Acute lymphocytic leukemia-associated cell membrane antigen.

Antisera were raised in New Zealand White rabbits against non-B, non-T acute lymphocytic leukemia (ALL) cells coated with antilymphocyte serum. Following minimal absorption with chronic lymphocytic leukemia (CLL) cells, the antiserum reacted mainly with non-B, non-T ALL cells. The following numbers of patients had leukemia cells that reacted with the ALL antisera: 13 of 18 with ALL, 3 of 27 with acute myelocytic leukemia, 1 of 8 with chronic myelocytic leukemia (CML), and 0 of 12 with CLL. The positive CML was a patient in CML blast crisis. Normal peripheral blood B- and T-lymphocytes and normal bone marrow were negative. Reactions of the anti-ALL serum (136K) were compared with the reactions of a rabbit anti-B-cell antiserum (63K) that reacted with approximately 70% of leukemia cells. Cultured lymphoblastoid cell lines from normal donors were negative by both cytotoxicity and immunofluorescence tests. However, by immunofluorescence testing, 8 of 17 known malignant lines from a variety of lymphoproliferative disorders were positive; 4 of these lines were of T-cell origin. By immunoprecipitation and polyacrylamide gel electrophoresis, the ALL antigen appeared to consist of a single polypeptide chain of approximately 98,000 daltons. The anti-ALL antiserum was not cytotoxic for normal myeloid stem cells (colony-forming units).     

Lymphoblasts with T-cell markers in five girls with acute lymphocytic leukemia.

In previous reports, children with acute lymphoblastic leukemia (ALL), who presented with T-cell markers on their lymphoblasts (T-lymphoblasts), have been predominantly older boys often with a mediastinal mass. These children are thought to constitute a subgroup of childhood ALL that has the poorest prognosis. Here, we report five girls with ALL, who presented with T-lymphoblasts but without a mediastinal mass. All responded well to chemotherapy and three of five are in maintained remission 21-33 months after diagnosis. The fourth patient died while in remission of causes other than leukemia and the fifth relapsed and died of infection two years after diagnosis. These observations suggest that girls with T-lymphoblasts may not have an adverse prognosis.     

Pattern of subtypes of acute lymphoblastic leukemia in India

Leukemic cells from 124 acute lymphoblastic leukemia (ALL) and 31 chronic lymphatic leukemia (CLL) were examined for sheep erythrocyte receptor (E), surface immunoglobulin (SIg) and their reactivity with a panel of monoclonal antibodies recognizing specific surface antigens including pan-T, Common ALL and Ia antigens. In acute lymphatic leukemia, 33% of patients reveal T-cell receptor associated with higher age group, mediastinal mass and high WBC count. Common ALL was predominant between 2 and 9-yr age group. Among chronic lymphatic leukemia, 2 patients were found to be T-CLL while 29 revealed presence of SIg. Ia antigen was detected in 44.4% of ALL and 64% fo CLL patients. The pattern of surface marker observed in our series may be related to our life style, socio-economic and environmental factors.     

Lymphomatous presentation of childhood acute lymphoblastic leukemia. A subgroup at high risk of early treatment failure.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.     

Surface immunoglobulin-positive lymphoblastic lymphoma. A report of three cases

Lymphoblastic lymphomas (LBL) are a morphologically homogeneous group of non-Hodgkin's lymphomas which are indistinguishable in tissue sections from acute lymphoblastic leukemia (ALL). Although initial immunologic studies of LBL suggested that these lymphomas are of the T-cell phenotype, investigations have recently described patients with LBL having pre-B-cell, "common" ALL, and natural killer cell phenotypes. The authors recently reported detailed immunophenotypic characteristics in 36 cases of LBL, including a single case of LBL with a surface immunoglobulin-positive B-cell phenotype. Three additional patients with LBL whose cells expressed monoclonal serum immunoglobulins are presented here. In addition, the neoplastic lymphocytes expressed several B-cell-associated antigens. The tumor cells in the single case tested were TdT-negative. Despite the unusual immunologic phenotype, the morphologic features in all three cases were characteristic of LBL. In addition to the previously reported single case, to the authors' knowledge these are the only reported cases of a previously unrecognized variant of LBL: surface immunoglobulin-positive, B-cell LBL.     

Lymphoblastic lymphoma in adults

Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.     

