Biomedical subjects

Amos Toren

Publications and source records attributed to Amos Toren.

At least 19 recordsLinked to original sources

PubMed2006

Psychological and cytokine changes in children and adolescents undergoing hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation is a therapeutic option of a large variety of diseases. It involves several physiological and psychological changes. Investigations of mood changes in patients undergoing hematopoietic stem cell transplantation are common. There are no studies however, on the relationship between changes in mood and physiological changes in hematopoietic stem cell transplantation in children and adolescents. We investigated the correlation between anxiety, depression and serum Interleukin-1beta (IL-1beta), IL-2 and IL-6. METHODS: Participants, 11 boys and 12 girls, aged 6-18 years, were administered the Children Depression Inventory (CDI) and the Spielberger State Anxiety Inventory for Children (SAIC), at four different points in time: at conditioning time when treatment is initiated (time 1 = T1), on the day of hematopoietic transplantation (T2), on the day of engraftment (T3) and a week after the engraftment (T4). At each of those times serum samples for cytokines determination were collected as well. RESULTS: Up to the time of engraftment depression and anxiety were relatively high but resolved subsequently. Globally, there was a significant time effect for anxiety (p = 0.0082). Namely, scores differ between times. Depression showed a similar trend, though this trend did not reach significance (p = 0.1394). Negative correlation was found between serum IL-1beta, IL-2 and IL-6 levels and anxiety (IL-2 and IL-6) and depression scores (IL-1beta and IL-2) at T4. The complex interaction between cytokines, depression and anxiety in children and adolescents undergoing hematopoietic stem cell transplantation merits further long-term studies under natural conditions and on laboratory models.

Adolescent↗

PubMed2006

MCP-1 in the cerebrospinal fluid of children with acute lymphoblastic leukemia.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokines. MCP-1 has been previously shown to have a major role in the migration of monocytes towards human leukemic cells, yet it cannot increase cytotoxic effects of monocytes on human leukemic cells. AIM: To determine levels of MCP-1 in the CSF of children during various stages of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A 19 children with ALL and without known CNS involvement were enrolled in the study. CSF samples were aliquoted at different stages of therapy (diagnosis, induction, and maintenance) and were frozen at -70 degrees C until use. MCP-1 was measured with a sandwich enzyme-linked immunoabsorbent assay. RESULTS: Mean MCP-1 levels in the CSF were 1762.38 pg/ml (range 522-5000 pg/ml). In children without CNS involvement at diagnosis, CSF MCP1 levels did not change over time and remained within this range throughout the diagnosis and treatment stages. CNS involvement was associated with an increased MCP-1 level following chemotherapy, in patients with CNS involvement from 840 to 3990 pg/ml (P<0.0001), and in patients without CNS involvement from 1134 to 1943 pg/ml (P-value of 0.0322). White blood cells found in the CSF at diagnosis have vanished after induction. CONCLUSIONS: CNS involvement in ALL is associated with significantly higher levels of MCP1 during therapy. This significant rise in MCP-1 levels might be one of the mechanisms involved in the regulation of CNS leukemia. Since chemokines target specific leukocyte subsets, inhibition of a single Chemokine ligand or receptor may have a circumscribed effect, endowing the inhibitor with a limited side effect profile. Chemokines should be considered as possible targets for therapeutic intervention.

Adolescent↗

PubMed2006

Human umbilical cord blood biology, transplantation and plasticity.

