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Clinical Cancer Research Vol. 5, 3906-3913, December 1999
© 1999 American Association for Cancer Research

Advances in Brief

Treatment of Therapy-Refractory B-Lineage Acute Lymphoblastic Leukemia with an Apoptosis-inducing CD19-directed Tyrosine Kinase Inhibitor1

Fatih M. Uckun2, Yoav Messinger, Chun-Lin Chen, Karen O’Neill, Dorothea E. Myers, Frederick Goldman, Carole Hurvitz, James T. Casper and Alexandra Levine

The Parker Hughes Cancer Center, Hughes Institute, St. Paul, Minnesota 55113 [F. M. U., C-L. C., K. O., D. E. M.]; Biotherapy Program, University of Minnesota Academic Health Center, Minneapolis, Minnesota 55455 [Y. M.]; Kenneth Norris Cancer Center, University of Southern California, Los Angeles, California 90033 [A. L.]; University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242 [F. G.]; Cedar Sinai Medical Center, Los Angeles, California 90048 [C. H.]; and University of Wisconsin, Milwaukee, Wisconsin 53226 [J. T. C.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1–0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2–3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 ± 5 h, mean residence time of 24 ± 5 h, and a systemic clearance rate of 20 ± 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20–87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The B-lineage-specific surface CD19 receptor is expressed at high levels on leukemic cells from the vast majority of ALL3 patients, but it is absent on the parenchymal cells of life-maintaining nonhematopoietic organs and bone marrow stem cells (1, 2, 3, 4, 5, 6, 7) . CD19 is physically associated with the Src family PTK to form transmembrane receptor PTK with important signal transducing functions (2 , 8 , 9) . These membrane-associated CD19-PTK complexes serve as endogenous p53-independent and Bcl2-independent regulators of apoptosis and play pivotal roles for survival as well as clonogenicity of B-lineage ALL cells (8 , 9) . B43-Genistein immunoconjugate selectively targets the naturally occurring PTK inhibitor genistein, an isoflavone (5,7,4'-trihydroxyisoflavone) isolated from the fermentation broth of Pseudomonas spp., which is also present in soybeans (10) , to the membrane-associated antiapoptotic CD19-Src family PTK complexes and triggers apoptotic cell death (8 , 9) . More than five logs of leukemic cells were killed by B43-Genistein in a SCID mouse xenograft model of human B-lineage ALL, which led to 100% survival from an otherwise invariably fatal leukemia (8) . At less than one-tenth the maximum tolerated dose, B43-Genistein was more effective than several standard chemotherapeutic agents (8 , 11) . B43-Genistein also conferred long-term tumor-free survival in SCID mice xenografted with fatal human B-lineage lymphoma (9) .

In a recent preclinical study, we evaluated the toxicity profile of B43-Genistein in cynomolgus monkeys (12) . Notably, at dose levels effective against human B-lineage ALL in SCID mice, B43-Genistein was very well tolerated by cynomolgus monkeys, and no test-article-related histopathological lesions were found in any of the five B43-Genistein-treated monkeys (12) . Furthermore, B43-Genistein showed a favorable pharmacokinetic profile in monkeys with a plasma half-life of 10–23 h, which indicated that a once daily i.v. administration schedule would likely allow us to achieve and maintain therapeutic drug levels in clinical settings (12) . Importantly, plasma samples from B43-Genistein-treated cynomolgus monkeys showed potent in vitro antileukemic activity against B-lineage ALL cells (12) . These preclinical studies collectively suggested that B43-Genistein may provide the basis for an effective treatment strategy for B-lineage leukemia patients who have failed standard therapy. We herein report the results of a pilot study of B43-Genistein (BB-IND-52,644) in 15 patients with refractory B-lineage ALL (including 6 ALL patients who had relapsed after BMT) and 1 patient with refractory CLL.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patients.
Between December 1996 and June 1998, seven children ranging in age from 4–20 yr (median, 15 yr) and eight adults ranging in age from 25–60 yr (median, 29 yr), who were diagnosed with CD19 antigen-positive B-lineage ALL and had relapsed following frontline or salvage chemotherapy or failed induction chemotherapy, as well as one 52-yr-old therapy-refractory CLL patient, were enrolled on this pilot clinical study of B43-Genistein. Patients were treated and followed at the Parker Hughes Cancer Center (St. Paul, MN), Fairview Medical Center (formerly the University of Minnesota Hospital, Minneapolis, MN), Children’s Hospital of Wisconsin (Milwaukee, WI), University of Iowa Hospitals and Clinics (Iowa City, IA), Cedar Sinai Medical Center (Los Angeles, CA), and the USC/Norris Cancer Center, University of Southern California (Los Angeles, CA). The clinical protocol was approved by the Institutional Review Boards of the participating Institutions. Informed consent was obtained from all patients or their guardians according to Department of Health and Human Services guidelines.

