Alpha-interferon-induced arthritis: clinical presentation treatment, and prevention.

OBJECTIVE: The therapeutic applications of alpha-interferon (IFN) have expanded greatly to include chronic viral hepatitis and malignant disorders. Autoimmune phenomena occur frequently with IFN therapy, but arthritis is uncommon. We describe the clinical features and treatment of IFN-induced arthritis. METHODS: A patient with chronic myelogenous leukemia who developed arthritis secondary to IFN therapy is presented. The clinical features and treatment of this condition in 37 additional cases are reviewed. RESULTS: The most common clinical presentation was symmetric polyarthritis. This was associated with antinuclear antibodies in 72% of patients and rheumatoid factor in 34%. Cessation of IFN, with or without the addition of antiinflammatory or remittive agents, resulted in remission of arthritis in 89% and 71% of the cases, respectively. Restarting IFN therapy resulted in recurrence of arthritis in 63%. In the patient described in this report, recurrence of arthritis was prevented by coadministration of hydroxychloroquine (HCQ) and prednisone. CONCLUSION: Arthritis is an uncommon complication of IFN therapy; but it may lead to cessation of this treatment modality. In such cases, coadministration of a remittive agent such as HCQ may enable reinstitution of IFN therapy without recurrence of arthritis.

Hairy cell leukemia: results of 2-chlorodeoxyadenosine therapy in Jerusalem.

Since the introduction of adenosine deaminase analogues the vast majority of patients with Hairy cell leukemia obtain lasting complete remission. In this report we describe our experience with 2 CdA in 18 patients with Hairy cell leukemia (HCL). Ten of these had failed previous interferon therapy, 6 were splenectomized before and of these, 4 had also received interferon. Sixteen of the 18 patients receiving 2 CdA achieved complete remission (CR), 1 patient is in good partial response (GPR) and 1 patient has relapsed. These results are in keeping with those reported from other larger centers and confirm the efficacy of 2-CdA. In this report IL-2 receptor (sIL-2R) levels were performed in most of the patients and found to be an accurate indicator of disease activity. Mean levels prior to therapy were 17200 U/ml (+/- 2500) and after successful therapy 970 U/ml (+/- 160). We confirm that 2-CdA treatment is the treatment of choice in HCL and suggest that sIL-2 levels be used as a parameter of disease activity.

Serum interleukin 1 beta levels as a marker in hairy cell leukemia: correlation with disease status and sIL-2R levels.

Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder of the B cell lineage. In the search for specific markers with prognostic significance we evaluated the clinical value of IL-1 beta and sIL-2R levels in HCL patients. HCL patients (25) were classified according to their clinical status as "active", "non active" disease or partial or complete remission and response treatment. We found a good correlation between IL-1 beta or IL-2R levels and disease activity: improved clinical status or response to different therapies were associated with decreasing IL-1 beta or sIL-2R levels. In contrast, lack of response to therapy or disease progression was reflected in increases in both IL-1 beta and sIL-2R levels. In some patients increases of both cytokines preceded clinical symptoms. In conclusion our results show that IL-1 beta and s-IL-2R levels may be used as reliable markers for monitoring HCL activity, assessing response to treatment and predicting early progression of disease.

Chronic Lymphocytic Leukemia in Young Adults: Report of Six Cases Under the Age of 30 Years.

We describe six rare patients with B-type CLL under the age of 30 years. All were males and four showed a relatively aggressive clinical course requiring initial chemotherapy at an early stage of their disease. Four of the six patients developed prominent generalized lymphadenopathy accompanied by splenomegaly and a rapid increase in the peripheral blood lymphocyte count or a doubling time of less than 12 months and were symptomatic. Of the six cases, one still has Stage A (0) disease, 16 months after diagnosis and has not yet been treated, while another 29 year old male, initially stage C (3) at diagnosis, progressed rapidly, despite chemotherapy and died after 42 months. Of the remaining four patients all responded well to treatment initially, however one 24 year old male has progressed rapidly from stage A (2) to Stage B (2), 14 months after initial response to chlorambucil and prednisone. Two patients remain in Stage A (0), two and eight years respectively after chemotherapy; while the patient with the longest follow up is currently 39 years old in good partial remission with Stage A (0) disease ten years after initial diagnosis, having responded well to Fludarabine, following a major flare up of his disease recently. The rare phenomenon of young patients with CLL is reviewed and management options relating to new therapeutic approaches for this sub-population of young patients are discussed.

Acute Monoblastic Leukemia with t(9;11) in a Patient Receiving Chemotherapy for Ovarian Cancer: Secondary Leukemia or Fortuitous Association of Two Neoplasias?

