Ongoing Management | GLIVEC (imatinib)

ONGOING TREATMENT IN PHILADELPHIA CHROMOSOME-POSITIVE (Ph+) CHRONIC MYELOID LEUKEMIA (CML)

According to the European LeukemiaNet (ELN), the ultimate goal of treatment is a stable or improving major molecular response (MMR) at any time point.¹

Patients should either have a stable or improving MMR (beyond 18 months) or they should reach an MMR (within 18 months at the latest).

Please click the links below for more information about today's evolving goals of therapy and learn how to apply a simple algorithm to evaluate response.

Achieving treatment goals — what are the goals that determine whether a patient is having an optimal response and by what time points should patients achieve them?

Evaluating goals — will the patient reach a stable or improving MMR in the long term?

Achieving Treatment Goals

REACHING TODAY�S TREATMENT GOALS

Evolving goals in Ph+ CML therapy

The goals of therapy for patients with Ph+ CML in the chronic phase (CP) have evolved.¹

What are the current goals of therapy for Ph+ CML-CP?

Achieve faster and deeper molecular responses
Prevent progression to accelerated phase or blast crisis (AP/BC) to extend survival
Minimize adverse events so that patients can adhere to their regimen

Obstacles to optimal response

A significant number of Ph+ CML-CP patients are not achieving treatment goals.

In the 8-year IRIS follow-up — 45% of patients were not successfully treated with imatinib²

Successfully Treated With Imatinib

When is a patient
response
suboptimal?

Learn more

For adult patients in whom GLIVEC therapy has not been successful, you may consider switching patients to nilotinib.³

Nilotinib was specifically designed to improve upon the molecular structure of GLIVEC as a way of preventing Ph+ CML resistance to the imatinib molecule⁴
Click www.tasigna.com to learn more about the clinical advantages of nilotinib

The European LeukemiaNet (ELN) recommendations outline response criteria for newly diagnosed patients in the following table.³

	Optimal response	Suboptimal response	Failure	Warnings
Baseline	NA (not applicable)	NA	NA	High risk CCA/Ph+*
3 months	CHR^� and at least minor CyR^� (Ph+ ≤65%)	No CyR^� (Ph+ >95%)	Less than CHR^�	NA
6 months	At least PCyR^� (Ph+ ≤35%)	Less than PCyR^� (Ph+ >35%)	No CyR^� (Ph+ >95%)	NA
12 months	CCyR	PCyR^� (Ph+ 1%-35%)	Less than PCyR^� (Ph+ >35%)	Less than MMR^\|\|
18 months	MMR^\|\|	Less than MMR^\|\|	Less than CCyR	NA
Any time	Stable or improving MMR^\|\|	Loss of MMR^\|\| Mutations^�	Loss of CHR^� Loss of CCyR Mutations^# CCA/Ph+*	Any rise in transcript levels CCA/Ph-

* Clonal chromosome abnormalities in Ph+ cells;CCA/Ph+ is a warning factor at diagnosis, although its occurrence during treatment (ie, clonal progression) is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least 2 Ph+ cells.
^� Complete hematologic response.
^� Cytogenetic response.
^� Partial cytogenetic response.
^# MMR indicates a ratio of BCR-ABL1 to ABL1 or other hourskeeping genes of ≤0.1% on the international scale.
^� BCR-ABL1 kinase domain mutations still sensitive to imatinib.
^|| BCR-ABL1 kinase domain mutations poorly sensitive to imatinib.

Patients with suboptimal responses may be at risk for developing resistance³
As you can see, the ELN recommendations consider 12 months an appropriate time frame within which to achieve MMR (failure to achieve MMR is considered a warning for subsequent suboptimal response)³
Anything less than MMR at 18 months is suboptimal³
Beyond 18 months (or at any time point of treatment), patients should have a stable or improving MMR, which is a prerequisite to ultimately reaching a status of undetectable disease (complete molecular response or better)³

References

Evaluating Treatment Response

EVALUATING TREATMENT RESPONSE

Patient Cases: What would you do?

The evaluation of treatment response is a critical part of the clinical decision-making process that can influence whether or not patients achieve today�s recommended treatment goals. The following case studies present examples of patients who may have evolving treatment needs. What would your recommended course of action be for these individual patients?

Click the links below to review each patient case:

Learn more about
nilotinib for GLIVEC-
resistant/intolerant
patients?

Read Now

What are the
most important
milestones of
treatment?

