CML Shejal Patel DO

Epidemiology CML accounts for 15% of newly diagnosed cases of leukemias in adults. Median age is 67 years In 2015, 6660 new cases of CML diagnosed in the US and 1,140 patients will die of CML. Since 2000, after introduction of imatinib, annual mortality in CML has decreased from 10-20% to 1-2%.

Pathogenesis The 3’ portion of ABL gene on chromosome 9 is translocated to BCR gene on chromosome 22 Breakpoints on chromosome 22 occur at 3 different locations yielding oncogenes of varying lengths Oncoproteins function as constitutively active tyrosine kinase which phosphorylates intracellular proteins  cell proliferation and survival P210 most common fusion protein in cml. P190 only in 1% of pts with cml. P190 found usually in setting of ALL

Pathogenesis 90% - 95% of patients with CML will have typical translocation of 9,22. Remaining have variant translocations (response to therapy and prognosis same as Ph+ CML)

Clinical Manifestations Fatigue, malaise Weight loss Excessive sweating Abdominal fullness, early satiety from splenomegaly Bleeding episodes Leukocytosis, anemia, thrombocytosis Extramedullary involvement ie lymph nodes, skin, soft tissue generally limited to patients in blast crisis.

Case 1 60 yo male with history of CAD comes to hematology clinic for evaluation of leukocytosis. Patient had an elevated white count for atleast a year. He says his most recent white count has been going up. His cbc from today shows wbc 36.5 hgb 14.6, plts 522, Seg 57%, Band 7%, Basophils 6%, Metamyelocytes 6%, Myelocytes 6%, Blasts 3%. On exam no lymphadenopathy but splenomegaly is present. What is your differential diagnosis and what workup do you want?

Differential diagnosis and workup Differential diagnosis: CML, Leukemoid reactions, corticosteroids, CMML, Chronic eosinophilic leukemia, Chronic neutrophilic leukemia, atypical CML , other myeloproliferative disorders, other Philadelphia chromosome positive malignancies. Workup: CMP, cbc with diff, peripheral smear, assess for splenomegaly, bone marrow biopsy and aspirate, bone marrow cytogenetics, quantitative RT-PCR for BCR/ABL1 blood

CML Diagnosis Diagnosis for CML confirmed with RT-PCR for BCR/ABL 1 and the bone marrow biopsy. Diagnosis of CML is made by confirmation of BCR/ABL 1 from conventional cytogenetics, FISH or RT-PCR. Patient from Case 1 has 8% blasts in bone marrow. What is his stage?

CML Staging Staging is based off of % of myeloblasts Chronic Phase <10% peripheral or bone marrow blasts Accelerated Phase  if any of the following true: peripheral or bone marrow blasts >10% but <20%, basophils making up atleast 20% of the white blood cells, high white blood cell counts that do not go down with treatment, very high or very low platelet counts that are not caused by treatment, new chromosome changes in the leukemia cells. Blast Phase  >20% blasts in peripheral or bone marrow blasts CML-blast phase presents as an acute leukemia (myeloid in 60%, lymphoid in 30%, megakaryocytic or undifferentiated in 10%

EUTOS score specifically designed for those who will get imatinib first line. Hasn’t been confirmed by other investigators in other studies.

MR 4.5– greater than or equal to 4.5 log reduction of bcr-abl 1.

Chronic Phase CML Treatment- First line Tyrosine kinase inhibitor Imatinib 400mg po daily Nilotinib 300mg po bid Dastinib 100mg po daily How would you treat patient in case 1?

Imatinib: Tyrosine kinase inhibitor The bcr-abl tyrosine kinase is a constituitively active kinase which functions by binding ATP and transferring phosphate from ATP to tyrosine residues on various substrates. This causes the excess proliferation of myeloid cells characteristic of CML. Imatinib functions by blocking the binding of ATP to the bcr-abl tyrosine kinase, inhibiting its activity. In the absence of tyrosine kinase activity, substrates required for bcr-abl function cannot be phosphorylated and subsequent cellular events are abrogated. Imatinib inhibits bcr/abl1 kinase, blocks platelet derived growth factor receptor(PGDFR) and c-kit tyrosine kinase. Savage et al. NEJM 2002

Imatinib Imatinib was FDA approved in 2001 in advanced CML. In Dec 2002, imatinib approved for first line treatment of CML based on IRIS study results. Prospective, multicenter, open-label,phase 3 randomized study (IRIS- international randomized study of interferon and STI571) comparing the standard arm ( recombinant interferon alfa and low dose cytarabine) compared to STI571 (imatinib). Enrolled 1106 adults age 18 to 70 yo old with diagnosis of chronic phase Ph+ CML (<15% blasts, <20% basophils, <30% blasts + promyelocytes in the peripheral blood and bm). 553 patients were in imatinib 400mg po daily arm and 553 patients in interferon alfa (gradually escalating doses with target dose of 5 million U per sq meter of body surface area per day) + low dose cytarabine arm (20mg/m2 x 10 days per month).

