scholarly journals The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 406-417 ◽  
Author(s):  
MR Grever ◽  
MF Siaw ◽  
WF Jacob ◽  
JA Neidhart ◽  
JS Miser ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Severe Combined Immunodeficiency ◽  
Single Agent ◽  
Cell Mass ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Central Nervous System Toxicity ◽  
Marked Rise

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2′-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2′-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

scholarly journals The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 406-417 ◽  
Author(s):  
MR Grever ◽  
MF Siaw ◽  
WF Jacob ◽  
JA Neidhart ◽  
JS Miser ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Severe Combined Immunodeficiency ◽  
Single Agent ◽  
Cell Mass ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Central Nervous System Toxicity ◽  
Marked Rise

Abstract A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2′-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2′-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.

Abnormal Erythropoiesis in Microgravity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3701-3701 ◽  
Author(s):  
Kun Xu ◽  
Keith V. Holubec ◽  
John E. Love ◽  
Thomas J. Goodwin ◽  
Arthur J. Sytkowski
Keyword(s):  
Blood Cell ◽  
Cell Line ◽  
Red Blood Cell ◽  
Bone Marrow Cells ◽  
Cell Mass ◽  
Erythroid Cell ◽  
Specific Marker ◽  
Murine Erythroleukemia

Abstract Humans and experimental animals subjected to microgravity, such as experienced during space flight, exhibit alterations in erythropoiesis, including changes in red blood cell morphology, survival and a reduction in red blood cell mass. Some of these alterations have been attributed to a disruption of normal in vivo erythropoietin physiology. However, human bone marrow cells grown on orbit showed a profound reduction in the number of erythroid cells, suggesting a cellular component. We now report the results of a study carried out on orbit on the International Space Station (ISS UF-1) in which an erythroid cell line was induced to differentiate. Rauscher murine erythroleukemia cells, a continuous cell line that can undergo erythropoietin (Epo)- or chemical-induced differentiation similar to normal erythropoiesis, were cultured for 6 days either in microgravity on board the ISS or on earth and then for 3 days in the absence or presence of 50 U Epo/ml or 0.7% dimethyl sulfoxide (DMSO). The cells were fixed, stored on orbit and returned to earth for study. Compared to ground-based controls, cells cultured in microgravity exhibited a greater degree of differentiation (hemoglobinization) (p<0.01). However, TER-119 antigen, a specific marker of the late stages of murine erythroid differentiation, was not detected on the surface of cells grown in microgravity. A significantly higher percentage (p<0.05) of cell clusters formed on orbit, whereas actin content appeared reduced. Furthermore, there was a more profound loss of actin stress fibers in microgravity following Epo or DMSO treatment. These results demonstrate abnormal erythropoiesis in vitro in microgravity and are consistent with the hypothesis that erythropoiesis is affected by gravitational forces at the cellular level.(Supported by NASA Grants NAG9-1368 and NAG2-1592 to AJS)

Combined Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC), an Active Regimen for Treated Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3133-3133 ◽  
Author(s):  
Marco Montillo ◽  
Sara Miqueleiz ◽  
Alessandra Tedeschi ◽  
Francesca Ricci ◽  
Eleonora Vismara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Synergistic Activity ◽  
Color Flow ◽  
Grade Iii

