Infectious complications after 2-chlorodeoxyadenosine therapy

Abstract: Infection is a common adverse event after therapy with nucleoside analogs, including 2-chlorodeoxyadenosine (CdA). However, the incidence of CdA-related infections has been poorly documented. In this study we compare, in the same patient population, the incidence of infectious episodes during the 6-month period before CdA to their incidence during the 6 months after initiating therapy. Ninety-five patients with hematological malignancies were studied. The incidence of infectious episodes almost doubled after CdA (0.87 vs. 0.47 during the pre-CdA period). The following factors were associated with an increased risk of infection after therapy: a history of previous chemotherapy, infection during the pre-CdA period and a diagnosis of chronic lymphocytic leukemia or of non-Hodgkin's lymphoma. Age, neutrophil and lymphocyte count at onset of CdA and time interval between diagnosis and therapy with CdA did not correlate with the infectious risk. The pattern of infections was modified after therapy with an increase of herpes virus infections (1 vs. 8 episodes, p = 0.04) and of fever of unknown origin (6 vs. 17 episodes, p = 0.03). In conclusion, a population at high risk for developing infectious complications after CdA therapy can be identified. Specific measures aimed at reducing the incidence of infectious events should concentrate on this population.     

Treatment of angioimmunoblastic lymphadenopathy with dysproteinemia using 2-chlorodeoxyadenosine

 Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is an atypical lympho-proliferative disorder with borderline features that often constitute a diagnostic challenge for the hematopathologist and a therapeutic dilemma for the treating clinician. Morphologically, the involved lymph nodes in this disorder are characterized by abnormal infilitration by immunoblasts and plasma cells, often in clusters or sheets. Regressed follicles may be seen; these are referred to as "burned out." Neovascularization is prominent, and a background of inflammatory cells is usually present. AILD was originally thought to represent an exaggerated autoimmune response. Because of the short median survival of the patients and the demonstration of T-cell clonality, AILD now is considered an aggressive lymphoma and is recognized as a subset of peripheral T-cell lymphoma by the REAL classification. In this article we present a patient with AILD who achieved durable patrial remission after treatment with one cycle of 2-chlorodeoxyadenosine. Received: 16 March 1994 / Accepted: 8 July 1996     

Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine

Langerhans cell histiocytosis (LCH) is a rare disorder which frequently involves the lungs of affected adults. Recent evidence suggests it is a clonal neoplastic disorder. Prognosis in this disease is variable, but in its multisystem form or when associated with progressive respiratory dysfunction, prognosis is poor. Recent case reports and a phase II trial of the antimonocyte drug 2-chlorodeoxy-adenosine (2CDA) have described success in treating LCH. We used 2CDA to treat a young Australian man with LCH involving lungs and bone. A complete symptomatic remission was achieved with no evidence of recurrence some 5 years after completion of chemotherapy.     

Hypereosinophilia during 2-chlorodeoxyadenosine treatment for hairy cell leukaemia

A 43-year-old male with newly diagnosed hairy cell leukaemia underwent a single course of 2-chlorodeoxyadenosine (2-CdA). Skin rash, facial swelling and marked eosinophilia developed 20 d after treatment and were resolved by 7 d of steroid therapy. Eosinophil peak in peripheral blood reached 1230 cells/μl. Flow cytometric analysis of the eosinophil population showed a high expression of the IL-2 receptor α-chain (CD25), representing up to 94% of gated cells. HLA-DR and CD4 antigens were constantly negative; eosinophils strongly reacted with the secretory form of the eosinophil cationic protein (ECP), recognized by EG2 monoclonal antibody. IL-5 serum levels were markedly elevated at the onset of eosinophilia, returned to normal levels after its disappearance and positively correlated with eosinophil count ( r  = 0.94, P  = 0.016). Eosinophilia is an uncommon finding after treatment with 2-CdA. It is unclear whether these phenomena represented a true allergic reaction to the drug or the effect of massive tumour cell lysis and haemopoietic pancytopenia with immunosuppression, which induced the release of IL-5 and possibly other cytokines.     

Cutaneous reactions in hairy cell leukaemia treated with 2-chlorodeoxyadenosine and allopurinol

The purine nucleoside analogue 2-chlorodeoxyadenosine (2-CdA) is currently considered by many as first-line therapy for hairy cell leukaemia. Cutaneous reactions have occasionally been reported with this drug, particularly if used with allopurinol. We report a high frequency of skin reactions in 15 consecutive patients with hairy cell leukaemia treated with 17 courses of 2-CdA. These reactions occurred only in those receiving allopurinol and, in two patients, were severe enough to warrant steroid therapy. The routine concomitant use of allopurinol is therefore not recommended in this setting.     

Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine

Langerhans cell histiocytosis (LCH) is a disorder characterized by proliferation of activated Langerhans cells. Immune dysregulation is believed to be part of the pathogenesis. Although current therapies are very effective at inducing remission, multiple recurrences and long-term sequelae are common for patients with low-risk disease, and a significant proportion of young patients die of their disease. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of 2-chloro-deoxyadenosine (2-CdA), a purine analogue with an antiproliferative effect on histiocytes and lymphocytes, in patients with recurrent or high-risk LCH. Six patients with recurrent LCH received 2-CdA (5-7 mg/m(2)/day for 5 days, repeated every 21-28 days). All patients achieved remission. With a median follow-up of 15 months (range, 3-25 months), 5 patients remain in remission. A patient with multisystem disease who recurred after 13 months, achieved a second remission with 2-CdA. Hematologic toxicity was minimal, and no infectious complications were documented. 2-CdA is among the most effective drugs for the treatment of LCH, and this is probably due to both its anti-proliferative and immunomodulatory effects. 2-CdA needs to be considered for the treatment of recurrent LCH. However, its incorporation into front-line treatment of patients with multi-system LCH needs further study.     

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA).

We administered one course of 2-chlorodeoxyadenosine (2CdA) at 4 mg/m2 daily for 7 days by continuous intravenous infusion to 46 patients with hairy cell leukemia. Complete remissions occurred in 36 patients (78%; 95% confidence limits, 63% to 89%), partial remissions in five (11%), and a minor response in one. One patient died of candida sepsis 3 weeks after beginning treatment and three patients were clearly resistant to therapy. These three either had morphologically atypical hairy cells, less than 20% of which expressed Ig light chain on the cell surface, or had failed prior treatment with deoxycoformycin and interferon-alpha. At a median of 37 weeks since discontinuation of therapy, recurrent thrombocytopenia has developed in one patient, whose marrow remains normal, while a bone marrow relapse has occurred in another patient, whose blood counts remain normal. Treatment produced a greater than 50% decrease in neutrophil count in 26 patients, which lasted 3 to 4 weeks and was associated with an increased incidence of febrile episodes. These episodes occurred in 21 patients but were associated with documented infection in only four patients. Decreases in the number of CD4+ lymphocytes appeared to occur regularly after treatment and have persisted for a median of 18 weeks without obvious clinical significance. Although years of follow-up will be needed, our results confirm Piro et al's observation (N Engl J Med 322: 1117, 1990) that 2CdA appears to be highly effective in the treatment of hairy cell leukemia.     

Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine

BACKGROUND AND OBJECTIVES: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL. DESIGN AND METHODS: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992. RESULTS: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively. INTERPRETATION AND CONCLUSIONS: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.     

Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.     

Fatal Mucor pneumonia after treatment with 2-chlorodeoxyadenosine for non-Hodgkin's-lymphoma

 Fungal infections, in addition to bacterial and opportunistic infections such as Pneumocystis carinii pneumonia, may evolve in patients with infectious complications due to iatrogenic immunosuppression. Aside from common Candida and Aspergillus species, rare fungi like Mucor must be considered in patients with neutropenia or prolonged impaired T-cell function. Here we report on a patient with a low grade lymphoma who was treated with 2-chlorodeoxyadenosine because of disease progression. After recovery from Pneumocystis carinii pneumonia he presented again with clinical signs of pneumonia. No pathogen was found on bronchoscopy and he died rapidly. In the lungs a massive necrosis was seen in which nonseptated hyphae identified as Mucor species were demonstrated. Received: 3 January 1996 / Accepted: 29 April 1996     

Long-term outcome of hairy cell leukemia treated with 2-chlorodeoxyadenosine

 The long-term results of both pretreated and previously untreated patients with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in patients who relapsed after 2-CdA treatment will be addressed. Forty-two consecutive patients (32 men, 10 women) with a median age of 56 years (range 32–75) at the time of initiation of 2-CdA treatment were analyzed. Ten patients were pretreated with either splenectomy (n=6) or interferon a (n=8) or deoxycoformycin (dCF) (n=3) or with all procedures in sequence. Two patients who did not respond to dCF did respond to 2-CdA. Median time to start of 2-CdA treatment of the ten pretreated patients was 47 months (10–160); 41 of the 42 (98%) achieved CR, and one patient reached a good partial response with a single cycle of 2-CdA. Ten of the 42 patients had no toxicities at all. Toxicities (WHO grades I–IV) were mainly of grades I and II; in one patient with a preexisting brain injury grade III neurotoxicity was seen, and one patient suffered a grade-IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2- to 3-month intervals, then at 6 months, and finally annually in all 42 patients. Median follow-up is 32 months (2–72). Disease-free survival from start of 2-CdA treatment is 75% at 6 years; 6/42 patients relapsed. Three of these patients were treated with 2-CdA again. All three patients reached another CR (+1, +2, +13). Four of the 42 patients had a second malignancy (carcinomas of the bladder, breast, cervix, prostate gland) before receiving 2-CdA. One patient died in CR due to the second malignancy. 2-CdA is a safe and effective treatment of HCL, inducing complete remissions in the majority of patients with only a single cycle of 2-CdA and a paucity of toxities. Responses are durable and long lasting. Patients relapsing following a treatment with 2-CdA seem to respond to this drug again. Received: July 30, 1998 / Accepted: October 26, 1998     

