Chronic Myeloid Leukemia (CML)

Chronic myeloid leukemia (CML) is a blood cancer caused by a single genetic accident — a chromosomal swap that creates the Philadelphia chromosome and a permanently switched-on growth signal in bone marrow cells. Before 2001, it carried a median survival of five to seven years. Today, targeted drugs called tyrosine kinase inhibitors (TKIs) have transformed CML into a manageable chronic condition for most people, and nearly half of patients who take TKIs long enough can eventually stop their medication and remain in remission indefinitely. This article explains exactly how CML works, how it is diagnosed and staged, which drugs are used and why, and what the realistic path forward looks like for someone newly diagnosed.

Table of Contents

  1. Overview and the Philadelphia Chromosome
  2. Phases of CML — Chronic, Accelerated, Blast Crisis
  3. The BCR-ABL1 Oncoprotein — Why TKIs Work
  4. Clinical Presentation and Symptoms
  5. Diagnosis — Blood, Marrow, and Molecular Testing
  6. Treatment — First-Line TKI Selection
  7. TKI Side Effects and Long-Term Management
  8. Monitoring Response — Milestones and MR4.5
  9. Treatment-Free Remission (TFR) — Stopping TKI
  10. Blast Crisis — Emergency Treatment
  11. Allogeneic Stem Cell Transplant
  12. Research Papers
  13. Connections
  14. Featured Videos

1. Overview and the Philadelphia Chromosome

CML is classified as a myeloproliferative neoplasm — a group of bone marrow disorders in which one abnormal blood stem cell multiplies out of control, flooding the blood with partly functional granulocytes (the infection-fighting white blood cells that include neutrophils, eosinophils, and basophils). Unlike most cancers, CML has a single, precisely identified genetic cause in almost every patient: the Philadelphia chromosome, a translocation between chromosomes 9 and 22 written as t(9;22)(q34;q11.2).

This swap fuses part of the ABL1 gene on chromosome 9 to part of the BCR gene on chromosome 22, creating the BCR::ABL1 fusion gene. The resulting protein is a tyrosine kinase — an enzyme that adds phosphate tags to proteins — stuck permanently in the "on" position. That constant signal tells bone marrow cells to divide and to ignore the normal stop signals, producing the massive overload of granulocytes that defines CML.

How common is it? CML accounts for roughly 15% of adult leukemias. In the United States about 8,900 new cases are diagnosed each year, at a rate of 1–2 per 100,000 people. The median age at diagnosis is 55–65 years, and it is slightly more common in men. CML in children is rare, making up less than 5% of pediatric leukemia.

Historical context. The Philadelphia chromosome was discovered in 1960 by Peter Nowell and David Hungerford at the University of Pennsylvania — making it the first consistent chromosomal abnormality identified in any cancer. The BCR-ABL1 fusion was characterized in the 1980s. The watershed moment came in 2001 when imatinib (Gleevec), the first drug designed to block BCR-ABL1 directly, received FDA approval. Clinical trials showed response rates that stunned the oncology world. Before imatinib, the average CML patient lived five to seven years; on modern TKI therapy, life expectancy is now near-normal for chronic-phase CML.

Causes and risk factors. The Philadelphia chromosome arises spontaneously in a single bone marrow stem cell — it is not inherited and cannot be passed to children. Ionizing radiation (demonstrated in atomic bomb survivors and people who received high-dose radiotherapy) and benzene exposure are the best-established risk factors, but most patients have no identifiable exposure. There is no hereditary CML syndrome.

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2. Phases of CML — Chronic, Accelerated, Blast Crisis

CML is not a single disease state — it evolves through up to three phases, each progressively more aggressive. About 90% of patients are diagnosed in the first and most treatable phase.

Chronic Phase (CP)

In chronic-phase CML the leukemic cells still differentiate reasonably normally — they just overproduce. The white blood cell count is markedly elevated (typically 50,000 to 200,000 cells per microliter, sometimes over 300,000), and the peripheral blood smear shows granulocytes at every stage of maturation: from blasts and promyelocytes all the way to mature band and segmented neutrophils. Basophilia (an elevated count of basophils, a type of granulocyte) is a hallmark finding. Blasts account for fewer than 10% of cells in the bone marrow. Symptoms are often mild or absent. Most patients are diagnosed in this phase because an abnormal routine blood count prompts investigation. With TKI therapy, five-year overall survival in chronic-phase CML exceeds 95%.