Dosage and Drug Administration.
B43-Genistein (BB-IND-52,644) was formulated as a sterile 1 mg/ml solution in 150 mM sodium chloride, 40 mM sodium phosphate (pH 7.4). The composition and physicochemical properties of B43-Genistein were previously reported in detail (13) . For i.v. administration, B43-Genistein was diluted in 10 ml/kg (maximum, 100 ml) normal saline. Because of the relatively long elimination half-life of B43-Genistein in nonhuman primates, a 1-h daily infusion schedule was used. Each treatment consisted of a 1-h continuous infusion given 15–20 min after premedication with standard doses of diphenhydramine (Benadryl) and acetaminophen (Tylenol). Patients were treated with one or two courses of therapy, each comprising either 10 consecutive days of treatment (Schedule A) or three weekly cycles of 3 consecutive days each for a total of nine doses (3 x 3 regimen; Schedule B). A starting daily dose level of 0.1 mg/kg/day was used in the first 10 patients; the dose was escalated to 0.18 mg/kg/day in three additional patients, and the highest dose of 0.32 mg/kg/day was used for the remaining three patients. Thirteen patients were treated according to Schedule A, and three patients were treated according to Schedule B. No intrapatient dose escalation was allowed in this study.

Pretreatment and Follow-Up Evaluation.
Medical histories, physical examinations, and laboratory studies were performed before enrollment and throughout the therapy program to monitor patients for potential toxic side effects of B43-Genistein. Laboratory studies included a complete blood count with differential, serum electrolytes, blood urea nitrogen, creatinine, liver function tests (bilirubin, ALT, AST, alkaline phosphatase), urine analysis, chest X-ray, pulse oximetry, electrocardiogram, gated cardiac pool scan or echocardiogram, and a pulmonary function test. These studies also were used to monitor toxic effects of B43-Genistein during and after therapy. Chest X-rays and echocardiograms were repeated on day 14 and whenever clinically indicated. Bone marrow status was assessed before treatment and on days 7, 14, and 28 to determine response to B43-Genistein (see below).

Pharmacokinetic Studies.
Patient samples for pharmacokinetic studies consisted of peripheral blood obtained at 1, 2, 4, 8, 12, 16, 18, and 24 h after completion of infusion on the 1st day of treatment. Pre- and 1-h postinfusion blood samples were obtained on all other days. Plasma levels of B43-Genistein were determined using a quantitative ELISA, as described in detail previously (12) .

Pharmacokinetic modeling and pharmacokinetic parameter calculations were carried out using the pharmacokinetics software, WinNonlin Program, Standard Version 2.1 (Pharsight Corporation, Mountain View, CA). Concentration data were weighted by 1/concentration. An appropriate pharmacokinetic model was chosen on the basis of the lowest weighted squared residuals, lowest Schwartz Criterion, lowest Akaike’s Information Criterion value, lowest SEs of the fitted parameters, and dispersion of the residuals (12 , 14 , 15) . The elimination half-life was estimated by linear regression analysis of the terminal phase of the plasma concentration time curve (12, 13, 14) . The AUC was calculated by the trapezoidal rule between the first (0 h) and last sampling time plus C/k, where C is the concentration at the last sampling time and k is the elimination rate constant (12 , 14 , 15) . Systemic clearance was determined by dividing the area under the first moment curve by AUC (12 , 14 , 15) . Statistical analysis was performed using the Instat Program V.2.03 (GraphPad Software, San Diego, CA). Statistical differences between pharmacokinetic parameter values were analyzed using a one-tailed t test; P < 0.05 was considered significant.