Heteroantiserum against acute lymphocytic leukemia raised to the lymphoblastoid cell line NALM-1

Antisera have been raised in rabbits to the lymphoblastoid cell line NALM 1 precoated with antilymphocyte serum (ALS). Following absorption with chronic lymphocytic leukemia cells (CLL) the antisera reacted mainly with acute lymphocytic leukemia (ALL) cells, and were very similar in specificity to antisera raised to ALL cells precoated with ALS. Leukemia cells from the following numbers of patients were positive for the anti-NALM 1 sera in a complement-dependent cytotoxicity test; 11/14 ALL, 3/15 acute myelocytic leukemia (AML), 1/5 chronic myelocytic leukemia (CML) and 0/8 CLL. Normal B and T peripheral blood lymphocytes were negative. The titer of the anti-NALM 1 sera against positive cells was 1:64 to 1:256 whereas the undiluted sera did not react with negative cells. Ten out of 11 of the positive ALL cells were of the non-B non-T type. However, cells from 1/4 T ALL patients and a cultured T ALL line 8402 were also positive. Six of 12 cultured lymphoblastoid cell lines were positive, all of which were of malignant origin. The molecular weight of the ALL antigen detected by anti-NALM-1 serum was determined by immunoprecipitation and sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) to be approximately 98,000 daltons.     

Immunologic and clinicopathologic features of common acute lymphoblastic leukemia antigen-positive childhood T-cell leukemia. A Pediatric Oncology Group Study

The immunologic and clinicopathologic features of common acute lymphoblastic leukemia antigen (CALLA)-positive and CALLA-negative T-acute lymphoblastic leukemia (ALL) and of CALLA-positive non-T, non-B ALL (common ALL) of childhood were compared. Twenty-seven percent of children with T-ALL had blasts that expressed CALLA. This expression was not associated with a significantly different incidence of expression of sheep erythrocyte-rosette receptors, glucocorticoid receptors, peanut agglutinin receptors, or T-cell antigens. CALLA-positive T-cell blasts were more likely to express a p24 leukemia-associated antigen (CD9, 50% versus 8%) and Ia antigens (39% versus 8%) than were CALLA-negative blasts. Patients with CALLA-positive and CALLA-negative T-ALL had similar clinicopathologic features at diagnosis. In contrast, compared to patients with common ALL, patients with CALLA-positive T-ALL were older, had higher leukocyte counts, and an increased incidence of splenomegaly, lymphadenopathy and mediastinal mass, similar to patients with CALLA-negative T-ALL. Patients with CALLA-positive T-ALL were more likely to achieve a complete remission (95% versus 83%, P = 0.055) and tended to have an increased duration of event-free survival (P = 0.07) than did patients with CALLA-negative T-ALL. The expression of T-cell antigens is more important than the expression of CALLA in defining biologically similar subgroups of childhood ALL. Preliminary evidence suggests that within T-ALL the expression of CALLA may be prognostically important.     

Lymphocyte plasma membranes. VI. Surface antigens of lymphocytes in chronic lymphocytic leukemia.

Surface antigens from lymphocytes of patients with chronic lymphocytic leukemia (CLL) and from normal peripheral blood lymphocytes (PBL) were examined by radioimmunoassay; antisera to lymphocytes (ALS) were used to bind the labeled antigens. Cells from patients with CLL, normal PBL, thymus cells (THY), and cultured human lymphoblasts (CHL) were labeled by lactoperoxidase-catalyzed iodination. ALS (prepared against THY and CHL) were used to bind the labeled antigens solubilized in nonionic detergent. PBL resembled THY, but the CLL resembled CHL. Thus ALS(CHL) had greater potency for CLL antigens than for PBL antigens when compared to ALS(THY). Furthermore, the electrophoretic profiles of the immunoprecipitates from CLL cells revealed a peak of approximately 30,000-35,000 mol wt, which was not found for PBL or THY, but was associated with CHL.     

Anti-GD3 monoclonal antibody analysis of childhood T-cell acute lymphoblastic leukemia: detection of a target antigen for antibody-mediated cytolysis

We have demonstrated in previous studies significant quantitative differences in the ganglioside content of leukemia cell membranes within immunological subclasses of acute lymphoblastic leukemia (ALL): The disialoganglioside GD3 (disialolactosylceramide) is increased in lymphoblasts with a T-cell immunophenotype compared to non-T-ALL blasts. Utilizing an indirect immunofluorescence assays with a monoclonal antibody to GD3(R24), pretreatment leukemic lymphoblasts from 80 children with ALL were assayed for GD3 expression. GD3 was observed in 75% of leukemic samples in which lymphoblasts exhibited a T-cell phenotype, whereas none of the 33 non-T-ALL samples tested exhibited GD3. Correlation between the expression of GD3 and various antigenic determinants of T-cell differentiation was restricted to CD2; 75% of CD2-negative T-cell ALL blasts failed to express GD3. Anti-GD3 immunoreactivity to T-ALL samples was not restricted to R24 in that two other monoclonal anti-GD3 antibodies were similarly reactive to T-ALL blasts. In vitro incubation of T-cell lymphoblasts with the anti-GD3 antibodies, R24 and C281 and human serum resulted in significant cytotoxicity, and R24 also mediated antibody-dependent cellular cytotoxicity by normal effector cells. Cytotoxicity was specific for those T-ALL blast cell populations which reacted with anti-GD3 as assessed by immunofluorescence microscopy. Since immunoreactivity with monoclonal antibody to GD3 was exclusively observed in a large population of immunophenotypically defined T-cell leukemic lymphoblasts, these studies suggest a possible immunodiagnostic and immunotherapeutic potential for anti-GD3 monoclonal antibodies in T-cell lymphoblastic malignancies.     

