Rates Of Deep Molecular Response Research Articles

Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Background: Oral ABL-targeted kinase inhibitors (TKIs) have transformed treatment of BCR::ABL+ (Philadelphia chromosome-positive, Ph+) acute lymphoblastic leukemia (ALL). Induction (IND) w/ corticosteroids (CS) and dasatinib (DAS) alone results in morphologic complete response (mCR) rates approaching 100% but low rates of measurable residual disease (MRD) negativity; addition of intensive chemotherapy to TKIs adds risks of myelosuppression. DAS + the CD3/CD19 bispecific T-cell engager blinatumomab (BLIN) is effective consolidation (CONSOL) for Ph+ ALL, though ABL kinase mutations conferring resistance can arise early in therapy (Foà, NEJM, 2020). We designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in mCR, w/ aim of expediting MRD clearance and suppressing resistant clones early in disease course, and including a maintenance (MAINT) phase of BLIN + TKI for pts in molecular response. Methods: We conducted a multicenter trial of TKI + CS IND and TKI + BLIN CONSOL + MAINT in adults (≥18 yrs) w/ newly-diagnosed (ND) Ph+ ALL (NCT04329325). Study schema is depicted in Figure 1. Pts received CS pre-phase w/ prednisone (PRED) or dexamethasone (DEX) followed by modified GIMEMA LAL1205 IND (DEX + DAS 140 mg/d w/ DAS dose adjustments or TKI change per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) MRD assessments including FACS and BCR::ABL1 PCR. Pts in mCR on d43 could proceed to CONSOL w/ 3 cycles (C) of TKI + BLIN 28 mcg/d IVCI, d1-28, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. TKI was given continuously including between BLIN cycles. Pts in protocol-defined complete molecular response (CMR; MRD negative by FACS and no detectable BCR::ABL1 transcripts) after CONSOL could proceed to MAINT (C4-7 BLIN + TKI, 28d off between cycles). The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of CONSOL (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Toxicities were defined by CTCAE v5.0. Results: 17 pts enrolled (12 women, 5 men) w/ median age 50 yrs (range 22-87); BCR::ABL1 transcript type p190 (n=15) or p210 (n=2). Median follow-up 11.7 months (range 3-24). All began DAS 140 mg/d as initial TKI; 4 changed TKI for DAS intolerance per protocol (bosutinib, n=2; ponatinib [PON], n=2) and remained on study; TKI was changed to PON in 1 other pt to optimize BCR::ABL1 transcript suppression pre-allogeneic transplant (alloHCT) and that pt was withdrawn from study. Two had interruption or delay of BLIN due to toxicity (grade [G] 3 transaminase elevation, n=1; G2 cytokine release syndrome, n=1); BLIN was resumed in both. Figure 2 lists nonhematologic adverse effects (AEs) seen in ≥2 pts at least possibly related to TKI or BLIN while on study. One pt developed G3 pancreatitis after DAS was changed to PON; TKI was changed back to DAS. There were no G4-5 AEs. All pts (100%) achieved mCR during IND (median d22). Ten achieved CMR to date (5 during IND, 5 during CONSOL) and 6 did not achieve CMR; determination pending in 1 pt. By FACS, 16/17 achieved BM MRD negativity; 13/14 evaluable pts had no evidence of malignant clonal IgH rearrangement (IgHR) by next generation sequencing (NGS). Notably, 3 pts w/ persistent low-level BCR::ABL1 transcripts had no evidence of malignant clonal IgHR by NGS but were withdrawn post-CONSOL as protocol required BCR::ABL1 PCR negativity to proceed to MAINT. Two pts relapsed, both after achieving CMR (one declined CONSOL and self-discontinued TKI; one had extramedullary (EM) relapse w/ ABL T315I mutation). Four pts underwent alloHCT in CR1 (rising MRD levels on study leading to change in therapy, n=1; persistent BCR::ABL1 PCR positivity, n=2; IKZF1 plus phenotype, n=1); one underwent alloHCT in CR2 following EM relapse. Conclusions: DAS + CS IND w/ addition of BLIN to TKI in mCR leads to high rates of deep molecular response w/ low risk of early relapse and low rates of severe regimen-related toxicity in pts w/ ND Ph+ ALL. Use of PON (vs DAS) as initial TKI w/ BLIN may further suppress resistant clones. Further f/u is needed to confirm durability of CMR w/ BLIN + TKI CONSOL ± MAINT in absence of alloHCT and whether pts w/ persistent BCR::ABL1 PCR positivity and no malignant clonal IgHR by NGS exhibit similar outcomes to those in CMR.

Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia

IntroductionLimited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML). Patients and MethodsThis retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index [BMI]). ResultsThe dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05). ConclusionsPatients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.

Interferon in chronic myeloid leukaemia: Is it useful for treatment-free remission?

The role of IFNα in chronic myeloid leukaemia patients who have achieved a deep molecular response (DMR) is still unknown. The study reported by Irani et al., which shows the prospective biological effects of the drug in combination with a second-generation tyrosine kinase inhibitor, pave the way for further clinical studies aimed at increasing the rate of DMR for a possible successful discontinuation. Commentary on: Irani et al. Immune modulation in chronic myeloid leukaemia patients treated with nilotinib and interferon-alpha. Br J Haematol 2023;202:1127-1136.

Subgroup analysis from a phase II trial of ponatinib and blinatumomab in relapsed/refractory (R/R) Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast phase.

e19038 Background: The chemotherapy-free combination of ponatinib and blinatumomab improved outcomes in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This regimen may also induce deeper responses and prolong remissions in patients (pts) with R/R Ph+ ALL and chronic myeloid leukemia in lymphoid blast phase (CML-LBP). Methods: In this phase II trial, pts with R/R Ph+ ALL or CML-LBP received up to 5 cycles of blinatumomab. Pts received ponatinib 30mg daily in Cycle 1, with dose reduction to 15mg daily once in complete molecular response (CMR). After completion of blinatumomab, ponatinib was continued for at least 5 years. 12 doses of prophylactic intrathecal chemotherapy were administered in all pts. Results: 21 pts were treated (14 R/R, 7 CML-LBP) between 2/2018 and 7/2022. The median age of the R/R Ph+ ALL and CML-LBP cohorts were 38 years (range, 24-61) and 67 years (range, 29-82), respectively. BCR:ABL1 transcripts were p190 in 93% of the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in Salvage 2+. Among the CML-LBP pts, 4 were de novo and 3 were transformed from previously treated CML (1 of whom had received prior therapy for LBP). Among the 14 pts with R/R Ph+ ALL, the rate of CR/CRi was 92% (12 of 13 evaluable pts), with CR in 11 (85%) pts. MMR was achieved in 86% and CMR in 79%. Six of 7 (86%) pts with CML-LBP achieved CR/CRi. Rates of MMR and CMR were 57% and 43%, respectively. The median follow-up is 24 months (range, 19-57) in the R/R cohort, and 27 months (range, 7-46) in the CML-LBP cohort. Among the 14 pts in the R/R cohort, 1 did not respond, 6 proceeded to ASCT (1 of whom relapsed and died), 4 did not undergo ASCT and relapsed after a median of 6.4 months (range, 2.7-8.1), 1 died in CR, and 2 are in ongoing response without ASCT after a median CR duration of 34 months (range, 17-51). Of the 5 relapses, 2 were hematologic only, 2 were in the CNS with MRD positivity in the bone marrow, and 1 was CNS only. The estimated 2-year EFS and OS for the R/R cohort were 50% and 64%, respectively. Among the 6 responders in the CML-LBP cohort, 3 relapsed and 3 are in ongoing response without ASCT after a median CR duration of 34 months (range, 3-43). The 2-year EFS and OS for the CML-LBP cohort are 38% and 50%, respectively. Grade 3 adverse events were febrile neutropenia, cytokine release syndrome, elevation of lipase and alkaline phosphatase in 1 pt each. There were no Grade 4-5 events. 1 pt discontinued ponatinib due to grade 3 portal vein thrombosis. 1 pt discontinued blinatumomab due to persistent grade 2 tremor. Conclusions: The combination of ponatinib and blinatumomab is an effective and well-tolerated chemotherapy-free regimen for pts with R/R Ph+ ALL. The rate of deep molecular response was relatively low in CML-LBP, suggesting that chemotherapy might still be needed in these pts. Clinical trial information: NCT03263572 .

