Chronic Leukemias: CLL, CML & Hairy Cell Leukemia
Three chronic leukemias, three very different game plans
Chronic lymphocytic leukemia: diagnosis and staging
Who and how. CLL is the most common adult leukemia in Western countries and is usually discovered on a routine CBC in a patient around 70. The diagnosis requires a sustained (at least 3 months) clonal B lymphocytosis of at least 5000/µL made up of small, mature-appearing lymphocytes. Smudge cells on the smear are fragile CLL cells crushed during slide preparation, an artifact that supports but never proves the diagnosis. The same disease presenting mainly in nodes with fewer than 5000/µL circulating clonal cells is called small lymphocytic lymphoma (SLL).
Flow cytometry. Peripheral blood flow cytometry confirms the diagnosis without a marrow biopsy: the cells are CD19+, CD5+, and CD23+ with dim CD20 and dim surface immunoglobulin restricted to a single light chain (κ or λ). Mantle cell lymphoma is also CD5+ but is CD23− and cyclin D1+; CD10 marks germinal-center lymphomas, and CD103 marks hairy cell leukemia.
| Stage | Findings | Risk |
|---|---|---|
| Rai 0 | Lymphocytosis only | Low |
| Rai I–II | Plus lymphadenopathy (I) or hepatomegaly/splenomegaly (II) | Intermediate |
| Rai III–IV | Plus anemia with Hb <11 g/dL (III) or platelets <100,000/µL (IV) | High |
| Binet A / B | Fewer than 3 / 3 or more involved lymphoid areas, no cytopenia | Low / intermediate |
| Binet C | Hb <10 g/dL or platelets <100,000/µL | High |
CLL: when and how to treat
Watch and wait. Early or asymptomatic CLL is observed with periodic CBCs, because treating early disease does not improve survival. A high lymphocyte count by itself is never an indication; leukostasis is rare in CLL even above 100,000/µL because small mature lymphocytes are deformable, unlike myeloblasts. Treatment is indicated for:
- B symptoms (fevers, drenching night sweats, significant weight loss) or disabling fatigue
- Progressive marrow failure with worsening anemia or thrombocytopenia
- Massive, progressive, or symptomatic lymphadenopathy or splenomegaly
- Lymphocyte doubling time shorter than 6 months
- Autoimmune cytopenias that do not respond to steroids
Pretreatment genetics. Before starting therapy, test for del(17p) by FISH, TP53 mutation, and IGHV mutation status. TP53-disrupted disease responds poorly to chemoimmunotherapy (FCR, bendamustine-rituximab, chlorambucil-based regimens) and is treated with a BTK inhibitor or venetoclax-based therapy, which work independently of p53. Unmutated IGHV predicts worse outcomes; isolated del(13q) is favorable.
BTK inhibitors. Ibrutinib and the more selective, better-tolerated acalabrutinib and zanubrutinib covalently block Bruton tyrosine kinase in the B-cell receptor pathway and are taken daily until progression. Ibrutinib causes atrial fibrillation, bleeding from platelet dysfunction (hold it around surgery and use caution with anticoagulants), hypertension, arthralgias, and diarrhea.
Venetoclax plus obinutuzumab. Venetoclax inhibits the antiapoptotic protein BCL-2 and, combined with the anti-CD20 antibody obinutuzumab, gives a fixed 12-month course. Because it kills CLL cells quickly, venetoclax starts with a 5-week ramp-up from 20 to 400 mg, with hydration, allopurinol, and tumor lysis laboratory monitoring; patients with a high tumor burden are hospitalized for the first doses. Neutropenia is the other main toxicity.
CLL complications
Autoimmune cytopenias. Immune dysregulation causes warm autoimmune hemolytic anemia (positive DAT, spherocytes, reticulocytosis, elevated indirect bilirubin and LDH) and immune thrombocytopenia. Glucocorticoids (with or without rituximab) are first-line; refractory cases prompt CLL-directed therapy, and splenectomy is reserved for refractory disease. Fludarabine can trigger or worsen AIHA.