We describe the clinical course of a 61 years old patient who developed fulminant acute monoblastic leukemia (MSA, FAB) while still on systemic chemotherapy for an advanced adenocarcinoma of the ovary. The leukemia developed following chemotherapy with Cyclophosphamide and Cisplatin (9 cycles), and then Cyclophosphamide and Carboplatin (6 cycles) resulting in a partial remission of the ovarian tumor. Survival from the onset of acute leukemia was extremely short and the cause of death was intracerebral bleeding. Cytogenetic analysis of the leukemic cells revealed a 9:11 translocation, a pattern usually occurring in de novo leukemias. The literature on the association of solid tumors, particularly ovarian cancer, with acute leukemia is reviewed; while systemic chemotherapy for ovarian cancer definitely increases the risk of secondary leukemia, especially if alkylating agents are administered, the occurrence of leukemia during the administration of chemotherapy for the solid tumor is distinctly unusual. Our patient seems to be an additional example of a recently described therapy-related variant of acute leukemia developing shortly after the onset of chemotherapy and characterized by a rapidly downhill clinical course, a monocytic lineage and a cytogenetic rearrangement t(9;11)(p22;q23). While the number of these newly described cases is still small, this additional example should increase the awareness of this potential association in Cisplatin-treated patients.

Late Relapse in Hodgkin's Disease: Report of Five Cases and a Review of the Literature.

During the past 15 years the treatment of Hodgkin's disease (HD) with chemo/radiotherapy has been shown to appreciably improve the long-term prognosis of patients, even those with more advanced disease. In the past it was accepted that the probability of primary relapse 5 years after achieving complete remission (CR) was small and a 5-year disease-free period was sufficient to be considered as a cure. During the past 15 years, however, more data has been published relating to late relapses in these patients after an initial "cure" has been achieved. This report briefly examines our own experience with five patients initially "cured" who relapsed 5 to 11 years after achieving CR and also reviews recent literature on the subject. The phenomenon of late relapse has thus become a more important issue in the management of patients with HD.

Primary lymphoma of the parotid gland: a report of twelve cases with a review of the literature.

Primary extranodal lymphoma of the salivary gland is an extremely rare disease. In this report we describe twelve cases of primary lymphoma of the parotid gland seen at a single centre, and review the relevant literature. The 12 cases were treated in different departments and did not receive a uniform therapeutic approach. All three patients with Hodgkin's disease are still alive and two are in complete remission after initial radiotherapy. One of these cases developed stage 4 disease and had to receive combination chemotherapy subsequently. Of the 9 non-Hodgkin's lymphoma (NHL) patients, four had low grade NHL and 5 intermediate or high grade NHL. Of these, 2 died with disseminated disease. However, 6 are still alive and well from 1 to 5 years after therapy. These cases were treated with surgery alone, radiotherapy alone or combination chemotherapy with an anthracycline-bearing regimen. Consequently, we are unable to draw any conclusions relating the success of therapy in these cases, nor can we suggest therapeutic guidelines on the basis of this study alone. The treatment of parotid lymphoma is discussed briefly in the light of the available literature. In most cases, symptoms related to an enlarging mass in the parotid region, were evident. In the light of the above data, we suggest that, despite its rarity, lymphoma of the salivary gland should always be considered in the differential diagnosis of a parotid mass. No correlation between lymphoma and Sjogren's syndrome was noted in the present study.

Non-Hodgkin's lymphoma in patients 80 years of age or older.

BACKGROUND: Very elderly patients (> or =80 years old) with non-Hodgkin's lymphoma (NHL) frequently have co-morbid conditions and are generally excluded from clinical trials or even from treatment. The optimal treatment of these patients is unknown. PATIENTS AND METHODS: We reviewed the records of 109 patients > or =80 years at diagnosis of NHL (65 F/44 M; median age: 84 years, range; 80-95). RESULTS: Seventy-eight patients (72%) had aggressive NHL, 25 (23%) had indolent and NHL, eight had unclassified disease. Advanced-stage disease was noted in 54%. Forty patients (39%) had a poor ECOG performance status (PS), and 52 (49%) had an intermediate or high risk International Prognostic Index (IPI). Seventy-nine patients (72%) were treated with chemotherapy and 37 (34%) with radiotherapy. Initial chemotherapy consisted of chlorambucil in 15, oral etoposide in 2, and combination protocol in 62. Only 16% of patients received full-dose therapy, and only 50% completed > or =6 cycles of combination chemotherapy. The overall response rate for the 69 evaluable patients was 84% (complete 56.5%, partial 27.5%). Overall 5-year survival for the whole group was 39%, and median survival time was 26 months. CONCLUSION: A high response rate can be achieved in very elderly NHL patients despite aggressive histology, poor prognostic features, and reduced doses of chemotherapy. Age alone should not be a contraindication to treatment.

Changes in the natural history of invasive pulmonary aspergillosis in neutropenic leukemic patients.

We describe five patients with acute leukemia who during the period of chemotherapy-induced neutropenia developed invasive pulmonary aspergillosis. Amphotericin B was initiated early in the febrile neutropenic episode at a dose of 1-1.5 mg/kg per day. Four of the five patients had normal chest films at the time amphotericin B was started and only later developed infiltrates, which subsequently progressed to cavitation formation with resolution of the infiltrates around the cavitations. This is compatible with primary aspergilloma or invasive pulmonary aspergillosis. The patients experienced partial (2 patients) or complete resolution (3 patients) of the process, and none died of the fungal infection. In the past, infection with invasive aspergillosis carried a high mortality. We believe that this positive outcome constitutes a change in the natural history of invasive pulmonary aspergillosis in neutropenic patients as a result of the early initiation of high dose amphotericin B. We recommend the early empiric use of amphotericin B therapy in febrile neutropenic patients not responding to broad-spectrum antibiotics, and that the minimal initial dose be 1 mg/kg per day especially in institutions carrying a high incidence of aspergillosis.

