Diagnosis and Management of Accelerated Phase CML
Diagnosis and Management of Accelerated Phase CML
Jonathan Webster, MD, and B. Douglas Smith, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
A 63-year-old Caucasian woman who first noticed nausea and early satiety about two months ago presents to your oncology office. One month ago, she developed increasing fatigue as well as night sweats. She was initially treated with doxycycline by her PCP due to a new rash on her leg without improvement in her symptoms, although her rash subsequently resolved. On exam she was noted to be afebrile with stable vital signs. Her abdominal exam was notable for a spleen tip that was palpable 12 cm below the costal margin. Review of her medical history was significant for insulin-controlled diabetes mellitus, hypothyroidism, hypertension and hyperlipidemia. She had no past surgical history. Her family history was unremarkable for malignancy. She was a non-smoker and did not use alcohol or other recreational drugs.
|Challenge Question 1:|
Laboratory tests revealed a normal CMP. Her CBC was notable for a WBC of 37.5K/mm3 with an abnormal differential comprised of 44% neutrophils, 1% lymphocytes, 27% eosinophils, 22% basophils, and 4% metamyelocytes. Her hemoglobin was 10.8 g/dL, which was decreased from 3 months prior when it had been normal at 13.9 g/dL. Her platelet count was 592K/mm3.
The patient’s presentation is notable for fatigue, leukocytosis, basophilia, eosinophilia, and splenomegaly. Her presentation raises concern for a number of different conditions that are discussed below along with laboratory features that allow these conditions to be distinguished.
- Chronic myeloid leukemia: The patient’s clinical symptoms are consistent with CML. The diagnosis of CML is confirmed by identification of the Philadelphia chromosome, or its product the BCR-ABL fusion gene. This can be confirmed by identification of the Philadelphia chromosome via conventional cytogenetics from a bone marrow biopsy, or identification of the BCR-ABL1 fusion gene via fluorescence in situ hybridization (FISH) from the peripheral blood or bone marrow.1
- Leukemoid reaction: This is usually seen in the setting of an infection, which was an initial diagnostic concern in this patient. There is no specific test to confirm this diagnosis, and thus it is a diagnosis of exclusion. However, the presence of a confirmed infection should raise suspicion for this diagnosis.
- Chronic myelomonocytic leukemia: The clinical symptoms of this disease can closely mimic CML, and the patients often present with anemia or thrombocytopenia. A monocytosis is a typical feature of this disease. It is distinguished from CML by the presence of prominent dysplastic changes in 2/3 myeloid lineages and the absence of the Philadelphia chromosome, BCR-ABL1 fusion gene, or its products.2
- “Atypical CML”: The clinical presentation can closely mimic typical CML with splenomegaly and a neutrophilic leukocytosis among the common signs. Dysplastic changes are seen in the neutrophils, and sometimes in other lineages as well. This can be differentiated from typical CML based on the absence of the Philadelphia chromosome.3
- Chronic eosinophilic leukemia: This disease is characterized by the presence of eosinophilia for more than 6 months, no evidence of diseases that are associated with reactive eosinophilia, evidence of organ involvement and either a clonal chromosomal abnormality OR two out of three of the following: immature eosinophil precursors accounting for >25% of the bone marrow or peripheral blood cells, myeloblasts accounting for >5% of the bone marrow or peripheral blood count, or eosinophils demonstrating positivity for naphthol chloroacetate esterase. The Philadelphia chromosome and BCR-ABL1 fusion gene are absent.4
- Chronic neutrophilic leukemia: Characteristic features include hepato/splenomegaly and persistent neutrophilic leukocytosis without dysplasia. The Philadelphia chromosome is absent.3
- Essential thrombocythemia: The characteristic feature is thrombocytosis in the absence of the Philadelphia chromosome. Studies in these patients have demonstrated that up to 50% of these patients have a detectable BCR-ABL fusion protein despite the absence of the Philadelphia chromosome.5
|Typical CML Symptoms|
The most common presenting symptoms of CML include fatigue, anorexia, and weight loss; although up to 40% of patients are asymptomatic at presentation. The most common exam finding is splenomegaly, which is present in up to 50% of patients. The median age of diagnosis is 53 years old. Labs often show a leukocytosis with a WBC typically >25K/mm3, thrombocytosis (present in 30-50% of cases), and basophilia.6
|Challenge Question 2:|
|Appropriate Testing When Concerned for CML|
When concerned for CML, the patient should undergo a bone marrow aspirate and biopsy with review of pathology for blasts and basophils. The aspirate should be sent for a karyotype analysis (conventional cytogenetics) to assess for the presence of the Philadelphia chromosome and/or fluorescence in situ hybridization (FISH) for the BCR-ABL1 fusion gene. FISH can be performed either on a bone marrow specimen or the peripheral blood. Additionally, peripheral blood should be sent for quantitative RT-PCR for BCR-ABL. This is helpful in establishing a baseline level of BCR-ABL. However, a positive BCR-ABL RT-PCR in the absence of evidence of the Philadelphia chromosome by cytogenetics or FISH is not diagnostic of CML, as low levels of BCR-ABL transcripts can be seen in the general population.1
|Back to the Patient: BM Biopsy Results|
BM Biopsy: CHRONIC MYELOGENOUS LEUKEMIA, ACCELERATED PHASE.
