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Keywords:

  • AILD;
  • treatment;
  • 2-CdA;
  • purine analogues

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Treatment of patients with angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) often constitutes a challenge for the clinical haematologist. Single- agent and combination chemotherapy have failed to increase the response rate or survival of patients with AILD. A total of seven patients with refractory or relapsed AILD were treated with 2-chlorodeoxyadenosine (2-CdA) for variable number of cycles. The overall response rate was 57% with two patients (28.5%) achieving complete and sustained response. 2-Chlorodeoxyadenosine appears to be an active agent for patients with previously treated AILD. Phase II studies evaluating the efficacy of this agent as front-line treatment for AILD are justified, especially in the absence of any effective therapy for this disorder.

Angioimmunoblastic lymphadenopathy with dysproteinaemia is a rare lymphoproliferative disorder characterized by fever, diffuse lymphadenopathy, hepatosplenomegaly, immune haemolytic anaemia, and polyclonal hypergammaglobulinaemia (Freter & Cossmann, 1993; Knecht, 1989). Typically, the involved lymph nodes show effacement of architecture, prominent neovascularization and infiltration by immunoblasts and plasma cells. The prognosis is poor with an estimated median survival of 18 months (Steinberg et al, 1988).

Treatment of AILD has been unsatisfactory, with only 25% of patients achieving complete and sustained remissions (Sallah & Gagnon, 1998). Atypical infections related to the underlying immune dysfunction or the treatment used remain the major cause of morbidity and mortality in this patient population.

2-Chlorodeoxyadenosine (2-CdA) has been shown to be an active agent in the treatment of spectrum of haematological malignancies including hairy cell leukaemia (Seymour et al, 1990), cutaneous T-cell lymphoma (Saven et al, 1992) and low-grade non-Hodgkin lymphoma (Kay et al, 1992). Based on these observations, 2-CdA was used as a salvage agent in seven patients, with refractory (four patients) or relapsed (three patients) AILD. We report in this study the response rate, follow-up, and toxicity associated with treatment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Patients were >18 years old with confirmed diagnosis of AILD by lymph node biopsy according to previously described criteria (Frizzera et al, 1975; Lukes & Tindle, 1975; Freter & Cossmann, 1993; Knecht, 1989). Briefly, the major histologic criteria that were required for the diagnosis of AILD included complete effacement of nodal architecture by a pleomorphic infiltrate of lymphocytes, immunoblasts and plasma cells, absence of germinal centres, and prominent arborization of postcapillary venules. These changes were seen in all lymph nodes examined. Expansion of the paracortical areas with extension of the pleomorphic infiltrate beyond the lymph node capsule was noted in five specimens, and interstitial deposits of periodic acid-Schiff positive substance were detected in four cases.

All patients had received at least one regimen of chemotherapy at least 4–8 weeks prior to treatment with 2-CdA. All patients had an Eastern Cooperative Group performance status of 0–2, and adequate hepatic and renal functions prior to salvage treatment with 2-CdA. Institutional review board approval was obtained and all patients signed written informed consent.

Pre-treatment evaluation included a complete history, physical examination, a complete blood count (CBC), a chemistry profile, a Coombs test, and serum protein electrophoresis. These tests were repeated before each cycle of chemotherapy.

All patients had a baseline chest radiograph, computed tomography scan of the chest, abdomen and pelvis, and bilateral bone marrow aspirate and biopsy. These staging studies were repeated after every two cycles of treatment and at the conclusion of therapy. Repeat lymph node biopsy was performed in three patients. 2-CdA was administered at 0.1 mg/kg/d by continuous intravenous infusion for a total of 7 d, given every 28–35 d.

Treatment-related toxicities were reported according to National Cancer of Institute guidelines.

For the purpose of this analysis a complete response (CR) was considered as absence of disease on clinical and staging studies, negative direct antiglobulin test, and normal bone marrow aspiration and biopsy, with no evidence of abnormal lymphoid aggregates. A partial response (PR) was defined as reduction by 50% of all involved areas. Normalization of antiglobulin test without reduction in size or areas of disease involvement, or any responses less than a PR were considered as no response (NR).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Data on seven evaluable patients were retrospectively analysed. The median age of the four men and three women was 55.5 years (range 38–73 years). Bone marrow involvement was present in four patients, and direct antiglobulin test was positive in three patients at the time of treatment with 2-CdA. Transformation to T-cell high-grade lymphoma was demonstrated on follow-up lymph node biopsy in two patients.