Abstract Fludarabine (F) in combination with cyclophosphamide (C) showed a relevant advantage over single-agent F in pts with relapsed CLL. Although minimal residual disease (MRD) remains detectable in many pts achieving CR, the combination of F and C seems to reduce MRD more efficiently. Still, pts in CR eventually relapse and require treatment, demonstrating the need for improved treatments able to further reduce or eliminate MRD and induce “better quality” and thus more durable responses. Alemtuzumab (CAM), anti-CD52 monoclonal antibody, acts synergistically with F in vitro and appears to have synergistic activity in vivo. Additionally, CAM is highly effective at clearing disease from bone marrow, the usual site of residual disease following purine analogue-based treatment. Therefore, we designed a phase II study to determine feasibility and efficacy, overall response rate (ORR)-duration of response-ability at clearing MRD, of a 4-weekly combination regimen consisting of F, C, and CAM (FCC). The study population is represented by pts with B-CLL with relapsed or refractory disease after at least one line of treatment. Subcutaneous route of administration of CAM has been adopted in this trial. MRD was measured by 4-color flow cytometry in the bone marrow. The FCC regimen consisted of F 40 mg/m2/d os (d 1–3), C 250 mg/m2/d os (d 1–3) and CAM 10 mg sc (d 1–3). This combination was repeated on d 29 for up to 6 cycles. The dose of CAM was increased after the first cohort of 10 treated pts from 10 mg to 20 mg sc. Currently, 25 pts have been enrolled in this trial. Median age was 57 years (range 42–79), 15/25 (60%) were male, 23/25 (92%) were in Binet stage B or C, median number of prior treatment regimens was 2 (range 1–4). In six (24%) pts 17p deletion was detected. IgVH unmutated was observed in 17 (68%) pts. At the moment of writing 19 pts are eligible for evaluation of toxicity and response. The ORR was 79%, with 7 (37%) pts achieving CR, 7 (37%) pts a PR, 1 (5%) pt a PRn. Three pts had SD, while 1 showed progression of the disease. MRD negativity was achieved in the bone marrow of 4/15 (27%) pts. Grade III-IV neutropenia episodes were observed in 43% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8% of cycles. Four major infections were recorded: two sustained by Mycobacterium tuberculosis (1 cutis, 1 lung), one by Nocardia (lung) and one by E. coli (sepsis). The patient with pneumonia due to M. tuberculosis died because of respiratory failure. CMV reactivation occurred in 6 pts: no CMV disease was recorded. After a median follow up of 10 m (range 1–22) 73% of responding pts did not progressed. In conclusion, results from the interim analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is feasible, safe, and effective in treating pts with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors and who had received.

scholarly journals A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 669-677 ◽  
Author(s):  
Weili Chen ◽  
Quanzhi Li ◽  
Wendy A. Hudson ◽  
Ashish Kumar ◽  
Nicole Kirchhof ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Hematologic Malignancy ◽  
Embryonic Stem ◽  
Hematologic Malignancies ◽  
Fusion Partner ◽  
Hematopoietic Malignancies ◽  
Long Latency ◽  
B Lymphoid

The 2 most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear. We produced Mll-AF4 knock-in (KI) mice by homologous recombination in embryonic stem cells and compared them with Mll-AF9 KI mice. Young Mll-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoietic organs. In vitro, bone marrow cells from young mice formed unique mixed pro-B lymphoid (B220+CD19+CD43+sIgM–, PAX5+, TdT+, IgH rearranged)/myeloid (CD11b/Mac1+, c-fms+, lysozyme+) colonies when grown in IL-7– and Flt3 ligand-containing media. Mixed lymphoid/myeloid hyperplasia and hematologic malignancies (most frequently B-cell lymphomas) developed in Mll-AF4 mice after prolonged latency; long latency to malignancy indicates that Mll-AF4–induced lymphoid/myeloid deregulation alone is insufficient to produce malignancy. In contrast, young Mll-AF9 mice had predominately myeloid deregulation in vivo and in vitro and developed myeloid malignancies. The early onset of distinct mixed lymphoid/myeloid lineage deregulation in Mll-AF4 mice shows evidence for both “instructive” and “noninstructive” roles for AF4 and AF9 as partners in MLL fusion genes. The molecular basis for “instruction” and secondary cooperating mutations can now be studied in our Mll-AF4 model.

GRN163L Inhibits Telomerase Activity in B-CLL Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5041-5041 ◽  
Author(s):  
Claudia Lin ◽  
Rajendra N. Damle ◽  
Nicholas Chiorazzi ◽  
Allison C. Chin
Keyword(s):  
Hematologic Malignancies ◽  
Telomerase Activity ◽  
Lymphocytic Leukemia ◽  
Telomerase Inhibition ◽  
Nuclear Compartments ◽  
Telomerase Inhibitor ◽  
Effective Inhibition ◽  
Xenograft Models

Abstract B-CLL cells, like many solid and hematologic malignancies, are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We and others have documented that CLL patients in poorer prognosis subsets, i.e., those without IgVH mutations, had shorter mean telomere lengths and higher telomerase levels than patients with IgVH mutations (Damle et al, 2004; Keating et al, 2003; Bechter et al 1998, Hultdin et al, 2003). Treatment with the telomerase inhibitor GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human hepatoma (Djojosubroto et al, 2005), ovarian carcinoma (Ertem et al, 2004, 2005), and multiple myeloma (CAG, MM.1S) cell lines in vitro and in vivo (AACR 2004 and 2005 Annual Meetings). Although no validated human B-CLL xenograft models exist, preliminary data indicate effective inhibition of telomerase in freshly thawed B-CLL cells upon exposure to GRN163L. We will present data demonstrating robust uptake of GRN163L into primary B-CLL patient cells, along with the subcellular distribution of the oligonucleotide into cytoplasmic and nuclear compartments. Comparison of the effect of GRN163L and a mismatch oligonucleotide control on telomerase inhibition will be described. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005.