The aspirate shows increased blasts (17%), increased eosinophils, and increased basophils.
Karyotype: 46, XX, t(9;22) (q34;q11.2) [20/20]
FISH: 85% of cells contained fusion of the BCR and ABL signals.
Quantitative PCR: 969 copies/1,000 of ABL. IS 252%.
|Accelerated Phase Definition|
There are two different definitions of accelerated phase as follows:
- Blasts 10-19% of WBCs in peripheral blood and/or nucleated bone marrow cells
- Peripheral blood basophils ≥20%
- Persistent thrombocytopenia (<100 X 109/L) unrelated to therapy, or persistent thrombocytosis (>1000 X 109/L) unresponsive to therapy
- Increasing spleen size and increasing WBC count unresponsive to therapy
- Cytogenetic evidence of clonal evolution
- Peripheral blood blasts ≥15% and <30%
- Peripheral blood blasts and promyelocytes ≥30%
- Peripheral blood basophils ≥20%
- Platelet count ≤100 x 109/L unrelated to therapy
- Clonal evolution
The MD Anderson definition is generally more widely accepted for entry into trials.
|Challenge Question 3:|
|Treatment Options for Accelerated Phase CML at Initial Presentation|
The treatment of and outcomes in accelerated phase CML have changed dramatically with the advent of tyrosine kinase inhibitors (TKIs). A retrospective study compared imatinib (Gleevec) with conventional therapies including interferon-α, decitabine, homoharringtonine, and the combination of daunorubicin and cytarabine for patients in accelerated phase. This study demonstrated a complete cytogenetic response in 43% of patients treated with imatinib versus 5% in patients treated with interferon-α, which was the most effective treatment prior to the discovery of TKIs. This translated into a significant increase in estimated 4-year survival (53% versus 42%).7 A subsequent study analyzing outcomes of patients with de novo accelerated phase CML demonstrated a complete cytogenetic response rate of 80% with imatinib versus 90% with second-generation TKIs (dasatinib and nilotinib), and a major molecular response rate of 63% with imatinib versus 76% with second-generation TKIs.8 Other studies have demonstrated the efficacy of second-generation TKIs following imatinib failure or intolerance for patients in accelerated phase.9,10
|Choosing and Dosing TKIs in Accelerated Phase|
- Imatinib, dasatinib, and nilotinib are all acceptable treatment options for CML in accelerated phase with no prior treatment. The second-generation TKIs (dasatinib and nilotinib) are sometimes preferred to imatinib, as the evidence suggests that they lead to a faster response and may have a slightly higher response rate.
