pentostatin and Lymphoproliferative-Disorders

Purine analogues have been shown to be active in a variety of B- and T-cell malignancies. Among them, pentostatin is also a tight binding inhibitor of adenosine deaminase (ADA), a key enzyme of purine metabolism. ADA is present in all human tissues, with the highest levels in the lymphoid system. Early clinical trials with pentostatin used high doses for acute lymphoblastic leukemias, which were characterized by high levels of ADA. Through the efforts of a few investigators, low-dose regimens that are active and well tolerated for indolent lymphoid malignancies have been developed. Myelosuppressive adverse effects have been shown to be minimal using these schedules. Lymphoplasmacytic lymphoma (LL) is an indolent chronic B-cell lymphoproliferative disorder moderately responsive to alkylating agents. All of the purine analogues have shown activity in LL. However, the advantage of pentostatin over the other agents is the relatively specific toxicity to lymphoid cells and the paucity of myelosuppression as a single agent. No direct comparisons of the agents have been investigated, although pentostatin may be considered to be preferred since it has not been associated with toxicity to myeloid progenitors in colony assays. This is of significance for patients who might benefit from high-dose chemotherapy with autologous stem cell transplantation.

Topics: Adenosine Deaminase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoproliferative Disorders; Pentostatin

CD26 is a surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) enzyme activity with multiple biological roles, including being intricately involved in immunoregulation as a T-cell activation molecule and as a regulator of chemokine function. T-cell lymphoid malignancies represent a heterogeneous group of diseases that are generally aggressive and are for the most part resistant to current treatment modalities. Previous studies showed that CD26 is expressed on selected T-cell neoplasms, suggesting a potential role for CD26 in tumor development. We review herein recent classification schemes for T-cell lymphoid malignancies that take into account various facets of their clinical presentation. In addition, we discuss findings supporting the conclusion that CD26 has an essential role in human T-cell activation, as well as its ability to regulate the biological effects of selected chemokines through its DPPIV activity. Finally, we will present recent work from our laboratory that indicates a potential role for CD26 as a molecular target for novel treatment modalities for T-cell lymphoid malignancies.

Topics: Adenosine Deaminase Inhibitors; Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Dipeptidyl Peptidase 4; Doxorubicin; Drug Design; Enzyme Inhibitors; Humans; Jurkat Cells; Leukemia, T-Cell; Lymphocyte Activation; Lymphocyte Cooperation; Lymphoma, T-Cell; Lymphoproliferative Disorders; Mice; Mice, SCID; Molecular Sequence Data; Neoplasm Proteins; Pentostatin; Prognosis; Transfection; World Health Organization

Three analogues of the purine 2-deoxyadenosine are available for the treatment of low grade lymphoproliferative disorders: pentostatin, cladribine and fludarabine. They have some common features in their mode of action, but differ both in their detailed pharmacology and the extent to which they have activity against specific lymphoid malignancies. Studies defining the scope of these drugs as single agents are now being followed by plans to exploit their potential synergy with other agents and clinically to define useful combination therapies.

Topics: Antineoplastic Agents; Cladribine; Humans; Lymphoproliferative Disorders; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Drug Resistance; Humans; Lymphoproliferative Disorders; Pentostatin; Purine Nucleosides; Vidarabine

Topics: Adenosine Deaminase Inhibitors; Animals; Clinical Trials as Topic; Humans; Leukemia; Lymphoma; Lymphoproliferative Disorders; Pentostatin

