Spontaneous remission of B-cell chronic lymphocytic leukemia associated with T lymphocytic hyperplasia in bone marrow. (Case Reports).

ABSTRACT: Spontaneous remissions in B-cell chronic lymphocytic leukemia (B-CLL) are rare and none of them has been studied with immunophenotyping (by flow cytometry and immunohistochemistry) and genotyping. In this patient, studied after spontaneous remission had occurred, there was a residual T-lymphocytic hyperplasia in the bone marrow with a normal CD4:CD8 ratio. Absolute CD4 and CD8 counts and CD4:CD8 ratio in the peripheral blood were normal. Flow cytometry revealed no B-CLL cells in the peripheral blood and less than 2% B-CLL cells in the bone marrow.

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THE PATIENT we are describing had a well-documented spontaneous remission of previously progressive B-cell chronic lymphocytic leukemia (B-CLL). This was accompanied by hyperplasia of the normal T lymphocyte population in his bone marrow.

CASE REPORT

In May 1992, this 83-year-old man had evaluation of extensive bilateral cervical, axillary, and inguinal adenopa-thy (up to 2.0 cm in diameter) present since September 1991. White blood cell count was 13,300/[mm.sup.3] with 59% mature lymphocytes. Inguinal lymph node biopsy revealed a diffuse well-differentiated B-CLL (small lymphocytic lymphoma/chronic lymphocytic leukemia). Flow cytometry disclosed a monoclonal population of B lymphocytes positive for CD20 with coexpression of GD5. Computed tomography (CT) of the abdomen and pelvis revealed no adenopathy or hepatosplenomegaly. A diagnosis of B-CLL, Binet stage B, (1) Rai stage I, (2) was established. The patient was observed every 1 to 3 months over the next several years, receiving no treatment of the B-CLL. He remained asymptomatic throughout.

Bilateral cervical, axillary, and inguinal adenopathy remained stable for several months. Then, nodes started receding spontaneously in 1993, and by March 1994 only a few small nodes (1.0 to 1.5 cm in diameter) remained, limited to the inguinal regions. Subsequently, the bilateral inguinal adenopathy disappeared completely and CT in 1998 confirmed complete resolution of all adenopathy.

The absolute lymphocyte count (Figure) gradually rose to a peak level of 36,200/[mm.sup.3] in October 1994, then fell spontaneously to the range of 23,000 to 27,000/[mm.sup.3], where it remained for several months. In January 1996, the absolute lymphocyte count began falling spontaneously again, and by August 1998 it was 1,100/[mm.sup.3].

In August and November 1998, bone marrow aspirates showed a focal lymphocytosis, the majority of the lymphocytes being small and mature with a minor component of small lymphocytes with irregular nuclei. The marrow core biopsy showed focal random and paratrabecular aggregates of small lymphoid cells comprising about 20% of the marrow. Immunohistochemical study showed the lymphoid aggregates were primarily T lymphocytes with infrequent individually distributed B lymphocytes.

Cell suspension immunophenotyping done at Impath (New York, NY) showed only a minor population (less than 2%) of monoclonal B lymphocytes indicative of residual B-CLL, confirmed by genotyping with a faintly positive immunoglobulin heavy-chain gene rearrangement (also done at Impath). These cells showed an immunophenotype typical of B-CLL with positivity for CD5, CD 23, CD43, CD19 expression greater than CD2O, and weak surface monoclonal [lambda] light chains. The T lymphocytes were polyclonal, and the CD4:CD8 ratio was 1.1:1 (within normal limits for bone marrow). The T-cell receptor gene showed a germline configuration.

Results of a cytogenetic study on bone marrow in August 1998 were normal. Another study done in November 1998 showed loss of Y chromosome in 4 of 20 metaphases, a frequent finding in aging men (studies done at Genzyme Genetics).

Flow cytometry of peripheral blood in December 1998 showed an absolute CD4 lymphocyte count of 740/[mm.sup.3] and an absolute CD8 lymphocyte count of 384/[mm.sup.3] with a CD4:CD8 ratio of 1.9:1 (normal). There were no B-CLL lymphocytes present.

The patient was last seen in follow-up in July 2000. At that time, his B-CLL was still in remission. There was no palpable adenopathy or hepatosplenomegaly. Absolute lymphocyte count was 1,100/[mm.sup.3] On Wright's stained smear, the lymphocytes were small, mature, and normal in appearance.

