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PubMed2002

Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies.

Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation between SPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.

Antibodies, Neoplasm↗

PubMed2002

Positive selection of CD34+ cells by immunoadsorption: factors affecting the final yield and hematopoietic recovery in patients with hematological malignancies and solid tumors.

There is a progressive increase in the use of selected hematopoietic progenitor cells after myeloablative therapy in patients affected by malignancies. Our goal was to determine which blood parameters, in the starting cell population, influence the concentration of CD34+ progenitors and the removal of unwanted cells in the final product. Also, we evaluated the hematopoietic recovery and toxicity associated with peripheral blood stem cell infusion. We retrospectively reviewed 53 procedures of positive selection of CD34+ cells, performed with the Ceprate SC immunoadsorption system, in 47 paticnts affected by various hematologic malignancies and solid tumors. An increased percentage of CD34+ cells in the starting fraction was associated both with the final purity and enrichment of CD34+ cells and with a decreased percentage of CD3+ and CD19+ cells in the final product. A low platelet count before selection had a borderlinc influence on the recovery of CD34+ cells. Forty patients received a median of 5 x 10(6) CD34+ cells per kg; the absolute neutrophil count (ANC) reached 0.5 x 10(9)/l in a median of 10 days whereas a PLT count above 20 x 10(9)/l was observed in 14 days. The reinfusion of selected CD34+ cells, containing a very low amount of dymethylsulfoxide. was well tolerated and no adverse reactions were observed. Autologous transplantation with selected CD34+ cells is a safe and well-tolerated procedure in patients affected by hematologic malignancies and solid tumors. Positive selection of CD34+ cells seems to be related to the quality of the apheresis products, particularly to the initial CD34+ cell and PLT content.

Antigens, CD34↗

PubMed2000

Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies.

Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.

Adult↗

PubMed1996

p16ink4a gene and hematological malignancies.

Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of regulators, the cyclin-dependent CDKkinases (CDKs). Recent studies have identified different CDK inhibitory genes (CDKis), and two of them, p16ink4a/MTS1/CDKN2 and p15ink4b/MTS2 are both mapped to chromosome 9p21 and inhibit cyclin D-CDK4 and -CDK6 complexes. A feedback regulatory loop involving pRb, p16ink4a, and CDKs seems to regulate G1/S phases transition. p16ink4a and p15ink4b are deleted in high frequency in human cell lines and in some fresh solid tumors. Point mutations of p16ink4a have also been sequenced, especially in familial melanomas and digestive cancers but preferential mechanism of p16ink4a/p15ink4b inactivation seems to be biallelic deletion. In hematological malignancies, homozygous deletions of p16ink4a and p15ink4b occur frequently in acute lymphoblastic leukemia (ALL) (14-40%), lymphoid type blast crisis of chronic myeloid leukemia (CML), and adult T cell leukemia (ATL), but p16ink4a deletions are more frequent than p15ink4b deletions, and hemizygous deletions of either p16ink4a and p15ink4b are rare. In ALL an association of homozygous deletions of p16ink4a and p15ink4b, and T-lineage, 9p abnormalities, and prognostic factors was found in some but not all reports. This review presents recent data on p16ink4a and p15ink4b functions and analyses their implications in hematological malignancies.

Adult↗

PubMed2006

Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells.

Proteasomal proteolysis relies on the activity of six catalytically active proteasomal subunits (beta1, beta2, beta5, beta1i, beta2i and beta5i). Applying a functional proteomics approach, we used a recently developed activity-based, cell-permeable proteasome-specific probe that for the first time allows differential visualization of individual active proteasomal subunits in intact primary cells. In primary leukemia samples, we observed remarkable variability in the amounts of active beta1/1i-, beta2/2i- and beta5/5i-type of subunits, contrasting with their constant protein expression. Bortezomib inhibited beta5- and beta1-type, but to a lesser extend beta2-type of subunits in live primary cells in vitro and in vivo. When we adapted the bortezomib-sensitive human acute myeloid leukemia cell line HL-60 to bortezomib 40 nM (HL-60a), proteasomal activity profiling revealed an upregulation of active subunits, and residual beta1/beta5-type of activity could be visualized in the presence of bortezomib 20 nM, in contrast to control cells. In a panel of cell lines from hematologic malignancies, the ratio between beta2-type and (beta1 + beta5)-type of active proteasomal polypeptides mirrored different degrees of bortezomib sensitivity. We thus conclude that the proteasomal activity profile varies in primary leukemia cells, and that the pattern of proteasomal subunit activity influences the sensitivity of hematologic malignancies toward bortezomib.

