Oncology

Chronic myelogenous leukemia

Chronic myeloid leukemia

What every physician needs to know:

Chronic myeloid leukemia (CML) is a malignant disease arising from a primitive hematopoietic stem cell in the bone marrow that involves all three myeloid lineages: granulocytes, erythroid cells, and megakaryocytes. Patients typically present with an elevated white blood cell count consisting primarily of mature neutrophils, although a smaller number of immature granulocytes are often present in the blood as well. CML is defined by the presence of the BCR/ABL1 fusion gene, which results from the reciprocal translocation t(9;22)(q34;q11.2). The Philadelphia chromosome refers to the abnormally short chromosome 22 in CML.

Most patients are first diagnosed while the disease is still in the chronic phase, and the differentiation and maturation of granulocytes proceeds relatively normally. Over time, CML can progress to a more advanced disease.

The accelerated phase is characterized by loss of response to previously effective therapy, increasing granulocytic dysplasia, loss of maturation in neutrophils with more immature cells in the circulation, increasing anemia or thrombocytopenia, increasing spleen size, constitutional symptoms of fever, sweats, and weight loss, and increasing reticulin fibrosis in the marrow. There may also be karyotypic evolution with the appearance of new chromosomal abnormalities in the Ph+ clone. The blast phase of CML or "blast crisis" develops as the malignant cells become arrested in their maturation at the blast stage; in many ways, CML in myeloid blast phase is indistinguishable from a rapidly progressive acute myeloid leukemia.

About one-third of newly diagnosed patients with CML in chronic phase have no symptoms, and the diagnosis is made on a routine blood count done for another purpose. The most common presenting symptoms are fatigue (usually related to mild to moderate anemia) and modest weight loss (most often due to early satiety from splenomegaly). Fever or bleeding are relatively uncommon.

Are you sure your patient has chronic myeloid leukemia? What should you expect to find?

The most definitive diagnostic test is a molecular genetic test to document the presence of the BCR/ABL1 fusion gene. This can be done with a FISH (fluorescence in situ hybridization) assay or by RT-PCR (reverse transcriptase polymerase chain reaction). Either of these tests can be done on granulocytes in the peripheral blood, as they do not require dividing cells. Alternatively, a bone marrow exam provides a sample of dividing marrow cells by aspiration that will demonstrate the t(9;22) by cytogenetic analysis of metaphase cells. In about 5% of CML patients, the t(9;22) cannot be seen cytogenetically, but the BCR/ABL1 fusion gene is invariably present by FISH or RT-PCR assays.

Beware of other conditions that can mimic chronic myeloid leukemia:

The differential diagnosis of CML includes:

  • Other myeloproliferative neoplasms (MPN)

That is, polycythemia vera, essential thrombocythemia, primary myelofibrosis, atypical CML, chronic neutrophilic leukemia.

  • Reactive leukocytosis or leukemoid reaction

  • Chronic myelomonocytic leukemia

Which individuals are most at risk for developing chronic myeloid leukemia:

Risk factors:

  • The median age is about 60 years old and it is very uncommon in children.

  • It occurs in both sexes.

  • CML is not familial.

  • CML has been associated with radiation exposure (e.g., nuclear fallout, uranium mining), benzene exposure, and prior chemotherapy for another disorder.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count and white blood cell differential count

Often the platelet count is elevated in addition to the white blood cell (WBC) count, but rarely to >1 million/μl. Most of the WBC's will be mature neutrophils (segs) and bands, but the entire spectrum of granulocytic differentiation (metamyelocytes, myelocytes, and a few promyelocytes and myeloblasts) is present. A high percentage of blasts or basophils may indicate more advanced disease.

Peripheral blood smear

The peripheral blood smear should be reviewed for dysplasia in the granulocytes. CML in chronic phase typically lacks any dysplasia. The presence of basophils is evidence for CML or another MPN and against a reactive leukocytosis.

Genetic test

To document the BCR/ABL1 fusion gene: FISH, RT-PCR, or metaphase cytogenetics on dividing cells. Only metaphase cytogenetics will reveal other chromosomal abnormalities that may be present, in addition to the t(9;22). Three way translocations do occur, but the fusion of BCR to ABL1 is always constant.