As the significance of hematopoietic stem cell transplantation (HSCT) is constantly rising, the scarcity of matched donors is proving to be a troubling issue. Cord blood (CB) is an important source of stem cells (SC) for transplantation. It has been used in the last two decades for approximately 4500 transplantations. Its collection, cryopreservation, banking and thawing techniques pose unique challenges to clinicians and researchers CB has abundant stem cell with impressive proliferative capacity. On the other hand, CB's immunological system has a naïve and more tolerant nature. Except for the biological aspects, few ethical issues have become a concern for transplantation teams who use CB. There are few advantages of CB over bone marrow, especially the lower rates of acute and chronic graft-versus-host disease (GVHD) after transplantation. On the other hand, there are relatively high rates of early treatment related mortality in cord blood transplantation (CBT). This is related to the small nucleated cell (NC) dose infused from each CB unit. The clinical experience in CBT, especially in children, is encouraging. When using adequate number of NC/kg, results in CBT for malignant and non-malignant diseases are comparable to bone marrow transplantation (BMT). In this article, a comprehensive review of the largest scale studies is presented. There is a continuous search for an optimal way to deal with delayed engraftment of CB and its implication. The current investigational, and also first clinical trials using diverse methods to overcome high rates of TRM are reviewed. Almost twenty years after the first CBT was preformed, many advocate for a routine parallel search, BM and CB, for unrelated donor. Future uses of CB might also be in the field of gene transfer and non hematopoietic injured tissues repair.

Bone Marrow Transplantation↗

PubMed2006

[The religious orthodox family in the pediatric hemato-oncology department].

BACKGROUND: Extensive research has been conducted on the subject of cultural influences on behaviors, attitudes, beliefs and interpersonal relations of patients in the medical world. Cancer is a life-threatening illness and the intense emotional reactions to it enhance the influence of subcultural behaviors and attitudes towards the illness, the treatments and towards the medical staff. AIMS: This paper aims to describe what happens at the encounter between the medical subculture, which is mainly secular, and the orthodox subculture, of the child treated for cancer and his family. METHOD: A support group of orthodox mothers was organized. The discussions were recorded and analyzed with "content analysis" method. This article presents the themes that evolved from the analysis, which relate to the effects of the cultural encounter. RESULTS: Themes of the discussions describe the way the child and his family cope with the illness during hospitalization and at home between hospitalizations. Specific difficulties of fathers, mothers, children and adolescents become apparent. Reference was made to the dilemma of doctor vs. Rabbi, two authorities managing the treatment process. CONCLUSIONS: When the medical staff is aware and sensitive to the unique difficulties of the orthodox child and his family, this will assist in coping with the pain of the illness. Similarly, awareness of the orthodox community and leadership to the hospital culture will also help the family in its ordeal.

Child↗

PubMed2005

Evolution of a T-B- SCID into an Omenn syndrome phenotype following parainfluenza 3 virus infection.

Mutations in both of the recombination activating genes (RAG)1 and RAG2 can lead to either T-B-severe combined immune deficiency (SCID) or Omenn syndrome (OS), two diseases presenting with totally different clinical and laboratory manifestations. The fact that the same mutations can cause either T-B- SCID or OS, even within the same family, lends credibility to the hypothesis that an additional factor (autoantigen or exoantigen) is required in certain circumstances for the development of OS phenotype. We investigated three patients from the same extended family who presented as T-B- SCID due to a homozygous mutation (G1305T) in the RAG2 gene. Our data support the notion that mutated RAG proteins may not always be sufficient to cause OS phenotype, and show evolution from a T-B- SCID into a typical OS phenotype subsequent to parainfluenza 3 virus infection.

B-Lymphocytes↗

PubMed2005

Co-existence of multiple subclones in TEL-AML1 at diagnosis of acute lymphoblastic leukaemia in association with submicroscopic deletion of AML1.

The TEL/AML1 (ETV6/RUNX1) fusion gene is the most common genetic rearrangement in paediatric acute lymphoblastic leukaemia (ALL). Although considered to be a low-risk leukaemia, it is associated with a relapse rate of 10-20%. The coexistence of different subclones at diagnosis, based on polymerase chain reaction (PCR) studies of IG/TCR gene rearrangement, with differential response to chemotherapy, was recently reported in this subtype of ALL. We wished to demonstrate such subclones at diagnosis by a recently developed technique of quantitative multiparametric fluorescence in situ hybridization (FISH). Bone marrow cells from 80 paediatric patients with ALL at diagnosis were analysed for the presence of the TEL/AML1 fusion gene by interphase FISH. Fourteen patients were positive for the translocation. Four of them had several subclones associated with various combinations of additional chromosomal abnormalities. The most striking was an atypical and unexpected hybridization pattern consistent with a submicroscopic deletion of the 5' region of the AML1 breakpoint. Other abnormalities included TEL deletion, trisomy and tetrasomy 21 as well as double TEL-AML1 fusion. The presence of numerous subclones in about 25% of patients with TEL/AML1+ ALL suggests extensive clonal evolution by the time of diagnosis.

