NCCN Establishes TKI Discontinuation Criteria in Updated CML Guideline

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia. The American Cancer Society estimates that about 8,990 new CML cases will be diagnosed in the United States in 2019 and about 1,140 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.Treatment-of-Chronic-Myeloid-Leukemia

The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients, and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. Further, it has been shown on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, precise criteria for stopping CML therapy have not been clearly defined.Monitoring-Molecular-Response-in-CML

Discontinuing TKI therapy after a Deep Molecular Response among patients with CML can potentially improve quality of life, minimize long term toxicities as well as drug-drug interactions, and reduce financial burden. Two important studies, STIM (Stop Imatinib) and EURO-SKI have set the stage for TKI discontinuation of TKI therapy in CML patients, who are in deep molecular remission, taking into consideration Sokal score at diagnosis, duration on TKI therapy and molecular response based on BCR-ABL transcripts log reduction. Sokal score is calculated using a formula that includes Age, Spleen size, Platelet count and percentage of Myeloblasts and has three risk groups: Low-risk (Sokal score<0.8), Intermediate-risk (Sokal score 0.8-1.2) and High-risk (Sokal score >1.2).

Stopping TKI therapy among CML patients appears to be safe and feasible in over 50% of the patients, although about 20% of these patients experience TKI withdrawal syndrome manifesting as musculoskeletal symptoms. Discontinuation of TKI therapy should only be considered in consenting patients after a thorough discussion of the potential risks and benefits.

Criteria for TKI Discontinuation: Outside of a clinical trial, TKI discontinuation should be considered only if a patient meets ALL the criteria listed below-

1) Age 18 years or older.

2) Chronic phase CML with no prior history of Accelerated or Blast phase.

3) On approved TKI therapy for at least 3 years.

4) Prior evidence of quantifiable BCR-ABL1 transcript.

5) Stable molecular response defined as MR4, (BCR-ABL equal to 0.01% or less IS), for 2 or more years as documented on at least 4 tests, performed at least 3 months apart.

6) Access to qPCR test that can reliably detect at least MR4.5 (BCR-ABL equal to 0.0032% or less IS), with results available within 2 weeks.

7) For patients who remain in Major Molecular Remission or MMR (MR3, BCR-ABL equal to 0.1% or less IS) after discontinuation of TKI therapy, the recommendations are monthly molecular monitoring the first year, every 6 weeks the second year and every 12 weeks thereafter, indefinitely.

8) TKI therapy should be promptly resumed within 4 weeks of a loss of MMR, with molecular monitoring every 4 weeks until MMR is re-established and then every 12 weeks thereafter, indefinitely. If a patient fails to achieve MMR after 3 months of TKI resumption, BCR-ABL kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for an additional 6 months.

9) Consultation with a CML Specialty Center is recommended regarding the appropriateness for TKI discontinuation, and potential risks and benefits of discontinuing therapy, including TKI withdrawal syndrome.

10) It is strongly encouraged to report the following to an NCCN CML Panel Member-

a) Any significant adverse event thought to be related to therapy discontinuation.

b) Progression to Accelerated or Blast phase at any time.

c) Failure to regain MMR after 3 months following treatment reinitiation.

NCCN guidelines updates: discontinuing TKI therapy in the treatment of chronic myeloid leukemia. Shah NP. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

TASIGNA® (Nilotinib)

The FDA on March 22, 2018 approved TASIGNA® for pediatric patients 1 year of age or older with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior Tyrosine Kinase Inhibitor (TKI) therapy. TASIGNA® is a product of Novartis Pharmaceuticals Corporation.

FDA Approves BOSULIF® for Newly Diagnosed Chronic Myeloid Leukemia

SUMMARY: The FDA on December 19, 2017 granted accelerated approval to BOSULIF® (Bosutinib) for treatment of patients with newly diagnosed Chronic Phase Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,950 new CML cases will be diagnosed in the United States in 2017 and about 1,080 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. BOSULIF® is a potent, dual Abl and Src tyrosine kinase inhibitor and was approved by the FDA in 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML) with resistance or intolerance to prior therapy.

Monitoring MMR in CMLThis new approval for BOSULIF® was based on the efficacy and safety data from BFORE trial, which is an ongoing randomized, open-label, multicenter, phase III study in which in 487 patients with Ph+ newly diagnosed Chronic Phase CML were randomized to receive either BOSULIF® 400 mg once daily (N=246) or GLEEVEC® (Imatinib) 400 mg once daily (N=241). The median age of patients was 53 years, the Sokal risk group was intermediate and high for 40% and 21% of patients, respectively, and over two thirds of the patients had an ECOG PS score of 0. Sokal score is calculated using a formula that includes Age, Spleen size, Platelet count and percentage of Myeloblasts and has three risk groups: Low-risk (Sokal score<0.8), Intermediate-risk (Sokal score 0.8-1.2) and High-risk (Sokal score >1.2). The Primary endpoint was Major Molecular Response (MMR) at 12 months, defined as BCR-ABL ratio on International Scale of 0.1% or less, which corresponded to 3 or more log reduction from standardized baseline.