Assessment of Toxicity, Immunogenicity, and Response.
Toxicities were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria. Complete remission was defined as the achievement of M1 bone marrow status (< 5% blasts) by day 28 of therapy with a granulocyte count of 1 x 103/µl, a platelet count of 100 x 103/µl (> 50,000/µl without transfusions for patients post-BMT), a hemoglobin level of 10 g/dl, and the absence of circulating leukemia cells in the peripheral blood or any evidence of extramedullary disease. PR was defined as complete disappearance of peripheral blasts and achievement of M2 bone marrow status (5–25% blasts) by day 28 of therapy. PD was defined as an increase of at least 25% in the absolute number of circulating blasts, or development of extramedullary disease. SD (stable disease) was defined as a lack of change in status of any of the parameters that would have resulted in CR, PR, or PD. The immunogenicity of B43-Genistein was assessed by evaluating patient plasma samples for levels of HAMAs generated against the mouse monoclonal B43 moiety of the immunoconjugate, as previously reported (15) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Demographic Features of Patients.
Fifteen patients had ALL, and 1 patient had CLL. Patient characteristics are detailed in Table 1Citation . There were 5 females and 11 males. The age of the patients ranged from 4–60 yr (median, 26 yr). Twelve patients were Caucasian, two were Hispanic, one was Asian, and one was Native American. Among the 15 ALL patients, two were in induction failure after initial diagnosis and 13 were in relapse. Of these 13 patients, 4 were in first relapse, 6 were in second relapse, 2 were in third relapse, and 1 was in fourth relapse. Three of the four patients in first relapse had failed reinduction attempts with standard chemotherapy agents (Table 1)Citation . Six of the 13 patients in relapse had a recurrence after either unrelated donor (n = 5) or matched sibling donor (n = 1) BMT. Leukemic cells from all 15 ALL patients expressed the B-lineage surface antigen CD19.


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  		Table 1 Patient characteristics

 
Toxicity and Antileukemic Activity of B43-Genistein.
Ten patients were treated with the starting dose of 0.1 mg/kg/day; four of these patients received one course and three patients received two courses according to Schedule A. Two patients received one course, and one patient received two courses according to Regimen B (Table 2)Citation . All 16 patients were evaluable for toxicity. B43-Genistein was well tolerated by all patients with no life-threatening side effects, and dose escalation proceeded as planned with the maximum tolerated dose not reached at dose levels up to 0.32 mg/kg/day. Seven patients had grade 2–3 fever, one patient each had grade 3 myalgia, grade 2 sinus tachycardia, grade 3 abdominal pain, grade 3 liver enzyme elevations, and grade 2 vascular leak syndrome (weight gain, peripheral edema, pleural effusion, no hypoalbuminemia, no respiratory, renal, or cardiac compromise, no hypotension). Of the six patients with grade 2–3 fever, four had fevers before initiation to B43-Genistein, likely due to their primary disease. B43-Genistein did not consistently increase the body temperature in patients with baseline fever. One additional patient (UPN 9) had Grade II fever concomitant with Pseudomonas bacteremia 96 h before initiation of B43-Genistein (which was effectively treated with tobramycin and imipenem) but no fevers while on B43-Genistein therapy. However, in two patients with no baseline fever, B43-Genistein therapy was associated with drug-related Grade II-III fever; UPN 3 had no baseline fever, had Grade II fever on days 4–8, Grade III fever on days 9–10, Grade II fever on days 11–14, and then no fever. UPN 14 had no baseline fever but developed Grade II fever with chills on day 1. Neither patient had evidence for an underlying infection as the cause of these fevers. There were no episodes of rash or other allergic reactions.


