Section of Hematology/Oncology, Department of Medicine, Medical College of Georgia, Augusta, GA, USA

Correspondence to: Dr A P Jillella, Section of Heme/Onc, BAA 5407, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA

Autoimmune thrombocytopenia after high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation occurs infrequently and only six cases meeting the criteria have been reported in the literature. All six of these patients had either acute myelogenous leukemia (AML) or lymphoblastic lymphoma (LBL). Immune thrombocytopenia following autologous transplantation in solid tumors has not been reported. We report the first case of autoimmune thrombocytopenia after high-dose chemotherapy and peripheral blood stem cell transplantation in a patient with breast cancer. A review of the literature has been conducted and treatment options are discussed. In two patients the condition resolved with treatment and in a third patient it improved. Immune-mediated thrombocytopenia in the post-transplant period is one of the causes of a low platelet count. It should be recognized promptly and treated. Bone Marrow Transplantation (2000) 26, 925-927.

breast cancer; autologous stem cell transplantation; autoimmune thrombocytopenia; ITP

The etiology of thrombocytopenia in the post-autologous transplantation period is extensive but usually includes causes such as delayed engraftment, infections, myelosuppressive effect of drugs and disease relapse. A rare cause of thrombocytopenia is immune-mediated destruction of platelets. There are several reports of immune-mediated thrombocytopenia after allogeneic transplantation.^1,2 However, there are few reported cases of autoimmune thrombocytopenia after autologous transplantation. A review of the literature revealed six well-documented cases of this phenomenon.^2,3,4,5,6 All the reported cases occurred in patients with either acute myelogenous leukemia or lymphoblastic lymphoma. To date, no cases of this phenomenon after autologous transplantation for solid tumors have been reported. The following is the first reported case of immune-mediated thrombocytopenia following myeloablative chemotherapy and peripheral blood stem cell transplantation for breast cancer. The literature of this rare entity has been reviewed and the treatment options and outcome in these patients are discussed.

Case history

A 58-year-old white female was diagnosed with a 2 ´ 2.5 cm lobular carcinoma for which she had a right modified radical mastectomy and axillary lymph node dissection. Twenty-one of 25 lymph nodes were positive for disease and the estrogen and progesterone receptors were positive. The only other significant past medical condition was vitiligo on the trunk. Because of the high risk of relapse, she was felt to be an appropriate candidate for high-dose chemotherapy and stem cell transplantation. She received four cycles of standard-dose chemotherapy with doxorubicin and cyclophosphamide (AC) followed by restaging which revealed no evidence of metastatic disease. Her complete blood count pre-transplant showed a white count of 6.7 ´ 10⁹/l, hemoglobin 12.1 g/dl and platelet count 336 ´ 10⁹/l. Stem cells were mobilized with chemotherapy consisting of etoposide and cyclophosphamide with G-CSF support. During white count recovery 47 ´ 10⁶/kg CD34⁺ cells were collected. The myeloablative regimen consisted of cyclophosphamide, thiotepa and carboplatin (CTCb) and all the harvested CD34⁺ cells were re-infused. The patient engrafted promptly and by day +8 was platelet transfusion independent with a platelet count of 23 ´ 10⁹/l. Her blood counts continued to improve and on day +21 the white count was 12.8 ´ 10⁹/l, hemoglobin 12.8 g/dl and platelet count 285 ´ 10⁹/l. At this point she complained of sinus fullness, cough and yellowish sputum production which was treated with 7 days of oral erythromycin. On day +41 a complete blood count revealed a white count of 9.1 ´ 10⁹/l, hemoglobin 12.2 g/dl and a platelet count of 14 ´ 10⁹/l. White cell differential included 38 neutrophils, 1 band, 52 lymphocytes and 9 monocytes. No evidence of bleeding was noted on physical examination and the spleen was not palpable. According to the patient, the vitiligo on the anterior abdominal wall had increased in extent. Serum chemistries were normal as were the total protein and serum electropheresis. Her medications included nadolol and nefazodone that she had been taking for several years. She had a clear nasal discharge and no other symptoms suggestive of infection. Since she did not have a fever or localizing symptoms, additional work-up for infection was not performed. A bone marrow aspirate and biopsy showed a normocellular marrow with normal maturation of all three cell lines and an increase in megakaryocytes. Flow cytometric findings showed that the lymphocyte gate in the CD45 side scatter map demonstrated predominantly T cells (95%) with an inverted CD4/CD8 ratio of 0.5 which suggests an increase in T suppressor (CD8) cells.

By day +48 there was no increase in the platelet count and the patient was started on prednisone at 1 mg/kg/day. On day +65 an antiplatelet antibody (PAIgG) test was carried out which was negative. By day +75 the platelet count was 70 + 10⁹/l; however, the patient developed Herpes zoster on the right arm and forearm. She was given acyclovir and by day +78 the platelet count had decreased to 7 ´ 10⁹/l in spite of receiving prednisone. Prednisone was discontinued and she was given intravenous immune globulin (IVIG) at 1 g/kg/day ´ 2 days. By day +87 the platelet count had risen to 275 ´ 10⁹/l. On day +95 the patient started radiation therapy to the right chest wall and by day +118 there was a decline in the platelet count to 134 ´ 10⁹/l. She was given another course of IVIG (1g/kg/day ´ 2 days) to ensure that the radiation therapy could be completed on schedule. On days +140 and +277 the platelet count was 164 ´ 10⁹/l and 249 ´ 10⁹/l respectively.

