Chronic myelogenous leukemia (CML)

Asciminib A third generation TKI, that effective in patients with relapsed disease.

10-year overall survival rates were 65.7% and 73.0% for patients who underwent transplant with and without pre-transplant exposure to TKI therapy, respectively.

For the entire cohort allogeneic stem cell transplantation (allo-SCT). the 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively.

Response rates with combinations of TKIs and chemotherapy are 40% in nonlymphoid CML-BP and 70-80% in lymphoid CML-BP.

Median survival times are 6 to 12 months, and 12 to 24 months, respectively.

The addition of TKIs to chemotherapy has improved the response rates and prolonged the median survival time in CML-BP.

The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome.

Characteristic hematologic findings include: absolutely Leuko cytosis with a left shift and classic myelocyte bulge with the usual blast count of less than 2%, nearly universal basophilia with absolute eosinophilia in 90% of cases, monocytosis but not an increased monocyte percentage, absolute monocytosis in in usual cases with a p190 BCR-ABL, normal or elevated platelet count, and thrombocytopenia.

Differential diagnosis includes chronic myelomonocytic leukemia, atypical CML, chronic neutrophilic leukemia and essential thrombocytosis.

In two thirds of patients in blast crisis the blasts are myeloid and in one third they are lymphoid.

Blast crisis is highly refractory to treatment with response rate to standard induction chemotherapy approximately 20% and the rate of complete remission less than 10%.

Assessment and treatment includes evaluation of the hematologic, cytogenetic, and molecular responses.

First cancer for which a molecular target therapy was developed.

TKIs block the BCR/ABL oncoprotein halting the constant signal for cell proliferation and survival, and are the primary therapy for chronic phase CML.

Hematologic response in general is referred to as the normalization of the WBC count and splenomegaly.

Cytogenetic and molecular response evaluations are focused on the assessment of the BCR-ABL abnormality.

Cytogenetic response is determined by the percentage of cells with the Philadelphia + metaphases, and assessment of the molecular response lies on quantitative reverse transcriptase polymerase chain reaction PCR-ABL transcripts, expressed on the International Scale (IS).

On the International Scale a major molecular response (MMR) is defined as a BCR-ABL transcript level of 0.1% or less, which represents a 3-log reduction from a standardize baseline.

A complete molecular responders is defined as a BCR-ABL transcript level that is undetectable by PCR assays.

Deep molecular responses (DMR) are correlated with survival.

Deep molecular responses identified by measuring blood BCR/ABL1 transcript levels using PCR.

MR 4.0 corresponds to a BCR/ABL1 ratio less than 0.01%, MR 4.5 corresponds to a ratio of less than 0.0032%, and MR 5 corresponds to a five log reduction or less than .001%.

Achievement of a sustained DMR opens the possibility of treatment discontinuation.

Early major cytogenetic response (CCyR) is associated with better overall survival and decreased disease progression.

Achieving a molecular response in the IRIS trial at early time points after initiation of TKI therapy with an achievement the BCR/ABL of less than 10% at three months is associated with improved long-term outcome.

Patients who achieve an early molecular response manifested by a 1 log reduction in BCR-ABL transcript levels have an event free survival of at least 85% (IRIS trial).

In the IRIS trial patients who achieve an MMR by 12 months had an event free survival of 91%, compared to 78% the patients did not contain this milestone: Speed of initial response matters.

Bone marrow transplant is the preferred treatment for younger patients with an HLA-matched sibling donor.

Transplantation of bone marrow from a matched sibling donor or an HLA matched unrelated donor produces equivalent outcomes in patients with chronic myelogenous leukemia, particularly if the transplant takes place within 1 year after diagnosis.

Among patients who undergo transplantation early in the chronic phase of the disease, the survival rate is approximately 70%.

Young patients treated with allogeneic transplant within 1 year of diagnosis have a 10-year survival rate of 50-55%.

10-20% of patients undergoing allogeneic transplant relapse within 3 years.

Because of the success rate with TKIs allogeneic hematopoietic cell transplantation is no longer recommended is a first line treatment of patients with chronic phase CML.

Lymphocytes from original allogeneic donors infused into relapsed patients can induce complete remission through graft-vs-tumor effect in 60-80% of patients.