- Dosing of TKIs for accelerated phase differs from chronic phase dosing as follows:
- Imatinib 600 mg PO daily (may escalate to 800 mg PO daily as tolerated) vs. 400 mg PO daily in chronic phase
- Dasatinib 140 mg PO daily (may escalate to 180 mg PO daily if not achieving a hematologic or cytogenetic response) vs. 100 mg PO daily in chronic phase
- Nilotinib 400 mg PO BID vs. 300 mg PO BID in chronic phase
|General Side Effects of TKIs|
Interactions and precautions11
- CYP3A4 substrate: Leads to increased levels with inhibitors such as diltiazem, verapamil, itraconazole, ketoconazole, clarithromycin, erythromycin and decreased levels inducers such as rifampin, phenobarbital, phenytoin, and St. John’s Wort
- Teratogen: Recommend discontinuation during pregnancy
- Neutropenia: Very uncommon after the initial 1-2 months, can be managed with a dose reduction or growth factors
- Anemia: Tends to be rare and can be managed with erythropoietin-stimulating agents
- Thrombocytopenia: Can be managed with dose reduction
- Hepatic dysfunction: Usually early and transient but acetaminophen and excessive alcohol should be avoided
- Rash: Usually mild and transient, but TKI should be stopped if more severe. Steroids can be beneficial
- Fatigue: Mild but can be persistent
- Diarrhea: Responds to antispasmodic drugs
- Nausea: Patients should take TKIs with a meal and a large glass of water to minimize nausea. Imatinib and bosutinib tend to cause more GI side effects than dasatinib and nilotinib
- Electrolyte abnormalities: These vary depending on the specific drug but include hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia
|TKI-Specific Side Effects|
- Edema: Varying severity but responsive to diuretics
- Periorbital edema: Very common and poorly responsive to diuretics
- Muscle cramps, myalgias, and arthralgias: Most prominent long-term side effect
- Platelet dysfunction: This was discovered based on platelet aggregation studies and is independent of thrombocytopenia16
- Pulmonary arterial hypertension: This usually resolves with cessation of dasatinib17
- Pleural and pericardial effusions: Management may require diuretics, thoracentesis, and pleurodesis18
- Peripheral edema and periorbital edema
- Elevated lipase and amylase
- Peripheral arterial occlusive disease: Nilotinib led to significantly more PAOD than imatinib in a retrospective review19
- QT prolongation: Patients on nilotinib should have serial ECGs to monitor their QTc
- GI side effects: Tend to be more prominent (ie, diarrhea, nausea, vomiting, etc.)
- Elevated lipase
|Back to the Patient|
She is started on dasatinib 140 mg PO daily. She does well with minimal nausea. Her blood counts respond appropriately after 2 months her CBC demonstrates a WBC of 2.1K/mm3 with a differential showing 54.2% neutrophils (ANC 1160), 24.3% lymphocytes, 9.9% eosinophils, and 2.1% basophils. Her hemoglobin is 10.7 g/dL. Her platelet count was 166K/mm3.
|Challenge Question 4:|
It is recommended that every patient initially have a bone marrow sent for cytogenetics and peripheral blood for measurement of BCR-ABL transcripts by RQ-PCR. If BCR-ABL transcripts are detectable by RQ-PCR, then it is reasonable to repeat RQ-PCR every 3 months for monitoring. This method is more sensitive for detecting CML than bone marrow cytogenetics. Bone marrow cytogenetics should be repeated at 6 months to confirm that the Philadelphia chromosome is negative. Thereafter, if a complete cytogenetic response is confirmed, then the level of BCR-ABL transcripts can be followed every 3 months and marrow cytogenetics should be repeated every 12 months as long as the level of BCR-ABL transcripts remains stable or declining. A greater than two-fold increase in the BCR-ABL PCR that has been confirmed by repeat testing should prompt kinase domain mutation testing, as this raises concern for the development of resistance to the TKI in patients who are compliant with treatment.20
Complete hematologic response21
- Complete normalization of peripheral blood counts with leukocyte count <10 cells x 109/L and platelet count <450 cells x 109/L
- No immature cells, such as myelocytes, promyelocytes, or blasts in the peripheral blood
- No signs and symptoms of disease with disappearance of palpable splenomegaly
- Complete: No Ph-positive metaphases
- Partial: 1-35% Ph-positive metaphases