Anergy in CLL: Moving Towards the Clinic

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4677-4677
Author(s):  
Benedetta Apollonio ◽  
Tania Veliz Rodriguez ◽  
Cristina Scielzo ◽  
Maria Teresa Sabrina Bertilaccio ◽  
Lydia Scarfò ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Nuclear Translocation ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Volume Growth ◽  
Lymphocytic Leukemia ◽  
Functional Features

Abstract B-Cell Receptor (BCR) triggering and responsiveness play a crucial role in the survival and expansion of Chronic Lymphocytic Leukemia (CLL) clones. In the recent past, several groups including ours have investigated the activation status of the signaling pathways originating from the leukemic BCR. Specifically we found that around 50% of CLL patients display a biochemical signature characterized by constitutive phosphorylation of ERK1/2 (pERK(+)) and constitutive nuclear translocation of NF-ATc1. These cases are unable to respond in vitro to BcR stimulation and are resistant to spontaneous apoptosis, thus resembling B lymphocytes previously anergized in vivo. Similar biochemical and functional features have been recently demonstrated in B leukemic cells persisting in the blood in patients treated with the BTK inhibitor, Ibrutinib, thereby making anergy an attractive target on the way to obtain eradication of the disease. CLL-associated B cell anergy can be specifically targeted by using different MAPK-inhibitors that have been shown to induce apoptosis selectively in the group of pERK(+) CLL. These data suggested that MAPK signalling can be efficiently inhibited in CLL for therapeutic purpose and that the phosphorylation status of ERK1/2 may represent a reliable biomarker to predict and monitor treatment response. However, even if the tested compounds were shown to be extremely efficient in inhibiting ERK1/2 phosphorylation in vitro, a lack of clinical activity was reported for many of them when tested in patients, mostly with solid tumors. In the present work, we used Trametinib, a specific MEK1/2 inhibitor, recently approved as a single-agent for the treatment of V600E mutated metastatic melanoma, and we investigated, at preclinical level, its activity in both primary CLL samples and a xenograft leukemic mouse model. Trametinib treatment completely inhibited constitutive ERK1/2 phosphorylation in 10 pERK1/2(+) samples at 3uM after 30 minutes treatment. Additionally, in 23 patients Trametinib treatment for 48 hours reduced cell viability in the cells from all 12 pERK1/2(+) patients (28,2% ± 3,5 mean survival) tested as compared to those from the pERK(-) group (11 cases, 58,1% ± 3,8 mean survival, p< 0,0001). To strengthen our in vitro data, we evaluated the effect of Trametinib administration in the xenograft Rag2-/-gc-/- mouse model subcutaneously transplanted with the CLL cell line MEC1, characterized by specific features of anergy. Mice were subcutaneously injected with 10x106 cells and then challenged with Trametinib (oral gavage with 1mg/kg or with vehicle alone) starting from day 21 after tumour injection for 14 days. The effect of the inhibitor was monitored by tumour volume growth. Trametinb administration delayed tumour growth (p<0.05 starting at days 27) and inhibited leukemic cell dissemination in the peripheral blood, peritoneal cavity and bone marrow. In summary, our data further support the idea that blocking anergic pathways may be highly effective not only in vitro but also in vivo with potential clinical implications at least in the subset of patients whose cells are characterized by anergic features, including those with persistent lymphocytosis when treated with Ibrutinib. The preclinical efficacy shown by Trametinib, a drug already approved for clinical use, warrants the implementation of controlled studies in CLL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4621-4634 ◽  
Author(s):  
Rosa Lapalombella ◽  
Qingxiang Sun ◽  
Katie Williams ◽  
Larissa Tangeman ◽  
Shruti Jha ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nuclear Export ◽  
Therapeutic Index ◽  
Hematologic Malignancies ◽  
Cysteine Residue ◽  
Lymphocytic Leukemia ◽  
Selective Inhibitors ◽  
Multiple Tumor

Abstract The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.