Radiation leukemogenesis: quantitative relationship between pre-leukemic cells in the thymus and lymphoma induction.

Fractionated irradiation of C57BL/6 mice induces a population of pre-leukemic (PL) cells that progress into mature thymic lymphomas after a latency of 4 to 6 months. Transfer of graded numbers of thymocytes from an irradiated mouse into recipient mice indicated that PL cells first appear in the thymus 6 weeks after irradiation. The initial proportion of the thymic PL cells is > or = 10(-5) and their frequency continuously increases with time, reaching > or = 10(-3) 10 weeks after irradiation. The PL cell population that emerges early during the pre-malignant latency consists of pleioclonal T lymphocytes. However, within 4 weeks a dominant PL clone can be detected which becomes the progenitor of a clonal lymphoma 9 to 15 weeks later. These results suggest that radiation leukemogenesis involves continuous accumulation of pleioclonal PL cells in the thymus, one of which is then selected for further maturation into frank lymphoma.

Aggressive bone destruction in acute megakaryocytic leukemia: a rare presentation.

Acute megakaryocytic leukemia (AMKL) is a rare subtype of acute myeloid leukemia which is more common in children. Although the bone changes in leukemia are well documented, there are only a few reports of the AMKL subtype. We present an exceptional case of a young girl with very aggressive AMKL, who demonstrated symmetrical destructive lesions of the long bones characteristic of this disease. Lytic lesions of the skull and jaws were also present, and these have not been previously described in AMKL.

Cutaneous findings in chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is a malignancy characterized by clonal expansion of B lymphocytes with distinct morphology and immunophenotype. The dermatological literature relating to CLL is sparse. A global descriptive survey of a large number of CLL patients has not previously been published. OBJECTIVES: To report the spectrum of dermatological conditions seen in a large series of CLL patients. METHODS: Skin complications in patients with established CLL were identified retrospectively from clinical and photographic records, principally a database of over 750 consecutive cases. These events were classified, enumerated and compared. RESULTS: Forty patients with 125 skin manifestations were identified and studied. Forty-one manifestations had documented clinical or histological atypia. In 21 of these 41 complications there had been no prior immunosuppressive therapy. We observed that cutaneous malignancies frequently presented atypically both clinically and histologically. There were 18 patients with 56 instances of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), and clinical atypia was more common with SCC than with BCC. Other cutaneous findings included varicella zoster (n = 6), leukaemia cutis (n = 3), acute graft-versus-host disease (n = 5), cutaneous drug eruptions (n = 9), multiple warts (n = 3), herpes simplex (n = 3), cutaneous T-cell lymphoma (n = 2), eosinophilic folliculitis (n = 2), malignant melanoma (n = 2) and Merkel cell tumour (n = 2). CONCLUSIONS: We have identified a range of dermatological conditions in CLL patients, with a tendency to atypical presentations. The atypia was independent of prior chemotherapy.

Prevention of herpes simplex virus (HSV) infection in recipients of HLA-matched T-lymphocyte-depleted bone marrow allografts.

The occurrence of HSV infection and the effect of prophylaxis with oral acyclovir were evaluated prospectively in 34 consecutive patients undergoing bone marrow transplantation (BMT). All allogeneic BMT procedures involved T-lymphocyte depletion for prevention of graft-vs.-host disease (GVHD). Five HSV-seronegative patients did not receive acyclovir, and they did not develop HSV infection. Oral acyclovir was administered to 15 HSV-seropositive BMT recipients; 14 untreated HSV-seropositive BMT recipients served as a control group. The adult dose of acyclovir was 400 mg three times a day on Days -6 to +14 and 200 mg three times a day on Days +15 to +90. Children received 500 mg/m2 per day divided into three equal doses on Days -6 to +14 and 250 mg/m2 per day again divided into three on Days +15 to +90. In the group on prophylaxis, only one developed HSV infection during the time prior to engraftment. In the reference group, 12 of 14 (85.7%) developed oral HSV infection within 0 to 16 days (median 11 days) after the transplantation. Time for engraftment (duration of neutropenia) was shorter in patients receiving acyclovir. After engraftment, HSV infection was not observed during administration or following discontinuation of acyclovir on Day 90, but occurred in three patients in whom acyclovir was discontinued on Days 25, 35 and 40 after BMT. In the untreated group, two patients had recurrence of HSV infection on Days 40 to 60, and one had two infectious episodes. GVHD occurred in only two recipients, neither of whom had HSV infection. We conclude that the incidence of HSV infection during the period until engraftment in recipients of T-lymphocyte-depleted BMT is high, similar to that reported by others in recipients of whole BMT. Relatively low-dose oral acyclovir administered for 90 days can effectively prevent HSV infections in previously HSV-seropositive BMT recipients and may also shorten the period until engraftment.