-drug therapy, while receiving maintenance chemotherapy for AML, including thioguanine and cytarabine. Pulmonary infiltrates resolved within 2 months of treatment. However, possibly due to the bone marrow toxicity of the tuberculostatic drugs, the patient tolerated only low doses of cytostatic therapy. The boy is now 14 months off tuberculostatic treatment and 8 months off AML therapy. He is in remission of AML and tuberculosis.     

A Case of T‐cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia

A 4‐year‐old male with the diagnosis of T‐cell acute lymphoblastic leukemia (T‐ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T‐cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array‐CGH) and whole‐exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T‐ALL.     

Granulocytic sarcoma presenting as pneumonia in a child with t(8;21) acute myelogenous leukemia: diagnosis by fluorescent in situ hybridization

Granulocytic sarcoma is a soft tissue collection of leukemic cells. The authors describe a 4-year-old boy with M2 acute myelogenous leukemia (AML) who presented with fever, mild nonproductive cough, and hematemesis. Although he was initially diagnosed with nodular pneumonia, rapid resolution of a pulmonary infiltrate following induction chemotherapy was suggestive of a pulmonary granulocytic sarcoma. Interphase fluorescent in situ hybridization (FISH) of the lung biopsy specimen for the t(8;21)(q22;q22) translocation confirmed the retrospective diagnosis of a well-differentiated pulmonary granulocytic sarcoma. Pulmonary granulocytic sarcomas may be underrecognized in children with AML; this may delay anti-leukemic therapy and may lead to ineffective therapy if misdiagnosed as pneumonia.     

Acute myeloblastic leukemia two years after diagnosis of non-Hodgkin lymphoma.

The 18-year-old white male developed acute myeloblastic leukemia (AML) 25 months after diagnosis of poorly differentiated lymphocytic lymphoma, diffuse pattern (PDLL-D), involving cervical, supraclavicular, and mediastinal lymph nodes as well as bone marrow. Treatment of the lymphoma consisted of 2,000 rads to the mantel area and 18 months of chemotherapy with intravenous (IV) methotrexate (400 mg/m2), vincristine, and prednisone, alternating every two weeks with IV cyclophosphamide (1,000 mg/m2), vincristine, and prednisone plus monthly intrathecal methotrexate. Thereafter, a complete remission was maintained without therapy until the onset of AML. Several pseudodiploid clones containing multiple structural rearrangements and a hypodiploid clone were identified in the circulating blood at the time of diagnosis of AML. Induction therapy consisting of cytosine arabinoside, 5-azacytidine, vincristine, and prednisone was unsuccessful, and the patient died of sepsis two months after diagnosis. This case calls attention to the increased risk for subsequent acute nonlymphocytic leukemia in patients previously treated for nonhodgkin lymphoma.     

Molecular cytogenetic findings of acute leukemia included in the Brazilian Collaborative Study Group of Infant acute leukemia

BACKGROUND: Chromosome abnormalities often occur prenatally in childhood leukemia, characterizing an early event in leukemogenesis. The majority of the abnormalities occurring in infants involve the MLL gene on chromosome band 11q23. We describe the molecular cytogenetic findings of 207 infant acute leukemia (IAL) cases included in the Brazilian Collaborative Study Group of Infant acute leukemia. PROCEDURE: The diagnosis of Acute Lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) was made according to morphology and immunophenotyping classification, followed by conventional karyotyping. Samples were then screened using RT-PCR for the presence of specific chromosome translocations. FISH assay for MLL rearrangements was performed only in cases with negative or inconclusive cytogenetic or PCR results. RESULTS: The characteristics of children with IAL were as follows: 115 boys and 92 girls, age range 0-23 months, mean age 12 months, 145 ALL, and 62 AML. A statistically significant association was observed between pro-B ALL cases and MLL+ve (P=0.0001) cases and the age group 0-3 months with MLL+ve (P=0.008) cases. Two rare cases of pro-T ALL with MLL+ve were found. Other than MLL rearrangements, various other molecular aberrations were detected including TEL/AML1+ve (n=9), E2A/PBX1+ve (n=4), PML/RARA+ve (n=4), and AML1/ETO+ve (n=2). Cytogenetic analysis revealed hyperdiploidy (n=6), del(7) in two cases and del(11)(q23) in seven cases. CONCLUSIONS: Our results show that not only MLL rearrangements, but also other molecular abnormalities occur before birth and may contribute to leukemogenesis.     