Subpopulations of human T lymphocytes. VI. Analysis of cell markers in acute lymphoblastic leukemia with special reference to Fc receptor expression on E-rosette-forming blasts

A variety of surface markers, terminal deoxynucleotidyl transferase (TdT) activity, morphologic appearance, and cytochemical composition were studied in a group of 16 patients (13 children, 3 adults) with acute lymphoblastic leukemia (ALL). In 9 children, no surface markers were detected on lymphoblasts (null-type ALL). Leukemic blasts of 4 children formed E-rosettes. These E-rosette-forming blasts from 3 adult patients with ALL, were studied for the presence of Fc receptors. Of the leukemic blasts from these 7 patients, 2--76% expressed receptors for IgG Fc. Only 3 of 7 patients showed 9--42% receptors for IgM Fc. In addition, complement receptors were investigated in 6 of those 7 patients with T-cell ALL. Complement receptors were detected on 9--70% of the E rosette forming blasts from all 6 patients. TdT activity was elevated in T-cell ALL and in children with null-type ALL. The heterogeneity of Fc receptor expression on leukemic blasts in these patients demonstrates a malignant proliferation of T cells in different stages of differentiation or maturation. This observation might be helpful in subclassifying T-cell leukemias with regard to prognosis and the response to therapy.     

Lineage alteration in precursor B cell acute lymphoblastic leukemia following T cell lymphoblastic lymphoma.

A 10-year-old girl was diagnosed with lymphoblastic lymphoma; staging evaluation revealed a large mediastinal mass and normal peripheral blood and bone marrow morphology. Tumor cell immunologic marker analysis and Southern blot gene rearrangement studies demonstrated a T-cell lineage. She achieved a complete remission following multi-agent chemotherapy; however, 19 months following initial diagnosis while on maintenance therapy, she presented with typical acute lymphoblastic leukemia (ALL). The bone marrow was replaced by lymphoblasts, though the mediastinum was normal and there was no peripheral lymphadenopathy. Repeat immunophenotypic and genotypic studies demonstrated a precursor B-cell ALL lineage without expression of the T-cell surface antigens present on the original neoplasm. Repeat genotypic analysis showed immunoglobulin heavy and light chain gene rearrangements without the T-cell receptor gamma and beta gene rearrangements noted in the original lymphoblastic lymphoma. The complete alteration of lineage in these lymphoblastic processes suggests the de novo occurrence of a second neoplasm or, alternatively, an ALL relapse from a lineage-uncommitted neoplastic lymphoid progenitor cell.     

Clinical and biologic correlates of insulin binding by leukemia lymphoblasts

The percentage of total ¹²⁵I-labeled insulin specifically bound to lymphoblasts was measured in 46 children with leukemia. Among 35 children with newly diagnosed acute lymphoblastic leukemia (ALL), specific insulin binding ranged from 0.09 to 14.8% per 10⁶ blasts. A lower level of insulin binding was correlated with T-cell surface markers (P<0.003), higher hemoglobin level (P<0.005), presence of a mediastinal mass (P<0.01), lower glucocorticoid receptor level (P<0.02), higher platelet count (P<0.04), age < 2 or > 10 yr (P<0.05), white blood cell count ≥ 100 × 10³/mm³ (P<0.06) and higher labeling index (P<0.07). It was not correlated with the presence of central-nervous-system disease, FAB classification, or sex. With a follow-up of 24 to 33+ months, insulin binding was not correlated with treatment outcome. Six patients with relapsed ALL and three with acute nonlymphoblastic leukemia showed insulin binding levels similar to those in newly diagnosed ALL patients. Blasts from one patient with B-cell ALL and one with chronic myelogenous leukemia were characterized by lower insulin binding, while lymphoblasts from a patient with T-cell lymphoma bound insulin at marginally detectable levels. In vitro studies with IM-9, NALM-1 and NALM-16 cell lines showed that changes in insulin binding caused by dexamethasone treatment were not correlated with hormone-induced cell death. Although study of insulin binding by malignant lymphoid cells may be important in understanding the biology of leukemic cells, it does not appear to have any obvious clinical utility.     

