Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma presenting simultaneously with acquired hemophilia and warm autoimmune hemolytic anemia

Abstract

Since both acquired factor VIII inhibitor in non-hemophiliac patients and warm autoimmune hemolytic anemia are uncommon disorders with no case-controlled trials, managing these diseases can be challenging. We present a case of a 75-year-old man in whom both diseases were present simultaneously with life-threatening bleeding. This case is an example of the successful initial management and long-term treatment of acquired hemophilia A, warm autoimmune hemolytic anemia, and chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, prednisone, and cyclophosphamide.

An acquired factor VIII inhibitor in non-hemophiliac patients has a mortality of 8% to 22% and has a low occurrence rate of approximately 1 out of 1,000,000 people per year (1). Autoimmune hemolytic anemia is also an uncommon disorder that occurs in 1 to 3 persons out of 100,000 per year with a mortality of about 11% (2). Since controlled trials are unavailable for both diseases because of their rarity, management can be challenging, especially if the diseases present simultaneously with life-threatening bleeding.

CASE PRESENTATION

A 75-year-old man with type 2 diabetes mellitus and chronic kidney disease was transferred to Scott & White Memorial Hospital from an outside facility with weight loss, bruising, and swelling of his left arm (Figure 1). An ultrasound of the left upper extremity was concerning for a subcutaneous hemorrhage. A computed tomography scan of the chest, abdomen, and pelvis was negative for hematoma but showed periaortic lymphadenopathy (largest 1 cm) and splenomegaly (20 cm), concerning for lymphoma. He had multiple laboratory abnormalities including a hemoglobin of 6.6 g/dL, an activated partial thromboplastin time of 91.1 sec, undetectable haptoglobin, elevated lactate dehydrogenase, and a positive direct antiglobulin specific for IgG. Flow cytometry performed on peripheral blood was consistent with chronic lymphocytic leukemia (CLL). The white blood cell count of 5.4 and the absolute lymphocyte count within normal limits at 2.42 made the clinical diagnosis consistent with CLL/small lymphocytic lymphoma (SLL). A Coombs test was positive for IgG, diagnosing warm autoimmune hemolytic anemia (WAHA). To evaluate the activated partial thromboplastin time, a mixing study was performed and did not correct appropriately. The factor VIII concentration was 0%, and the factor VIII inhibitor titer was elevated at 18.4 Bethesda units/mL, consistent with acquired hemophilia A (AHA). Bone marrow results (Figure 2) and immunohistochemical stains (Figure 3) corroborated the diagnoses.

Figure 1.

Subcutaneous hemorrhaging in our patient with a factor VIII inhibitor.

Figure 2.

A bone marrow biopsy showing markedly increased cellularity, estimated at approximately 70%, with evidence of trilineage maturation with ample megakaryocytes, erythroid precursors, and maturing granulocytes. Multiple lymphocytic aggregates are identified.

Figure 3.

Immunohistochemical stains showing strong positivity for (a) PAX-5, (b) CD20, (c) CD5, and (d) kappa (magnification 400×). Strong positivity was also shown for Zap-70, and lambda showed nonspecific staining. This was interpreted as consistent with CLL with about a 40% involvement of the marrow.

Initial treatment consisted of prednisone therapy (1 mg/kg daily) and transfusion support with red blood cells. Recombinant factor VII was utilized for acute bleeding. The patient's hemolysis resolved on prednisone, but he continued to be dependent on transfusions with progressive subcutaneous hemorrhaging. Cyclophosphamide (100 mg daily) and rituximab therapy (375 mg/m² weekly for 2 weeks) were initiated. One week later, the patient's factor VIII concentration had improved to 5%, and his factor VIII inhibitor titer had decreased to 1.5 Bethesda units/mL. He was continued on cyclophosphamide and prednisone at discharge; 2 months later, he had a factor VIII inhibitor titer of 0.25 Bethesda units/mL and factor VIII activity of 34%. Factor VIII activity eventually normalized, the inhibitor titer returned to 0, and the spleen was no longer palpable. Prednisone was tapered and cyclophosphamide was continued, resulting in durable remission over 3 years to date.

DISCUSSION

An acquired factor VIII deficiency is a rare bleeding disorder usually presenting with purpura and/or soft tissue bleeding. Factor VIII inhibitors mostly consist of IgG1 and IgG4 autoantibodies acting against the factor VIII molecule and interfering with the coagulant activity of factor VIII (4). Factor VIII inhibitors interfere with factor VIII binding to factor IXa and disrupt the binding of factor VIII to von Willebrand factor and phospholipids (3). Given the rarity of the disease, no case-controlled studies have been performed to discern appropriate treatment of AHA (5). Initial management of AHA focuses on achieving control of bleeding episodes and inhibitor suppression (6). Long-term inhibitor suppression or eradication often requires immunosuppressive therapy. Achieving complete remission (CR) (undetectable inhibitor level) is crucial because patients who do not achieve CR have worsened survival (7). The combination of prednisone and cyclophosphamide is the current mainstay of treatment and leads to remission in 66.7% of patients (3). Rituximab is often considered a second-line treatment, but some believe it should be used first line with prednisone and cyclophosphamide if the inhibitor titer is >5 (4).

The European Acquired Haemophilia Registry is the largest dataset analyzing immunosuppressive treatment in AHA (7). Based on results from the registry, steroids combined with cyclophosphamide achieved the best remission rates, showing CR in 70% of patients (7). The registry also showed increased rates of relapse with the use of steroids with cyclophosphamide when compared with rituximab-based regimens. Rituximab-based regimens had a CR of 59% and a 3% relapse rate (compared with a relapse rate of 12% with steroids and cyclophosphamide) (7). Rituximab alone was least likely to achieve a stable CR and required a longer time to achieve negligible inhibitor levels and normal factor VIII levels in the registry (6).

The diagnosis of WAHA is confirmed when other forms of anemia have been excluded and there are laboratory signs of hemolysis. Hemolysis in CLL develops secondary to IgG antibodies produced by nonmalignant B-cell clones directed against red blood cell antigens, leading to clearance by the spleen and extravascular hemolysis (8). The first-line treatment is steroids, 1 mg/kg/day, but this results in long-term remission in <15% to 20% of patients (9). Second-line treatments include azathioprine at 3 to 4 mg/kg/day, cyclophosphamide (low or high dose), or rituximab at 375 mg/m². Rituximab results in response rates of 60% to 70%, but only 20% of patients achieve 5 years of remission (9).

Treatment of WAHA and CLL has been found to be successful with rituximab, cyclophosphamide, and dexamethasone, resulting in a response rate of 89.5% in a small cohort of 26 patients (8). When also considering AHA, the combination of cyclophosphamide, steroids, and rituximab achieved a quick and durable response. Immunosuppression was the focus of treatment, given the known immune-mediated dysfunction that occurs in patients with CLL, which likely contributed to AHA and WAHA.