Infection. Hypogammaglobulinemia, together with neutropenia and treatment-related immune defects, makes infection the leading cause of death. Recurrent sinusitis and pneumonia with encapsulated bacteria (S. pneumoniae, H. influenzae) are typical. IVIG is given for recurrent serious infections with low IgG; inactivated vaccines (pneumococcal, influenza, recombinant zoster) are recommended, and live vaccines are avoided.
Richter transformation. About 2–10% of patients develop an aggressive lymphoma, usually DLBCL and rarely Hodgkin lymphoma. Clues are rapid growth of one node group, new B symptoms, rising LDH, or hypercalcemia. PET-CT directs excisional biopsy to the most FDG-avid node, since a random node may show only the underlying CLL. Prognosis is poor; treatment is DLBCL-type chemoimmunotherapy followed, when feasible, by allogeneic transplant.
Chronic myeloid leukemia
Pathogenesis and presentation. The Philadelphia chromosome, t(9;22), fuses BCR with ABL1 to create a constitutively active tyrosine kinase that drives myeloid proliferation. Middle-aged adults present with fatigue, weight loss, early satiety, and splenomegaly, or with an abnormal routine CBC. The WBC is often above 100,000/µL and spans every stage of granulocyte maturation with a myelocyte peak, accompanied by basophilia, eosinophilia, and frequently thrombocytosis. Most patients are in chronic phase at diagnosis.
Diagnosis. FISH or RT-PCR for BCR-ABL1 on peripheral blood confirms the diagnosis, and marrow aspiration defines the phase and karyotype. The leukocyte alkaline phosphatase (LAP) score is obsolete, and JAK2 V617F testing belongs to the other myeloproliferative neoplasms.
| Feature | CML | Leukemoid reaction |
|---|---|---|
| Cause | Clonal BCR-ABL1 neoplasm | Severe infection (e.g., C. difficile colitis), inflammation, hemorrhage |
| Smear | All maturation stages, myelocyte peak, basophilia, eosinophilia | Mostly mature neutrophils with toxic granulation, Döhle bodies, vacuoles |
| LAP score | Low | High |
| Spleen | Often enlarged | Usually normal |
| Course | Requires a TKI | Resolves when the cause is treated |
| TKI | Signature toxicities and notes |
|---|---|
| Imatinib | Periorbital and peripheral edema, muscle cramps, rash |
| Dasatinib | Pleural effusions, bleeding, pulmonary arterial hypertension |
| Nilotinib | QT prolongation, hyperglycemia, pancreatitis, peripheral arterial disease; taken fasting |
| Bosutinib | Diarrhea |
| Ponatinib | Active against T315I; arterial thrombosis, hypertension |
| Asciminib | Allosteric (myristoyl-pocket) inhibitor; also active against T315I |
Monitoring. Quantitative RT-PCR for BCR-ABL1 on the International Scale is checked every 3 months. Goals are 10% or less by 3 months and a major molecular response (0.1% or less, a 3-log reduction) by about 12 months. Loss of response prompts confirmation of adherence, testing for ABL1 kinase-domain mutations, and a switch of TKI; the T315I gatekeeper mutation blocks imatinib, dasatinib, nilotinib, and bosutinib.
Blast phase. With 20% or more blasts, CML behaves like acute myeloid or lymphoid leukemia and is treated with a TKI plus induction chemotherapy, followed by allogeneic stem cell transplant.
Hairy cell leukemia
Clinical picture. Middle-aged men present with fatigue, infections, and massive splenomegaly without lymphadenopathy. The CBC shows pancytopenia with a characteristic monocytopenia, which explains the predisposition to atypical mycobacterial (MAC) infections. Marrow aspiration yields a dry tap because of reticulin fibrosis.
Diagnosis and treatment. Small B cells with hairlike cytoplasmic projections are TRAP+, CD11c+, CD25+, and CD103+, and nearly all classic cases carry BRAF V600E. The purine analog cladribine induces durable complete remissions in most patients; splenectomy is no longer first-line.