Of the seven patients, four had refractory disease and three had relapsed from partial response. The number of previous treatment regimens ranged from one to three (median two). A total of 22 cycles of 2-CdA were administered with a median of three cycles to each patient. The characteristics of the patients included in this study are depicted in Table I. Patient 1 has been reported previously (Sallah & Bernard, 1996).

Table 1. Table I. Characteristics of seven patients with AILD treated with 2-CdA. CHOP, cyclophosphamide, adriamycin, vincristine and prednisone; COP, cyclophosphamide, vincristine and prednisone; MVPP, nitrogen mustard, vinblastine, prednisone and procarbazine; PR, partial response; CR, complete response; NA, not available.Thumbnail image of

Two patients (28.5%) achieved a CR; the 95% confidence interval ranged from 22% to 72%. Two patients (28.5%) achieved a PR (95% confidence interval 16–63%). The median duration of response was 10.5 months (range 3–21+). The two patients who achieved a CR have remained in CR for 21 and 19 months respectively.

Non-haematological toxicity included fever without documented infection in two patients (28.5%); mild nausea and phlebitis were observed in one patient each. Grade 3 or 4 neutropenia was experienced by 3/7 patients (42.8%), grade 3 or 4 thrombocytopenia by two patients (28.5%), and grade 3 or 4 anaemia by one patient (14%).

Infectious complications were observed in three patients (42.8%). One patient had Pneumocysitis carinii, and a second patient developed cytomegalovirus pneumonitis. In one patient blood cultures were positive for P. aeuruginosa; also, in the same patient, granulomatous disease of the lung developed but biopsy and cultures failed to demonstrate growth of fungal or mycobacterial elements.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

The underlying disease process in AILD is poorly understood. Even though morphologic, immunologic and molecular abnormalities have been identified, their role in the pathogenesis of this disorder is still unknown.

The diagnosis of AILD remains a challenge for the haematopathologist and the clinical haematologist. Reactive lymphoid hyperplasia, T-cell lymphomas and Hodgkin disease are always considered in the differential diagnosis of this disorder (Sallah & Gagnon, 1998; Steinberg et al, 1988). The main histologic criteria supporting the diagnosis of AILD are the generalized effacement of the nodal architecture, infiltration by immunoblasts, plasma cells and occasionally eosinophils, and prominent vascularization. The presence of clusters or sheets of immunoblasts suggests high-grade lymphoma rather than AILD. In our view the diagnosis of AILD should always be made from a lymph node rather than an extranodal site. As in other atypical lymphoproliferative diseases, immunophenotypic features and molecular analysis have not always been helpful in establishing the nature of this disorder. Therefore it is not surprising that none of the major lymphoma classification systems has included AILD as a separate entity.

The course of patients with AILD is often variable and complicated by infections with conventional and opportunistic organisms, and by transformation into high-grade lymphomas. Unfortunately there are no established prognostic factors for patients with AILD, and single-agent or combination chemotherapy drugs have failed to significantly improve their survival. Most investigators, however, agree that achieving a CR is a prerequisite for long-term survival in this disease.

In the current analysis 2-CdA was used as salvage treatment in seven patients with refractory-relapsed AILD. Complete and sustained response was achieved in two patients, with an overall response rate of 57%. The high activity that the 2-CdA has shown in the treatment of T-cell malignancies (Saven et al, 1992) may account for the good response rate noted in this heavily pre-treated population. Other investigators have reported successful treatment of AILD using fludarabine (Ong, 1996). This suggests that purine analogues may be effective in the treatment of this disorder.

The toxicity observed in this study compares favourably with previous studies using 2-CdA for treatment of haematological malignancies (Kong et al, 1998).

Based on these encouraging results, and in the absence of standard treatment, phase II trials using 2-CdA for the treatment of patients with AILD are recommended and may provide an active front-line therapy for this disorder.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References
  • 1
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  • 2
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