Discussion

This patient clearly had immune-mediated thrombocytopenia as demonstrated by an increase in megakaryocytes in the bone marrow aspirate in the face of a low platelet count. Additional support for the diagnosis is the fact that she responded both to steroids and IVIG. The platelet associated IgG (PAIgG) was negative. However, this test was ordered after the patient had been treated with steroids for 17 days. Additionally, this test has a positive predictive value of 46% and a negative predictive value of 82%.⁷ A review of the literature revealed six other cases of autoimmune thrombocytopenia (Table 1) post autologous transplant. Four patients had acute myelogenous leukemia (AML) and two had lymphoblastic lymphoma (LBL). One case of thrombocytopenia post autologous transplant in a breast cancer patient due to alloimmunization has been reported.⁸ Two other cases of possible autoimmune thrombocytopenia in patients with lymphoblastic lymphoma have been reported although evidence for this was inconclusive.⁹ It is interesting that all the reported cases of autoimmune thrombocytopenia post autologous transplant have been in either AML or LBL. This is the first reported case of autoimmune thrombocytopenia post autologous transplant in a solid tumor patient.

While the exact mechanism for the development of autoimmune thrombocytopenia is not known, several theories have been proposed. These include transient immune system imbalance post transplant, impaired suppressor T cell function, immune dysregulation due to thymic function damage caused by irradiation and chemotherapy, imbalances in the helper/suppressor T cell populations, altered expression of self antigens occurring as a result of physical damage to stem cells during in vitro handling of marrow prior to reinfusion and viral infections that occur during the post-transplant period.⁶ Our patient had a marked increase in T lymphocytes and there was an inversion of the CD4/CD8 ratio.

From a treatment perspective, one patient was treated with prednisolone with prompt resolution of the thrombocytopenia.⁴ A second patient was treated with prednisone with an initial improvement in the platelet count followed by a drop in the count. A splenectomy was planned but the patient had recurrent disease and received an allogeneic transplant.² A third patient was suspected of having a pulmonary fungal infection and danazol was used instead of prednisolone with prompt resolution of the thrombocytopenia.⁵ Our patient did not have a sustained response to prednisone but responded very quickly to IVIG. Even though experience is limited, immune-modulating drugs seem to be quite effective in the treatment of this condition. If there is a contraindication to treatment with prednisone, agents such as IVIG or danazol may be reasonable options. While uncommon, autoimmune thrombocytopenia should be considered in the differential diagnosis of thrombocytopenia in the post-transplant period and treated promptly.

1 Minchinton RM, Waters AH, Kendra J, Barrett AJ. Autoimmune thrombocytopenia acquired from an allogeneic bone-marrow graft. Lancet 1982; 2: 627-629, MEDLINE

2 Klumpp TR, Block CC, Caligiuri MA et al. Immune-mediated cytopenia following bone marrow transplantation: case reports and review of literature. Medicine 1992; 71: 73-83, MEDLINE

3 Ashihara E, Shimazaki C, Hirata T et al. Autoimmune thrombocytopenia following peripheral blood stem cell autografting. Bone Marrow Transplant 1993; 12: 297-299, MEDLINE

4 Sivakumaran M, Hutchinson RM, Pringle H et al. Thrombocytopenia following autologous bone marrow transplantation: evidence for autoimmune aetiology and B cell clonal involvement. Bone Marrow Transplant 1995; 15: 531-536, MEDLINE

5 Matsuishi E, Anzai K, Dohmen K et al. Sonographic diagnosis of venocclusive disease of the liver and danazol therapy for autoimmune thrombocytopenia in an autologous marrow transplant patient. Jpn J Clin Oncol 1990; 20: 188-192, MEDLINE

6 Garcia Vela JA, Ona F, Monteserin MC et al. Autoimmune thrombocytopenia after marrow transplantation (letter). Am J Hematol 1994; 46: 375, MEDLINE

7 Kelton JG, Powers PJ, Carter CJ. A prospective study of the usefulness of the measurement of platelet-associated IgG for the diagnosis of idiopathic thrombocytopenic purpura. Blood 1982; 60: 1050-1053, MEDLINE

8 Roy V, Verfaille CM. Refractory thrombocytopenia due to anti-Pl^A1 antibodies following autologous peripheral blood stem cell transplantation: case report and review of literature. Bone Marrow Transplant 1996; 17: 115-117, MEDLINE

9 Ritz J, Sallan SE, Bast RC et al. Autologous bone marrow transplantation in CALLA-positive acute lymphoblastic leukaemia after in vitro treatment with J5 monoclonal antibody and complement. Lancet 1982; 2: 60-63, MEDLINE

Table 1  Autoimmune thrombocytopenia post autologous transplant