T-cell leukemia with thymic involution.

The prognosis of acute lymphoblastic leukemia is affected adversely by T-cell markers on the malignant lymphoblasts. Direct involvement of the thymus has been assumed because of frequent mediastinal enlargement in these patients and the important role of the thymus in certain mouse leukemias. We report here an adult with T-cell leukemia and mediastinal enlargement who had physiologic involution of the thymus. The possible role of diphenylhydantoin in the pathogenesis of this disease is reviewed. The possible usefulness of Nu/Nu mouse xenografting for the study of this lethal disorder is discussed.     

Antigenically defined subgroups of lymphoblastic lymphoma. Relationship to clinical presentation and biologic behavior

A large panel of monoclonal antibodies and polyclonal antisera were used to ascertain the immunophenotypic characteristics of 36 lymphoblastic lymphomas (LBL). Results showed that this group of lymphomas have significant immunologic heterogeneity. Of the 36 cases, 33 were positive for T-cell antigens; among these, 22 cases were classified as T-cell LBL (TLBL, Group 1) based on their expression of T-cell-restricted and T-cell-associated antigens, and five expressed the common acute lymphoblastic leukemia antigen in addition to T-cell-associated antigens (Group 2). Six cases showed strong reactivity with anti-Leu-11 antibody, which defines a specific subtype of lymphocytes considered to have a natural killer (NK) function (Group 3). Two additional cases had a "pre-B" cell phenotype (Group 4), as determined by reactivity with BA-1 and BA-2 monoclonal antibodies, which react with immature and pre-B-lymphocytes. The neoplastic cells in the remaining case showed monoclonal surface membrane immunoglobulin of the IgMD heavy chain and kappa light chain type (Group 5). Despite immunophenotypic heterogeneity, the morphologic features were essentially similar in all cases. When the clinical features for each immunologic group were compared, however, two statistically significant findings resulted: (1) the frequency of mediastinal masses was highest in TLBL (Group 1, P less than 0.01), and (2) the male-female ratio was significantly lower in patients with LBL expressing NK-associated antigens (Group 3) than in the other groups of patients (P less than 0.01). Our data indicate that LBL can be divided into several immunologic subtypes; larger, prospective clinicopathologic studies are required to determine the clinical significance of the immunophenotypic classifications of LBL.     

Adult T-cell leukemia: a report on two white patients

Two white European males are reported with adult T-cell leukemia (ATL), a disease first described in Japan, but recently also in the U.K. and U.S.A. Both patients presented with lymphadenopathy, but without a mediastinal mass. In addition, one patient had skin infiltrates and the other had hepatosplenomegaly. Morphologic and ultrastructural examination of the blasts in bone marrow and lymph node biopsy revealed a predominance of polymorphic lymphoid cells with pronounced nuclear irregularities and a semi-mature chromatine pattern. Histopathology of the lymph nodes showed a diffuse infiltration with medium-sized lymphoblasts with irregular nuclei. The blasts in the bone marrow formed E rosettes with sheep erythrocytes, lacked terminal deoxynucleotidyl transferase (Tdt) activity but expressed the Ia-like antigen; although the majority of the cells reacted with a polyclonal anti-T-cell serum, they were negative for OKT3. In one patient a helper/inducer phenotype (OKT4+) was found in the lymphoblasts of bone marrow and lymph node, while in the other only in the lymph node. The difference between bone marrow and lymph node phenotype is discussed. To our knowledge, these are the first two European patients reported with ATL, a disease clearly different from convoluted T-cell acute lymphocytic leukemia.     

Rabbit antiserum against a non-T, non-B leukemia cell line that carries the Ph1 chromosome (NALM-1): antibody specific to a non-T, non-B acute lymphoblastic leukemia antigen.

Rabbit immune sera against human cells of a non-T, non-B leukemia cell line bearing the Ph1 chromosome (NALM-1) were characterized. After proper and exhaustive absorption, the sera were tested by indirect membrane immunofluorescence on a panel of 19 human hematopoietic cell lines with T-, B-, or non-T, non-B cell surface characteristics. The absorbed sera reacted specifically with NALM-1 cells but not with cells of another Ph1-positive cell line, K-562. Four of the 6 leukemia T-cell lines, 2 of the 4 leukemia-lymphoma B-cell lines, all of 4 acute lymphoblastic leukemia (ALL) lines with non-T, non-B cell characteristics, and uncultured cells of all patients with non-T, non-B cell ALL were reactive with the antisera. A cross-absorption study of the antisera suggested that a single antigenic complex is involved in this antigen specificity. The antigen involved appears to be a common non-T, non-B ALL one that has been described previously.     