Pentostatin, a potent inhibitor of adenosine deaminase, is an antineoplastic agent which has been studied in the treatment of a variety of lymphoproliferative disorders. It is particularly effective in the treatment of hairy cell leukaemia, achieving complete remissions in 33 to 92% of patients, and has useful activity in treating B cell chronic lymphocytic leukaemia, prolymphocytic leukaemia, adult T cell leukaemia/lymphoma and cutaneous T cell lymphoma refractory to conventional chemotherapy. Initial results suggest that in the treatment of hairy cell leukaemia pentostatin achieves a more rapid response and higher frequency of complete remission with longer duration than interferon-alpha 2a, although it is still not known if some patients experiencing complete remission have been cured. The drug has yet to be directly compared with other promising purine analogues such as cladribine and fludarabine, and results of such comparisons are required before the ultimate role of pentostatin in the treatment of hairy cell leukaemia can be clearly established. However, pentostatin does produce a substantial response in a difficult therapeutic area and should be considered for initial treatment of hairy cell leukaemia.

Topics: Humans; Lymphoproliferative Disorders; Pentostatin; Treatment Outcome

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Multiple Myeloma; Pentostatin; Vidarabine

Laboratory and clinical data relating to the use of 2'-deoxycoformycin in human disease are reviewed. Pentostatin is an inhibitor of adenosine deaminase, an enzyme that is important for purine metabolism, but more than one mechanism may be involved in its cytotoxic action. Early studies with dCF employed large doses and for the most part were conducted in patients with acute lymphocytic leukaemia: responses were brief and relatively few, and severe renal, hepatic, and central nervous system toxicity were encountered, leading to temporary abandonment of clinical trials. More recently, it has been shown that dCF is effective in much smaller doses, with considerably less toxicity. It has proved to be more effective in low-grade lymphoid malignancies (chronic leukaemias, indolent lymphomas) than in more undifferentiated neoplasms (acute leukaemias, lymphoblastic and immunoblastic lymphomas), and is outstandingly effective in hairy cell leukaemia, both as initial therapy and after failure of splenectomy and interferon. Pentostatin is profoundly immunosuppressive: generally this is considered a disadvantage but its potential therapeutic exploitation merits investigation. Despite extensive knowledge of its biochemical effects, the optimal dose regimen of dCF and the value of combining it with purine antagonists remain to be defined.

Topics: Antineoplastic Agents; Coformycin; Humans; Lymphoproliferative Disorders; Pentostatin; Ribonucleosides

Topics: Adult; Animals; Antibodies, Monoclonal; Burkitt Lymphoma; Cats; Cattle; Cell Differentiation; Chickens; Child; Coformycin; Disease Models, Animal; Humans; Interleukin-2; Japan; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred AKR; Pentostatin; T-Lymphocytes

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Topics: Adolescent; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Crohn Disease; Cytarabine; Epirubicin; Epstein-Barr Virus Infections; Etoposide; Fatal Outcome; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunosuppressive Agents; Liver; Lymphoma, T-Cell, Peripheral; Lymphoproliferative Disorders; Male; Methylprednisolone; Pentostatin; Receptors, Antigen, T-Cell, gamma-delta; Remission Induction; Spleen; Transplantation, Homologous; Vidarabine

We describe the occurrence of myelodysplastic changes (hypogranular myeloid series and Pelger cells, dyserythropoiesis with ring sideroblasts) in five of 31 patients with chronic lymphoproliferative disorders after treatment with purine analogues. The bone marrows of 31 patients with chronic lymphoproliferative disorders before and after treatment with purine analogues were reviewed. The majority of patients had received extensive prior treatment, but none had dysplastic changes prior to treatment with purine analogues. We suggest that a purine analogue may have been responsible for dysplastic change and that further follow-up of this phenomenon is warranted.