Lactate dehydrogenase level in the serum

An elevation in this enzyme level is roughly proportional to the mass of leukemia cells that are turning over.

Bone marrow trephine biopsy and aspiration for cytology and histology

The ratio of myeloid to erythroid (M:E) cells is markedly elevated, often to greater than 20:1. Increased numbers of blasts or promyelocytes, or increased reticulin fibrosis in the marrow can indicate more advanced disease.

Mutation analysis

Mutation analysis for acquired mutations in the ABL1 kinase domain that interfere with the binding of tyrosine kinase inhibitors (TKI) to the active site of the enzyme is rarely revealing at initial diagnosis. However, this DNA sequence assay can be very useful if a patient is losing their response to a TKI drug or presents with more advanced disease.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of chronic myeloid leukemia?

Imaging is not typically required, and is not useful in making the diagnosis. In some cases, a computed tomography (CT) scan of the abdomen or an ultrasound exam may be useful to evaluate the size of the spleen and/or to diagnosis a splenic infarction if left upper quandrant abdominal pain is present.

If you decide the patient has chronic myeloid leukemia, what therapies should you initiate immediately?

Patients who do not have symptoms rarely require emergency interventions. Because most of the circulating cells in patients with CML in chronic phase are mature neutrophils, even those with hyperleukocytosis (WBC count greater than 100,000/μl) often have no symptoms.

It is important for patients to stay well hydrated. Because of the increased turnover of myeloid cells, hyperuricemia may be present, and for this reason allopurinol is also indicated.

Patients with more advanced disease and large numbers of blasts and promyelocytes in the blood may develop symptoms from leukostasis; the emergency treatment is leukapheresis and institution of hydroxyurea to lower the WBC count rapidly.

More definitive therapies?

The definitive treatment for patients with CML in chronic phase involves one of the oral TKIs: imatinib, dasatinib, or nilotini. These anticancer drugs have been remarkably well-tolerated and quite effective; 80-90% of patients will achieve a complete cytogenetic response (CCyR), often within 3-6 months after starting a TKI. The majority of patients achieve a major molecular response (MMR), defined as the reduction in the number of messenger RNA (mRNA) transcript copies for BCR/ABL1 in peripheral blood leukocytes by more than three logs (to less than 0.1% by an international scale (IRIS study [International Randomized Trial of Interferon versus STI-571) as measured by quantitative RT-PCR.

Progression-free and overall survival are markedly improved in patients achieving CCyR or MMR by 12 months. An early molecular response is highly beneficial, and patients whose BCR/ABL transcript levels fall to <10% (IS) relative to a normal housekeeping gene such as ABL1 by 3-6 months have a significantly better overall survival.

Many of these remissions appear quite durable and have been shown to persist for more than 10 years so far. However, a resistant subclone of CML can arise in a small fraction of patients treated with any one of the TKIs; typically this happens within the first 1-3 years. This finding requires switching to an alternative TKI or consideration of an allogeneic hematopoietic stem cell transplant (HCT). Two additional TKIs (bosutinib and ponatinib) have been approved for patients with resistance or intolerance to imatinib, dasatinib, or nilotinib. Ponatinib is the only TKI that is effective against CML with an acquired T315I mutation in BCR/ABL1.

Additional therapies that are beneficial in CML include:

  • Hydroxyurea

- Hydroxyurea is frequently used at diagnosis to lower the elevated WBC count in a controlled fashion prior to starting a TKI.

  • Interferon

- Interferon has been used alone (in the past) or in combination with low dose cytarabine or, more recently, with imatinib to induce complete cytogenetic responses in chronic phase CML.

  • Busulfan

- Busulfan is a potent alkylating agent that was used in the past to suppress the myeloproliferation in CML, but currently it has a role only as part of an allogeneic HCT procedure.

  • Allogeneic HCT

- Allogeneic HCT has been proven to cure CML, but this treatment is accompanied by considerable toxicity and chronic complications. Nevertheless, this treatment is recommended for CML patients with advanced disease that no longer responds to TKI therapy.