Bone Marrow Cells↗

PubMed2005

CD133-positive hematopoietic stem cell "stemness" genes contain many genes mutated or abnormally expressed in leukemia.

Affymetrix human Hu133A oligonucleotide arrays were used to study the expression profile of CD133+ cord blood (CB) and peripheral blood (PB) using CD133 cell-surface marker. An unsupervised hierarchical clustering of 14,025 valid probe sets showed a clear distinction between the CD133+ cells representing the hematopoietic stem cell (HSC) population and CD133-differentiated cells. Two hundred forty-four genes were found to be upregulated by at least twofold in the CD133-positive cells of both CB and PB compared with the CD133-negative cells. These genes represent the hematopoietic "stemness," whereas the 218 and 304 upregulated genes exclusively in PB and CB, respectively, represent tissue specificity. Some of the stemness genes were also common to HSC genes found to be upregulated in several recently published studies. Among these common stemness genes, we identified several groups of genes that have an important role in hematopoiesis: growth factor receptors, transcription factors, genes that have an important role in development, and genes involved in cell growth. Sixteen selected stemness genes are known to be mutated or abnormally regulated in acute leukemias. It can be suggested that key hematopoietic stemness machinery genes may lead to abnormal proliferation and leukemia upon mutation or change of their expression.

AC133 Antigen↗

PubMed2005

Epidermal growth factor receptor gene amplification and expression in disseminated pediatric low-grade gliomas.

OBJECT: Pediatric low-grade gliomas (LGGs) are the largest group of central nervous system neoplasms in children. Although these tumors are generally benign, 5 to 10% of patients with pediatric LGGs present with leptomeningeal dissemination. The genetic and biological nature of these tumors is poorly understood. The authors looked for certain molecular abnormalities that may differentiate disseminated gliomas from the other pediatric LGGs. METHODS: Comparative genomic hybridization (CGH) was applied to 18 pediatric LGGs. Six cases featuring disseminated pediatric LGGs were compared with 12 control cases involving nondisseminated pediatric LGGs. Fluorescence in situ hybridization (FISH) analysis and immunohistochemical analysis were used to highlight further specific genetic targets. The CGH revealed multiple chromosomal abnormalities in five of six cases with disseminated gliomas and in six of 12 control cases. No correlation was found between the number of chromosomal abnormalities and dissemination status. Amplification of chromosome 7 was noted in four of six cases with disseminated gliomas as opposed to one of 12 control cases (p = 0.02). The FISH analysis revealed epidermal growth factor receptor (EGFR) amplification in one case negative to chromosome 7 amplification by CGH, raising the amplification cases to five of six (p = 0.0038). Immunohistochemical analysis for EGFR was positive in six of six cases and in two of 12 control cases (p = 0.0015). At the end of a mean follow-up period of 7.2 years, all patients with disseminated gliomas are alive with variable but slow disease progression. CONCLUSIONS: The high rate of EGFR gene amplification and protein expression in disseminated pediatric LGGs is intriguing and may have implications for our understanding of the role of EGFR in glioma genesis. Targeted therapies may be available for these children. Larger-scale studies are needed to establish further these findings.

Central Nervous System Neoplasms↗

PubMed2004

Design principle of gene expression used by human stem cells: implication for pluripotency.