In patients with lymphoid blast crisis the response rate to standard chemotherapy is 50% but remissions are short-lived.

Cytogenetic response provides the strongest indicator of treatment success, and CCyR is highly correlated with long-term outcome.

Minor cytogenetic response with 35-90% of metaphase cells still with BCR ABL abnormality.

A major molecular response would be BCR–ABL transcript level 0.1% or less IS ( international scale).

The time to response is important as responses as early as 3 months after the start of therapy have the greatest probability of a favorable long-term outcome with the use of tyrosine kinase inhibitors.

Patients who achieve only a one log reduction which is approximately equivalent to a BCR-ABL:ABL ratio of 10% in the international scale, at 3 months have a significantly lower probability of achieving a major molecular response, 13% in 3 months, compared with those with a 1-2 log reduction, 69%, or those with more than a 2 log reduction, 100% (Hughes T et al).

Greater than 80% of patients who enter complete cytogenetic response with alpha-interferon are alive for more than 10 years.

Allogeneic stem-cell transplantation during blast crisis has a 5-year survival rate of only 6%.

Tyrosine kinase inhibitors have improved ten-year survival from historic experience of 20% to an estimated rate of 85%.

Estimated 7-10 year survival in patients with newly diagnosed CML with imatinib is 85-90%, but is 93-95% if only CML associated deaths are considered.

International Randomized Study of Interferon (IRIS) evaluated interferon plus cytosine arabinoside versus imatinib in 1106 patients with newly diagnosed CML: imatinib complete response 95% vs. interferon alfa and low dose cytosine at 55%, complete cytogenetic response 76% vs. 15% and progression free survival at 18 months 97% vs. 91%, respectively, and the molecular response at 12 months 40% vs., 2%, respectively.

In a randomized study of untreated patients to receive imatinib alone at 400 mg daily, imatinib plus cytarabine 20 mg per meter squared per day on days 15-28 of each 28 day cycle, or pegylated interferon 90 mcg weekly, or imatinib alone at 600 mg daily: at 12 months the cytogenetic response was similar in all groups, and the molecular response was highest among patients receiving imatinib and pegylated interferon (30%) compared to 14% with imatinib alone (Preudhomme C et al).

IRIS trial at 6 year analysis: overall survival rate with imatinib was 88%, progression free survival 93% and event free survival rate 83%.

Major molecular response is a more sensitive predictor of long-term progression free survival than complete cytogenetic response and has been established in the IRIS study.

Molecular response predicts long-term outcomes and patients that fail to achieve a two log reduction in BCR/ABL transcript level at the time of complete cytogenetic response or a three-log reduction at any time thereafter experience significantly shorter progression free survival times.

Patients who achieve only a one-log reduction in BCR/ABL transcript at three months have a lower probability of achieving a major molecular response, 13% at three months, compared to those with a 1-to 2-log reduction, 69%, or those who have more than a two-log reduction, 100%.

There is little difference in survival or cytogenetic response among young or older patients with early CML with imatinib.

During year 2 of the IRIS study 7.55 of patients on imatinib experienced an event and 2.8% progressed to advanced phase or blast crisis, while the 6 year analysis revealed the event rate dropped to 0.4% and 71% of those who had a complete cytogenetic response, 71% retained that response.

In the IRIS study the cumulative raise cytogenetic response were 69% at one year 87% at 5 years and 89% at 7 years (Brien SG, Drucker BJ).

The 8 year follow-up of the IRIS study showed event free survival of 81%, progression free survival of 93%, and overall survival of 86% in patients remaining in imatinib for 8 years (Deininger M et al).

Imatinib has a response rate of 55% in myeloid blast crisis and a complete remission rate of 11%.

Imatinib has a response rate of 70% and a 20% complete remission rate in lymphoid blast crisis.

Imatinib at 400 mg per day 75% of patients enter a complete cytogenetic remission, and with 800 mg/day 90% achieve that type of response.

When resistance to imatinib occurs increasing the dose to 800 mg/day can overcome such resistance but responses are of short duration and tolerability of high dose medication is a problem.

In a single institution study of CML patients receiving imatinib after interferon failure, with a median follow-up of 114 months: 67% had a complete cytogenetic response, 63% achieved a major molecular response, and at seven years 35% were in complete cytogenetic remission, 32% were in major molecular response and 11% had undetectable BCR/ABL levels on molecular testing (Kantarjian H et al).