After 12 or more months of follow up, the MMR at 12 months was 47.2% in the BOSULIF® group and 36.9% in the GLEEVEC® group (P=0.02) and the time to achieve a MMR was shorter in the BOSULIF® group (P<0.02). The Complete Cytogenetic Response (CCyR) at 12 months was also significantly higher with BOSULIF® versus GLEEVEC® (77.2% vs 66.4%; P< 0.008), with the time to achieve a CCyR, shorter for BOSULIF® (P<0.001). The most common adverse reactions in the BOSULIF® group included rash, nausea, diarrhea, abdominal discomfort, thrombocytopenia, increased ALT and AST levels.

It was concluded that BOSULIF® is an important and useful treatment option for patient with newly diagnosed Chronic Phase CML. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Initial results from the BFORE trial. Cortes JE, Gambacorti-Passerini C, Deininger MWN, et al. J Clin Oncol. 2017;35 (suppl; abstr 7002).

TASIGNA® (Nilotinib)

The FDA on December 22, 2017 updated the product label for TASIGNA® to include information on TASIGNA® discontinuation, post-discontinuation monitoring criteria, and guidance for treatment re-initiation in patients taking TASIGNA® for Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) who have achieved a sustained Molecular Response (MR 4.5). TASIGNA® is a product of Novartis Pharmaceuticals Corp.

BOSULIF® (Bosutinib)

The FDA on December 19, 2017 granted accelerated approval to BOSULIF® for treatment of patients with newly-diagnosed Chronic Phase (CP) Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). BOSULIF® is a product of Pfizer Inc.

SPRYCEL® (Dasatinib)

The FDA on November 9, 2017, granted regular approval to SPRYCEL®, for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) Chronic Myeloid Leukemia (CML) in the Chronic Phase. SPRYCEL® is a product of Bristol-Myers Squibb Co.

ASH – 2016 Discontinuing Tyrosine Kinase Inhibitors is Feasible in Some Patients with CML

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

The European Stop TKI (EURO-SKI) trial was conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in Deep Molecular Response (DMR). This trial enrolled 821 patients with chronic phase CML without prior TKI failure, in DMR (BCR-ABL <0.01% on the International Scale – MR4) for at least one year, following treatment with either Imatinib, Nilotinib or Dasatinib. Following cessation of treatment with TKIs, patients were followed up testing by RQ-PCR (Real-time Quantitative Polymerase Chain Reaction) every 4 weeks for the first 6 months followed by every 6 weeks, the first year and every 3 months thereafter. Molecular recurrence was defined by the loss of the Major Molecular Response (BCR-ABL <0.1% IS – MR3) at any one point.

It was noted that after stopping TKI therapy, 62% showed no evidence of molecular recurrence at 6 months, and 52% showed no recurrence at 24 months. Patients who had taken a TKI for more than 5.8 years before stopping, were significantly less likely to experience relapse within the first 6 months and had a Molecular Relapse Free Survival at 6 months of 65.5% compared with 42.6% for those on treatment for 5.8 years or less. Further, each additional year of TKI therapy increased a patient’s chances of maintaining Major Molecular Response successfully at 6 months by 16%, after TKI therapy was discontinued. Most of the patients who experienced molecular recurrence were able to regain their previous remission level, after resuming TKI therapy and none of the patients in the study had progression to advanced stage.

The authors concluded that stopping TKI therapy of CML patients appeared safe and feasible in over 50% of the patients and longer duration of therapy with TKIs (5.8 years or more) prior to stopping therapy with TKIs, was associated with a higher probability of Molecular Recurrence Free Survival. Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial. Mahon F-X, Richter J, Guilhot J, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 787.

TASIGNA® Maintains Durable Deep Molecular Responses Even after Treatment Discontinuation in Chronic Phase CML

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC®, share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that deep molecular response (MR4.5) is a new molecular predictor of long term survival in CML patients and was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trial – Following REsponsE in De nOvo CML-CP Patients) is a single arm, open-label, international, multicenter phase II study, which evaluated Treatment-Free Remission (TFR) of patients with CML-Chronic Phase, after stopping TASIGNA® (Nilotinib), following frontline treatment with this agent. This analysis included 215 patients Philadelphia Chromosome positive (Ph+) CML patients in the Chronic Phase, who received at least 2 years of frontline treatment with TASIGNA® and had achieved a Molecular Response 4.5 (BCR-ABL International Scale 0.0032%). Patients then continued TASIGNA® for an additional year (Consolidation Phase) with close monitoring for sustained deep molecular response using real-time quantitative PCR assessments at 12-week intervals. Patients who had a molecular response no worse than MR4 (0.01% or less) in the last assessment of the Consolidation phase (N=190), were then eligible to stop treatment (TFR phase). The median age of these patients was 55 years. The median time from study entry to first MR4.5 was 18 months. The median duration of treatment on TASIGNA® prior to TFR was 43 months.