Concomitant Ewing sarcoma and acute lymphoblastic leukemia in a 5-year-old girl

Malignancies from the Ewing family of tumors and acute lymphoblastic leukemia (ALL) are not known to be associated with each other. A 5-year-old girl was incidentally found to suffer from acute lymphoblastic leukemia during bone marrow staging for Ewing sarcoma of the radius. The simultaneous presence of two distinct neoplasms was confirmed by RT-PCR, with EWS/FLI1 type 1 rearrangement in the bone tumor and TEL/AML1 rearrangement in the marrow. She was treated with chemotherapy, radiotherapy, and surgery and was in remission of both diseases 31 months after diagnosis.     

High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia

In acute myeloid leukemia (AML), the leukemia-initiating cell is found within the CD34(+)/CD38(-) cell compartment. Over the last years evidence grew that AML is initiated and propagated by leukemic stem cells (LSCs). Conceivably, these most immature leukemia cells are more resistant to therapy and subsequently initiate relapse. The authors studied 17 patients with childhood AML treated according to the AML-BFM 98/04 protocol. At diagnosis, the authors determined the characteristic immunophenotype of the leukemic cells by flow cytometry and investigated the expression of CD34, CD38, and CD45 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)/CD45(-/low)) enriched for LSCs in many cases of AML. The authors compared the fraction of this population of all myeloid cells at diagnosis with event-free survival. Kaplan-Meier analysis revealed significant higher event free survival of patients with low CD34(+)/CD38(-)/CD45(-/low) cell proportion (<0.68%) compared to patients with high burden of this population (>0.83%; log-rank P < .04). This correlation was not found for the total number of CD34(+) cells. This is the first study to show that a higher proportion of immature CD34(+)/CD38(-)/CD45(-/low) blasts at diagnosis correlates with unfavorable prognosis in childhood AML. The results suggest that a large CD34(+)/CD38(-)/CD45(-/low) population reflects a higher fraction of LSCs, leading to increased chemotherapy resistance and elevated relapse rate. Thus the initial frequency of CD34(+)/CD38(-)/CD45(-/low) cells may serve as a prognostic marker in pediatric AML. Future treatment in childhood AML should specifically target this immature population as well as the mature blast population.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

Ex vivo chemopurging of autologous bone marrow with 4-hydroperoxycyclophosphamide to eliminate occult leukemic cells. Laboratory and clinical observations

The application of autologous bone marrow transplantation (ABMT) in treating acute leukemias in children has been limited by the presence of residual occult viable leukemic cells in the marrow cell suspension. One approach to this problem is the ex vivo treatment ("purging") of the autograft to eradicate these tumor cells yet spare the normal lymphohematopoietic stem cells. Initial studies of acute myeloid leukemia (AML) in a rodent model demonstrated that incubation with 4-hydroperoxycyclophosphamide (4HC), a congener of cyclophosphamide and an active alkylating agent in aqueous solution, could effectively eliminate viable AML cells from marrow cell suspensions without apparent toxicity to normal stem cells. We have conducted clinical trials of ABMT with 4HC-treated marrow in children with acute leukemia in remission; marrow was collected, treated ex vivo with 4HC (100 micrograms/ml), and cryopreserved in liquid nitrogen until reinfusion. Children received pre-ABMT conditioning with either high-dose cyclophosphamide and total body irradiation (CY-TBI) for acute lymphocytic leukemia (ALL) or high-dose busulfan and cyclophosphamide (BU-CY) for AML. Of nine children who underwent ABMT with 4HC-treated marrow for ALL in second complete remission (CR2), all relapsed (eight in the marrow, one in the central nervous system) at a median of 5 months (range, 2-17) after ABMT and all have died with relapsed ALL or as a consequence of its treatment. Twenty-nine children with AML (five in CR1, 24 in CR2) received autografts with chemopurged marrow at a median remission duration of 3 months (range, 2-15). Three patients died from sepsis during aplasia; 10 children (one in CR1 and nine in CR2) relapsed with AML at a median of 7 months (range, 2-23) after ABMT, for an actuarial relapse rate of 47%. Sixteen patients with AML (four in CR1, 12 in CR2) are in unmaintained remission at a median of 16 months (range, 6-102) after ABMT, for an actuarial disease-free survival of 49%. Although ABMT with 4HC-treated marrow appears to have a limited role in the treatment of children with ALL who lack a suitable related donor, the results in AML are encouraging and compare favorably with both syngeneic and allogeneic BMT in similar groups of patients.     