In the above study the tenure estimated survival was 68% with a progression free survival rate of 67%.

Less than 5% of patients have a polymerase chain reaction (PCR) negative for Bcr/Abl when treated with 400 mg per day of imatinib.

Imatinib the standard of care for front line treatment of chronic phase CML.

International Randomized Study of Interferon and ST1571 trial imatinib as initial treatment 87% achieved complete cytogenetic remission at some time, with progression free survival of 83% and overall survival of 89% at 5 years: 69% of patients remained on the drug.

In the IRIS study most adverse events in the imatinib group we’re grade 1-2, with most being superficial edema, nausea, muscle cramps and rashes.

In the IRIS study the most common nonhematologic grade 3-4 adverse events for patients on imatinib or musculoskeletal pain 2.7%, joint pain 2.4% and abdominal pain 2.4%.

In the IRIS study in the hematologic adverse events occurred with neutropenia in 14.3% of patients, thrombocytopenia and 7.8%, and 3.1% developed anemia with imatinib.

Undetectable levels of Bcr/Abl may improve long-term event-free survival.

Risk of developing blast crisis 25% each year.

Three methods used to monitor patients response to treatment include hematologic, cytogenetic and molecular.

Management milestones in the treatment of chronic phase disease includes an achievement of complete hematologic response at three months, a complete cytogenetic response at 12 months, and a major molecular response at 18 months (Baccarani M et al).

Achievement of complete cytogenetic response is a surrogate marker for survival, and patients who achieve such and major molecular response within 12 months after a mediation of therapy have a low risk of long-term progression.

The overall relapse rate for newly diagnosed patients with chronic phase of disease treated with imatinib was 16% at a median follow-up of 54 months, but only 7% for those patients with a complete cytogenetic response.

For patients treated with imatinib and in whom the BCR/ABL messenger RNA levels were reduced by at least 3 log the relapse rate was only 3% at 54 months and no patient progressed to accelerated or blast crisis.

Rate of progression of newly diagnosed chronic phase CML patients on imatinib is about 4% per year.

After 60 months of therapy with imatinib complete cytogenetic response was 69% by 12 months and 87% by 60 months.

After 60 months of therapy with imatinib an estimated 7% of patients progressed to accelerated or blast phase.

After 60 months of therapy with imatinib the overall survival was 89%.

97% of patients that demonstrated a complete cytogenetic response within 12 months of thrombocytopenia initiation of imatinib did not progress to accelerated or blast phases by 60 months.

Approximately 30% of patients with chronic phase disease treated with imatinib discontinued therapy after 5 years because of unlsatisfactory therapeutic effects or toxicity.

Taking TKIs for 3 years, and if in complete molecular response at least 2 years considering stopping the drug is appropriate.

TKI selection in the first line is based on risk score and TKI toxicity profile as well as the patient’s age, comorbid conditions, and ability to tolerate treatment.

Generic imatinib should be frontline therapy for all newly diagnosed patients.

If patients have a high risk CML or are very young, clinicians may consider dasatinib or nilotinib to have a higher chance of achieving durable complete molecular response.

Guidelines recommend imatinib for low risk score patients and dasatinib and nilotinib for those with intermediate or high-risk scores.

In patients with a low risk score the dasarinib may be preferred for patients with a history of heart disease, arrhythmias, pancreatitis or hyperglycemia, while Nilotinib may be chosen for those with a history of lung disease or at risk for pleural effusion.

Patients with deep molecular response to TKI therapy may have therapy discontinued, though molecular relapse is common, occurring in 50% of cases.

Second TKI discontinuation is also possible in a significant number of patients.

The addition of interferon alfa to imatinib yielded better short-term results, but no difference in progression free or overall survival.

Mutations including T3151 cause resistance to imatinib and to second line tyrosine kinase inhibitors dasatinib and nilotinib as such agents have difficulty to binding to the T3151 mutation.

T3151 mutation in which a point mutation in the BCR/ABL fusion gene results in the substitution of isoleucine for threonine in position 315 of the protein, confers resistance to a first and second generation TKIs.

The T3151 mutation is observed in 0–25% of patients with CML in most series, with higher rates of occurrence in relapsed disease compared to de novo disease.