IRIS study: INF vs Imatinib d/ced 68 (12%) 474 (86%) Imatinib 400 mg/d N=553 11 (2%) Eligibility - Age 18-70 yrs CML-CP, Ph+ Dx in six mon R INF + Ara-C N=553 318 (58%) Equal characteristics between both groups except, more chromosomal abnormalities other than Ph+ in imatinib group. High crossover rate in INF arm bc of intolerance. d/ced 175 (31%) 60 (11%) O’Brien et al. NEJM 2003

IRIS study: Results † P<0.001 for the comparison with the imatinib group

IRIS study: Results Freedom from progression to acc/blast None of the pts with documented MMR at 12 months progressed to accelerated or blast phase. Because of high rate of crossover(90%) from interferon alpha to imatinib within a year of study, survival benefit for imatinib vs interferon could not be demonstrated in this trial. In historical comparisonss survival benefit has been better with imatinib vs inteferon. Freedom from progression to acc/blast phase at 12 months: 98.5% vs 93.1% PFS at 12 months: 96.6% vs 79.9%

8 yr IRIS followup Estimated EFS was 81% and freedom from progression to AP/BC was 92%. Estimated OS was 85% at 8 year and 93% when only CML related deaths and those prior to SCT were considered. Only 55% of patients enrolled in IRIS study remained on therapy at 8 yr follow up time.

Imatinib Toxicity Grade 3/4 neutropenia and thrombocytopenia GI disturbances Edema Rash Musculoskeletal complaints Skin hypopigmentation(reversible with stopping or dose reduction) Chronic fatigue CHF and cardiotoxicity (1.7%)

High dose Imatinib TOPS study: Phase III, N=476, dose 400mg vs 800mg - At 12 months: CCyR 66% vs 70% (p=0.35), MMR 40% vs 46% (p=0.2) - MMR & CCyR occurred earlier with higher dose (at 3 & 6 months) - High dose imatinib resulted in faster and higher response rates between treatment arms but adverse events were more frequent with high dose imatinib. Cortes et al. J Clin Oncol 2010 German CML IV study, Phase III, N=1551, 3 arms-400mg, 800mg, 400mg + interferon - At 12 month, MMR (44%, 59%, 46% respectively in order as listed above) better in 800mg arm - 3 yr OS and PFS no different between different arms. With 800mg dose more rapid acheivement of MMR in low and intermediate risk groups Hehlmann et al. J Clin Oncol 2014 Conclusions: - High dose imatinib induces higher and faster CCyr and MMR compared to standard dose imatinib early on, but no difference in response rates at 12 months when compared to standard imatinib dose. - High dose imatinib associated with higher rates of discontinuation, reduction or interruption of therapy because of side effects. - High dose can be considered in case of failure or suboptimal response

Dasatinib Dasatinib is a second generation TKI, that is 350 times more potent than imatinib in vitro. It inhibits ABL1 and SRC family of kinases. It can bind to both active and inactive conformation of ABL 1 kinase domain, resulting in activity against nearly all BCR-ABL 1 mutations resistant to imatinib except T315I. FDA approved dasatinib 100mg daily for newly diagnosed CP-CML in 10/2010 based on DASISION trial.

Dasatinib Toxicity Reversible inhibition of platelet aggregation Qt prolongation Pleural effusion (29% in CP, 50% in AP, 33% in BP). Prior cardiac history, HTN, and those getting twice daily dosing of dasatinib are at increased risk. Reversible pulmonary arterial hypertension. Should permanently stop drug if this occurs. Cytopenias GI

Dasatinib vs Imatinib in newly dx CML-CP: DASISION Trial 100mg PO QD (n = 259) Eligibility Treatment-naive CML-CP R Imatinib 400mg PO QD (n = 260) Primary Endpoint: CCyR by 12 months Other Endpoints: Rate of CCyR, time to CCyR, rate of MMR, time to MMR, PFS, OS Shah N et al. Blood 2010;Abstract 206.

