The signs and symptoms of ALL reflect the expansion of the leukemic clone in the bone marrow with impairment of normal hematopoiesis and the infiltration of nonhematopoietic tissues by the leukemic cells. The etiology of the suppression of normal hematopoiesis is not clear. Decreased numbers of normal progenitors, deficient production of normal hematopoietic growth factors, and production of inhibitory cytokines by the malignant clone have all been advocated as causes.

The most common initial symptoms of ALL are attributable to anemia, neutropenia, and thrombocytopenia. They are manifested by fatigue, weakness, fever, weight loss, and bleeding. Frequently, there is no detectable infectious cause of the fever, which may be due to ALL itself. The symptoms usually present abruptly but may be misdiagnosed as being related to an infectious process unless a detailed blood and bone marrow study is performed. Patients, especially children, may have severe pain resulting from an overgrowth of leukemic cells in the bone marrow; this most frequently affects the lower sternum and occasionally large joints and sometimes is due to bone marrow necrosis.

Almost 80% of patients with ALL have lymphadenopathy. Lymph nodes are usually painless and movable. The spleen and the liver are also frequently enlarged, with up to 70% to 75% of patients presenting with hepatomegaly and/or splenomegaly. Even when the liver is infiltrated, liver function is usually preserved. Lymph node, liver, and spleen enlargement is a representation of tumor burden and, therefore, when extensive, correlates with a poor prognosis. Other organs, such as the kidney cortex (in one third of cases), may be involved but usually without functional impairment. Less frequently, the lungs, heart, eyes, and gastrointestinal tract are involved. Skin involvement is seldom seen and is almost always associated with the pre-B-cell phenotype.

Central nervous system (CNS) involvement is seen in 5% of children and in less than 10% of adults with ALL. It is often seen among patients with mature B-cell ALL. However, many patients will eventually develop CNS disease if not adequately treated. Leukemia in the CNS presents with symptoms of increased intracranial pressure in 90% of cases, including headache, papilledema, nausea, vomiting, irritability, and lethargy. Signs of meningismus are common, and cranial nerves may also be affected, most frequently nerves III, IV, VI, and VII.

Testicular involvement is clinically evident in 1% of children with ALL at diagnosis, but it may be occult in as many as 25%. The testicles represent a "sanctuary site," where disease can persist after systemic therapy. The testicles can be a frequent site of relapse, seen in up to 10% to 15% of children in some series, but this is rare in adults. Disease in the testes presents as painless enlargement and firmness. Although involvement is usually unilateral, bilateral involvement is frequently diagnosed when a biopsy is performed. The disease is characterized by interstitial involvement, but the seminiferous tubules are affected later.