Human embryonic stem cells (ESC) are undifferentiated and are endowed with the capacities of self-renewal and pluripotential differentiation. Adult stem cells renew their own tissue, but whether they can transdifferentiate to other tissues is still controversial. To understand the genetic program that underlies the pluripotency of stem cells, we compared the transcription profile of ESC with that of progenitor/stem cells of human hematopoietic and keratinocytic origins, along with their mature cells to be viewed as snapshots along tissue differentiation. ESC gene profiles show higher complexity with significantly more highly expressed genes than adult cells. We hypothesize that ESC use a strategy of expressing genes that represent various differentiation pathways and selection of only a few for continuous expression upon differentiation to a particular target. Such a strategy may be necessary for the pluripotency of ESC. The progenitors of either hematopoietic or keratinocytic cells also follow the same design principle. Using advanced clustering, we show that many of the ESC expressed genes are turned off in the progenitors/stem cells followed by a further down-regulation in adult tissues. Concomitantly, genes specific to the target tissue are up-regulated toward mature cells of skin or blood.

Cell Differentiation↗

PubMed2004

Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia.

BACKGROUND: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the reduced folate carrier (RFC). Impaired drug transport is a documented mechanism of MTX resistance in patients with ALL; however, to the authors' knowledge it is not known whether inactivating RFC mutations are a contributing factor. METHODS: The authors devised a genomic polymerase chain reaction-single strand conformational polymorphism assay followed by sequencing and screened the entire RFC coding region for sequence alterations in DNA from 246 leukemia specimens from patients with diverse ethnic variation, 24 at the time of recurrence and the rest at the time of diagnosis. This cohort was comprised of 203 B-precursor ALL specimens (82.5%), 32 T-lineage ALL specimens (13%), and 11 acute myeloblastic leukemia specimens (4.5%). RESULTS: Of 246 DNA samples, only 3 diagnosis B-precursor ALL specimens (1.2%) were found to harbor alterations in the RFC gene, including heterozygous single nucleotide changes resulting in D56H and D522N substitutions in the first extracellular loop and the C-terminus of this transporter, respectively. The third sample had a sequence alteration in exon 3 that could not be identified because of the lack of availability of DNA. CONCLUSIONS: Whereas inactivating RFC mutations are a frequent mechanism of MTX resistance in human leukemia cell lines and in patients with osteosarcoma, they are not common and do not appear to play any significant role in intrinsic or acquired resistance to MTX in childhood leukemia. This is the first study of RFC mutations in multiple pediatric leukemia specimens.

Antimetabolites, Antineoplastic↗

PubMed2004

Favorable early response of secondary chronic myeloid leukemia to imatinib.

Second malignant neoplasms are gradually becoming a recognized long-term complication of successful cancer treatment, and they usually respond poorly to conventional therapy and have an unfavorable outcome. Chronic myeloid leukemia (CML) is a clonal panmyelopathy, rarely seen in children with a specific cytogenetic aberration-the Philadelphia chromosome. The translocation generates an aberrant tyrosine kinase, which drives the malignant process in CML and which is also the molecular target for successful treatment of CML with imatinib. It is also exceedingly rare as a secondary malignant neoplasm in both adults and children. We report two cases of secondary CML. The first occurred after successful treatment for nasopharyngeal carcinoma in a child, and the second after treatment for lymphoma in an adolescent. Both patients had an excellent response to treatment with imatinib and attained complete cytogenetic remissions. We conclude that secondary CML may respond favorably to treatment with imatinib.

Adolescent↗

PubMed2004

Successful umbilical cord blood transplantation for Fanconi anemia using preimplantation genetic diagnosis for HLA-matched donor.

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, and a high incidence of myelodysplasia and acute myeloid leukemia. Stem cell transplantation is the only curative treatment. In the absence of matched- sibling donor, an alternative mismatched family or matched unrelated donor can be used, but the results are inferior to the matched-sibling transplant and carry a high risk of morbidity and mortality. Preimplantation genetic diagnosis (PGD) has been increasingly used in recent years for mutation analysis for many genetic disorders and results in the birth of healthy children, saving the need for the termination of pregnancy of an affected embryo. The use of PGD for combined analysis of mutation and HLA-matching was reported for the first time in 2001. This enables the birth of an unaffected child who can serve as a donor for an affected sibling in need for stem cell transplantation. We report successful cord blood transplantation for a Fanconi anemia patient from his HLA-matched sibling, born after PGD that included mutation analysis for Fanconi anemia and HLA typing. PGD can provide an unaffected donor for a sibling affected by genetic disease in the absence of a compatible related donor.