Animals↗

PubMed1998

[Quantitative analysis of multidrug resistance phenotype in hematological malignancies].

Cells with multidrug resistance (MDR) phenotype express P-glycoprotein (P-gp) on the cell membrane, which functions as a drug-efflux pump. To quantify the expression of the gene encoding P-gp (multidrug resistance 1; MDR1) and assess P-gp function, we developed competitive reverse transcription-polymerase chain reaction (RT-PCR) assay using heterologous competitor RNA and flow cytometric analysis using rhodamine 123 (Rh123; an artificial substrate for P-gp), respectively. First, we adjusted the assays by analyzing leukemia sublines showing various levels of MDR1 expression. The MDR1 expression in leukemia sublines quantified by competitive RT-PCR assay showed linearity over a wide range, and the results were parallel with those of MDR1 expression measured by Northern blot analysis, the P-gp antigen expression measured by flow cytometric analysis using MRK16, P-gp function analysis by Rh123 dye-efflux assay, and MDR phenotype. Then, we applied these assays to leukemic cells from patients with hematological malignancies. All 69 samples from 64 patients were successfully assayed, and the range of MDR1 expression was from 1.6 to 100 amol/microgram RNA. Since subpopulations of normal lymphocytes show a low degree of P-gp function, strict gating of leukemia cells was mandatory for dye-efflux assay of clinical samples. MDR1 expression in normal lymphocytes was below 8 amol/microgram RNA. By comparison to MDR1 expression quantified by competitive RT-PCR assay with P-gp function assessed by Rh123 dye-efflux assay in gated leukemic cells, more than 8 amol/microgram RNA was regarded as positive MDR1 expression in the leukemic cells themselves. These data suggest that these assays are suitable for evaluating P-gp expression and function in clinical samples when the proper cut-off value is used and may provide insights into the contribution of P-gp to drug resistance in hematological malignancies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies.

Over the last decade, major advances have been made in the elucidation of mechanisms involved in leukemogenesis, and this is particularly true with regard to deregulated protein tyrosine kinase (PTK) activation. This progress had led to the development of small molecules that specifically inhibit the abnormally activated kinase. The first example of such targeted therapy is imatinib-mesylate, an inhibitor of the BCR-ABL fusion gene that is found in more than 90% of patients with Philadelphia positive (Ph+) chronic myeloid leukemia (CML) and in 20-30% of those with Ph+ acute lymphoblastic leukemia (ALL). The excellent clinical results obtained with imatinib in CML have completely changed the therapeutic approach to this disease, and imatinib is now the gold standard for treatment of newly diagnosed CML. This has instigated a tremendous effort to develop targeted PTK therapy based on the presence of over 40 chromosomal translocations that lead to deregulation of 12 different PTK associated with various hematologic malignancies. That deregulated PTK are also involved in the pathogenesis of acute leukemia is underlined by the frequent occurrence of mutations leading to constitutive activation of the FLT3. Experimental as well as clinical evidence supports a model of acute leukemia based on the co-operation of constitutive active PTK with mutations of transcriptional regulators. Here we review the general impact of mutated PTK on the pathogenesis of various hematologic malignancies. We also discuss the development of new targeted therapies and strategies to circumvent the increasing problems related to the emergence of drug resistance by targeting downstream signaling mediators that are essential for transformation by deregulated PTK.

Animals↗

PubMed1982

Malignant hematologic disorders in two Robertsonian 13;14 translocation carriers.

Two patients with a malignant hematologic disorder appeared to carry a constitutional Robertsonian 13;14 translocation. The presence of this translocation in relation to hematologic diseases is discussed. No conclusion can be made at present on the observed association. The translocation might predispose to malignant transformation, but its presence might also be purely coincidental.

Anemia↗

PubMed1998

Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation.