What other therapies are helpful for reducing complications?

Allopurinol is often prescribed for the first several weeks when TKI therapy is begun in a newly diagnosed patient, to reduce the risk of hyperuricemia and urate nephropathy.

Red blood cell transfusions are useful to treat the anemia that is sometimes present at diagnosis and may worsen during the first several weeks of TKI therapy.

The WBC count can fall very rapidly when potent TKI therapy is begun, and ironically, patients with CML may actually become neutropenic. This is a sign of effectiveness and not toxicity from the drug. Rather than stopping the TKI, supportive care with prophylactic antibiotics or filgrastim has been recommended.

Because erythroid progenitors and megakaryocytes are also part of the neoplastic Ph+ clone in CML, the red blood cell count and platelet count may fall as the TKI therapy takes effect, but they recover when normal hematopoiesis regenerates several weeks later.

What should you tell the patient and the family about prognosis?

The goal of treatment is to achieve a molecular remission in which the BCR/ABL1 fusion gene products are no longer detectable by molecular assays. The prognosis for long life is excellent. There can be some chronic side effects; however, these are rarely so severe as to interfere with daily activities. Adherence to daily oral treatment appears essential, as clinical trials indicate that missing doses correlates with significantly worse long term outcomes. Each TKI has a distinct toxicity profile. Ponatinib and nilotinib have resulted in arterial and venous vascular events and heptatic toxicity; dasatinib may cause pleural effusions and pulmonary hypertension.

"What if" scenarios.

Safety during pregnancy has not been established for the TKI's that are approved for the treatment of CML. Patients are strongly recommended to discontinue their TKI if pregnancy occurs. Depending upon the status of their disease, interferon can be substituted. Patients with diabetes or hypertension benefit from rigorous control of these disorders, which may worsen during TKI therapies.

Pathophysiology

The Philadelphia chromosome, which results from the reciprocal translocation, t(9;22)(q34;q11.2), is the hallmark of CML. This chromosomal rearrangement results in the formation of a unique fusion gene BCR/ABL1, which is present only in the malignant hematopoietic cells and their progeny. This mutation results in a constitutively active tyrosine kinase, initiating a signalling cascade that dysregulates the otherwise tight control of myeloproliferation.

What other additional laboratory studies may be ordered?

Chemistry panel on blood to assess renal function and uric acid level.

VII. What's the evidence?

Baccarani, M, Deininger, MW, Rosti, G. "European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013". Blood. vol. 122. 2013. pp. 122-872.

(These guidelines focus on the front- and second-line use of imatinib, dasatinib, and nilotinib for newly diagnosed patients with CML in chronic phase, and explain the rationale and treatment alternatives for patients who have optimal or suboptimal responses or treatment failure to imatinib. They will be updated in 2016.)

Druker, BJ, Guilhot, F, O'Brien, SG. "Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia". N Engl J Med. vol. 355. 2006. pp. 355-2408.

(The outcomes for the 553 patients initially assigned to frontline imatinib therapy in the IRIS trial showed a high fraction having complete cytogenetic responses and major molecular responses. There was a low level of side-effects and few progression events after the first 3 years of treatment.)

Giles, FJ, Abruzzese, E, Rosti, G. "Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy". Leukemia. vol. 24. 2010. pp. 1299-1301.

(Nilotinib is a rationally designed drug that has improved binding characteristics to the active site of the BCR-ABL enzyme. This phase II trial documented its effectiveness in patients who had CML that did not respond to other TKI therapies.)

Giles, FJ, le Coutre, PD, Pinilla-Ibarz, J. "Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up of a phase II study". Leukemia. vol. 27. 2013. pp. 107-112.

(45% of patients achieved a CCyR, and deeper molecular responses at 3 and 6 months were highly correlated with progression-free and overall survival at 48 months.)

Guilhot, F, Apperley, J, Kim, D-W. "Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase". Blood. vol. 109. 2007. pp. 109-4143.