Asciminib As Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)-H. Jean Khoury Cure CML Consortium Study

Background: Although tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients with CML, there remains need for improvement as less than 50% achieve sustained MR4.5 by 10 years (sine qua non for treatment discontinuation) and approximately 40% need change of therapy within 5 years because of lack of efficacy or unacceptable toxicity. Asciminib is a potent allosteric inhibitor of BCR::ABL1, effective in vitro against BCR::ABL1 mutations that confer resistance to ABL-competitive tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of resistant clones, potentially increasing the depth of molecular response in a greater number of patients compared with single-agent treatment. In a phase I study of asciminib, 48% of patients with CP-CML resistant to or intolerant of multiple prior TKIs achieved a major molecular response. The significant efficacy of asciminib in this setting suggests it might be more effective than other available options in achieving deep early responses in patients with newly diagnosed CML. Our goal in this study is to evaluate the role of asciminib in the treatment of patients with newly diagnosed CML-CP. Study Design and methods: This study is a multicenter phase 2, non-randomized open-label single-group study of asciminib in patients with newly diagnosed CP-CML (NCT05143840). The primary outcome is to evaluate the proportion of patients attaining MR4.5 within 12 months of therapy. In addition, patient reported outcomes will be collected at multiple timepoints. Patients will receive asciminib 40 mg orally twice daily. Peripheral blood BCR::ABL1 by RQ-PCR will be monitored in a central lab. Patients who do not achieved MR4.5 after 24 months of single agent asciminib will be offered the addition of nilotinib with the goal to attain MR4.5. In those instances, nilotinib will be started at 300 mg BID added to asciminib. Patients will discontinue study treatment if they experience disease progression, treatment failure according to ELN criteria or unacceptable toxicity. Patients who, after three years of asciminib +/- nilotinib, achieve sustained MR4.5 for at least 2 years may discontinue study treatment for an attempt at treatment-free remission. Sustained MR4.5 is defined as BCR::ABL1<0.0032% for approximately 2 years or more on at least 4 tests performed approximately 3 months apart. The primary objective of this study is to determine the rate of deep molecular response (DMR), defined as BCR::ABL1 <0.0032% IS by RQ-PCR at 12 months with asciminib compared to historical second generation TKI. With a total of 50 subjects, the study will have a 90% power to detect a 13.5% difference with an improvement of DMR at 12 months from 5% (based on historical experience with second generation TKIs used in frontline setting) to 18.5%. The exploratory endpoint of evaluating the rate of DMR after adding nilotinib at 24 months for patients not in DMR will be assessed at 36 months (after 12 months on combination therapy) and compared to the historical rate of 25% DMR with single agent nilotinib at 36 months. The study will have a 82% power to detect a 10% difference, 95% power to detect 15% difference and 99% power to detect a 20% difference.

Outcomes in Patients with Chronic Myeloid Leukemia in the Chronic Phase Randomized to Dasatinib or Imatinib after Suboptimal Responses to 3 Months of Imatinib Therapy: Final 5-Year Results from DASCERN