Blood Donors↗

PubMed2004

Risk of venous thromboembolism in pediatric patients with brain tumors.

BACKGROUND: Venous thromboembolism (VTE) is a common event in adults with malignant brain tumors approaching 24% throughout the course of the disease. The high morbidity and mortality of this complication yielded several protocols for prevention of the disease in adults undergoing neurosurgery for brain tumors and possible primary prevention afterwards. We investigated the incidence and complications of VTE in pediatric neuro-oncology patients. PROCEDURE: We analyzed, retrospectively, the files of all consecutive patients under the age of 18 years who were hospitalized for the treatment of brain tumors between the years 1990 and 2003 in two leading, closely related, Israeli neuro-oncology centers. RESULTS: A total of 462 children were analyzed. Three hundred eighty-four patients underwent surgery and 78 were treated medically. Only three (0.64%) of the patients developed clinical episodes of VTE that were treated conservatively. Two of these patients developed intracranial bleeding while on secondary prevention for the disease. CONCLUSIONS: Although this study has considerable limitations in terms of retrospective design, heterogeneous group of patients and diagnoses, the changing awareness for thrombosis over the last 14 years and the inclusion of symptomatic VTE events only, our surprising data suggest that, as opposed to adults, the risk of clinically significant VTE in children with brain tumors may be exceedingly low. These findings set the stage for future forthcoming evaluations in view of the prospective studies that were done in adults and the possible significant implications for the prevention and possible etiologies of the disease.

Brain Neoplasms↗

PubMed2004

Karyotypic evolution pathways in medulloblastoma/primitive neuroectodermal tumor determined with a combination of spectral karyotyping, G-banding, and fluorescence in situ hybridization.

Medulloblastomas (MBs) or primitive neuroectodermal tumors (PNETs) represent 15%-30% of pediatric brain tumors and are the most common brain tumors in children; they are rare in adults. Classification of these tumors is based on tissue morphology and is often controversial and problematic. Karyotypic analysis of these tumors using conventional cytogenetic methods is often a difficult process that may be hindered by a limited number of metaphase cells and poor chromosome morphology, often leading to only partial characterization of the chromosomal abnormalities. We investigated three primary human tumors and four cell lines (CHO-707, DAOY, D-341, and PFSK) utilizing a combination of conventional G-banding, spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH) techniques. A high level of intratumoral heterogeneity was seen, with multiple numerical and structural chromosomal aberrations. The chromosomes most frequently involved in structural aberrations were chromosomes 1 (14 rearrangements), 7 (9 rearrangements), and 21 (9 rearrangements). The chromosomes most frequently involved in numerical aberrations were chromosomes 1, 12, and 13 (four cases) and chromosomes 14, 17, 19, 21, 22, and X (three cases). Numerous aberrant chromosomes were characterized only with the SKY analysis, and based on these findings multiple clones were identified, facilitating analysis of karyotypic evolution. The most frequent evolution mechanism was via polyploidization, followed by acquisition of additional numerical or structural aberrations (or both); however, the results showed that the karyotypic evolution process in these tumors is typically divergent and complex.

Adult↗

PubMed2004

Psychiatric morbidity and quality of life in children with malignancies and their parents.

Recent improvements in prognosis necessitate considering the emotional responses of children with malignant diseases and of their parents. This prospective study assessed 20 children and adolescents and their 36 parents within 2 weeks of diagnosis and after 1 and 6 months. Fifty-three percent exhibited moderate to severe posttraumatic symptoms right after diagnosis that decreased significantly after 1 month. Children with high-risk disease reported the most severe symptoms. Unexpectedly, children with low-risk disease exhibited more severe symptoms than those with moderate risk. Depressive symptoms decreased significantly during the period, but anxiety symptoms did not. Moreover, quality of life did not change. Twenty percent of parents exhibited posttraumatic symptoms on initial evaluation. Mothers' symptoms did not change, but fathers' symptoms decreased with those of their children. Several procedures and experiences were identified as causes of traumatic stress responses.