Accelerated Phase (AP)

Accelerated phase signals that the leukemic clone is evolving and becoming less controlled. By the European LeukemiaNet (ELN) 2020 definition, AP is present if any of the following develop:

Patients who are found in AP at diagnosis or who progress from CP despite TKI require intensified treatment and earlier discussion of stem cell transplant.

Blast Crisis (BC)

Blast crisis is defined as 20% or more blasts in the peripheral blood or bone marrow — the CML has effectively transformed into acute leukemia. About 70% of blast crises are myeloid (resembling AML) and 30% are lymphoid (TdT-positive; resembling ALL). Lymphoid blast crisis is somewhat more responsive to TKI-based therapy. Without prompt and aggressive treatment, median survival in blast crisis is three to six months. Achieving a second chronic phase and proceeding urgently to allogeneic stem cell transplant is the only path to potential long-term survival.

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3. The BCR-ABL1 Oncoprotein — Why TKIs Work

Understanding what drives CML at the molecular level explains why tyrosine kinase inhibitors are so effective and what makes resistance possible.

Normal ABL1. The ABL1 gene on chromosome 9 encodes a nonreceptor tyrosine kinase called c-Abl. In normal cells, c-Abl activity is tightly regulated — it is mostly switched off, only activating briefly in response to specific signals. It participates in cell growth, DNA-damage responses, and differentiation.

The BCR-ABL1 fusion. The translocation t(9;22) joins the 5' end of BCR to the kinase domain of ABL1. The resulting fusion protein is constitutively active — its kinase function never switches off. This permanently-on enzyme drives downstream signaling through three critical pathways:

The net result is a clone of myeloid cells that proliferates without limits, resists apoptosis, and gradually accumulates additional mutations leading to disease progression.

Three BCR-ABL1 variants. The precise location of the chromosomal breakpoint determines which fusion protein is made. The p210 protein (major breakpoint) is found in nearly all CML patients and in one-third of Philadelphia-chromosome-positive ALL. The p190 protein (minor breakpoint) is found in two-thirds of Ph+ ALL and occasionally in CML, where it is associated with monocytosis. The p230 protein (micro breakpoint) is rare and causes a milder neutrophilic variant of CML.

How TKIs block BCR-ABL1. Tyrosine kinase inhibitors are small molecules that slip into the ATP-binding pocket of the ABL1 kinase domain. Without ATP, the kinase cannot transfer phosphate groups to its targets — the signaling cascade stops. The leukemic cells, having lost their main survival signal, undergo apoptosis. Normal cells tolerate TKIs because they have many other survival pathways; the CML clone is uniquely dependent on BCR-ABL1.

Resistance mutations. The most clinically important resistance mechanism is a point mutation in the ABL1 kinase domain that prevents the TKI from binding. The T315I mutation — a threonine-to-isoleucine substitution at position 315, the so-called "gatekeeper" residue — confers resistance to imatinib, dasatinib, nilotinib, and bosutinib simultaneously. Only ponatinib (a third-generation TKI) and asciminib (a STAMP inhibitor that acts at an entirely different binding site on ABL1) retain activity against T315I. Mutation testing is essential when any TKI fails.

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4. Clinical Presentation and Symptoms

CML is notorious for its insidious onset. A significant proportion of patients — perhaps 20–40% — have no symptoms at all and are diagnosed only because a routine blood test reveals an abnormally high white blood cell count. For those who do have symptoms, the following are typical:

Most Common Symptoms

Physical Examination Findings

The most characteristic finding on examination is a palpable, often massive spleen. Unlike many conditions that cause mild splenomegaly, CML can produce one of the largest spleens seen in clinical medicine — firm, smooth, moving with respiration, and sometimes tender if splenic infarction has occurred. Hepatomegaly is present in a minority of patients. Lymph node enlargement is uncommon in chronic-phase CML; if prominent lymphadenopathy is found, accelerated or blast-phase disease or a lymphoid transformation should be considered.