Introduction: Dasatinib has demonstrated superior responses versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP) (Cortes JCO 2016). Achievement of early molecular response (EMR; BCR::ABL1 ≤ 10% International Scale [IS]) at 3 months increases the probability of subsequent deep molecular response (DMR) and improves survival (Cortes JCO 2016, Hochhaus Leukemia 2016). However, ⅓ of pts treated with imatinib did not reach an EMR (Hughes Blood 2014); there are no standard treatment strategies for these pts. DASCERN (NCT01593254) is the first prospective, randomized, phase 2b trial to demonstrate the potential benefit of switching early to dasatinib in pts with no EMR after 3 months of initiating imatinib. At 12 months, pts randomized to dasatinib had significantly higher major molecular response (MMR) rates versus imatinib (29% vs 13%, primary endpoint) (Cortes Leukemia 2020). At 3 years, cumulative MMR rates were 67% and 40% with dasatinib and imatinib, respectively (Cortes EHA 2020 EP756). Switching to dasatinib did not increase the incidence of treatment-emergent adverse events (AEs). Here we report the results from the final 5-year analysis. Methods: Pts with complete hematologic response but no EMR at 3 months after initiating imatinib 400 mg were randomized 2:1 to an early switch to dasatinib (100 mg) or continue imatinib (≥ 400 mg). Pts who experienced subsequent failure with imatinib (per European LeukemiaNet 2013 recommendations at the time of the study) crossed over to dasatinib. The intent-to-treat (ITT) population included all pts randomized to each arm, irrespective of crossover status. Study endpoints included time to MMR and molecular response 4.5 (MR4.5; 4.5-log reduction in BCR::ABL1 levels; ≤ 0.0032% IS), progression-free survival (PFS), overall survival (OS), and safety. Results: At a median follow-up of 80 months (data cutoff, April 24, 2022), 174 and 86 pts with no EMR after imatinib were randomized to dasatinib and imatinib, respectively; 46 (53%) imatinib-randomized pts experienced subsequent imatinib failure and crossed over to dasatinib in a median of 9.5 months. Detailed baseline characteristics have been previously reported (Cortes EHA 2020 EP756). The median age was 37 years, and 73% of patients were Asian. All pts discontinued treatment, mainly due to study drug toxicity (26 [10%]), and other reasons (176 [68%], mostly study completion); 6 (2%) discontinued due to death. The MMR rate by 5 years in the ITT population was 77% and 44%, respectively, for pts in the dasatinib and imatinib arms. After accounting for crossover, cumulative MMR rates were 74% with dasatinib and 44% with imatinib; 65% of pts who crossed over from imatinib to dasatinib achieved MMR (Figure). Across the 5-year study period, more pts randomized to dasatinib than imatinib achieved MR4 and MR4.5 (MR4, 52% vs 31%; MR4.5, 36% vs 26%). Only 1/46 pts who later crossed over to dasatinib after imatinib failure achieved MR4.5. PFS in the ITT population was 94% in both treatment arms. PFS was numerically lower in pts who later crossed over to dasatinib after imatinib failure (90%). OS in the ITT population was similar between both arms (96% vs 95%). OS in pts who crossed over to dasatinib was 94%. Six additional deaths were reported since the 3-year follow-up. Any grade treatment-related AEs were experienced by 149 pts (87%) randomized to dasatinib, 69 (80%) randomized to imatinib, and 37 patients (80%) who crossed over to dasatinib. Treatment-related pleural effusion occurred in 31 pts (18%) randomized to dasatinib (n = 6 grade 3/4), 9 pts (20%) who crossed over to dasatinib after imatinib failure (n = 2 grade 3/4), and 0 pts who remained on imatinib (no crossover). Conclusions: At the final 5-year follow-up, sustained clinical benefit was observed from an early switch to dasatinib after suboptimal responses to 3 months of imatinib. MMR and DMR rates were higher in pts randomized to dasatinib versus imatinib. Overall, the safety profile was consistent with previous reports. These results complement the previous findings that switching to dasatinib promptly after a lack of EMR with imatinib increases the chance of achieving DMR, which may improve outcomes in pts with CML-CP. Therefore, this study further highlights the significance of achieving optimal responses early during treatment. Study support: Funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors.