- Major: 0-35% Ph-positive metaphases (complete + partial)
- Minor: >35% Ph-positive metaphases
- Complete molecular response: No detectable BCR-ABL mRNA by QPCR (IS) using an assay with a sensitivity of at least 4.5 logs below the standardized baseline
- Major molecular response: BCR-ABL1 transcripts 0.1% by QPCR (IS) or ≥3-log reduction in BCR-ABL1 mRNA from the standardized baseline, if QPCR (IS) is not available
- Any sign of loss of response (defined as hematologic or cytogenetic relapse)
- 1-log increase in BCR-ABL transcript levels with loss of MMR should prompt marrow evaluation for loss of CCyR but is not itself defined as relapse
|Back to the Patient|
She maintains stable counts for 2 years. FISH for BCR-ABL is checked every 6 months and demonstrates a decline from 20% containing the fusion of BCR-ABL at 6 months to 4.4% at 12 months to undetectable at 18 months. Serial RT-PCR demonstrates a decline in the IS (BCR-ABL1/ABL1) to 77% at 3 months, 38% at 6 months, 10.5% at 9 months, 6.3% at 12 months, and 1.2% at 18 months. Unfortunately, at 30 months, her BCR-ABL1/ABL1 IS rises to 5%, and repeat FISH from the bone marrow demonstrates an increase in BCR-ABL to 5.7%. Kinase domain mutation testing demonstrates a T315I mutation.
|Challenge Question 5:|
|Management of TKI Resistance|
In compliant chronic phase patients, studies have shown that the presence of a kinase domain mutation along with a failure to achieve a complete cytogenetic response are the two major prognostic factors that predict risk of progression.25 Kinase domain mutations can confer resistance to TKIs. The T315I kinase domain mutation is present in up to 20% of patients with tyrosine kinase inhibitor-resistant disease and confers resistance to all approved BCR-ABL tyrosine kinase inhibitors except ponatinib. In a study of patients with known T315I mutations in chronic phase, 66% achieved a major cytogenetic response with ponatinib.26
|Side Effects of Ponatinib26|
- Arterial thrombotic events: cardiovascular, cerebrovascular, and peripheral vascular
- Rash and dry skin: These occurred, respectively, in 40% and 39% of patients on the initial trial but few were grade 3 or 4
- Abdominal pain: This is also quite common occurring in 27% of patients with 7% characterized as severe (ie, grade 3/4)
- Elevated lipase, amylase, and pancreatitis: 21% of patients on the initial study developed elevated lipase with 7% developing frank pancreatitis
- Elevated LFTs: This included elevations in AST, ALT, and GGT
- Fatigue, arthralgia and myalgia: These complaints were common but rarely severe (≤2% of patients reported grade 3/4 toxicities)
|Back to the Patient|
The patient is started on ponatinib 45 mg PO daily. Her blood counts remain stable and after 3 months RT-PCR demonstrates a decline in her IS to 1.8%. Her BCR-ABL fusion gene is again undetectable by FISH. The patient subsequently presents with epigastric abdominal pain, nausea, and vomiting. A serum lipase is elevated, and a CT scan demonstrates stranding around the pancreas consistent with pancreatitis.
|Challenge Question 6:|
- Pancreatitis is a common side effect of ponatinib and generally occurs early in the course of treatment. Of the 29 patients who developed pancreatitis during the initial trial, all 29 resumed ponatinib and only 3 developed recurrent pancreatitis.26 Thus, it is likely safe to resume ponatinib.
- Given the significant side effects of ponatinib and the lack of viable alternatives for patients with T315I mutations who have progression of disease on ponatinib or are intolerant, the current recommendation is for all patients with T315I mutations to undergo allogeneic bone marrow transplantation. Prior studies in this setting have shown that patients who undergo transplant in chronic or accelerated phase generally have much improved overall survival compared to those who undergo transplant in blast crisis.27
The diagnosis of accelerated phase CML is based on results of the complete blood count, bone marrow biopsy, and exam findings. The initial treatment of accelerated phase CML in treatment-naïve patients is with a tyrosine kinase inhibitor. If the patient subsequently develops evidence of disease progression, then kinase domain mutation testing is indicated. T315I mutations can be managed with ponatinib as a bridge to allogeneic bone marrow transplantation.