Topics: 2-Chloroadenosine; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Deoxyadenosines; Female; Humans; Lymphoproliferative Disorders; Male; Myelodysplastic Syndromes; Pentostatin; Vidarabine

2'-Deoxycoformycin (DCF) is an experimental drug with specific lymphocytotoxic activity which has proved effective in the treatment of some lymphoproliferative syndromes (LPS). This paper deals with the results achieved in 6 patients with LPS, five of them with T-cell and one with B-cell malignancies, who received DCF as initial (2 cases) or salvage (4 cases) therapy. One patient with adult T-cell leukaemia-lymphoma achieved complete remission maintained for 36 months of follow-up; partial remission was attained in three others and the remaining two patients failed to respond to the treatment. Kidney toxicity was seen in three cases, and in two of them it was necessary to stop the treatment. Kidney toxicity was seen in three cases, and in two of them it was necessary to stop the treatment. Other untoward effects included nausea and vomiting (2 patients), myoclonus, dysaesthesia of the limbs and conjunctivitis arida (one case each). No haematologic or infectious complications were present in association with DCF treatment.

Topics: Adenosine Deaminase Inhibitors; Antineoplastic Agents; Drug Evaluation; Humans; Kidney Diseases; Lymphoproliferative Disorders; Pentostatin; T-Lymphocytes

The new monoclonal antibody (MoAb) B-ly7 was tested for its value in bone marrow diagnosis in patients with hairy cell leukemia (HCL). Cryostat sections of bone marrow biopsies were examined by an indirect immunoperoxidase technique. Lymphoma cells from all of 26 HCL cases investigated displayed strong surface membrane staining with the MoAb B-ly7, whereas tumor cells from only one of 63 patients with other lymphoproliferative disorders of B cell type reacted with this antibody. The strong reactivity of hairy cells (HCs) with this marker was not altered after therapy as demonstrated on control biopsies taken from patients treated with interferon(IFN)-alpha-2 or 2'deoxycoformycin(DCF) six-64 weeks after start of treatment. This fact as well as the very low number of B-ly7 positive cells found in a series of 13 normal bone marrow biopsies (mean: 0.3% of bone marrow cells, range: 0.0%-1.0%), which could easily be distinguished from HCs by their lower staining intensity and their morphological appearance, provided the basis for the detection of even single HCs. In our hands, in terms of sensitivity the immunohistological detection of HCs using the MoAb B-ly7 was not only superior to classical morphological techniques but also to other immunohistological parameters usually applied for this purpose. Therefore, this MoAb provides a marker for the identification of HCs, hence monitoring disease activity in HCL, and particularly for a critical response evaluation in patients undergoing treatment with IFN-alpha or DCF.

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Bone Marrow; Humans; Interferon Type I; Leukemia, Hairy Cell; Lymphoproliferative Disorders; Pentostatin

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Blood Transfusion; Cell Line; Coformycin; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Lymphocytes; Lymphoproliferative Disorders; Male; Mutation; Nucleoside Deaminases; Pentostatin; RNA, Messenger

2'-Deoxycoformycin, a tight-binding adenosine deaminase inhibitor, was administered to 11 adult patients with refractory lymphoproliferative diseases. Total doses ranged from 1.0 to 13.5 mg/kg. Inhibition of lymphoblast adenosine deaminase was obtained in all cases and tumor cytoreduction was noted in eight of ten cases, but no clinically meaningful remissions were obtained. Major toxicities occurred in five patients and included pulmonary edema, renal failure, central nervous system toxicity, hypotension, and death. Toxicity prevented retreatment in several cases in which marked cytoreduction occurred. Deoxyadenosine triphosphate accumulated to a variable extent in the red blood cells of all patients, and a reciprocal decrease in erythrocyte adenosine triphosphate was noted in all cases but one. All patients who suffered major organ toxicity had red blood cell deoxyadenosine triphosphate/adenosine triphosphate ratios greater than 1.3. These data suggest that the degree of replacement of adenosine triphosphate by deoxyadenosine triphosphate in erythrocytes reflects the biochemical milieu which may result in systemic toxicity following treatment with 2'-deoxycoformycin.

Topics: Adenine Nucleotides; Adenosine Deaminase Inhibitors; Adolescent; Adult; Aged; Coformycin; Erythrocytes; Female; Humans; Lymphocytes; Lymphoproliferative Disorders; Male; Middle Aged; Pentostatin; Ribonucleosides