pentostatin and Leukemia--Myeloid

In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.

Topics: Adult; Aged; Aged, 80 and over; Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antigens, CD; Antigens, CD19; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; CD52 Antigen; Cell Adhesion Molecules; Cell Membrane; Combined Modality Therapy; Glycoproteins; Humans; Immunotherapy; Lectins; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Lymphatic Metastasis; Lymphocytes; Middle Aged; Pentostatin; Rats; Rituximab; Sialic Acid Binding Ig-like Lectin 2; Simplexvirus; Stem Cell Transplantation

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2'-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. PNA enhance the cell concentration of Ara-CTP, which is active metabolite of Ara-C. It is likely that the addition of granulocyte colony stimulating factor (G-CSF) may further improve the effects of FA (FLAG) or 2-CdA (CLAG). The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. An alternative approach to increase FLAG activity might be the addition of investigational drugs with novel mechanism of action, such as topoiromerase I inhibitors. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto--or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. Few studies have analyzed the role of PNA in CML. 2-CdA, FAMP and DCF can induce hematologic response in chronic phase of CML but cytogenetic responses have not been observed. Preliminary results suggest, that PNA used alone or in combination may be used as palliation in blast phase of the disease. However, currently, the role of these agents in CML is insignificant because of the high activity of Glivec in this disease. Finally, PNA, especially FA play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients, possibly also with myeloid malignancies.

Topics: Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cladribine; Clinical Trials as Topic; Cytarabine; Drug Synergism; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Pentostatin; Peripheral Blood Stem Cell Transplantation; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine

Purine analogs are effective in the treatment of several chronic lymphoproliferative disorders (CLPD) including hairy cell leukemia (HCL). To date, little evidence exists that these drugs are oncogenic. We report a case of HCL in a 66-year-old male treated with 2-deoxycoformycin. Just over 1 year following completion of his treatment, falling platelet and white cell counts were associated with the development of dysplastic features in his bone marrow and a rising blast cell count, culminating in the development of acute myeloid leukemia (AML). To the best of our knowledge only two previous cases of AML have been linked to treatment of HCL with purine analogs, both with 2-chlorodeoxyadenosine. We emphasize the need for long term follow up of patients treated with purine analogs and suggest that even those who are apparently cured be monitored periodically.

Topics: Acute Disease; Aged; Antimetabolites, Antineoplastic; Fatal Outcome; Humans; Leukemia, Hairy Cell; Leukemia, Myeloid; Leukocyte Count; Male; Myelodysplastic Syndromes; Neoplasms, Second Primary; Pentostatin; Platelet Count

The differentiation-inducing effect of clinically applicable analogs of deoxyadenosine on myelomonocytic leukemia cells was examined. Monocytoid leukemia cells were more sensitive to the analogs than were erythroid or myeloid leukemia cells based on the inhibition of cell growth and induction of cell differentiation. Monocytoid leukemia cells were highly sensitive to combined treatment with 2'-deoxycoformycin (dCF) and 9-beta-D-arabinofuranosyladenine (Ara A) for inducing cell differentiation. Ara A induced the differentiation of monocytoid leukemia U937 and THP-1 cells at concentrations which were 1/1000-10000 of that at which it induced the differentiation of other cell lines in the presence of dCF. In combination with a low concentration of 1alpha,25-dihydroxyvitamin D3 (VD3), the induction of the monocytic differentiation was greater in monoblastic U937 cells. Adenosine deaminase-resistant analogs such as fludarabine (FLU) and cladribine (CdA) also induced the differentiation of human myelomonocytic leukemia cells, and these analogs synergistically enhanced the differentiation induced by all-trans retinoic acid (ATRA) or VD3. CdA was the most potent analog for inducing the differentiation of myeloid leukemia NB4 and HL-60 cells in the presence or absence of ATRA. These findings indicate that dCF + Ara A and CdA may be effective for the therapy of acute monocytoid and myeloid leukemia, respectively.