Cyclin A is a cell cycle regulatory protein that functions in mitotic and S phase control in mammalian cells. However, in contrast to other G1 phase regulatory proteins, such as cyclin D, retinoblastoma protein and p16INK4A, cyclin A seems not to be commonly involved in tumorigenesis. Recently, a second human cyclin A--cyclin A1--has been identified. In contrast to cyclin A which is expressed throughout embryonic development and in adult tissue, the expression of cyclin A1 has been reported to be restricted to embryonic and germ line cells. We have confirmed the absence of cyclin A1 mRNA from normal peripheral blood leukocytes of seven healthy donors by single step reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, we have examined the expression of cyclin A1 mRNA in 173 peripheral blood samples of 162 patients with various hematological malignancies. Cyclin A1 mRNA was detectable in 11 of 11 patients with acute myeloid leukemia, three of three patients with acute biphenotypic leukemia, eight of eight patients with myelodysplastic syndrome, 59 of 69 patients with chronic myelogenous leukemia (CML) at diagnosis, 13 of 15 patients with CML in blastic transformation, 10 of 18 patients with chronic lymphocytic leukemia, two of nine patients with essential thrombocythemia, and only two of 10 patients with acute lymphoblastic leukemia (ALL) with both cyclin A1 RT-PCR positive ALL leukemias being undifferentiated relapses. In addition, cyclin A1 mRNA was found in one of six leukapheresis products, harvested from individuals without hematological disorders. Taken together, cyclin A1 is expressed in the majority of myeloid and undifferentiated hematological malignancies as well as in normal hematopoietic progenitor cells. We conclude that cyclin A1, a protein potentially involved in G1/S phase progression of immature cells, might be necessary for proliferation of early hematopoietic progenitor cells and their leukemic counterparts being blocked at that stage of differentiation.

Cell Cycle↗

PubMed1995

Membrane-bound/soluble IL-2 receptor (IL-2R) and levels of IL-1 alpha, IL-2, and IL-6 in the serum and in the PBMC culture supernatants from 17 patients with hematological malignancies.

The present study investigated the peripheral blood mononuclear cells (PBMC) blastic responses to PHA, PHA plus recombinant IL-2 (rIL-2) and rIL-2 alone; the expression of membrane-bound IL-2R on PHA-stimulated PBMC; and the levels of IL-1 alpha, IL-2, IL-6, and sIL-2R in serum and in culture supernatants from PHA-stimulated PBMC in 17 patients with with non-Hodgkin's lymphoma (NHL), 4 with Hodgkin's lymphoma (HL), 5 with Hairy cell leukemia, 1 with chronic myelogenous leukemia, and 1 with chronic lymphocytic leukemia. The patients with HL and NHL with active disease (AD) were separated from those in clinical remission. The patients with AD were studied at diagnosis (obviously before therapy) and the patients in clinical remission were out of therapy since at least 6 mo. The lymphocyte blastogenic response to PHA was significantly lower in patients with HL and NHL with AD than in the control group. The response to rIL-2 alone was in the same range in the control group and in HL and NHL AD patients. By adding rIL-2 to PHA there was an increase of the blastogenic response of the same patients. The percentage of CD25 expressed on PHA-stimulated lymphocytes from patients with HL and NHL AD and from normal subjects is in the same range. Serum levels of IL-2, IL-6, and sIL-2R were significantly higher in HL and NHL AD patients than in controls as well as in all other hematological malignancies. Supernatants derived from PHA-stimulated PBMC were assessed for the presence of cytokines and sIL-2R by ELISA. The levels of IL-2, IL-6, and sIL-2R were significantly lower in HL and NHL AD patients than in controls as well as in all other hematological malignancies.

Adult↗

PubMed2002

Invasive Aspergillus infections in hematologic malignancy patients.