(Dasatinib was initially approved for the treatment of CML based on its effectiveness and good side-effect profile in patients with advanced disease. The patients enrolled on this phase II study had all previously received imatinib and either did not tolerate it or had resistant disease.)

Hughes, TP, Saglio, G, Kantarjian, HM. "Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase with frontline nilotinib or imatinib". Blood. vol. 123. 2014. pp. 1353-1360.

(Failure to achieve an early molecular response (EMR; BCR/ABL >10% (IS)) at 3 or 6 months predicts poor outcomes for patients with chronic phase CML. High Sokal risk score was associated with a igh rate of EMR failure on imatinib but not on nilotinib.)

Kantarjian, H, Shah, NP, Hochhaus, A. "Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia". N Engl J Med. vol. 362. 2010.

(The second generation TKI dasatinib produced a higher rate of complete cytogenetic responses at 12 months than did standard imatinib treatment, in this randomized trial enrolling patients with newly diagnosed CML in chronic phase.)

O'Brien, SG, Guilhot, F, Larson, RA. "Interferon and low-dose cytarabine compared with imatinib for newly diagnosed chronic phase chronic myeloid leukemia". N Engl J Med. vol. 348. 2003. pp. 348-994.

(This report describes the initial results of the IRIS study, a phase III trial involving 1,106 patients with newly diagnosed CML in chronic phase. It clearly established imatinib as the superior treatment compared to the previous standard of interferon and low dose cytarabine.)

(This report of the pivotal IRIS study established a major molecular response as an important "safe haven" that was associated with a very low probability of progression of CML to accelerated or blast phase.)

(This three arm randomized trial between standard imatinib therapy and the second generation TKI, nilotinib, in the ENESTnd trial demonstrated higher rates of molecular response and fewer progression events with no increase in toxicity for patients receiving either one of the two dose levels of nilotinib.)

Radich, JP, Kopecky, KJ, Appelbaum, FR. "A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia". Blood. vol. 120. 2012. pp. 3898-3905.

(The proportion of patients achieving CCyR was superior with dasatinib (84% vs 69%), as was the 12-month molecular response by patients achieving > 3-log, > 4-log, and > 4.5-log reduction in BCR-ABL transcript levels. Overall and progression-free survival was similar in the 2 arms.)

Shah, NP, Guilhot, F, Cortes, JE. "Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study". Blood. vol. 123. 2014. pp. 123-2317.

(Dasatinib is a second generation TKI that inhibits both BCR/ABL and SRC tyrosine kinases. This randomized dose-optimization trial demonstrated its effectiveness for CML in chronic phase that was resistant to imatinib.)

Hochhaus, A, Saglio, G, Hughes, TP, Larson, RA, Kim, DW, Issaragrisil, S. "Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial". Leukemia. 2016 Feb 3.

(After 5 years of follow up on the ENESTnd study, the patients who had been randomly assigned to nilotinib had fewer progression events, higher overall survival, and higher molecular response rates, than those assigned to standard imatinib therapy.)

Larson, RA. "Is there a best TKI for chronic phase CML". Blood. vol. 126. 2015 Nov 19. pp. 2370-5.

(The 3 TKIs approved for frontline use are compared for their efficacy and toxicities.)

Mahon, FX. "Discontinuation of tyrosine kinase therapy in CML". Ann Hematol. vol. 94. 2015 Apr. pp. S187-93.

(It is now clear that a small fraction of CML patients can safely discontinue TKI therapy.)

Hehlmann, R, Müller, MC, Lauseker, M, Hanfstein, B, Fabarius, A, Schreiber, A. "Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV". J Clin Oncol. vol. 32. 2014 Feb 10. pp. 415-23.

(A deep molecular response is reached by a majority of CML patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib.)

Kalmanti, L, Saussele, S, Lauseker, M, Müller, MC, Dietz, CT, Heinrich, L. "Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV". Leukemia. vol. 29. 2015 May. pp. 1123-32.

(Ten years after enrolling on the German CML IV trial, progression-free survival was 82%, overall survival 84%, and 89% had achieved a major molecular remission.)
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