Learn More

Case 1: Madeline, a 66-year-old retired gym teacher who takes care of 2 grandchildren

Presents with increasing fatigue, splenomegaly (barely palpable)

Lab results	WBC: 30 x 10⁹/L; 77% neutrophils, 15% metamyelocytes/myelocytes, 4% promyelocytes, 2% blasts, 2% basophils HgB: 12.2 g/dL (13.5-17.7), PLT 140 x 10⁹/L (150-400)
Diagnostic results	Cytogenetic, 100% Ph+ metaphases; RQ-PCR, BCR-ABL mRNA positive
Treatment	Imatinib 400 mg/day
Follow-up	2 weeks: mild rash, Grade 2 diarrhea managed with topical antihistamines and antidiarrheal 3 months: CHR 6 months: CHR, minor CyR (40% Ph+ metaphases); 5.6% BCR-ABL to control gene ratio by international scale [IS] 12 months: CCyR; 3.2% BCR-ABL to control gene ratio by IS
Key considerations	How satisfied are you with the patient's response at 6 months? What would be the rationale for the treatment decision at that time?
Supporting data	Evidence suggests failure to achieve PCyR or CCyR at 6 months lowers EFS at 6 years (~60% EFS)¹ Median survival for patients who progress to AP/BC is only 2 years²

Case 2: Mike, a 49-year-old owner of a heating and air conditioning company

Presents with increasing fatigue
History and physical show anemia

Lab results	WBC: 150 x 10⁹/L; 67% neutrophils, 25% metamyelocytes/myelocytes, 2% promyelocytes,4% blasts, 2% basophils HgB: 9.8 g/dL (13.5-17.7), PLT 370 x 10⁹/L (150-400)
Diagnostic results	Cytogenetic, 100% Ph+ metaphases; RQ-PCR, BCR-ABL mRNA positive
Treatment	Imatinib 400 mg/day
Follow-up	1 month: CHR; Grade 2 muscle cramps 6 months: CHR, no cytogenetic response, no reduction in BCR-ABL mRNA transcripts
Key considerations	How satisfied are you with the patient's response at 6 months? Would you order other tests, and if so, what might they tell? What would be your treatment decision?
Supporting data	Patient meets criteria for treatment failure according to ELN/NCCN guidelines^3,4 Failure to achieve any CyR at 6 months Guidelines recommend mutational testing to rule out T315I mutation, which would make alternate TKI therapy futile^4,5 In addition, assessment of adherence should be made in cases of treatment failure

Case 3: Matilda, a 56-year-old retail clerk at a department store

Presents to ER with severe left shoulder pain (upper quadrant)
Weight loss, swelling of lower extremities, and loss of appetite
Extreme splenomegaly (10 cm BCM)

Lab results	WBC: 239,000, HgB: 8.7 g/dL, PLT 231,000 BM: <5% blasts, hypercellular, granulocytes PB: 7% blasts
Diagnostic results	Cytogenetic, 100% Ph+ metaphases; RQ-PCR, BCR-ABL mRNA positive
Treatment	Hydroxyurea 5 g/day x 7 days; imatinib 400 mg/day
Follow-up	3 months: CHR 6 months: PCyR; 32% BCR-ABL to control gene ratio by IS 12 months: CCyR; 3.2% BCR-ABL to control gene ratio by IS 18 months: CCyR; 1% BCR-ABL to control gene ratio by IS 24 months: CCyR; 3.2% BCR-ABL to control gene ratio by IS 30 months: 10% increase in Ph+ metaphases; 32% BCR-ABL to control gene ratio by IS
Key considerations	How satisfactory is the patient's best molecular response? What would be your treatment decision?
Supporting data	Best response was a 2.0-log reduction in BCR-ABL (1% BCR-ABL to control gene ratio by IS) at 18 months Evidence suggests this is consistent with a CCyR; however, it does not meet the response criteria of an MMR (=3.0-log reduction or =0.1% BCR-ABL/ABL by IS)⁶ ENESTnd and IRIS studies have demonstrated that no patient who achieved an MMR progressed^7,8 Median survival for patients who progress to AP/BC is only 2 years²

Case 4: Prashan, a 66-year-old lawyer and grandfather

Presents with shortness of breath and fatigue
Splenomegaly 24.5 cm by CT scan

Lab results	WBC: 224,000; 1% blasts (BM) and 6% (PB) HgB: 12.3 g/dL, PLT 129,000
Diagnostic results	Cytogenetic, 100% Ph+ metaphases; RQ-PCR, BCR-ABL mRNA positive
Treatment	Imatinib 400 mg/day
Follow-up	1 month: severe bone pain, fatigue, and GI intolerance; PLT dropped to 35,000, causing many skipped doses No difference in RQ-PCR BCR-ABL mRNA from baseline
Key considerations	Is there a rationale for changing therapy instead of rechallenging with imatinib? How would you continue to monitor this patient's response? What would you look for at 3 months?
Treatment considerations	Severe nonhematologic adverse events and thrombocytopenia with no evidence of response may provide a rationale for switching