Emergencies at Presentation

When the white blood cell count is extremely high (above 300,000/µL), blood viscosity rises sharply and leukostasis can develop. Leukemic cells sludge in small blood vessels and block flow, causing priapism (a medical emergency in men), retinal vein occlusion with vision changes, splenic infarction, and rarely pulmonary leukostasis with shortness of breath. These patients require urgent cytoreduction with hydroxyurea and sometimes leukapheresis before starting TKI therapy.

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5. Diagnosis — Blood, Marrow, and Molecular Testing

Diagnosing CML requires confirming the Philadelphia chromosome or BCR::ABL1 fusion, assessing disease phase, and establishing a quantitative molecular baseline for future monitoring.

Complete Blood Count and Peripheral Smear

The CBC typically shows a markedly elevated white blood cell count — most commonly 50,000 to 200,000 cells per microliter at diagnosis. The peripheral blood smear reveals the full spectrum of myeloid maturation, from early blasts through promyelocytes, myelocytes, metamyelocytes, and band neutrophils to fully mature segmented cells. This orderly "left shift" is distinct from acute leukemia (which shows blasts without the intermediate stages). Absolute basophilia is the most characteristic peripheral blood feature of CML — it distinguishes CML from a leukemoid reaction (a reactive elevation of white cells due to infection or stress, which shows toxic granulation and a high leukocyte alkaline phosphatase score rather than basophilia). Eosinophilia is also common. Platelets may be elevated, normal, or low depending on phase.

Leukocyte Alkaline Phosphatase (LAP) Score

The LAP score is low or absent in CML because the leukemic neutrophils lack this enzyme, which normal neutrophils contain. A high LAP score favors a leukemoid reaction or polycythemia vera rather than CML. This test is less commonly ordered now that molecular testing is widely available, but remains useful in resource-limited settings.

Bone Marrow Biopsy and Aspirate

The bone marrow is hypercellular with panmyeloid hyperplasia — all myeloid cell lines are expanded, with a markedly elevated myeloid-to-erythroid ratio (10:1 or higher is typical). Blasts should be counted carefully to confirm disease phase. Conventional cytogenetics (karyotype) detects the Philadelphia chromosome in approximately 95% of CML patients and identifies any additional chromosomal abnormalities that signal accelerated disease.

FISH for BCR::ABL1

Fluorescence in situ hybridization (FISH) uses fluorescent probes that bind to the BCR and ABL1 genes. In cells with the translocation, the probes co-localize, confirming the BCR::ABL1 fusion. FISH is more sensitive than standard karyotype for detecting the fusion and can be performed on peripheral blood as well as marrow. It is useful when the karyotype is uninformative (poor metaphases) and in monitoring early in treatment.

Quantitative RT-PCR for BCR-ABL1 — The Gold Standard for Monitoring

Reverse transcription polymerase chain reaction (RT-PCR) detects BCR-ABL1 messenger RNA and can find as few as one CML cell among 100,000 to 1,000,000 normal cells — extraordinary sensitivity. Results are expressed on the International Scale (IS), a standardized system that allows comparison of values across different laboratories and over time. A BCR-ABL1 IS of 100% means the patient has CML and has had no treatment; as TKI therapy works, this number falls toward zero. All response milestones are defined using this scale. Establishing the baseline BCR-ABL1 IS value at diagnosis is essential for interpreting future measurements.

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6. Treatment — First-Line TKI Selection

Four tyrosine kinase inhibitors are FDA-approved for newly diagnosed chronic-phase CML. The choice is individualized based on cost, patient comorbidities, and treatment goals.