Leukemic blasts with markers of four cell lineages in Down's syndrome (“megakaryoblastic leukemia”)

Among 16 patients with Down's syndrome (DS) and acute leukemia admitted to our department during a ten year period, 6 were diagnosed as acute megakaryoblastic leukemia (AMkL). The diagnosis was based on clinical and hematologic criteria, confirmed in three patients with the use of monoclonal antibodies (MoAb) specific for megakaryocytic antigens. In these three, and in a fourth patient, the leukemic blasts were positive for other myeloid, lymphoid and erythroid markers in MoAb testing. We suggest that AMkL in DS is a mixed lineage leukemia with blasts presenting a variety of cell surface antigens, indicating origin from an early progenitor cell with the capability of megakaryocytic differentiation. Of the 6 patients with AMkL, 4 treated with standard AML protocols are in complete continuing remission (CCR) with observation periods from 57+ to 148+ months. © 1993 Wiley-Liss, Inc.     

Bilateral breast relapse in acute myelogenous leukemia

We present the case of an 11.5-year-old girl with M1 acute myelogenous leukemia (AML) who had isolated extramedullary relapse develop in both breasts 12 months after diagnosis and 7 months off chemotherapy. She received further chemotherapy, focal radiation therapy, then underwent a matched, unrelated bone marrow transplant and continues in remission 37 months later. Review of the literature revealed 10 cases in other children younger than 21-years-old with AML and breast involvement. These cases are summarized, and potential pathophysiologic mechanisms of spread are discussed. Breast involvement in AML is rare in children. However, regular breast examinations should be performed as part of routine follow-up in all girls with AML.     

Presentation of M4 acute myeloid leukemia in anuric renal failure with hyperuricemia and enlarged kidneys

Extramedullary acute myeloid leukemia (AML) is not uncommon. It has been shown to involve the kidneys in most postmortem cases but is most often clinically insignificant. By contrast, acute tumor lysis syndrome is rare in AML, especially at initial diagnosis. The authors report the management of a patient with AML who had acute tumor lysis syndrome that was probably potentiated by renal leukemia and resulted in renal failure. This patient achieved remission with dose-modified induction chemotherapy administered while he was dialysis-dependent.     

Osteoarticular manifestations as initial presentation of acute leukemias in children and adolescents in Bahia, Brazil

OBJECTIVE: This study was to determine the prevalence and characteristics of the osteoarticular manifestations on initial clinical presentation of acute leukemias (ALs) on childhood in the state of Bahia, Brazil. MATERIALS AND METHODS: This retrospective study assessed the medical records of 406 patients with AL from January 1995 to December 2004. RESULTS: Acute lymphocytic leukemia (ALL) was diagnosed in 313 (77.1%) patients and acute myeloid leukemia (AML), in 93 (22.9%) patients, including 241 males (59.4%) and 165 females (40.6%). Age ranged from 9 months to 15 years (average: 6.18 y). The most common presenting features were fever (18.5%), musculoskeletal diffuse tenderness (15.0%), pallor (11.4%), and leg tenderness (5.7%). Prior referral to our center, the most frequent initial diagnosis was anemia (15.8%), leukemia (15.0%), amygdalitis (3.7%), and rheumatic fever (2.7%). Osteoarticular manifestations were found on 54.7% of the patients with AL, with a higher frequency among patients between 1 and 9 years of age (58.7%, P=0.0007). The presence of joint tenderness (16.2% in ALLx5.4% in AML), arthritis (26.6% in ALLx9.7 in AML), bone tenderness (26.1% in ALLx16.1% in AML), limb tenderness (49.5% in ALLx25.8% in AML), and antalgic gait (32.8% in ALLx9.7% in AML) had higher prevalence on ALL. The large joints, chiefly the knees (10.6%), ankles (9.4%), elbows (4.4%), and shoulders (3.6%) were more often affected. CONCLUSIONS: AL should be considered on the differential diagnosis of osteoarticular symptoms of unknown etiology in children.     

Simultaneous diagnosis of acute lymphoblastic leukemia and peripheral neuroblastic tumor in a child

We report the case of a 3-year-old girl with a mediastinal mass, severe anemia, leukocytosis and neutropenia, in whom, after initial suspicion of metastatic neuroblastoma, a final diagnosis of concurrent ganglioneuroblastoma and acute lymphoblastic leukemia was made. The mediastinal tumor was surgically excised and the child subsequently underwent chemotherapy for acute lymphoblastic leukemia. The patient remains in complete remission from both diseases 4 years after the diagnosis and 24 months after completion of all treatment. The simultaneous occurrence of 2 different neoplasms in a child is very infrequent, and no comparable cases are reported in the literature.     

Blast crisis of chronic myeloid leukemia: diagnosis prompted by T(8;9)

T(8;9) is a relatively new translocation that has been reported in a few patients with chronic myeloid leukemia (CML) but never in acute myeloid leukemia (AML). We report here a patient who presented with AML with t(8; 9). He lacked the Philadelphia chromosome but tested positive for the gene by the polymerase chain reaction method. This confirmed the diagnosis of CML with blast crisis, and appropriate treatment could be instituted