Cytotoxic chemotherapy usually entails a combination of several different agents, with the goal of reducing or eliminating tumor cells. Normal hematopoietic and stromal cells are also affected (Figs. 15.1, 15.2, 15.3and 15.4) (1, 2, 3, 4, 5, 6).

This type of therapy produces three morphologic stages in the bone marrow: cell death within the first week, hypocellularity at 1 to 2 weeks, and regeneration at approximately 2 weeks and thereafter. The first posttherapy marrow biopsy specimen is usually taken at 2 weeks (14 days), and thus the initial stages of cell death are often missed.

At 10 to 14 days, the marrow is usually depleted of hematopoietic cells. Aspirate smears may show eosinophilic ground substance and mucoid strands between particles. Sections show the absence of hematopoietic cells, with a relative sparing of or increase in lymphocytes and plasma cells. The marrow sinusoids are dilated. The intersinusoidal area is filled with loose fibrinous material, hemorrhage, and foamy histiocytes. Fat cells are shrunken and surrounded by eosinophilic material. The persistence of leukemic blasts at this point is a poor prognostic sign.

Regeneration begins with the appearance of small erythroid colonies in the interstitial space (sometimes as early as 5 days), followed by scattered myeloid precursors, and finally by megakaryocytes. Hematopoietic dysplasia may be present during regeneration, which should not necessarily be taken as evidence of recurrent disease. Megakaryocytes growing back after chemotherapy may show hyperplasia and dysplastic changes; in extreme cases, they resemble acute megakaryocytic leukemia (Figs. 15.5, 15.6and 15.7).

During this phase, it may be difficult to differentiate normal precursors from leukemic blasts. Immunophenotyping and cytogenetic studies may be helpful in this regard. Ultimately, repeat biopsy after the passage of time is the most reliable way to ascertain whether tumor is present. Concomitant with marrow regrowth is a recovery in peripheral blood cell counts.

Specific bone marrow changes are difficult to link with specific agents because most cases are treated with multiagent chemotherapy. Dysplastic changes, both transient and permanent (clonal), occur with many of the commonly used drugs. Megaloblastic change is particularly associated with hydroxyurea and methotrexate (Figs. 15.8 and 15.9).

Differentiation therapy is used in the treatment of granulocytic malignancies, primarily acute promyelocytic leukemia. It not only induces maturation in the malignant cells but in many instances eliminates the malignant clone without affecting normal hematopoietic cells. Differentiation therapy is frequently combined with cytotoxic therapy for greater efficacy.

Hematopoietic growth factors are used primarily to promote recovery of peripheral cell counts after chemotherapy and radiotherapy but have also, on occasion, helped to produce clinical remission of clonal hematopoietic disease.