DISCUSSION

Spontaneous complete remissions (SCR) in B-CLL have been reported previously, and the incidence of this has been estimated by some authors to be about In a number of these cases, SCR was documented only by peripheral blood data and clinical findings. Second malignancies appeared in several patients, usually months or years after the patient had entered 8CR. Significant numbers of patients had received some form of treatment for B-CLL before entering 8CR. Some of the patients had infections (usually viral) immediately preceding 8CR, and two patients had received smallpox vaccinations before remission. In some of the cases reported, a normal OK4:OK8 ratio was observed in the peripheral blood after the patient entered SCR. (3) Various mechanisms were postulated to be operating, including immunoregulatory, immunomodulatory, cytotoxic, endogenous interferon release, or antigenic competition. None of these cases was studied with flow cytometry, immunohistochemistry, or genotyping of peripheral blood, bone marrow, o r lymph nodes. T-lymphocyte hyperplasia in the bone marrow, present in this case, has not been previously reported. In this case, spontaneous regression in lymph nodes began nearly 2 years before absolute lymphocyte counts in the peripheral blood began to fall. The whole process, from beginning regression in lymph nodes to complete remission in peripheral blood, took about 5 years. Observations in this case do not prove that spontaneous remission of B-CLL was caused by preservation or enhancement of normal T-lymphocyte activity, but they do establish conclusively that this was a remission-associated event that has not been recognized in previously reported cases.

Although the in vivo role of T lymphocytes in the proliferation and accumulation of neoplastic B cells in B-CLL is not known, data from in vitro studies clearly indicate that T cells and their products play an important role in regulating, by various mechanisms, the malignant B cells. (8,9) The prominence and persistence of T cells in this patient's bone marrow suggest that the level of T-lymphocyte activity might be an important determinant of the natural history of B-CLL in the individual patient and might be a useful prognostic indicator. Only through studies relating prognosis to number and function of T cells can the impact of T cells on survival in B-CLL be addressed.

Our patient did not exhibit the inversion of the CD4:CD8 ratio to less than 1 as has been previously reported and postulated to be responsible for abnormalities in immune regulation. (10,11) Perhaps the preservation of CD4 helper cells in our patient prevented T-cell anergy toward the neoplastic B cells and contributed to his spontaneous remission.

CONCLUSIONS

This patient had a spontaneous remission of B-CLL, stage B. An important remission-associated event was an expanded normal T-lymphocyte population in the bone marrow. The level of T-lymphocyte activity may be one of the important determinants of the status of B-CLL in the individual patient and might be a useful prognostic indicator.

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References

(1.) Binct JL, Auguler A, Dighlero C, et al: A new prognostic classification of chronic lymphocytic leukemia derived from multivariate survival analysis. Cancer 1981; 48:198-206

(2.) Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219-234

(3.) Ribera JM, Vinolas N, Uabanoi Ipizua A, et al: Spontaneous complete remission in chronic lymphocytic leukemia: report of three cases and review of the literature. Blood Cells 1987; 12:471-479

(4.) Holmes JA, Whittaker JA: Spontaneous remission in chronic lymphocytic leukemia. Br J Haematol 1988; 69:9799

(5.) Buchi G, Termine G, Zippala C, et al: Spontaneous complete remission of CLL. report of a case studied with monoclonal antibodies. Acta Haematol 1983; 70:198-201

(6.) Han T: Spontaneous remission in chronic lymphocytic leukemia: an update, commentary. Blood Cells 1987; 12:481-483

(7.) Weirnick PH: Spontaneous remission of hematologic cancers. Natl Cancer Inst Monogr 1976; 44:35-38

(8.) Tinhofer I, Marschitz I, Kos M, et al: Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-l/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia Blood 1998; 91:4273-4281

(9.) Buhmann R, Nolte A, Westhaus D, et al: CD40-activated B-cell chronic lymphocytic leukemia cells for tumor immunotherapy: stimulation of allogeneic versus autologous T cells generates different types of effector cells. Blood 1999; 93:1992-2002

(10.) Herrmann F, Lochner A, Philippen H, et al: Imbalance of T-cell subpopulations in patients with chronic lymphocytic leukemia of the B cell type. Clin Exp Immunol 1982; 49:157-162

(11.) Platsoucas CD, Galinski M, Kempin 5, et al: Abnormal Tlymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies. J Immunol 1982; 129:2305-2312

RELATED ARTICLE: KEY POINTS

* None of these cases was studied with flow cytometry, immunohistochemistry, or genotyping of peripheral blood, bone marrow, or lymph nodes. T-lymphocyte hyperplasia in the bone marrow, present in this case, has not been previously reported.

* Observations in this case do not prove that spontaneous remission of B-CLL was caused by preservation or enhancement of normal T-lymphocyte activity, but they do establish conclusively that this was a remission-associated event that has not been recognized in previously reported cases.

* The prominence and persistence of T cells in this patient's bone marrow suggest that the level of T-lymphocyte activity might be an important determinant of the natural history of BOLL in the individual patient and might be a useful prognostic indicator.

* Perhaps the preservation of CD4 helper cells in our patient prevented T-cell anergy toward the neoplastic B cells and contributed to his spontaneous remission.

From the Memphis Cancer Center and the Pathology Group of the Midsouth, Memphis, Tenn.

Reprint requests to Jefferson D. Upshaw, Jr., MD, Memphis Cancer Center, 1068 Cresthaven, Suite 500, Memphis, TN 38119.