Results: Primary end-point Imatinib (n = 260) Dasatinib (n = 259) p-value Confirmed CCyR (by 12 months) 66% 77% 0.007 Confirmed CCyR (by 18 months) 70% 78% 0.0366 CCyR = No Ph-positive metaphases in bone marrow (FISH not allowed). Confirmed CCyR = CCyR detected in two consecutive assessments at least one month apart. Shah N et al. Blood 2010;Abstract 206.

Results: Secondary Endpoints at 24 months Imatinib Dasatinib CCyR (24 months)* 82% 86% Time to CCyR 6 months 3.2 months BCR ABL reduction by 4.5 log (24 months)* 8 % 17 % MMR (24 months)* 46% 64% Time to MMR 36 months 15 months Transformation to advanced phase CML 5 % 2.3% OS (at 24 months) 95.2% 95.3% PFS (at 24 months) 92.1% 93.7% cCCyr at 24 months. * is statistically significant Kantarjian et al. Blood Feb 2012

Kantarjian et al. Blood Feb 2012 Figure 4. Forest plot comparing differences in rates of drug-related nonhemato- logic and grade 3/4 hematologic adverse events for patients treated with dasatinib or imatinib. Kantarjian et al. Blood Feb 2012

5yr followup In both arms, patients who achieved BCR-ABL1 < 10% (IS) at 3 months more often reached CCyR, MMR, and MR4.5 by 5 years, had higher rates of OS and PFS, and had a lower transformation rate (3% v 14% to 15% in patients who did not achieve BCR-ABL1 < 10% at 3 months) . Cumulative 5 yr MMR was 76% in dasatinib arm and 42% in imatinib arm (p=0.0022) Estimated 5yr OS was 91% for dasatinib and 90% for imatinib. Estimated 5yr PFS was 85% for dasatinib and 86% for imatinib. By 5 years, 4.6% in dasatinib arm and 7.3% in imatinib arm transformed to AP/BP. Results continue to support Dasatinib as a possible first line treatment for CML. Cortes et al. JCO July 10 2016

Nilotinib A second generation TKI that is 30-50 times more potent than imatinib. FDA approved based on ENESTnd trial June 2010 for first line treatment of CP- CML. Since 2007 had been approved for those who were imatinib resistant or intolerant

Nilotinib Toxicity Fluid retention Edema Muscle cramps Grade 3/4 neutropenia/thrombocytopenia Grade ¾ elevations in lipase, bilirubin, hyperglycemia, hypophosphatemia Qt prolongation Increased vascular events including peripheral arterial occlusive disease.

Nilotinib vs Imatinib in newly dx CML-CP: ENESTnd Trial 400 mg PO QD (n = 283) Eligibility Treatment-naive CML-CP R Nilotinib 300 mg PO BID (n = 282) Nilotinib 400 mg PO BID (n = 281) Primary Endpoint: Major molecular response at 12 months Other Endpoints: Durable MMR (at 24 months) Complete cytogenetic response (CCyR) Progression to accelerated/blast phase (AP/BC) Progression-free survival (PFS), overall survival (OS) Hughes TP et al. Blood 2010;Abstract 207.

Saglio et al. NEJM June 2010

ENESTnd Trial: Results Imatinib 400 mg QD Nilotinib 300 mg BID 400 mg BID 18-months follow-up p-value MMR 40% 66% <0.0001 62% CMR 6% 21% 17% CCyR 74% 85% 82% 0.017 Progression to AP/BC 4.2% 0.7% 0.006 0.4% 0.003 CML-related deaths (n) 8 2 — 1 OS 96.9% 98.5% 0.28 99.3% 0.03 Hughes TP et al. Blood 2010;Abstract 207.

ENESTnd Trial :Conclusions Nilotinib demonstrates superior efficacy compared to imatinib Higher rates of MMR and CCyR Lower rates of transformation to accelerated/blast phase Nilotinib resulted in fewer CML-related deaths compared to imatinib Nilotinib 300mg bid was tolerated best, longer follow-up does not show any change in the adverse-event profile of nilotinib Hughes TP et al. Blood 2010;Abstract 207.

5 year followup MMR 77% in both arms of nilotinib and 60% for imatinib. (p<0.0001%) 4.5 log reduction of BCR/ABL 1 transcript in 56% of nilotinib 300mg arm, 55% in nilotinib 400mg arm, 33% in imatinib arm (p<0.0001%) Transformation by year 5 to AP/BP: 3.9% in 300mg arm, 2.1% in 400mg arm, 7.4% in imatinib arm (p 0.06 and 0.003) Conclusions: Nilotinib continues to give more superior molecular responses in CML patients with few progressions to accelerated or blast phase.