Simple SummaryApproximately 50–60% of patients with chronic myeloid leukemia (CML) achieve a stable deep molecular response (DMR) after tyrosine kinase inhibitor (TKI) therapy. The achievement of DMR is a prerequisite for treatment-free remission. Repurposing statins is a straightforward strategy for enhancing molecular response in CML treatment. Second-generation TKIs have been reported to exhibit cardiovascular toxicity. Thus, statins have been widely prescribed for patients with CML undergoing second-generation TKI therapy for modifying cardiovascular risk factors, such as hyperlipidemia. Furthermore, the results of this study support the therapeutic benefit of the concomitant use of statins in TKI therapy for patients with CML. Additionally, the potential additive effects of statins and TKIs enhance the DMR rate in patients with CML, rendering these effects clinically relevant in these patients. In particular, this combination is a strong candidate for the achievement of DMR in patients with CML who have not achieved DMR with TKI therapy alone.Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.

CML-393: Incidence of Deep Molecular Response and Its Association with Clinical and Molecular Variables in Patients with Chronic Myeloid Leukemia Treated with Imatinib in a Population with Limited Health Resources

Context Since deep molecular response (DMR) confers a better progression-free survival in chronic myeloid leukemia (CML), it is now a primary goal and also is an absolutely requirement for therapy discontinuation. Objective Here, we investigate the incidence of DMR and its association with clinical and molecular variables. Design Retrospective cohort of patients ≥18 years with chronic-phase CML treated with imatinib for at least 12 months. The primary objective was to explore the accumulate incidence of DMR and analyze the following variables: age, gender, Sokal risk, variant of the BCR/ABL1 transcript, imatinib exposure time, body mass index (BMI) and albumin and its association with the achievement of DMR. Results Ninety-six patients with a mean follow-up of 8 years were analyzed. The cumulative rate of DMR at the last follow-up was 65.62%, and the median time to document DMR was 63.13 months. The clinical and molecular variables were compared among three groups of response: no major molecular response (NO MMR), major molecular response (MMR), and DMR; the median age was 44.36, 35, and 42.87 years (p= 0.25); the median BMI was 27.71, 26.69 and 27.53 kg/m2 (p= 0.91); the median concentration of albumin was 4.18, 3.95, and 3.93 g/dL (p= 0.22); and the median time of exposure to imatinib was 63.82, 101.2, and 114.7 months (p= 0.0001). respectively. Patients with a high Sokal risk were associated with a lower incidence of MMR and DMR compared with a low risk (27.27% vs. 54.54% and 20.63 vs. 50.7%, respectively, p=0.007). The proportion of patients with a known transcript (incidence of e14a2 variant) was higher than e13a2 (31.25% vs 23.95%) but without statistically significant differences between the groups (p=0.99). Conclusions Incidence of DMR to imatinib exposure in our population is similar and even higher than reported in the literature regarding the several available data. The above findings, despite not following strict molecular monitoring, suggests that molecular monitoring by qRT-PCR can be performed in a longer interval. In this study, the prolonged exposure time to imatinib and the low Sokal risk, were significantly associated with a deeper molecular response.

Chronic myeloid leukemia: update on treatment and survival prediction

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by the Philadelphia chromosome, t (9;22)(q34;q11.2), which causes the generation of the BCR-ABL1 oncoprotein with constitutively active tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of CML. Optimal treatment decisions at specific time points in patients with suboptimal response minimizes the risk of disease progression and CML-related death. The expected survival for patients with CML treated with TKI is now similar to that of the general population. Given the stable clinical course over the years, treatment-free remission (i.e., functional cure) can be considered in patients with sustained deep molecular response. Second-generation TKIs achieved higher rates of deep molecular response than imatinib, which could translate to increased candidates for functional cure without TKI therapy. The third-generation TKI, ponatinib, brought a new hope to patients who failed multiple TKIs because of resistance and/or intolerance. EUTOS long-term survival (ELTS) score can guide optimal treatment selection.

Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic phase: the D-NewS Study of the Kanto CML Study Group.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24months and were able to maintain DMR for an additional 2years. Ten patients (38.5%) achieved DMR maintenance after 12months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1months. The cumulative DMR rates at six and 12months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.