After 48 weeks without treatment, 51.6% of the 190 patients in the TFR phase remained in MMR and did not require re-initiation of treatment. Of the 86 patients who restarted treatment with TASIGNA® due to loss of MMR, 99% were able to regain MMR and 88% were able to regain MR4.5. The median time to MMR for these patients was 7.9 weeks and for MR4.5 was 13.1 weeks. About 25% of the patients experienced musculoskeletal pain during the first year of the TFR phase, which is an expected adverse event from TKI withdrawal.

The authors concluded that TFR is clinically meaningful and a high rate of sustained MR4.5 leads to stable disease. TASIGNA® is the first Tyrosine Kinase Inhibitor to demonstrate successful TFR in a large proportion of eligible patients after relatively short duration of treatment of 3.6 years. Over 50% of patients who stopped therapy were able to remain treatment free at 48 weeks. The authors recommended that frequent patient monitoring during Treatment-Free Remission (TFR) period, allows timely determination of loss of MR4.0 and MMR and the need for treatment re-initiation. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study. Hochhaus A, Masszi T, Giles FJ, et al. J Clin Oncol 34, 2016 (suppl; abstr 7001)

BCR-ABL Transcript Type May Predict Outcomes in Patients with Chronic Phase CML Treated with Tyrosine Kinase Inhibitors

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation-t(9;22), between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Even though the reciprocal translocation resulting in the formation of Philadelphia chromosome involves a fairly constant breakpoint in the ABL gene on chromosome 9, the breakpoint in the BCR gene on chromosome 22 can vary, resulting in different BCR-ABL transcript types. There has been ongoing debate whether the type of transcript, has prognostic significance, for patients with newly diagnosed chronic phase CML. Over 95% of patients with CML have expression of e13a2 (b2a2), e14a2 (b3a2), or both transcripts, coding for p210 BCR-ABL tyrosine kinase, whereas a small minority of patients express rare variants such as e1a2 transcripts, which code for p190 BCR-ABL, which is associated with aggressive disease. Previously published studies have shown that expression of certain type of transcripts may predict response to therapy, as well as outcomes.

The purpose of this study was to evaluate the prognostic relevance of the commonly expressed BCR-ABL transcripts in patients with chronic phase CML and the influence of the transcript type, on molecular and cytogenetic responses, across chronic phase CML patients, treated with different Tyrosine Kinase Inhibitors (TKI). This analysis included 481 treatment naïve patients with chronic phase CML treated with different TKI modalities, expressing e13a2 (42%), e14a2 (41%), or coexpression of both e13a2 with e14a2 (18%) transcripts. These patients were treated with 4 different frontline TKIs which included, GLEEVEC® (Imatinib) 400 mg daily (N=69), GLEEVEC® 800 mg daily (N=199), SPRYCEL® (Dasatinib) 50 mg twice daily or 100 mg daily (N=105) and TASIGNA® (Nilotinib) 400 mg twice daily (N=108).

It was noted that patients with e13a2 transcripts who received GLEEVEC® 400 mg had an inferior Complete Cytogenetic Response (77%) compared with other TKI modalities (90-95%). Unlike these patients, patients with e14a2 transcripts or those expressing both e13a2 and e14a2 transcripts treated with GLEEVEC® 400 mg, had a Complete Cytogenetic Response rate of 93%, which was similar to treatment with other TKI modalities (93-96%). Even though the time to Complete Cytogenetic Response was 3 months and similar in all treatment groups, the trend for lower rates of Complete Cytogenetic Response and Major Cytogenetic Response for the e13a2 transcript cohort compared with the e14a2 cohort, persisted even at 60 months. Patients with e13a2 treated with GLEEVEC® 400 mg similarly had an inferior Major Molecular Response (MMR) at all time points than individuals with e14a2 and inferior MR4.5, compared with those treated with other TKI modalities. In patients with e14a2 transcripts, the MMR and MR4.5 rates were generally similar with all TKI modalities. In a multivariate analysis, patients with e14a2 alone or those with coexpressed e13a2, achieved an earlier and deeper response, compared to those with e13a2 transcripts, and predicted for longer event-free and transformation-free survival.