Summary of Phase 3 frontline

Back to Case 1 How to treat this patient? Imatinib, Dasatinib, Nilotinib all are options When choosing can use patients age, comorbidities and TKI toxicity profile to make decision. Some advocate in younger to use 2nd gen TKI for deeper response (for possible therapy discontinuation?) Second generation TKI are considered in higher risk disease.

How to monitor patients on TKI- by ELN Clonal chromosomal abnormalities. CCA in Ph+ cells which define failure if newly arisen . Cytogenetics from bone marrow at 3month and 6month if PCR not available.

NCCN guidelines

NCCN guidelines

Monitoring Those that don’t at 3months have BCR ABL 1 transcript <10% IS it has been shown with all 3 frontline TKIs that those patients are consider high risk for progression and less survival. When 3month benchmark not made unclear whether changing TKI will change longterm outcome. So some recommend no change and seeing at 6 months what results are. Mutational analysis if concerned for progression.

NCCN guidelines

2nd or subsequent line treatment TKI- Dasatinib, Nilotinib, Bosutinib, Ponatinib Bosutinib – 2nd generation TKI. Common Side effects: Diarrhea, n/v, rash, grade ¾ thrombocytopenia, anemia, neutropenia, Qt prolongation, pleural effusions(low rate), muscle cramps, cardiac toxicity. BELA trial: phase 3 compared Bosutinib 500mg with imatinib 400mg in front line CML. Did not meet primary endpoint of Ccyr at 12 month. At 12 months, Ccyr were 70% for Bosutinib and 68% for Imatinib(p=0.601). Hence not recommended as first line. Has been tested in 3rd line and in AP and BP-CML. Ponatinib- 3rd generation TKI, 500 times more ptoent than imatinib in inhibiting BCR-ABL 1. First TKI that works against T315I mutation. Side effects: Rash, dry skin, abdominal pain, grade ¾ neutropenia, anemia, thrombocytopenia, pancreatitis, edema, ascites, pleural or pericardial effusion, hepatoxicity, liver failure, arterial thrombotic events Ponatinib only approved for T315I mutation or patients who have not responded to two or more TKIs. Imatinib 800mg has been shown to overcome primary resistance but for short time.

2nd or subsequent line treatment Omacetaxine, formerly called homoharringtonine, induces apoptosis by down regulating the anti-apoptotic protein myeloid cell leukemia-1. Can use in T315I mutation. Side effects: NF, anemia, neutropenia, thrombocytopenia. Was approved by FDA in 10/2012 for treatment of patients with CP-CML or AP-CML who are intolerant to 2 or more TKIs or those with resistant disease not responding to prior treatment with 2 or more TKIs. CML 202 study-62 patients with CP-CML- CHR 77%, MCyr 23%, CCyr 16%. MMR was achieved in 17% of patients and T315I clone was reduced to below detection limits in 61% of patients. At 19 month followup, median PFS 7.7 months, median OS not reached. In 51 patients with AP-CML, CHR 29%, minor cytogenetic response 11%. Those with a history of T315I mutation had PFS 5.9 months and OS 18.7 months. In 44 patients with BP-CML, CHR 7%, PFS 2.2 and OS 3.5 months. Those with T315I mutation, PFS 1.9 months and OS 3.5 months.

2nd or subsequent line treatment Allo-SCT-consider in those who fail atleast 2 TKIS or have T315I mutation. Older agents: hydroxyurea, interferon alpha, cytarabine.

TKI Duration STIM (stop imatinib) trial tested risk of relapse in 100 patients on imatinib with ongoing complete molecular response(CMR) for greater than 2 years who stopped treatment. 61% experienced molecular relapse, with 95% of the events occurring within 7 months of stopping imatinib. Almost all patients were able to achieve CMR once imatinib therapy was restarted. Low risk Sokal score and duration of imatinib therapy >60months predicted for continued CMR after therapy cessation. It is not recommended to stop TKI therapy at this point.

AP-CML treatment TKI Clinical Trial Omacetaxine

BP—CML treatment Lymphoid Myeloid Clinical Trial ALL type induction chemo + TKI TKI + steroids Myeloid AML type induction chemo + TKI TKI

Ready to test your knowledge?