The incidence of invasive Aspergillus (IA) infections in patients with hematologic malignancies continues to increase. The most common species include Aspergillus fumigatus (approximately 90% of cases), A. flavus, A. niger, A. terreus, and A. nidulans. Most infections involve the pulmonary parenchyma, though systemic dissemination of the fungus from a primary pulmonary focus or the paranasal sinuses after hyphal invasion into blood vessels is frequent. Early diagnosis and initiation of appropriate antifungal therapy has been shown to improve the prognosis of patients afflicted with this condition. The definitive diagnosis of IA is based on showing the hyphal invasion in tissue specimens together with a positive culture for Aspergillus species from the same specimen. The detection of circulating fungal antigens and DNA seems to be a promising, rapid, and sensitive diagnostic tool for early diagnosis of aspergillosis. The current antifungals available for the treatment of IA include amphotericin B deoxycholate and lipid formulations, itraconazole and caspofungin acetate. New investigational antifungal drugs include the triazoles voriconazole, posaconazole and ravuconazole, liposomal nystatin, and 2 echinocandin derivatives (anidulafungin [VER-002] and micafungin [FK463]). Preventive measures include reduction of environmental exposure of patients from sources of infection and anti-fungal prophylaxis. Specialized air-handling systems capable of excluding Aspergillus spores, such as high-efficiency particulate air (HEPA) filtration with or without laminar air flow ventilation has proven to be very efficacious. Targeted antifungal prophylaxis for hematologic patients who are at high risk for developing invasive fungal infections is not currently standardized.

Antifungal Agents↗

PubMedDate not supplied

Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.

BACKGROUND: Patients with hematologic malignancies in relapse after allogeneic bone marrow transplantation can be treated by infusing leukocytes from the original stem cell donor. METHODS: The published literature on donor lymphocyte infusion (DLI) was reviewed. RESULTS: DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response. CONCLUSIONS: Novel methods of augmenting the antitumor efficacy of DLI and of dissociating the graft-vs-leukemia effect from GVHD are needed. These studies will require an improved understanding of the cellular and molecular mechanisms of alloreactivity and the development of novel agents to control the nature and intensity of the alloimmune response.

Blood Transfusion↗

PubMed1998

Management of patients with hematologic malignancies and aplastic anemia who are refractory to platelet transfusions.

Patients with hematologic malignancies or aplastic anemia may have reduced responses to platelet transfusions after multiple transfusions of standard red blood cells or platelet components. This situation, conventionally described as 'refractoriness' to platelet transfusions, may result from immune or non-immune causes. Non-immune causes include fever, infections, hypersplenism, disseminated intravascular coagulation, antibiotics, or veno-occlusive disease. Immune causes include platelet-reactive alloantibodies, which are typically antibodies to human leukocyte antigens (HLA) or, less commonly, antibodies to human platelet antigens (HPA). Transfused HLA-matched platelets often have satisfactory posttransfusion survivals, but few transfusion services have the donor and logistical resources to sustain a prolonged course of platelet transfusions requiring four-antigen matches. The availability of commercially marketed kits for crossmatching samples of potential donors' platelets with a recipient's serum has facilitated donor-recipient matching. Also, platelet crossmatching may be used to select a suitable unit of from several candidates platelets that have been identified to be partial HLA matches. The high likelihood of decreased efficacy of platelet transfusions in HLA-alloimmunized recipients makes avoidance of exposure to HLA-bearing leukocytes a priority. This goal is facilitated by lowering transfusion 'triggers' for cellular blood components, particularly for prophylactic platelet transfusions, by reducing the leukocyte content of components by leukocyte-reduction filters and, possibly by ultraviolet-B irradiation of leukocyte-containing products.

Anemia, Aplastic↗

PubMed1998

Derivative chromosomes of 11q23-translocations in hematologic malignancies. European 11q23 Workshop participants.

Cytogenetic and molecular analyses of 11q23/MLL positive hematologic malignancies show that der(11) encodes the critical 5'MLL/3'partner gene transcript. The role of der(non-11) bearing the 5'partner/3'MLL fusion is less certain. The cytogenetic evidence for der(11) as the critical partner was investigated. Among 1680 cases (550 workshop and 1130 published) 31 cases displayed a three-way (29 cases) or four-way (two cases) translocation and 26 had only one of the derivatives. The critical junction created by t(11;n)(q23;n) was seen in all six cases of t(1;11)(q21;q23), in both cases of t(6;11)(q27;q23), in all six cases of t(11;19)(q23;p13), in nine of 11 cases with t(4;11)(q21;q23) and in 17 of 20 cases with t(9;11)(p21-22;q23). These findings support the evidence for der(11) encoding the critical leukemogenic fusion transcript. In contrast, additional change involving duplication of one of the derivatives resulted in duplication only of the non-critical der(non-11) as follows: +der(4)t(4;11)(q21;q23) [9/553], +der(6)t(6;11)(q27;q23) [3/61], +der(9)t(9;11)(p21-22;q23) [5/291] and +der(19)t(11;19)(q23;p13) [6/164]. A literature search of other neoplastic disorders showed that either derivative may be duplicated. Duplication of the non-critical derivative is the norm in AML patients with t(8;21)(q22;q22) or t(15;17)(q22;q12-21). We suggest that the genomic imbalance, rather than over-expression of the noncritical 5'partner/3'MLL, is likely to be the important outcome.