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  		Table 2 Toxicity and biologic activity of B43-Genistein in leukemia patients

 
One ALL patient (UPN 5) in early bone marrow relapse was not evaluable for response because he had patchy bone marrow disease (no evidence of disease in bone marrow specimens from the left posterior iliac crest but evidence of disease with focal clusters of blasts in the bone marrow specimens from the right posterior iliac crest) with only 3% lymphoblasts on study entry. In 10 of the remaining 14 ALL patients evaluable for response, there was no evidence of a therapeutic benefit. Of these 10 patients, 9 had progressive disease either while on or shortly after cessation of therapy and one patient had stable disease (Table 2)Citation . Among the remaining four patients, one (UPN 6) had markedly decreased bone pain and reduced transfusion requirements but persistent M3 marrow status (stable disease) after B43-Genistein therapy (Table 2)Citation . Two patients (UPN 3 and UPN 8) achieved an M1 marrow status, and one patient achieved an M2 marrow status by day 28 (Table 3)Citation .


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  		Table 3 Antileukemic activity of B43-Genistein in therapy-refractory ALL patients

 
UPN 3, a 20-yr-old female in third bone marrow relapse following a matched sibling allogeneic BMT, with 84% leukemic cells in her pretreatment bone marrow, achieved M1 marrow status by day 14, had evidence of trilineage hematopoiesis in her bone marrow with normal cellularity, and no detectable leukemic cells by day 28, followed by complete peripheral hematological recovery by day 35. This patient had an isolated central nervous system relapse while on maintenance chemotherapy 19 months after B43-Genistein therapy, which was effectively treated with intrathecal and systemic chemotherapy and local radiation therapy, and she remains in continued complete bone marrow remission for 27+ months (Table 3)Citation . UPN 7, a 32-yr-old male in first therapy-refractory bone marrow relapse with 53% leukemic cells in his pretreatment bone marrow and 3% leukemic cells in peripheral blood (absolute blast count = 81/µl) achieved an M2 marrow status with concomitant clearance of peripheral blasts by day 28. UPN 8, a 15-yr-old male in second therapy-refractory bone marrow relapse following an unrelated donor BMT with 99% blasts in his pretreatment bone marrow achieved complete bone marrow remission with 4% blasts by day 28. However, this patient developed a rapidly progressive extramedullary relapse and died of progressive leukemia on day 57, although his bone marrow and peripheral blood remained free of leukemic blasts (Table 3)Citation .

None of the four ALL patients who showed a response to B43-Genistein (i.e., UPN4 with stable marrow disease but decreased bone pain and reduced transfusion requirements, UPN7 who achieved an M2 marrow status, UPN3 and UPN8 who achieved an M1 marrow status) had circulating leukemic cells in their peripheral blood at the time of study entry. By comparison, 9 of the 10 evaluable nonresponders had circulating leukemic cells ranging from 196 x 106/liter to 22,680 x 106/liter (Table 1)Citation . All responders were treated at the 0.1 mg/kg/day dose level, and three of them had relapsed after undergoing BMT.