scholarly journals A Dual Bcl-2/xL Inhibitor Induces Tumor Cell Apoptosis in a Hematopoietic Xenograft Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5304-5304 ◽  
Author(s):  
Ammar Adam ◽  
Kate Byth ◽  
Paul Secrist ◽  
Alwin Schuller ◽  
Corinne Reimer ◽  
...  
Keyword(s):  
Single Agent ◽  
Family Members ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Dual Inhibitor ◽  
Platelet Recovery

Abstract Over-expression of the antiapoptotic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional standard of care therapies. Because Bcl-2 family members play key, but partially overlapping, roles as regulators of apoptosis, simultaneous inhibition of both Bcl-2 and Bcl-xL could serve as a promising anticancer strategy. Clinical validation of this concept has been demonstrated with multiple agents targeting different Bcl2 family members. For example, recent Phase I/II trials of the dual Bcl-2 / Bcl-xL inhibitor Navitoclax demonstrated a 20% response rate in relapsed, refractory CLL patients. However, in this study dosing was often limited by chronic thrombocytopenia, a well established side effect of inhibiting Bcl-xL. Here we disclose for the first time a novel and potent BH3 mimetic (Bcl2-32), with nanomolar binding affinity for Bcl-2 and Bcl-xL, (Ki = 3.3 and 8.5nM respectively). In contrast to Navitoclax which requires daily oral administration for activity, Bcl2-32 has shown promising efficacy on an intermittent dosing schedule that allows full platelet recovery between doses. In this poster, we describe the in vitro and in vivo activity profile of Bcl2-32 in a variety of cell types that highlights its potential as a dual inhibitor of Bcl2 and BclXL. In addition to exhibiting potent single agent anti-cancer activity in a sensitive Acute Lymphocytic Leukemia (RS4; 11) model with (TGI >100%, P < 0.001), Bcl2-32 also potentiates the effectiveness of standard chemotherapeutic agents in less sensitive DLBCL xenograft models. Taken together, these data suggest that Bcl2-32 represents an exciting development opportunity as single agent or in combination in a broad range of hematopoietic malignancies. Disclosures Adam: Astrazenenca: Employment. Secrist:AstraZeneca: Employment.

scholarly journals Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in Preclinical Models

2021 ◽  
Author(s):  
Shih-Shih Chen ◽  
Jacqueline Barrientos ◽  
Gerardo Ferrer ◽  
Priyadarshini Ravichandran ◽  
Michael Ibrahim ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Therapeutic Interventions ◽  
T Cell Migration ◽  
Dual Inhibition ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

Abstract Inhibitors of Bruton’s Tyrosine Kinase (BTKi) and phosphoinositide 3-kinase (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Here we demonstrate in vitro and in vivo the essential roles of PI3K-δ for CLL B-cell survival and migration and of PI3K-γ in T-cell migration and macrophage polarization; and more efficacious inhibition in CLL-cell burden by dual inhibition of PI3K-δ,γ. We also report an ibrutinib-resistant CLL case, whose clone exhibited BTK and PLCγ2 mutations, responded immediately to single agent duvelisib with a redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells. CLL samples from patients progressed on ibrutinib were also responsive to duvelisib in patient-derived xenografts irrespective of BTK mutations. Our data support dual inhibition of PI3K-δ,γ as a valuable approach for therapeutic interventions, including patients refractory to BTKi.

scholarly journals Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations With In Vitro and In Vivo Chemoresponses

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3379-3389 ◽  
Author(s):  
Shinichi Kitada ◽  
Janet Andersen ◽  
Sophie Akar ◽  
Juan M. Zapata ◽  
Shinichi Takayama ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Caspase 3 ◽  
Single Agent ◽  
White Blood Cells ◽  
Lymphocytic Leukemia ◽  
In Vitro Chemosensitivity ◽  
Apoptotic Protein

Abstract B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder caused primarily by defective programmed cell death (PCD), as opposed to increased cell proliferation. Defects in the PCD pathway also contribute to chemoresistance. The expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2–binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious interpretation of these observations. Higher levels of the anti-apoptotic protein BAG-1 were also marginally associated with failure to achieve CR (P = .04). Apoptosis-regulating proteins were not associated with patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were correlated with high numbers (>105/μL) of white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various apoptosis-regulating proteins. Although larger prospective studies are required before firm conclusions can be reached, these studies show the expression in B-CLLs of multiple apoptosis-regulating proteins and suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro chemosensitivity data, however, do not appear to be particularly useful in predicting responses in B-CLL.

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