Treatment of refractory large granular lymphocytic leukemia with 2-chlorodeoxyadenosine

A 50-year-old man with large granular lymphocytic leukemia (CD3+, CD8+) complicated by severe pancytopenia and life-threatening infections refractory to therapy with prednisone, methotrexate, cyclosporine, and G-CSF is described. Treatment with two cycles of 2-chlorodeoxyadenosine (2-CDA) at 0.1 mg/kg by continuous intravenous infusion for 7 days each cycle resulted in resolution of cytopenias and clearance of leukemic cells. T-cell receptor gene rearrangement, initially present, was not detectable after therapy with 2-CDA. The rapid and complete response to 2-CDA after unsuccessful attempts with prior therapy suggests that 2-CDA should be considered for initial treatment of this disorder. Am. J. Hematol. 54:329–331, 1997. © 1997 Wiley-Liss, Inc.     

Efficacy of 2-chlorodeoxyadenosine in refractory factor VIII inhibitors in persons without hemophilia

The authors examined the efficacy of 2-chlorodeoxyadenosine (2-CDA) in the treatment of refractory inhibitors to factor VIII in persons without hemophilia. The drug was administered to 6 patients at a dose of 0.1 mg/kg as a 24-hour continuous infusion for a total of 7 days each cycle. An average of 3 immunosuppressive regimens per patient had been administered prior to enrollment in this study. The median inhibitor titer against human and porcine factor VIII before treatment with 2-CDA was 31 Bethesda units (BUs) and 9 BU, respectively. The median inhibitor titer against human and porcine factor VIII after treatment was 3.5 BU and 1.5 BU, respectively. The median time to reach nadir inhibitor titer in this study was 137 days, whereas the median time to reach a 50% increase in factor VIII was 117 days. No major toxicity was observed in any patient in this study. Patients with acquired inhibitors to factor VIII refractory to conventional immunosuppressive therapy may respond favorably to 2-CDA.     

Effect of 2-chlorodeoxyadenosine therapy on bone marrow fibrosis in hairy cell leukemia

The study shows the influence of 2-chlorodeoxyadenosine therapy on bone marrow fibrosis in patients with hairy cell leukemia. Eighteen patients were studied; bone marrow fibrosis was graded 0-4 according to the quantity and pattern of distribution of reticulin. The grade of bone marrow fibrosis was established before the therapy and then in 12- and 24-month intervals. Patients showed complete remission after the therapy and remarkable reduction of bone marrow fibrosis.     

New rearrangement pattern after treatment of hairy-cell leukemia with 2-chlorodeoxyadenosine

Leukemic hairy cells are clonally proliferating B-lymphoid cells with clonal rearrangements of genes for immunoglobulin chains. We describe a patient with a new hairy-cell clone after treatment with 2-chlorodeoxyadenosine (2-CdA). In this patient, a single course of 2-CdA resulted in good partial remission of hairy-cell leukemia, but Southern blot analysis of bone marrow biopsies and polymerase chain reaction using seminested amplifications with consensus primers revealed a new rearranged band 4 months after therapy with 2-CdA. Four years after therapy, the patient is in complete clinical remission and both bands disappeared during follow-up. The new rearranged band might have been related to prior treatment of hairy-cell leukemia with 2-CdA.     

Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes

2-Chlorodeoxyadenosine (CdA), an adenosine-deaminase-resistant purine deoxynucleoside, is markedly toxic toward human T-lymphoblastoid cell lines in vitro and is an effective agent against L1210 leukemia in vivo. The present studies have examined the toxicity, and in some cases, metabolism, of CdA in (1) multiple established human cell lines of varying phenotype, (2) leukemia and lymphoma cells taken directly from patients, (3) normal bone marrow cells, and (4) normal peripheral blood lymphocytes. Nanomolar concentrations of CdA blocked the proliferation of lymphoblastoid cell lines with a high ratio of deoxycytidine kinase to deoxynucleotidase. The drug had virtually no effect on the growth of cell lines derived from solid tissues. The CdA inhibited the spontaneous uptake of tritiated thymidine by many T and non-T, non-B acute lymphoblastic leukemia cell specimens at concentrations less than or equal to 5 nM. The same concentrations did not impair either thymidine uptake or granulocyte-monocyte colony formation by normal bone marrow cells. In common with deoxyadenosine, but unlike several other agents affecting purine and purine metabolism, CdA was lethal to resting normal T lymphocytes and to slowly dividing malignant T cells. In both resting and proliferating lymphocytes, the CdA was phosphorylated by deoxycytidine kinase and entered a rapidly turning over nucleotide pool. Dividing lymphocytes also incorporated abundant CdA into DNA. The selective toxicity of CdA toward both dividing and resting lymphocytes may render the drug useful as an immunosuppressive or antileukemic agent.