Chromosome Aberrations↗

PubMed1984

Clostridium difficile. Colonization and toxin production in a cohort of patients with malignant hematologic disorders.

We examined 45 (80%) of 56 consecutive adult patients with malignant hematologic disorders who were hospitalized during a 15-week period at Emory University Hospital, Atlanta. Stool samples for Clostridium difficile culture and cytotoxin assay were obtained on admission and then weekly during each patient's hospitalization. On admission, four patients had detectable C difficile in their stool samples, which was associated with prior antimicrobial use but not with prior cancer chemotherapy. One of the four patients with positive stool samples also had toxin present in the stool sample and was the only one with diarrhea. Eight (36%) of 22 patients hospitalized for one or more weeks had C difficile isolated from at least one stool specimen. The positive cultures showed no clustering in time, and no risk factors were identified for colonization. Only seven of 15 culture-positive stool samples and three of seven toxin-positive samples were associated with diarrhea.

Adult↗

PubMed1992

Serum erythropoietin titers in hematological malignancies and related diseases.

Serum erythropoietin (Epo) titers in patients with various hematological malignancies and related diseases were determined by radioimmunoassay. Serum Epo titer was inversely correlated with hemoglobin concentration in iron deficiency anemia, aplastic anemia, myelodysplastic syndromes (MDS), acute leukemia, malignant lymphoma, multiple myeloma and myelofibrosis, but there was no correlation between serum Epo titer and hemoglobin concentration in chronic myelogenous leukemia or polycythemias. Serum Epo titers in aplastic anemia were much higher than those in iron deficiency anemia. Serum Epo titers in MDS, malignant lymphoma and multiple myeloma differed considerably among patients. Serum Epo titers in untreated polycythemia vera were significantly lower than in treated polycythemia vera or secondary polycythemia.

Anemia↗

PubMed1999

Novel biologic approaches to hematologic malignancies.

Biologic agents have made a major impact on the treatment of hematologic malignancies and will continue to play a major role as we better understand their function in normal and malignant cell regulation. The examples provided in this chapter are a brief introduction to the potential of these agents. Many have yet to be used in conjunction with current cytotoxic therapy in these diseases, and perhaps combinations will prove even more successful. This possibility provides substantial ground for further investigation and therapy.

Bone Marrow Transplantation↗

PubMed1997

Molecular cytogenetics of childhood hematological malignancies.

Cytogenetic and molecular analyses are essential for the classification of childhood hematologic malignancies. Nearly all children with leukemia should have an adequate cytogenetic analysis which in 80-90% is expected to show clonal chromosomal abnormalities. Moreover, with the availability of appropriate gene probes and sophisticated molecular techniques, genetic rearrangements become detectable in the majority of leukemia patients. Genetic abnormalities often associate with particular clinical-biological characteristics of the disease. In ALL, for example, genetic alterations together with distinct immunologic and clinical features, define various subgroups. In AML, unique cytogenetic rearrangements have been identified and associated with distinct morphological subgroups. Apart from the diagnostic assessment, cytogenetic studies provide valuable prognostic information which may influence treatment choices. Molecular analysis has also become of important value in the management of children with leukemias, as it serves, for example, to identify genetic abnormalities not detected by chromosomal analysis and to monitor residual disease during treatment and follow-up. Thus, genetic analyses of leukemic cells provide information of clinical relevance as well as contributing to our understanding of leukemogenesis. Alternative classifications of acute leukemias which take into account genetic information are being proposed. The available cytogenetic and molecular data have then to be included in clinical protocols, either by selecting individualized therapies in certain leukemia subtypes or by modifying treatment according to quantification of residual disease. We are closer to our main goal which is not only to classify 100% of childhood leukemias accurately, but to cure all of them.

Child↗