Imatinib (Gleevec) — First Generation

Imatinib was the first BCR-ABL1 inhibitor and remains a valid first-line option, particularly because generic versions are now widely available at a fraction of the original cost. The landmark IRIS trial (published in the New England Journal of Medicine in 2003) showed imatinib dramatically superior to interferon-alpha, the previous standard of care. At ten-year follow-up, overall survival was 83.3% (CML-specific survival 95.2%) — an unprecedented result for a blood cancer at the time. Standard dose is 400 mg once daily by mouth. Most common side effects: peripheral and periorbital edema (fluid retention, particularly around the eyes), nausea (take with food), muscle cramps, and skin rash.

Dasatinib (Sprycel) — Second Generation

Dasatinib is approximately 140 times more potent than imatinib in laboratory assays and achieves deeper molecular responses faster. It is active against most imatinib-resistant BCR-ABL1 mutations, with the critical exception of T315I. The DASISION trial showed superior rates of major molecular response at 12 months compared to imatinib. Standard dose: 100 mg once daily. The most characteristic side effect is pleural effusion — fluid accumulating around the lung — which occurs in 20–35% of patients over time. Mild effusions are managed with a temporary dose hold; persistent or symptomatic effusions may require diuretics, corticosteroids, or dose reduction. Pulmonary arterial hypertension is a rare but serious complication that requires periodic echocardiographic monitoring. QTc prolongation and cytopenias also occur.

Nilotinib (Tasigna) — Second Generation

Nilotinib achieves deep molecular remission more rapidly than imatinib and showed superior milestone rates in the ENESTnd trial. Standard dose: 300 mg twice daily on an empty stomach (food increases absorption and QTc risk, so it must be taken without food). The principal safety concern with nilotinib is cardiovascular toxicity: peripheral arterial occlusive disease (leg pain with walking, non-healing foot ulcers, limb ischemia), cerebrovascular events, and accelerated coronary artery disease occur at meaningful rates with long-term use. Nilotinib should be avoided or used with extreme caution in patients with existing cardiovascular risk factors, diabetes, hypertension, or smoking history. Other adverse effects include elevated indirect bilirubin (related to UGT1A1 gene polymorphisms), blood glucose elevation, and QTc prolongation.

Bosutinib (Bosulif) — Second Generation (and SRC Inhibitor)

Bosutinib inhibits both ABL1 and SRC family kinases. Its favorable profile in some respects: no meaningful cardiovascular toxicity (unlike nilotinib), no significant fluid retention or pleural effusions (unlike dasatinib), and once-daily dosing at 400 mg. Its main drawback is gastrointestinal toxicity — diarrhea occurs in the majority of patients, though it is usually manageable with dose modification and antidiarrheal agents. The BELA trial established bosutinib as a first-line option. It is a reasonable choice for older patients with cardiovascular comorbidities who cannot tolerate nilotinib.

How to Choose

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7. TKI Side Effects and Long-Term Management

All TKIs have off-target effects because ABL1, c-KIT, and PDGFR (platelet-derived growth factor receptor) are closely related kinases and most inhibitors block more than one. Understanding these effects allows patients and their care teams to anticipate and manage them rather than being caught off guard.

Effects Shared Across TKI Class

Fertility, Pregnancy, and TKI

All TKIs are teratogenic (FDA Pregnancy Category D) and must be stopped before conception. Women with CML who wish to become pregnant face a complex challenge: TKIs cannot be continued during pregnancy, but stopping them risks disease relapse. The recommended approach is to achieve a sustained deep molecular response (MR4.5) before attempting pregnancy and then either transition to treatment-free remission (see below) or, if TFR is not possible, use interferon-alpha, which does not cross the placenta and has a decades-long track record in hematologic malignancies. If accidental first-trimester TKI exposure occurs, imatinib has the most reassuring safety data; dasatinib and nilotinib are associated with a higher rate of fetal abnormalities in case series.

Long-Term Monitoring Schedule

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8. Monitoring Response — Milestones and MR4.5

Monitoring TKI response in CML is one of the most precisely defined processes in oncology. The European LeukemiaNet (ELN) 2020 guidelines specify exactly what BCR-ABL1 level should be reached by which time point — and what to do if it is not.

Response Vocabulary

ELN 2020 Milestones

Quantitative BCR-ABL1 RT-PCR from peripheral blood is checked every three months throughout the first year, then every three to six months once in stable deep remission.

