Chronic myeloid leukemia

I. What every physician needs to know.

Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm (MPN). MPNs are stem cell-derived clonal disorders with proliferation of one or more of the components of myeloid lineage.

CML patients carry a fusion gene called breakpoint cluster region-abelson (BCR-ABL) fusion gene derived from a balanced translocation between the long arms of chromosome 9 and 22; t(9;22) (q34;q11) also known as Philadelphia (Ph) chromosome. This fusion gene encodes a protein product with strong tyrosine kinase catalytic activity, and is leukemogenic. This deregulated tyrosine kinase is implicated in the pathogenesis of CML.

II. Diagnostic Confirmation: Are you sure your patient has chronic myeloid leukemia?

  • Peripheral blood: Hallmark features are neutrophilia and immature circulating myeloid cells with more than 50% of patients presenting with a WBC count >100,000 with blasts usually <2%.

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  • Leukocyte alkaline phosphatase score is almost always low.

  • Bone marrow and peripheral blood with Ph chromosome. Sensitivity for both is equal with either RT-PCR or FISH. Conventional cytogenetics miss approx. 5% of cases. FISH can identify unusual variant rearrangements. RT-PCR can differentiate between p210 and p190 BCR-ABL products. The latter is much more common in Ph+ ALL.

  • RT-PCR is preferred over FISH because of lower cost, ability to differentiate between different break point products and a lower false positive rate than FISH during quantitative monitoring for response to therapy.

A. History Part I: Pattern Recognition.

CML has a biphasic or triphasic clinical course:

  • Chronic phase – 85% of patients present with this phase at the time of diagnosis. White blood cell (WBC) count is usually controlled with medication. It usually lasts between about 4 years and longer in patients who receive newer therapies and have a good response (hematologic/cytogenetic remission). Recent studies suggest single measurements of BCR-ABL transcripts at 3 months is a good way to predict those patients who will do poorly. It is characterized by less than 10% blasts in peripheral blood and marrow.

  • Accelerated/transitional phase – occurs 3-6 months before the next phase and presents with progressive impaired neutrophils. This phase may last for several months and is characterized by the appearance of either peripheral or marrow blasts greater than or equal to 10%, but less than 20% and promyelocytes greater than or equal to 20%, peripheral blood basophils greater than or equal to 20%, or platelet counts less than 100k cells/microL or greater than 1000k cells/microL which are unresponsive to therapy. Median survival without a stem cell transplant (SCT) or tyrosine-kinase inhibitors (TKIs) is only 12-18 months.

  • Blast/acute phase – is similar to acute leukemia (ALL) or acute myeloid leukemia (AML). This phase is resistant to usual treatments and is characterized by peripheral and bone marrow blasts greater than or equal to 20%, extramedullary blast proliferation or large foci or clusters of blasts in bone marrow biopsy. Survival is 3-6 months for older patients and slightly longer for younger patients.

A typical patient with CML is a male in his fourth and fifth decade of life (median age of 50) that usually presents in the chronic phase of the disease. He is usually asymptomatic and is diagnosed by incidental finding of leukocytosis on a routine blood test (WBC greater than 100k/microL, platelet greater than 600k-700k/microL) or splenomegaly on a routine physical exam.

During the chronic phase, symptomatic patients complain of non-specific symptoms such as loss of energy, left upper quadrant pain, early satiety and decreased exercise tolerance. Most of these symptoms are related to an enlarged spleen and liver during this phase. An enlarged spleen causes early satiety and decreased appetite by pressing on the stomach, hypermetabolic state of fever, chronic fatigue, weight loss, excessive sweating, and left upper quadrant (LUQ) “gripping” pain due to spleen infarction. Priapism is another frequently encountered symptom secondary to hyperviscosity due to increased circulating leukocytes.

During the accelerated phase, myelofibrosis increases, anemia is worse and splenomegaly is not controllable by medication.

During the blast phase patients present with easy bruising, bleeding, massive splenomegaly and prominent constitutional symptoms. Skin and tissue infiltration is very common in this phase.

B. History Part 2: Prevalence.

CML accounts for 20% of adult leukemias with annual incidence of 1-2 cases per 100,000 and exposure to ionizing radiation is the only known risk factor.

C. History Part 3: Competing diagnoses that can mimic chronic myeloid leukemia.

Chronic neutrophilic leukemia – patients could present with hepatosplenomegaly due to granulocytic infiltration. However, usually there is toxic granulation in neutrophils, high leukocyte alkaline phosphatase (LAP) score, and no Ph-chromosomes.

Other myeloproliferative disease (polycythemia vera, essential thrombocythemia or primary myelofibrosis) – bone marrow evaluation is usually helpful. CML shows small megakaryocytes while others have large atypical megakaryocytes. The non-CML myeloproliferative disorders are typically BCR/ABL and Ph-chromosome negative and don’t respond to standard CML treatments.

Atypical CML – distinguished from CML by the appearance of dysplasia in neutrophils, megakaryocytes, and erythroid forms. Usually found in older age than CML with anemia and/or thrombocytopenia. Can progress to AML. Ph-chromosome and BCR/ABL negative.