Topics: Acute Disease; Adenosine Deaminase Inhibitors; Antimetabolites, Antineoplastic; Calcitriol; Cell Differentiation; Cladribine; Deoxyadenosines; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; HL-60 Cells; Humans; K562 Cells; Leukemia, Myeloid; Monocytes; Neoplasm Proteins; Neoplastic Stem Cells; Pentostatin; Tretinoin; Tumor Cells, Cultured; U937 Cells; Vidarabine

2'-Deoxycoformycin (dCF), a specific and potent inhibitor of adenosine deaminase, has demonstrated significant antitumor effect on lymphoid malignancies. The drug induced functional and morphologic differentiation of myeloid leukemia cells in combination with 2'-deoxyadenosine (dAd), but not dCF alone. NB4, a cell line derived from a patient with t(15; 17) acute promyelocytic leukemia (APL) underwent granulocytic differentiation when treated with all-trans retinoic acid (ATRA) or dCF plus dAd, but not with cytosine arabinoside. Pre-exposure of NB4 cells to ATRA greatly potentiated differentiation induced by dCF plus dAd, but pretreatment with dCF plus dAd before exposure to ATRA was less effective. Differentiation of NB4 cells was effectively induced by clinically applicable concentrations of dCF in combination with dAd. These findings may provide useful information about induction of differentiation in vivo.

Topics: Antibiotics, Antineoplastic; Cell Differentiation; Cytarabine; Deoxyadenosines; Drug Combinations; Growth Inhibitors; HL-60 Cells; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Pentostatin; Tretinoin; Tumor Cells, Cultured

Both established cell lines and human leukemic cells in circulating blood which were incubated in vitro with 2'-deoxyadenosine (AdR) plus adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), showed different metabolic responses depending upon the histologic and immunologic types of leukemia. The leukemic T-cell lines in tissue culture were 200-fold more sensitive than B-cell lines to the toxic effect of deoxyadenosine. The increased sensitivity of T-cell lines to AdR plus dCF was associated with the accumulation of deoxyadenosine triphosphate (dATP) in the cells. In established cell lines, an inverse correlation was observed between ED 50 of AdR plus dCF and the relative increase of dATP levels in the cells after the incubation of the cells with AdR plus dCF. In circulating leukemic cells that had been incubated with AdR and dCF, dATP arose in all groups but the correlation was not found between the sensitivity of AdR and the relative dATP accumulation. The failure to find the correlation in patients's leukemic cells may be attributed to the heterogeneity of the response of the blasts to AdR and dCF.

Topics: Acute Disease; B-Lymphocytes; Cell Line; Cells, Cultured; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Growth Inhibitors; Humans; Leukemia; Leukemia, Experimental; Leukemia, Myeloid; Pentostatin; Ribonucleosides; T-Lymphocytes; Thymidine

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.

Topics: Acute Disease; Adenosine Deaminase Inhibitors; Adolescent; Antibodies, Monoclonal; Antigens, Surface; Bone Marrow; Coformycin; Humans; Karyotyping; Leukemia; Leukemia, Myeloid; Male; Nucleoside Deaminases; Pentostatin; Phenotype; Ribonucleosides; T-Lymphocytes

Topics: Adenosine Deaminase; Antineoplastic Agents; Clinical Enzyme Tests; Coformycin; DNA Nucleotidylexotransferase; DNA Nucleotidyltransferases; Humans; Leukemia, Myeloid; Nucleoside Deaminases; Nucleotides; Pentostatin; Ribonucleosides

Leukemic cells incubated in vitro with 2'-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2'-deoxy-coformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD50, the concentration of dAdo that caused 50% inhibition of the incorporation of 3H-thymidine into cells in the presence of 20 microM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with 14C-dAdo plus DCF, a good correlation was observed between the LD50 and the ratio of 14C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The accumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto-ATPase, less well with cytoplasmic 5'-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5'-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.

Topics: Adenosine Deaminase; Adolescent; Deoxyadenine Nucleotides; Deoxyadenosines; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Lymphocytes; Lymphoma; Male; Nucleotidases; Pentostatin; Thymidine; Vidarabine