The T315I Gatekeeper Mutation

When a patient's BCR-ABL1 PCR fails to decline appropriately or rises after initial response, BCR-ABL1 kinase domain mutation sequencing should be ordered. The T315I mutation (threonine substituted by isoleucine at position 315 of ABL1) is the most important because it renders imatinib, dasatinib, nilotinib, and bosutinib all ineffective simultaneously. Only two drugs retain meaningful activity: ponatinib (a third-generation TKI designed specifically to overcome T315I) and asciminib (a STAMP inhibitor — Specifically Targeting the ABL Myristoyl Pocket — which blocks BCR-ABL1 at a completely different site from all other TKIs and retains activity against T315I at the 200 mg twice-daily dose).

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9. Treatment-Free Remission (TFR) — Stopping TKI

For many patients, the possibility of stopping TKI therapy while remaining in remission is transformative — freeing them from daily medication, its costs, its side effects, and the psychological weight of feeling perpetually "in treatment." This is now an established and evidence-based goal for eligible patients.

Who Is Eligible to Attempt TFR?

Evidence from Clinical Trials

The landmark STOP Imatinib (STIM) trial published in Lancet Oncology in 2010 first demonstrated that long-term imatinib could be safely discontinued in patients who had achieved a sustained complete molecular remission. About 40% of patients maintained MMR at 12 months after stopping. Subsequent trials with second-generation TKIs (ENESTfreedom for nilotinib, DASFREE for dasatinib) showed similar or slightly better TFR rates. The consistent finding across trials: approximately 40–50% of eligible patients remain in TFR at two to five years after stopping TKI.

What Happens When CML Returns?

Molecular relapse — the BCR-ABL1 level rising above MMR after TFR — is not a catastrophe. It is expected in roughly half of patients who attempt TFR. Almost all patients who restart their prior TKI rapidly recapture deep molecular remission (over 95% success). The BCR-ABL1 level typically begins rising within the first six months after stopping; patients who remain in MR below detection at 12 months have an excellent chance of durable TFR. There is no evidence that attempting TFR and restarting TKI after relapse compromises long-term outcomes.

TKI Withdrawal Syndrome

An unexpected finding from TFR trials: up to 30% of patients experience musculoskeletal pain — diffuse myalgias and arthralgias — after stopping TKI. The mechanism is not fully established but may relate to loss of c-KIT inhibition on mast cells, altering inflammatory mediator release. The syndrome is usually mild and self-limiting over weeks to a few months. Knowing about it in advance prevents unnecessary anxiety and premature TKI restart.

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10. Blast Crisis — Emergency Treatment

Blast crisis is the most feared complication of CML and constitutes a true oncologic emergency. Once 20% or more blasts appear in the blood or marrow, the disease has transformed into what is functionally acute leukemia, and the prognosis without immediate and aggressive treatment is measured in months.

Myeloid Blast Crisis (70%)

Myeloid blast crisis resembles AML and is treated similarly: intensive induction chemotherapy (typically high-dose cytarabine plus an anthracycline, the "7+3" backbone) combined with a TKI. Adding a TKI to AML-type induction is not standard for de novo AML, but is essential in CML blast crisis because the leukemic cells remain BCR-ABL1-dependent. The goal is to achieve a second chronic phase, at which point the patient must proceed to allogeneic stem cell transplant as rapidly as possible. Without transplant, remissions from blast crisis are brief. Ponatinib is often preferred as the TKI partner in blast crisis because it is the most potent available and active against T315I, which commonly arises as blast crisis develops.

Lymphoid Blast Crisis (30%)

Lymphoid blast crisis is treated as Philadelphia-chromosome-positive ALL. Regimens typically include a TKI plus a steroid and often a multi-agent chemotherapy backbone (hyper-CVAD or similar). Dasatinib is particularly useful in lymphoid BC because it crosses the blood-brain barrier, providing some central nervous system penetration. Blinatumomab, a bispecific T-cell engager (BiTE) antibody that redirects T cells against CD19-positive lymphoblasts, has shown activity in Ph+ ALL and is increasingly incorporated in lymphoid BC regimens. As with myeloid BC, the goal remains bridge to allo-SCT.