Chronic myelomonocytic leukemia (CMML) – unlike CML, bone marrow exam shows prominent dysplastic changes in two or more of the myeloid lineages.

Leukemoid reaction – distinguished from CML by featuring toxic granulation in neutrophils, high LAP score, there is an obvious cause for leukocytosis (usually infection), no myelocyte bulge.

Chronic eosinophilic leukemia – some tendencies to progress to AML and some respond to standard CML therapy. However, there is no Ph-chromosome and no BCR/ABL gene fusion detected.

Other Ph-chromosome positive diseases (some types of ALL and AML) – distinguished from CML when analyzed at molecular levels which show heterogeneous Ph-chromosome positive cells (i.e. in Ph-positive ALL the cells are restricted to lymphoid cells versus CML in a blast phase which would be Ph-positive in lymphoid cells and neutrophils).

D. Physical Examination Findings.

Splenomegaly is the most common physical finding in CML patients (more than 50%) with the spleen extending more than 5cm below the L costal margin. Spleen size correlates with white blood cell (WBC) counts (i.e. the largest spleens are seen in patients with high WBC counts) and it shrinks with decreased WBC counts during the appropriate treatment of the disease.

The extramedullary hematopoiesis occurring in the spleen causes hepatomegaly. Hyperviscosity and leukostasis can cause symptoms with WBC counts of, or over 300k/600k cells/microL. Fundus exam in these patients may show venous obstruction, papilledema and bleeding.

E. What diagnostic tests should be performed?

1. What laboratory studies should be ordered? How should the results be interpreted?

Peripheral blood exam
  • High WBC count with a little bit of everything on the smear: similar presentation to bone marrow with the presence of different midstage progenitor cells (myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells (RBCs). Helpful in differentiating the blast/acute phase from AML where these cells are absent.

    Normal lymphocyte count (note that the percentage may be low due to dilution effects in differential count).

  • Increased mature granulocytes/neutrophils with low score for leukocyte alkaline phosphatase stains which is due to decreased apoptosis and accumulation of these cells with low enzymes level. Mild basophilia and eosinophilia that gets worse when transitioning to blast phase.

  • Mild to moderate normochromic normocytic anemia.

  • Platelet counts can be low, normal, or increased, often on the higher side (different from acute leukemia).

Bone marrow exam
  • Hypercellular consisting of the myeloid cell line and its progenitor cells.

  • Increased megakaryocytes.

  • Mild fibrosis seen with reticulin stain.

Cytogenic studies
  • Ph1-chromosome found in almost all patients and is present throughout the clinical course of the disease. Order karyotyping, fluorescence in situ hybridization (FISH) analysis, or reverse transcription polymerase chain reaction (RT-PCR) to look for this abnormality. This fusion gene is also seen in ALL (p190 variant) or non-lymphocytic leukemia and rarely in other myeloproliferative disorders (i.e. polycythemia vera or essential thrombocythemia).

  • Additional chromosomal abnormalities such as evidence of another Ph-positive clone or other cytogenetic abnormalities (e.g. monosomy 7, trisomy 8, trisomy 19 and abnormalities of chromosome 17). These are usually associated with progression to accelerated and blast phases or resistance to TKI’s.

  • BCR-ABL has the more common translocation associated with a 210 kd protein product. There is a more downstream translocation leading to a 230 kd protein found in uncommon CML variants and have a more indolent course. A more upstream translocation leads to a smaller 190 kd protein product seen in Ph-positive ALL but can rarely be detected in CML alone or coexpressed with the more common p210BCR-ABL product.

Other findings
  • Low or zero LAP score.

  • Hyperuricemia and high LDH due to high bone marrow turnover.

2. What imaging studies should be ordered to help establish the diagnosis?

Splenomegaly and hepatomegaly can be detected on computed tomography (CT) scan, but most of the time it can be detected in physical exam and imaging is not necessary.

III. Default Management.

Patients with CML should be under the care of a hematologist-oncologist. Without effective treatment all CML patients will usually transition to the blast/acute phase resembling ALL or AML with dismal outcomes. The following is a brief summary of overall approach to treatment of these patients:

Treatment goals in CML include achieving hematologic remission (i.e. normal complete blood count (CBC) and physical exam), cytogenetic remission (i.e. normal chromosome with no Ph-chromosome positive cells), and molecular remission (i.e. negative polymerase chain reaction (PCR) results for mutational BCR/ABL messenger RNA). The attempt to achieve molecular remission aims for the cure and survival prolongation of the patient.

Tyrosine kinase inhibitors (TKIs) are among the standard initial approach to treatment of CML. These agents inhibit tyrosine kinase activity of the BCR/ABL abnormality in all phases of the disease and therefore inhibit the proliferation and induce apoptosis in BCR/ABL positive cells and leukemic cells.