Question 1 Which of the following is not an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with chronic myeloid leukemia (CML) in the chronic phase? (A) Cytogenetic relapse at 18 months after achieving initial hematologic remission (B) First-line treatment in a chronic-phase CML (CP-CML) patient (C) No cytogenetic response at 6 months (D) Partial cytogenetic response at 18 months (E) Presence of T571 mutation in patients who failed to respond to tyrosine kinase inhibitors (TKIs)

Question 2 A 42-year-old man previously diagnosed with Philadelphia (Ph) chromosome– positive CP-CML presents for treatment monitoring. Six months ago, the patient was started on imatinib (400 mg/day). At 3-month follow-up, the patient achieved complete hematologic remission. At the current presentation, repeat cytogenetic analysis of the bone marrow is performed, which reveals a decrease in the Ph positive metaphases from 100% to 20%. However, a novel clonal trisomy 8 abnormality is documented in 5 of 16 Ph-negative metaphases. The bone marrow morphology is normal, and the patient remains in complete hematologic remission. How should this patient be treated? (A) Change imatinib to dasatinib (B) Continue with imatinib at the same dose (C) Increase imatinib to 800 mg/day (D) Perform allogeneic HSCT as soon as possible

Question 2 The correct answer is (B), continue with imatinib at the same dose. Clonal cytogenetic abnormalities such as trisomy 8 have been reported in Phnegative cells from patients diagnosed with CP-CML who were undergoing treatment with imatinib. Although the significance of these findings is uncertain, it appears that these abnormalities are transient in many cases and disappear with continued therapy. Rarely, myelodysplasia was also found. A clear distinction should be made if the clonal abnormalities occur in Ph-positive cells, which represents clonal evolution. Clonal evolution is associated with clinical progression and worse outcome, particularly when other features of accelerated-phase CML are present.3 In the case discussed here, the trisomy 8 clonal abnormality was not associated with the Ph chromosome. Recent reports also indicate that the prognosis of clonal evolution in the absence of Ph positive chromosome is good. Therefore, changing the treatment strategy (including switching to another TKI, considering HSCT, or increasing the dose of imatinib) is not warranted since the patient achieved the expected therapeutic milestones.

Question 3 Which of the following statements best characterizes the side effects associated with nilotinib treatments? (A) Monitoring of hepatic transaminases is not required because their elevation is extremely rare (B) Neutropenia and thrombocytopenia (grade 3/4) are rare side effects and are present in only 5% of cases (C) Nilotinib has no significant interactions with other drugs (D) Nilotinib therapy is frequently associated with severe fluid retention and pleural effusions (E) QT prolongation can occur with nilotinib therapy, and a baseline electrocardiogram should be obtained prior to starting treatment

Question 4 Which of the following statements about monitoring patients receiving imatinib treatment for CP-CML is correct? (A) After a patient achieves a major cytogenetic response, quantitative fluorescence in situ hybridization analysis should be performed in peripheral blood every 3 months (B) Conventional bone marrow cytogenetic analysis should be performed every 3 months (C) 1-Log increase of BCR-ABL transcript levels as determined by quantitative reverse– transcript polymerase chain reaction (qRT-PCR) without achieving major molecular response should prompt the physician to obtain cytogenetic analysis of the bone marrow (D) qRT-PCR for BCR-ABL transcript levels is extremely helpful in monitoring patients who have persistent Ph-positive chromosome in bone marrow karyotype analysis

Question 5 A 32-year-old man with a history of CP-CML that was previously treated with HSCT (matched sibling donor) 3 years ago and who achieved complete cytogenetic and molecular remission presents for his semi-annual follow-up visit. Repeat qRT-PCR analysis of the peripheral blood for BCR-ABL transcripts reveals a 2-log increase with respect to his baseline levels. Cytogenetic analysis of the bone marrow aspirate reveals that 5 of the 20 metaphases assessed are Ph-positive. All of the following are potential treatment options for this patient EXCEPT (A) Consider a clinical trial (B) Order a donor lymphocyte infusion (DLI) (C) Repeat qRT-PCR in 3 months to assess if BCRABL transcript levels increase (D) Start treatment with imatinib or dasatinib

References Jabbour et al. CML:2016 update on diagnosis, therapy and monitoring. AJH: vol91:no2, Feb 2016 p253-265. Nccn.org Uptodate.com Erter et al. Current approach to treating chronic myeloid leukemia. Hospital Physician Board Review Manual, Hematology vol4, part 1, p 1-3. O’Brien et al. Imatinib compared with interferon and low dose cytarabine for newly diagnosed CP CML. NEJM 2003; 348: 994-1004. Deininger et al. IRIS 8 year followup: sustained survival and low risk for progression of events in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib. Blood 2009; 114. Abstract #1126.

References