Pharmacokinetic Features of B43-Genistein.
Pre- and posttreatment intact B43-Genistein plasma levels obtained on days 1 and 5 of B43-Genistein therapy, as well as the average B43-Genisten plasma level throughout the treatment course, are shown in Table 4Citation . Among 10 ALL patients treated at the first dose level of B43-Genistein (i.e., 0.1 mg/kg/day), peak drug levels varied from 55 ng/ml to 2192 ng/ml on day 1 (mean ± SE = 491 ± 184) and from 48 ng/ml to 6497 ng/ml on day 5 (mean ± SE = 1501 ± 615). Among the remaining patients treated at the higher dose levels of B43-Genistein, peak drug levels varied from 246 ng/ml to 1384 ng/ml on day 1 (mean ± SE = 811 ± 201) and from 572 ng/ml to 6336 ng/ml on day 5 (mean ± SE = 2700 ± 889). The average B43-Genistein levels ranged from 67–1841 ng/ml for the 0.1 mg/kg/day dose level and from 148-4343 ng/ml for the higher dose levels (Table 4)Citation . Among 12 patients (11 ALL patients and 1 CLL patient) with complete pharmacokinetic data sets, a one-compartment pharmacokinetic model was fitted to the day 1 plasma concentration-time curves in eight cases, and a two-compartment model was applied for the analysis of data in the remaining four cases. B43-Genistein showed slow elimination with a mean residence time ranging from 5.1–59 h (mean ± SE = 24 ± 5 h) and systemic clearance ranging from 5–44 ml/h/kg (mean ± SE = 20 ± 3 ml/h/kg; Tables 4Citation and 5Citation ), which is consistent with its large molecular weight and previously reported pharmacokinetics in mice (8 , 11) and nonhuman primates (12) . Representative plasma concentration versus time curves from two patients treated at the 0.1 mg/kg dose level and two patients treated at the 0.18 mg/kg dose level are depicted in Fig. 1Citation .


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  		Table 4 Systemic immunoconjugate exposure levels in leukemia patients treated with B43-Genistein

 

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  		Table 5 Summary of pharmacokinetic data

 


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  		Fig. 1. Pharmacokinetics of B43-Genistein in leukemia patients. Shown are plasma concentration versus time curves for B43-Genistein in four representative cases. Lines represent single compartment model simulations; symbols depict measured plasma concentrations. See Table 4Citation for more details.

 
The estimated volume of distribution at steady state (Vss) was much larger than the physiological plasma volume of 40 ml/kg and ranged from 118–636 ml/kg (mean ± SE = 332 ± 45). This is most likely due to a rapid uptake of B43-Genistein by CD19-expressing leukemia cells throughout the body. The estimated AUC values ranged from 3,126–39,530 µgxh/L (mean ± SE = 9,711 ± 2,678 µgxh/L; Tables 4Citation and 5Citation ). The pharmacokinetic parameter values are summarized in Table 5Citation according to the applied dose level. The values for AUC were 3.4-fold higher for patients treated at the 0.18 mg/kg/day dose level than the AUC values for patients treated at the 0.1 mg/kg/day dose level (20,712 ± 7,722 µgxh/L versus 6,044 ± 1,100 µgxh/L, P = 0.004; Table 5Citation ).

Immunogenicity of B43-Genistein.
Eleven patients were examined for development of HAMA against the murine monoclonal antibody moiety of B43-Genistein. No HAMA were detected in any of the day 7 or day 14 posttreatment samples or any of the pretreatment blood samples. However, moderate levels of HAMA ranging from 20–87 ng/ml were detected in the day 28 blood samples from three (UPN 5, 6, and 7) of nine cases examined (Table 6A)Citation . Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield any measurable immunoconjugate levels in the plasma, whereas treatment of a HAMA-negative patient (UPN 10) did, indicating that the administered B43-Genistein molecules are rapidly cleared from circulation due to the HAMA (Table 6B)Citation .


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  		Table 6 Immunogenicity of B43-Genistein in leukemia patients

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In the current first pilot clinical study of B43-Genistein, we have tested its safety, biological activity, pharmacokinetics, and immunogenicity in adults and children with refractory B-lineage ALL. Our data indicate that doses between 0.10 mg/kg/day and 0.32 mg/kg/day administered for 10 consecutive days or for 9 days in a 3-week regimen, are well-tolerated by both children and adults. The primary drug-related toxicity noted was a grade 2 or 3 fever.