Imatinib was the first TKI approved in 2001. The next generation TKIs (nilotinib, dasatinib, bosutinib) have been shown to be more effective in inducing molecular remission. They are used for intolerance or resistance to imatinib. Resistance to TKIs develop due to point mutations that affect the tyrosine kinase domain (TKD) in 50-90% of cases and gene-amplification in <10% of cases. None of these TKIs are effective against the gatekeeper T315I mutation that causes a structural change that closes the ATP-binding pocket of BCR-ABL. The third generation TKI ponatinib has shown activity in CML patients with T315I mutations.

Imatinib is still the front-line treatment for CML. IRIS trial demonstrated major molecular response (MMR) of 86%, overall survival and event-free survival at 8 years were 85% and 81%, respectively. The estimated freedom from progression to accelerated and blast phase was 92%. The duration of therapy after complete molecular response (CMR) is still not clear.

In patients with WBC counts greater than 300k cells/microL, the acute symptoms of hyperviscosity, tissue infiltration and leukostasis can be relieved by leukapheresis, which can safely decrease the WBC counts. Imatinib, other TKIs, IFNa and induction-type chemotherapy regimens are also used for cytoreduction.

Stem cell transplant (SCT) is usually reserved for adults who fail TKIs but is a reasonable consideration as first-line therapy in children and younger adults, where allogeneic stem cell transplantation has about a 60-85% chance of a cure. This should be weighed against the risk of developing graft versus host disease. (GVHD). Across all ages, the incidence of acute GVHD ranges from 8-63%, with severe and fatal GVHD affecting 20% and 13% of the patients, respectively.

Reduced-intensity conditioning (RIC) regimens are producing intriguing results with decreased transplantation-related toxicity. While allogeneic myeloablative SCT can cure up to 40% of patients with CML in accelerated phase, the salvage rate for SCT in blast phase is dismal.

C. Laboratory Tests to Monitor Response To, and Adjustments in, and Side Effects of Management.

During successful therapy, splenomegaly improves as the WBC counts decrease with disappearing of intermediate cell lines and blasts in peripheral blood.

Patients on TKI therapy are monitored by using quantitative PCR and FISH analysis to count the percentage of bone marrow cells with Ph-chromosome positivity every 3-6 months. These methods are used to follow the cytogenetic response in all phases of CML. The goal is 100% normal cells after 1-2 years of treatment, therefore patients with minimal residual disease (MRD) should continue on maintenance therapy as long as needed.

The new generation of TKIs are associated with serious side effects. Dasatinib is associated with pleural effusion, nilotinib is associated with biochemical changes in liver function and QT interval prolongation, bosutinib is associated with GI side effects and alteration in liver function and ponatinib is associated with serious vaso-occlusive side effects.

IV. What's the Evidence?

Neumann, F, Herold, C, Hildebrandt, B. “Quantitative real-time reverse-transcription polymerase chain reaction for diagnosis of BCR-ABL positive leukemias and molecular monitoring following allogeneic stem cell transplantation”. Eur J Haematol. vol. 70. 2003. pp. 1-10. (This study analyzes the reliability of RT-PCR for monitoring molecular response in CML.)

Alattar, M, Kantarjian, H, Jabbour, E. “Clinical significance of complete cytogenetic response (CCyR) and major molecular response (MMR) achieved with different treatment modalities used as frontline therapy in chronic myeloid leukemia (CML) chronic phase (CP) [abstract]”. Blood (ASH Annual Meeting Abstracts). vol. 118. 2011. (This study compares outcomes with different TKI’s used as front line therapy.)

Saglio, G, Kim, DW, Issaragrisil, S. “Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia”. N Engl J Med. vol. 362. 2010. pp. 2251-2259. (This study compares nilotinib to imatinib and shows superiority of nilotinib. Imatinib continues to frontline despite superiority of second generation TKI’s in a few studies by surrogate markers, mostly due to lack of long-term benefit data.)

Cortes, J, Kim, D-W, Pinilla-Ibarz, J. “Initial findings from the PACE trial: a pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation [abstract]”. Blood (ASH Annual Meeting Abstracts). vol. 118. 2011. (Establishes the role of ponatinib in patients with T315I mutation.)

Hughes, TP, Hochhaus, A, Branford, S. “Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS)”. Blood. vol. 116. 2010. pp. 3758-3765. (This trial shows that early molecular response predicts longer event free survival.)

Kantarjian, HM, Shan, J, Jones, D. “Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response”. J Clin Oncol. vol. 27. 2009. pp. 3659-3663. (This study demonstrates the significance of molecular response despite complete cytogenetic response as risk for CML progression.)

Mahon, FX, Rea, D, Guilhot, J. “Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: update results of the STIM study [abstract]”. Blood (ASH Annual Meeting Abstracts). vol. 118. 2011. (Discusses duration of treatment with TKIs. This is still unclear.)

Baccarani, M, Rosti, G, Castagnetti, F. “Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: A European LeukemiaNet Study”. Blood. vol. 113. 2009. pp. 4497-4504. (This study compares outcomes with different dosages of imatinib and response rates with imatinib.)