Donor Search and Urgency

Any patient who develops accelerated or blast-phase disease should have a donor search initiated immediately — this means human leukocyte antigen (HLA) typing of the patient, immediate referral to a transplant center, and family typing if siblings are available. The window between achieving a second chronic phase and the next progression is often narrow, and delays in transplant evaluation cost lives.

Prognosis in Blast Crisis

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11. Allogeneic Stem Cell Transplant

Allogeneic stem cell transplant (allo-SCT) was the only treatment capable of curing CML before TKIs changed the landscape. Today it is reserved for a specific and increasingly narrow set of indications, but it remains critically important for patients who need it.

Current Indications for Allo-SCT in CML

The Graft-Versus-Leukemia Effect

CML benefits from one of the strongest graft-versus-leukemia (GvL) effects of any hematologic malignancy. Donor immune cells (particularly T lymphocytes) recognize and kill residual CML cells. This was first demonstrated dramatically when CML that relapsed after transplant could be brought into molecular remission by infusing additional donor T cells — called donor lymphocyte infusion (DLI) — without additional chemotherapy. This powerful GvL effect means that post-transplant CML management focuses heavily on immune reconstitution and may allow BCR-ABL1 monitoring to guide DLI timing before full clinical relapse occurs.

Transplant Outcomes

Outcomes from allo-SCT in CML depend critically on disease phase at the time of transplant:

Conditioning regimens can be myeloablative (busulfan + cyclophosphamide or fludarabine-based; suited for younger, fit patients) or reduced-intensity (for older patients or those with comorbidities). Chronic graft-versus-host disease remains the principal cause of long-term morbidity after successful transplant, affecting quality of life in a significant proportion of survivors.

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12. Research Papers

  1. O'Brien SG et al. (2003) — Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia. New England Journal of Medicine. PMID 12637609. DOI 10.1056/NEJMoa022457.
  2. Saglio G et al. (2010) — Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (ENESTnd Trial). New England Journal of Medicine. PMID 20421968. DOI 10.1056/NEJMoa0912614.
  3. Kantarjian H et al. (2010) — Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia (DASISION Trial). New England Journal of Medicine. PMID 21199804. DOI 10.1056/NEJMoa1006641.
  4. Mahon FX et al. (2010) — Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncology. PMID 20965785. DOI 10.1016/S1470-2045(10)70208-X.
  5. Cortes JE et al. (2012) — A Phase 3 Trial of Bosutinib versus Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia (BELA Trial). Journal of Clinical Oncology. PMID 22547599. DOI 10.1200/JCO.2011.38.7522.
  6. Druker BJ et al. (2006) — Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. New England Journal of Medicine. PMID 17151364. DOI 10.1056/NEJMoa062867.
  7. Hochhaus A et al. (2020) — European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. PMID 31894206. DOI 10.1038/s41375-020-0776-2.
  8. Nowell PC and Hungerford DA (1960) — A minute chromosome in human chronic granulocytic leukemia. Science. DOI 10.1126/science.132.3438.1488. (The original Philadelphia chromosome discovery; Science 132:1488.)
  9. Deininger M et al. (2005) — The molecular biology of chronic myeloid leukemia. Blood. PMID 15944424. DOI 10.1182/blood-2004-11-4400.
  10. Cortes JE et al. (2013) — Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias (PACE Trial). New England Journal of Medicine. PMID 24180494. DOI 10.1056/NEJMoa1306494.
  11. Hochhaus A et al. (2017) — Long-term outcomes of imatinib treatment for chronic myeloid leukemia. New England Journal of Medicine. PMID 28343198. DOI 10.1056/NEJMoa1609324.
  12. Rea D et al. (2017) — Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. PMID 28900001. DOI 10.1182/blood-2017-05-782532.

Search PubMed for More CML Research

  1. Chronic myeloid leukemia imatinib treatment
  2. CML treatment-free remission TKI discontinuation
  3. BCR-ABL1 tyrosine kinase inhibitor resistance
  4. CML blast crisis treatment

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13. Connections

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