B43-Genistein as a single agent induced bone marrow responses in 3 of 14 evaluable ALL patients (21%), all of whom had failed multiple previous therapies and 2 of whom had relapsed after a BMT. However, in the remaining 11 ALL patients (as well as the one CLL patient), there was no evidence of an objective therapeutic benefit from the B43-Genistein treatment. The reasons for this heterogeneous response profile of ALL patients remain unknown. It is possible that patients with circulating leukemic cells are less likely to respond to B43-Genistein due to rapid recruitment of the infused B43-Genistein molecules to the CD19 receptors on the surface of peripheral blasts. Notably, none of the four ALL patients who showed a response to B43-Genistein had circulating leukemic cells in their peripheral blood at the time of study entry. By comparison, 9 of 10 evaluable ALL patients who did not respond had circulating leukemic cells. The identification of factors contributing to the favorable response of certain ALL patients to this new treatment modality as well as the determination of a biologically optimal dose level will be the focus of our correlative laboratory investigations to be conducted as an integral part of the future clinical studies of B43-Genistein.

The plasma elimination half-life of B43-Genistein in cynomolgus monkeys ranged from 10–23 h (12) , prompting the hypothesis that a once daily i.v. administration is likely to be sufficient for achieving and maintaining active drug levels in clinical settings. This hypothesis was confirmed in the present study, which demonstrated that the pharmacokinetic features of B43-Genistein in ALL patients are favorable with a mean plasma residence time of 24 ± 5 h. The only other two tyrosine kinase inhibitors tested clinically, the tryphostin RG13022 and quercetin showed substantially less favorable pharmacokinetics with elimination half-lives of less than 1 h (16 , 17) . Notably, the estimated volume of distribution at steady state was much larger than the physiological plasma volume of 40 ml/kg and ranged from 119–860 ml/kg (mean ± SE = 332 ± 45 ml/kg). This is most likely due to a rapid uptake of B43-Genistein by CD19-expressing leukemia cells and/or normal B-lineage lymphoid cells expressing CD19.

A major and obvious limitation for the B43-Genistein therapy is the development of antibodies against the murine monoclonal antibody moiety of the immunoconjugate. Although the patient population of the present study was heavily immunosuppressed because of prior chemotherapy and/or BMT, and the applied immunoconjugate is directed against normal B-cells as well, three of nine cases examined developed high-affinity HAMA by day 28. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield any measurable immunoconjugate levels in the plasma, whereas treatment of a HAMA-negative patient (UPN 10) did, suggesting that the administered B43-Genistein molecules are rapidly cleared from circulation due to the HAMA. Use of humanized anti-CD19 antibodies and/or concomitant use of immunosuppressive therapy may reduce the likelihood of a host antibody response.

To our knowledge, this is the first clinical evaluation of a tyrosine kinase inhibitor as an antileukemic agent. The favorable pharmacokinetic characteristics, coupled with the lack of significant toxicity and ability to elicit responses in some of the heavily pre-treated patients indicates that the clinical potential of B43-Genistein should be investigated further in clinical trials.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by research grants from the Parker Hughes Trust and the National Cancer Institute (CA-72157 awarded to F.M.U.), NIH. During part of this study, F.M.U. was a Stohlman Scholar of the Leukemia Society of America (New York, NY). Back

2 To whom requests for reprints should be addressed, at Hughes Institute, 2665 Long Lake Road, Suite 330, St. Paul, MN 55113. Phone: (651) 697-9228; Fax: (651) 697-1042. Back

3 The abbreviations used are: ALL, acute lymphoblastic leukemia; PTK, protein tyrosine kinase; CLL, chronic lymphocytic leukemia; BMT, bone marrow transplantation; AUC, area under the concentration curve; UPN, unique patient number; PD, progressive disease; PR, partial remission; SD, stable disease. Back

Received 5/27/99; revised 8/26/99; accepted 8/27/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Uckun F. M., Burkhardt A. L., Jarvis L., Jun X., Stealey B., Dibirdik I., Myers D. E., Tuel Ahlgren L., Bolen J. B. Signal transduction through the CD19 receptor during discrete developmental stages of human B-cell ontogeny. J. Biol. Chem., 268: 21172-21184, 1993.[Abstract/Free Full Text]
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