Lymphoma with Recurrent Cycles of Spontaneous Remission and Relapse — Possible Role of Apoptosis

Abstract

W E describe a patient with a unique mantle-cell lymphoma, with cycles of acute illness alternating with spontaneous remissions. During the acute phase the patient had fever, generalized lymphadenopathy, hepatosplenomegaly, increased liver-enzyme concentrations, leukocytosis, and thrombocytopenia. These bouts remitted after two to three weeks without treatment. Fifteen such cycles were documented over a period of 50 months.During the acute phase blast-like B lymphocytes in the blood expressed surface IgM, IgD, and CD5, whereas during clinical remission a small population of IgM and CD5 ϩ lymphocytes persisted. Two B-cell clones with differently rearranged heavy-chain genes consistently appeared in the blood during the recurrent acute phases. During the spontaneous remissions, one clone (termed the "acute clone") regressed while the second clone remained relatively stable. These findings suggest that proliferation and death of the acute-clone cells determined the cyclic nature of the disease. The lymphoma cells of the acute phase, but not those of remission, were shown to undergo spontaneous apoptosis in vitro. This process was enhanced by inhibitors of messenger RNA and protein synthesis, suggesting that it was regulated by preexisting factors with short halflives. No molecular alterations were demonstrated in bcl -2 and p53 genes, which are known to regulate apoptosis. C ASE R EPORTA 61-year-old man was hospitalized in March 1990 because of a high fever, perspiration, abdominal pain, and vomiting of one week's duration. Physical examination revealed generalized lymphadenopathy, splenomegaly (spleen palpable 3 cm below the costal margin), and hepatomegaly (liver tip palpable 5 cm below the costal margin). Laboratory tests revealed a hemoglobin level of 14 g per deciliter, leukocytosis (68,000 leukocytes per cubic millimeter), and a platelet count of 44,000 per cubic millimeter. The differential white-cell count showed 12 percent segmented and 88 percent mononuclear cells, 70 percent of which were blast-like, with large cleaved nuclei and prominent nucleoli. Examination of the bone marrow showed heavy infil-tration by the lymphoid cells with the same morphologic features. A lymph-node biopsy revealed intermediate-grade malignant lymphoma of the diffuse mixed, predominantly small-cleaved-cell type. Cellsurface markers of peripheral mononuclear cells showed that 80 to 90 percent were B cells expressing IgMk and CD5 but not CD10. The diagnosis of mantle-cell lymphoma was established. The t(11;14) translocation, common in mantle-cell lymphoma, 1 was not detected.The bilirubin concentration was 2.8 mg per deciliter (48 m mol per liter), the serum uric acid concentration was 9.6 mg per deciliter (571 m mol per liter), the blood urea nitrogen concentration was 56 mg per deciliter (20 mmol per liter), and liver-enzyme levels were substantially increased. Serologic tests for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, human T-cell lymphotropic virus type I, herpesviruses 1 and 6, and hepatitis A, B, ...

Proliferation Response of Leukemic Cells to CD70 Ligation Oscillates with Recurrent Remission and Relapse in a Low-Grade Lymphoma

“…CD70 and CD27 mAbs were applied to examine the possible involvement of cell surface CD70 and CD27 in activation and regression of the leukemic attacks. We have found that the rate of apoptosis of the leukemic cells was not affected by either CD70 or CD27 mAb, suggesting that cell surface CD70 and CD27 are not involved in the accelerated apoptosis of the acute phase cells or the slow apoptosis of the remission phase cells (22). However, PMA-mediated proliferation of the leukemic cells from remission phases, but not that of the acute phase cells, was considerably enhanced by CD70 mAb.…”

“…Extreme changes in the rate of apoptosis of the leukemic cells during the leukemic cycle (22,23) and oscillation in expression of some BCL-2 family genes (24) prompted us to examine the possible involvement of membrane CD70 and CD27 in apoptosis. Leukemic cells from acute phases and remission periods were incubated with 1-9 g/ml mAb directed to CD70 or CD27, (KI-24 or 1A4, respectively).…”

“…Thus, initiation of the attacks was indicated by high fever followed by a burst of blastlike lymphocytes in the blood peaking on the third day and decaying spontaneously within 2-3 wk. During remission periods 10 -60% of the mononuclear cells were the clonal IgM, CD5 ϩ CD19 ϩ leukemic cells (22). cDNA microarrays, representative of ϳ12,000 genes, were used to compare transcriptional profiles of the leukemic cells during remission periods and on days 3, 5, 7, and 11 of the attack.…”

“…We have reported previously a case of CD5-positive B cell lymphoma, diagnosed as atypical CLL/SLL, which is characterized by recurrent acute waves of active disease (22,23). The patient experienced within 8 years 27 cycles of leukemic waves followed by spontaneous partial remissions.…”

“…Nonetheless, 10 -60% of the peripheral lymphocytes were monoclonal B cells. The remission periods lasted 2-7 mo (22). Transient bouts of serum TNF-␣ and IL-10 preceded the acute phases, which were characterized by coexistence of CD40L ϩ T lymphocytes and lymphoma cells in the bone marrow (23).…”