Adolescent↗

PubMed2004

Paediatric cerebral sinus vein thrombosis. A multi-center, case-controlled study.

The etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians' decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.

Adolescent↗

PubMed2003

MYH9 spectrum of autosomal-dominant giant platelet syndromes: unexpected association with fibulin-1 variant-D inactivation.

The autosomal-dominant giant platelet syndromes (Fechtner, Epstein, and Sebastian platelet syndromes and May-Hegglin anomaly) represent a group of disorders characterized by variable degrees of macrothrombocytopenia with further combinations of neutrophil inclusion bodies and Alport-like syndrome manifestations, namely, deafness, renal disease, and eye abnormalities. The disease-causing gene of these giant platelet syndromes was previously mapped by us to chromosome 22. Following their successful mapping, these syndromes were shown to represent a broad phenotypic spectrum of disorders caused by different mutations in the nonmuscle myosin heavy chain 9 gene (MYH9). In this study, we examined the potential role of another gene, fibulin-1, encoding an extracellular matrix protein as a disease modifier. Eight unrelated families with autosomal-dominant giant platelet syndromes were studied for DNA sequence mutations and expression of the four fibulin-1 splice variants (A-D). A mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family, whereas no MYH9 mutations were identified. Unexpectedly, fibulin-1 variant D expression was absent in affected individuals from all eight families and coupled with expression of a putative antisense RNA. Transfection of the putative antisense RNA into H1299 cells abolished variant D expression. Based on the observation that only affected individuals lack variant D expression and demonstrate antisense RNA overexpression, we suggest that these autosomal-dominant giant platelet syndromes are associated, and may be modified, by aberrant antisense gene regulation of the fibulin-1 gene.

Base Sequence↗

PubMed2003

Intravenous busulfan-based conditioning prior to allogeneic hematopoietic stem cell transplantation: myeloablation with reduced toxicity.

OBJECTIVE: Allogeneic transplantation is a potentially curative treatment for hematologic malignancies but is associated with a high rate of complications. Busulfan is a common component of pretransplant conditioning but has an erratic and unpredictable bioavailability when administered orally. Intravenous (IV) busulfan was recently introduced into clinical practice. Prior studies showed consistent and predictable drug delivery with tight control of busulfan plasma levels, avoiding over- and under-dosing. This study was designed to define the role of IV busulfan in different transplant and disease settings. PATIENTS AND METHODS: The study included 43 patients with various hematologic malignancies conditioned with high-dose IV busulfan-containing regimens prior to allogeneic transplantation. The donors were HLA-matched siblings (n=24), matched unrelated (n=14), or 1-antigen mismatched related donors (n=5). Outcome parameters were recorded. RESULTS: Forty-two patients had initial engraftment. The toxicity profile was favorable. No patient developed veno-occlusive disease of the liver. Acute graft-vs-host disease (GVHD) grades II-IV occurred in 18 patients (42%). Six patients died of treatment-related causes, five of complications related to acute GVHD, and only one died of organ toxicity. Actuarial non-relapse-related mortality risk was 10% at day 100 and 18% at 2 years posttransplant. The actuarial 2-year overall survival and disease-free survival (DFS) rates were 63% and 44%, respectively. Disease status other than refractory relapse, myeloid disease, and no severe GVHD posttransplant predicted for longer DFS in a multivariant model. CONCLUSIONS: IV busulfan-containing regimens allow consistent engraftment of allografts from related and unrelated donors such that myeloablation is administered with a toxicity profile typical of non-myeloablative conditioning. Favorable outcome was seen in patients with myeloid leukemias and in early or intermediately advanced disease; however, this regimen may not be sufficiently cytoreductive in patients with very advanced or active leukemia and in acute lymphoblastic leukemia. IV busulfan merits further study to better define its role as a preferred substitute for oral busulfan in pretransplant conditioning.

Adolescent↗