Approximately 5-20% of patients with CML and Philadelphia positive ALL have the “gatekeeper” T3151 BCR/ABL mutation conferring resistance to TKIs.

The T 3151 mutation is a point mutation in the BCR/ABL fusion gene that results by the substitution of isoleucine for threonine in position 315 of the protein and convers resistance to all first and second generations TKIs.

Ponatinib is a third line TKI active against T3151.

Nilotinib use may be superior to imatinib as a first-line therapy for CML, based on the rates of major molecular response and complete cytogenetic response.

In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENESTnd) 846 patients with newly diagnosed Philadelphia chromosome positive CML were enrolled and randomized to 300 mg of nilotinib twice daily , 400 milligrams twice daily or 400 mg of imatinib once daily: at one year the nilotinib arms were significantly better than the imatinib arm achieving major molecular response (44% vs 22%), and for complete cytogenetic response approximately 79% of patients receiving nilotinib compared with 65% of patients treated with imatinib (Saglio G).

Nilotinib is a BCR-ABL inhibitor that is more potent and more selective than imatinib and is a successful second line agent and is approved for first-line usage at a dosage of 300 mg b.i.d.

In a study of 519 patients with treatment naïve CML randomized to dasatinib 100 mg once daily or imatinib 400 mg once daily: the median time to major molecular response was faster in the dasatinib arm 6.3 versus 9.2 months for imatinib, a higher major molecular response 45% versus 28%, respectively-suggesting this agent as initial therapy may lead to improved long-term clinical benefits (Kantarjian H et al).

In the above study the overall twelve-month survival was 97.2% for dasatinib and 98.8% for imatinib, complete cytogenetic response rate was twice as high for dasatinib .

Dasatinib induces a complete cytogenetic response in approximately 50% of patients who do not have a response to imatinib or cannot tolerate it (Hochhaus A, Shah NP).

Dasatinib compared to imatinib induced significantly faster and higher rates of complete cytogenetic response and major molecular response given to newly diagnosed patients with chronic CML (Kantarjian H).

In the above study of 519 patients the rate of complete cytogenetic response was 77% for dasatinib and 66% for imatinib, and the rate of major molecular response rate was 46% vs 28%: achieving complete cytogenetic response within 12 months is associated with better long-term progression free survival, dasatinib may improve long-term outcomes among patients with newly diagnosed CML.

Second line tyrosine kinase inhibitors, on average reduce the cumulative incidence of transformation to accelerated phase/ blast phase in the first 2-3 years from about 5% to 1.5% compared to Imatinib.

In a direct comparison of Dasatinib and nilotinib the drugs have similar efficaciousness and both are equally recommended for first-line treatment.

Dasatinib and nilotinib should be reserved for patients at highest risk, those with lots of disease and young patients

BCR-ABL mutations occur in approximately 50% of patients resistant to imatinib.

Up to 20% patients resistant to imatinib have a T3151 mutation.

Omacetaxine can overcome the T1351 mutation.

Bosutinib in the BEFORE study showed a significantly higher 12 month major molecular response than imatinib, but with higher gastrointestinal events and trans Amina’s events elevations.

Ponatinib (Iclusig)is a kinase inhibitor indicated for the treatment of chronic phase, accelerated phase or blast phase CML that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia that is resistant or intolerant to prior kinase inhibitor therapy.

Ponatinib management result in durable responses after 4 years in heavily pretreated patients with CML

Ponatinib is an approved tyrosine kinase inhibitor with potent activity against native and resistant BCR-ABL, including T3151 mutation.

Most frequent mechanism of resistance to imatinib is the point mutations in the catalytic domain of BCR-ABL.

Mutations account for 36-48% of patients that are not responsive to imatinib, and can occur after treatment.

The French CML Intergroup conducted a study the Stop Imatinib (STIM) study: 100 patients with chronic or accelerated phase CML in a sustained complete molecular response, defined as greater than five log reduction in BCR-ABL and ABL levels for at least two years: after stopping Imatinib molecular relapse was noted in 54 patients after a median follow-up of 17 months and the remaining 46 patients remained in complete molecular response at a median follow-up of 14 months with an overall probability of maintaining a complete molecular response at 12 months of 43%.

In the above study 39% of patients were able to maintain stable molecular responses after discontinuing imatinib and 42% were able to discontinue the drug without needing treatment.

