Aseptic bone necroses in leukemia patients in childhood and adolescence

Four children with leukemia (1.6% of all leukemia patients) treated between 1979 and 1984 developed aseptic bone necroses, all of them at multiple sites. The average time from starting chemotherapy to developing bone necroses has been 19 months (range 9 to 28 months). This is a well known complication of corticoid therapy, but corticoids may not be the only aetiological factor. Other antineoplastic agents and leukemia for itself have been associated with aseptic bone necroses. Bone and joint pain caused by aseptic bone necroses can mimic leukemic relapse, so the diagnosis may be difficult. The increasing number of long term survivors in childhood leukemia, who underwent aggressive polychemotherapy, could make this problem more common in the near future.     

Aseptic osteonecrosis in children treated for acute lymphoblastic leukemia and aplastic anemia

We report six children, five with acute leukemia and one with aplastic anemia, who during chemotherapy have developed severe aseptic bone necrosis. Although there is no definite proof, our data are highly suggestive of incriminating corticosteroid therapy in large cumulative doses as the main pathogenetic factor.     

Isolated testicular leukemia following bone marrow transplant for acute lymphocytic leukemia. The need for pretransplant testicular biopsies

Bone marrow transplantation has become an accepted mode of treatment for children with acute myelocytic leukemia in their first remission and acute lymphocytic leukemia after their first bone marrow relapse. Two-year survival rates of 50% can be achieved in patients undergoing transplant during remission, in contrast to a 2-year survival of 15% in those undergoing transplant while still in marrow relapse. Recurrence of bone marrow leukemia relapse is a significant cause of marrow transplant failure. Overt or occult testicular relapse occurs in 10-15% of males with acute lymphocytic leukemia receiving or having completed standard therapy regimens for control of their disease and frequently leads to a subsequent bone marrow relapse. This paper describes a child with acute lymphocytic leukemia who received a successful marrow transplant following bone marrow relapse and developed testicular leukemia relapse approximately 20 months after transplant. The experience with this child suggests that bilateral testicular biopsies should be a mandatory part of the routine evaluation to screen for residual leukemia before bone marrow transplantation.     

Hypopyon in acute lymphoblastic leukemia

A child with acute lymphoblastic leukemia had central nervous system relapse 23 months after diagnosis while in bone marrow remission. This was followed by leukemic involvement of the eye as the only site of relapse 7 months later. Leukemic cells layered out in the anterior chamber and cytologic examination was the only way to make a definitive diagnosis of leukemic hypopyon. Topical treatment is generally ineffective and radiotherapy is the treatment of choice. The prognosis with this complication depends on whether it occurs during therapy or after therapy has been discontinued.     

Biology and pathogenesis of CNS leukemia

Despite routine preventive central-nervous-system (CNS) therapy, 5-10% of children with acute lymphoblastic leukemia continue to suffer CNS relapse. In a majority of these patients, bone marrow relapse ensues and is usually fatal. A better understanding of the biology and pathogenesis of CNS leukemia is needed to develop more effective methods of prevention and treatment of this adverse complication of acute leukemia. Concepts of the origin and proliferation of leukemic cells in the CNS are reviewed, as well postulated mechanisms of their ingress into and egress out of the CNS.     

Bone marrow necrosis and thrombotic complications in childhood acute lymphoblastic leukemia

Two children with bone marrow necrosis at diagnosis or at relapse of acute lymphoblastic leukemia (ALL) had thrombotic complications 15 and 17 days after starting remission induction therapy including prednisone, vincristine, and L-asparaginase. The close temporal relationship of these two relatively rare events suggests that bone marrow necrosis is a predisposing factor to the development of thrombosis.     

Bone marrow necrosis and thrombotic complications in childhood acute lymphoblastic leukemia.

Two children with bone marrow necrosis at diagnosis or at relapse of acute lymphoblastic leukemia (ALL) had thrombotic complications 15 and 17 days after starting remission induction therapy including prednisone, vincristine, and L-asparaginase. The close temporal relationship of these two relatively rare events suggests that bone marrow necrosis is a predisposing factor to the development of thrombosis.     

Erythroid hypoplasia. An unusual presentation of childhood acute lymphocytic leukemia.

A 3-year-old girl had pancytopenia and bone marrow erythroid hypoplasia. The pancytopenia resolved without therapy, but the erythroid hypoplasia persisted for four months in spite of a five-week course of corticosteroid therapy. She responded briefly when androgens were added to the corticosteroid regimen, but within three weeks of stopping therapy she developed acute lymphocytic leukemia. The differential diagnosis of RBC aplasia in childhood is discussed. To our knowledge, this is the first case reported with erythroid hypoplasia as a prodrome of acute lymphocytic leukemia of childhood.     

Avascular necrosis of bone following combination chemotherapy for acute lymphocytic leukemia

Avascular necrosis of bone (AVNB) is a known complication of systemic adrenocorticosteroid therapy, and one which is thought to be dose-related. However, despite the large amounts of prednisone which have been used in the standard treatment of acute lymphocytic leukemia (ALL), AVNB rarely has been reported in children with that disease. We described our experience with one adolescent with ALL who developed multifocal AVNB presenting as bone pain after aggressive chemotherapy that included a high cumulative dose of corticosteroids as well as other antitumor agents, some of which also have been associated with AVNB. Four similar cases from the literature are reviewed. Because the bone pain of AVNB can mimic that of leukemic relapse, this is an important entity to be aware of, and one which may become more common with increasingly aggressive combination chemotherapy.     

Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: Failure of subsequent treatment with cyclophosphamide,cytosine arabinoside,vincristine and prednisone (COAP)

Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 21/2–5 years of continuous disease-free remission, 20–25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequte for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.     

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13–29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.     

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide.

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13-29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.     

Leukemia in a Child with a History of Medulloblastoma

Leukemia of mixed lineage, was diagnosed in a 6.5-year-old boy with a history of medulloblastoma, 38 months after his initial cancer diagnosis. Therapy had included craniospinal radiation and nitrosourea-based chemotherapy. In addition, onset of leukemia was preceded by therapy with recombinant growth hormone for short stature. Although rare, leukemia is a treatment-related complication for patients with past brain tumors whose follow-up should therefore include surveillance with complete blood counts.     

Abdominal malignant mesothelioma following autologous bone marrow transplantation: a case report

Secondary malignancies are a well-known late complication occurring in patients who undergo bone marrow transplant (BMT) during childhood. A boy with acute lymphoblastic leukemia experienced a BM relapse at the age of 14 years and underwent an autologous BMT conditioned with TBI and melphalan. Sixteen years later a malignant mesothelioma of the peritoneum was diagnosed. A surgical approach according to the Sugarbaker technique and hyperthermic peritoneal perfusion with CDDP and Adriamycin were performed. The patient is alive and well after a follow-up of 20 months. To the authors' knowledge this is the first case of mesothelioma as a secondary malignancy after BMT.     

A rare case of adenoviral fulminant hepatic necrosis after chemotherapy

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

A RARE CASE OF ADENOVIRAL FULMINANT HEPATIC NECROSIS AFTER CHEMOTHERAPY

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

Aseptic osteonecroses in the treatment of childhood acute leukaemias

The incidence of aseptic osteonecroses in the therapy of acute leukaemias in children has been studied. Out of 551 children treated at the Children's Hospital in Münster from 1971 to 1985, 6 developed osteonecrosis, an incidence of 1.09%. Of these children, 5 showed unilateral or bilateral necrosis of the femoral head. The osteonecroses occurred 8–109 months after initiation of the primary therapy or of the relapse treatment. The corticoid doses did not differ from those administered to other leukaemia patients without necrosis. Only 1 patient had received prednisone continuously for 1 year, at a total dose of 20.5 g/m² of body surface area. Of these 6 children, 4 had been immobilized for several weeks before or during therapy. Two children had presented with pain-related relieving posture of the joints in which subsequently the osteonecrosis developed. Inactivity associated with the cortisone therapy seems to be an important factor in the development of aseptic osteonecroses.     

Juvenile chronic myelocytic leukemia: experience with intensive combination chemotherapy

Six children with juvenile chronic myelocytic leukemia (JCML) with adverse prognostic features were treated with intensive combination chemotherapy similar to that utilized in patients with acute nonlymphocytic leukemia (ANLL). Despite obtaining hematologic remissions after induction therapy, clinical findings of extramedullary disease persisted. The use of intensive post-induction chemotherapy did not erradicate persistent extramedullary disease, and all patients developed hematologic relapse and progressive disease at a median of 8 months. The median survival of the treated patients was 15 months. The use of intensive ANLL therapy in poor prognosis JCML does not improve the survival rates reported with less intensive regimens but does have value in producing hematologic remissions that may be useful in preparing patients for bone marrow transplant.     

Abdominal Malignant Mesothelioma Following Autologous Bone Marrow Transplantation: A Case Report

Secondary malignancies are a well-known late complication occurring in patients who undergo bone marrow transplant (BMT) during childhood. A boy with acute lymphoblastic leukemia experienced a BM relapse at the age of 14 years and underwent an autologous BMT conditioned with TBI and melphalan. Sixteen years later a malignant mesothelioma of the peritoneum was diagnosed. A surgical approach according to the Sugarbaker technique and hyperthermic peritoneal perfusion with CDDP and Adriamycin were performed. The patient is alive and well after a follow-up of 20 months. To the authors' knowledge this is the first case of mesothelioma as a secondary malignancy after BMT.     

Aseptic femur head osteonecrosis during treatment of acute lymphoblastic leukemia in the child]

Avascular femoral head necrosis (AFN) is an uncommon complication of acute lymphoblastic leukemia (ALL) occurring in association with serious functional late effects. One of the many risk factors is high-dose corticosteroid therapy. CASE REPORT: Three children belonging to a series of 266 patients developed AFN. The diagnosis was not made immediately when X-rays were normal. In spite of the fact that treatment was begun as soon as possible, the three children had a difference in the length of their legs, with reduction of their walking perimeter and, in one case, an arthroplasty was necessary. CONCLUSION: If some patients treated for ALL limp or suffer when walking or when practising sports, the diagnosis of AFN is to be evoked. The diagnosis is not only based on simple X-rays but also on magnetic resonance imaging, which is more sensitive and reveals lesions earlier. The treatment consists of immobilization of the hip, whether or not associated with surgical procedures.