Some aspects of immunological and cytochemical markers in leukemia

Summary The value of immunological and of cytochemical markers for understanding of pathophysiology and for diagnosis in different subtypes of leukemia is discussed.Abbreviations used in this paper AML Acute myeloid leukemia - AMoL acute monocytoid leukemia - ALL acute lymphoid leukemia - ANAE acid -naphtyl acetate esterase - APh acid phosphatase - B-ALL (-CPL,-CLL) B-lymphoid acute (prolymphocytic, chronic) leukemia - C-Ag membrane antigen of common ALL - C-ALL common ALL whose cells react with a specifically absorbed antiserum against ALL of non-T, non-B variety - CLL chronic lymphoid leukemia - CPL chronic prolymphocytic leukemia - E rosettes with sheep erythrocytes - Ia immune response antigen - M-Ag myeloid antigen - POX peroxidase - SmIG surface membrane Ig - T-Ag T-lymphocyte antigen - T-ALL (-CPL,-CLL) T-lymphocyte antigen-positive acute (prolymphocytic chronic) lymphatic leukemia - TdT terminal deoxynucleotidyl transferase - UAL undifferentiated acute leukemia     

The development of acute myelomonocytic leukemia in a patient with acute lymphocytic leukemia

A diagnosis of acute lymphocytic leukemia (ALL) was made from a peripheral blood and bone marrow specimen from a 59-year-old woman. Typical-appearing lymphoblasts were positive for periodic acid-Schiff (PAS) reaction, but negative for peroxidase, Sudan black B (SBB) and non-specific esterase (NSE) stains. Lymphoblasts failed to form non-immune rosettes and had no surface membrane immunoglobulins. However, lymphoblasts exhibited an "Ia-like" membrane antigen and markedly stimulated allogeneic lymphocytes in a mixed lymphocyte reaction (MLR). These cytochemical and immunologic studies were considered characteristic of null-cell subtype of ALL. Thirteen months later, the peripheral blood and bone marrow specimens contained numerous myelomonoblasts characterized by a weak or negative PAS stain and strongly positive peroxidase, SBB, and NSE reactions. Electron micrographs of the bone marrow suggested that the majority of leukemic cells were myelomonocytic and a minority of cells were lymphoblasts. In addition, myelomonoblasts in liquid cultures appeared to differentiate into mature macrophages. These data suggest the development of acute myelomonocyte leukemia in a previous case of ALL.     

Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia

BackgroundThe discovery that purine nucleoside phosphorylase (PNP) deficiency leads to T-cell lymphopenia was the basis for introducing PNP inhibitors for T-cell leukemias. Forodesine is an orally bioavailable PNP inhibitor with picomolar potency. Because T lymphoblasts and indolent chronic lymphocytic leukemia (CLL) B cells inherently elicit favorable pharmacokinetics to accumulate deoxyguanosine triphosphate (dGTP), forodesine demonstrated promising activity in preclinical and clinical settings for patients with T-cell acute lymphoblastic leukemia (T-ALL) and B-cell CLL (B-CLL). However, the use of forodesine in B-cell ALL (B-ALL) is unknown.Patients and MethodsLeukemic blasts obtained from pediatric patients with de novo B-ALL (n = 10) were incubated with forodesine and deoxyguanosine (dGuo), and the biological end points of apoptosis, intracellular dGTP accumulation, and inhibition of RNA and DNA synthesis were measured. Additionally, adult patients with B-ALL (n = 2) were intravenously infused with 80 mg/m²/d daily for 5 days. After therapy, clinical response, toxicity, laboratory biomarkers including PNP enzyme inhibition, and plasma forodesine, dGuo, and intracellular dGTP levels were analyzed.ResultsOur in vitro investigations demonstrated that forodesine treatment inhibited proliferation and induced modest apoptosis in de novo B-ALL lymphoblasts. There was time-dependent accumulation of dGTP and inhibition of RNA and DNA synthesis. During therapy, neither patient achieved a complete response (CR), but there was disease stabilization for several weeks in both patients. There was significant maintained inhibition of PNP enzyme in red blood cells, accumulation of forodesine and dGuo in plasma, and intracellular dGTP accumulation in both patients.ConclusionOur preclinical and clinical investigations suggest that forodesine has activity in B-ALL. However, it needs to be either infused with dGuo or combined with established chemotherapeutic agents based on mechanistic rationale.