Molecular relapse occurred in 42 of 69 patients at 61% with at least 12 months of follow up, and all but two relapses occurred within six months of TKI discontinuation.

In the above study, after re-introduction of a imatinib 26 patients again achieved complete molecular remission and the other 16 patients had decreases in BCR-ABL levels.

In the TWISTER study- relapse free interval among 40 patients enrolled was 47% at two years and all patients with sensitive to re-treatment with imatinib.

Treatment free remission rates are higher with second-generation TKIs than with imatinib owing to the relatively deeper and more sustained molecular responses achieved with the newer agents.

Second generation TKIs are highly effective in newly diagnosed chronic phase CML, with long-term overall survival expected to be similar to that of aged match controls.

Second generation TKI’s  compared with imatinib generally result in faster cytogenetic and molecular responses, with less progression to advanced phase CML, and as of yet no significant differences in overall survival in patients start with the imatinib versus the second generation TKI.

Imatinib of tyrosine kinase inhibitors has best toxicity profile, nilotinib associated with vascular events, dasatinib associated with pulmonary hypertension, bosutinib associated with mild renal effects, and ponatinib has vascular events.

The speed and death of response in the above study were related because early molecular response was predictive of patients are able to obtain the landmark molecular response of at least 4.5 log reduction in BCR-ABL.

In a 2016 European Hematology Association Congress phase 3 trial demonstrated TKI’s can be safely stopped in selective patients with chronic phase CML who had maintained a deep molecular response for around 6 years.

In the above study 62% of patients were still in major molecular remission 6 months after stopping TKI therapy, 56% were still in remission after 24 months.

DESTINY Study found by putting patients on half dose therapy as a precursor to stopping treatment appears to eliminate most adverse effects, reduce costs and yields better relapse free survival rates.

Nilotinib and dasatinib are both able to place a higher percentage of treated patients in the position to discontinue treatment than does imatinib.

Patients achieved molecular response of at least a 4.5 log reduction in BCR-ABL transcript levels have improved overall survival compared with patients with only 2-3 log reductions, and patients who achieve this level reduction do not experience disease progression.

Imatinib is an effective treatment in children in chronic phase with response rates similar to rates reported in adults.

Imatinib treatment in children is associated with a complete hematologic response, complete cytogenetic response and major molecular response rates of 98%, 61%, and 31% at 12 months, respectively (Millot F et al).

Monitoring treatment assesses response to treatment, allows for the ability to recognize poor drug adherence, and detect treatment failure at the earliest possible time.

Ponatinib binds to the BCR/ABL active site and has potent activity against native BCR/ABL and BCR/ABL mutants, including T3151.

Randomized trials of dasatinib and nilotinib versus imatinib have shown that second line TKIs have greater efficacy against CML in first generation TKIs as measured by achievement of her 3-log reduction in BCR-ABL gene transcript levels.

The incidence of progression to accelerated or blast phase CML can be reduced by using second line TKIs.

TKI treated patients with CML have a higher incidence of vascular events.

Long term TKI therapy side effects include cardiovascular events in pulmonary hypertension.

Treatment-free remission is one of the primary goals in CML.

TWISTER study enrolled patients with sustained deep molecular remission for at least two years with first line imatinib:Suggestions are that patients in deep molecular remission for at least two years before stopping therapy will have a 90 to 95% chance of regaining molecular remission if relapse occurs when reintroducing the drug.

In the above 47% patient remained free of disease at 24 months.

Patients in chronic phase (CP) responding to therapy with tyrosine kinase inhibitors (TKIs) can expect to have a normal lifespan.

Patients with accelerated phase (CML-AP) or blast phase (CML-BP) may receive initial therapy with TKIs with newer generation TKIs like dasatinib or ponatinib preferred over imatinib, to reduce the CML burden, and be considered for early allogeneic stem cell transplantation (allo-SCT).

Response rates with combinations of TKIs and chemotherapy are 40% in nonlymphoid CML-BP and 70-80% in lymphoid CML-BP.

Median survival times are 6 to 12 months, and 12 to 24 months, respectively.

Treatment free remission (TFR) rationale is to reduce TKI related adverse events, minimizing pharmacologic and economic factors associated with lifelong therapy, and preventing toxicities.