The authors concluded that the type of BCR-ABL transcript may determine outcomes in patients with chronic phase CML. Patients with e13a2 transcripts have lower platelet count and inferior outcomes with GLEEVEC® 400 mg, whereas patients with e14a2 have favorable outcomes regardless of TKI treatment modality. Further, expression of e14a2 or both e14a2 and e13a2 predicts optimal responses and longer Event Free Survival and Transformation Free Survival. Thus BCR-ABL transcript type may help in selecting the appropriate treatment and may predict outcomes in patients with chronic phase CML. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Jain P, Kantarjian H, Patel KP, et al. Blood 2016;127:1269-1275

Choosing Appropriate Therapy in Chronic Myeloid Leukemia

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes approximately 10% of all new cases of leukemia. The American Cancer Society estimates that 6,660 new CML cases will be diagnosed in the United States in 2015 and about 1,140 people will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Gleevec® (Imatinib) inhibits the BCR-ABL tyrosine kinase and is the standard first line treatment, of Ph chromosome positive (Ph+) leukemias. Lack of response due to resistance to GLEEVEC® and in some instances drug intolerance, has led to the development of newer agents including Second and Third generation Tyrosine Kinase Inhibitors (TKIs). Resistance to Gleevec® and other TKIs sharing the same therapeutic target (BCR-ABL kinase), has been attributed to point mutations in the ABL kinase domain, amplification of the BCR-ABL gene as well as other BCR- ABL independent mechanisms such as upregulation of SRC kinases. Mutation analysis at the time of TKI failure, utilizing high sensitivity sequencing techniques such as Next Generation Sequencing, can give clinically relevant information related to low level mutations and compound mutations and this information in turn, can dictate choice of second line therapy. The Second generation TKIs, TASIGNA® (Nilotinib) and SPRYCEL® (Dasatinib) although initially approved for second line treatment of CML after GLEEVEC® resistance or intolerance, are now FDA approved for the treatment of newly diagnosed Chronic Phase CML. This approval was based on the rapid and superior Major Molecular Responses (MMR) noted, when compared to GLEEVEC®. Now, that the Second generation TKIs are being used as first line therapy, the choice of second line therapy after failure with Second generation TKIs has become more nebulous. It is clear however that, patients with primary cytogenetic resistance to first and second line therapy do not benefit from sequential therapy with Second generation TKIs and BCR-ABL mutation analysis should be performed in all patients who develop TKI resistant disease. Before switching from a Second to a Third generation TKI such as Ponatinib, the following considerations should be taken into account

BCR-ABL Mutations and Sensitivity to Second Generation TKIs

1) Patients with F317L/V/I/C mutations are more sensitive to TASIGNA® (Nilotinib) or BOSULIF® (Bosutinib) than to SPRYEL® (Dasatinib)

2) Patients with V299L mutation are more sensitive to TASIGNA® than to BOSULIF® or SPRYCEL®

3) Patients with Y253F/H, E255K/V, and F359V/I/C mutations are more sensitive to SPRYCEL® or BOSULIF® than to TASIGNA®

Tolerability of Second Generation TKIs

1) Patients who experience pleural effusion during SPRYCEL® treatment might better tolerate TASIGNA® or BOSULIF®

2) Patients who experience rash during treatment with TASIGNA® or BOSULIF® could be switched to SPRYCEL®

3) Some toxicities common with other TKIs such as pleural effusion and cardiac toxicity are less common with BOSULIF® and this agent also has activity against many BCR-ABL kinase domain mutations resistant to GLEEVEC®, SPRYCEL® and TASIGNA®, with the exception of T315I mutation.

It should be noted that Second generation TKI as third line therapy has limited value in majority of the patients with CML. ICLUSIG® (Ponatinib) is a Third generation kinase inhibitor approved for the treatment of patients with T315I positive CML or T315I-positive Philadelphia Chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL) and for whom no other TKI is indicated. Other treatment options include SYNRIBO® (Omacetaxine Mepesuccinate), a first-in-class Cephalotaxine and a semi synthetic purified Homoharringtonine (HHT) compound. Unlike Tyrosine Kinase Inhibitors , SYNRIBO® is a protein synthesis inhibitor and reduces the levels of multiple Oncoproteins including BCR-ABL, BCL-2, MCL-1 and promotes apoptosis of leukemic stem cells. This agent is presently approved for the treatment of Chronic or Accelerated phase Chronic Myeloid Leukemia (CML) with resistance and/or intolerance to two or more Tyrosine Kinase Inhibitors, with cytopenias being the most common toxicity. Allogeneic Hematopoietic Stem Cell transplantation should be considered for eligible patients with T315I mutation not responding to ICLUSIG®, those with mutations resistance to second and third generation TKIs and patients with Accelerated or Blast phase CML, following remission with TKIs. Use of Second- and Third-Generation Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia: An Evolving Treatment Paradigm. Jabbour E, Kantarjian H and Cortes J. Clinical Lymphoma, Myeloma & Leukemia 2015;15:323-334