Nilotinib Vs Nilotinib Plus Pegylated Interferon α (Peg-IFN) Induction and Nilotinib or Peg-IFN Maintenance Therapy for Newly Diagnosed BCR-ABL1 Positive Chronic Myeloid Leukemia Patients in Chronic Phase (TIGER Study): The Addition of Peg-IFN Is Associated with Higher Rates of Deep Molecular Response

Introduction: The TIGER (CML V)-study* (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon α2b (Peg-IFN) 30-50μg/week as first line therapy for chronic myeloid leukemia (CML) patients (pts) in chronic phase and discontinuation of therapy after Peg-IFN maintenance (Figure). Methods: In August 2012, recruitment started with a pilot phase, aiming to validate the recommended dose of Peg-IFN. 25 pilot phase patients were treated with the combination of NIL 2*300 mg daily and Peg-IFN (30-50μg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). During the main phase of the study, 692 newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/Peg-IFN combination according to the outcome of the pilot phase. Results: Within 5 years, a total of 717 pts (429 male; median age 51 years, range 18-85; 12.9% EUTOS high risk) were recruited from 109 sites in Germany, Switzerland, and the Czech Republic. 702 pts with typical BCR-ABL1 transcripts (97.9%) were eligible for molecular follow-up assessments according to the international scale (IS). Fifteen pts (2.1%) expressed atypical BCR-ABL1 transcripts. 692 pts were randomized after EUTOS risk stratification to receive NIL monotherapy (n=353) or NIL/PEG-IFN combination therapy (n=339). Median observation time since recruitment was 41 months. Up to now, 477 pts concluded the induction phase by achieving a confirmed major molecular response, MMR (BCR-ABL1 transcript levels ≤0.1% IS, which qualified for entering the maintenance phase of the study using NIL or Peg-IFN monotherapy. During the maintenance phase, 199 pts achieved or sustained MR4 (BCR-ABL1 ≤0.01% IS) for at least one year and then discontinued all therapy. While the rate of MMR at 12 and 18 mo - the first primary endpoint of the study - was not different between the treatment arms, adding Peg-IFN to upfront NIL significantly improved rates of MR4 and MR4.5, BCR-ABL1 ≤0.0032% IS) (Table). In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. After NIL discontinuation, during Peg-IFN maintenance therapy, rate of molecular recurrence (BCR-ABL1 &amp;gt;1% IS) after 18 mo was 28%. From 199 pts who discontinued all therapy, 63 experienced a molecular relapse (BCR-ABL1 &amp;gt;0.1%). Relapse free survival by 18 mo after treatment discontinuation was 61% in the total cohort. By protocol, it is too early to assign relapse rates to the randomized treatment arm. Frequencies of adverse events after 24 mo of therapy were 90 and 92% (grade 1-5) and 36 and 42% (grade 3-5) for NIL vs NIL/Peg-IFN, respectively. Adverse events of special interest (all grades) were fatigue in 34.6 vs 40.4%, thrombocytopenia in 13.3 vs 18.9% and elevation of the alanin aminotransferase (ALAT) in 11.0 vs 18.9% of pts in the NIL vs NIL/Peg-IFN arms, respectively. Fifteen pts (2.1%) progressed to accelerated phase or blast crisis; 22 pts (3.1%) received an allogeneic stem cell transplantation, 10 of them after disease progression. In total, 22 pts (3.1%) died, 16 during the induction phase, 4 in the maintenance phase and 2 in treatment free remission. Four deaths were related to CML, 3 to vascular complications. Conclusions: This per protocol interim analysis demonstrates feasibility of the first-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Peg-IFN, when added upfront to NIL further increases the rates of MR4 and MR4.5, which may translate into higher rates oftreatment free remission. *The study is being conducted on behalf of the German CML Study Group, the Swiss Group for Clinical Cancer Research (SAKK) and the East German Study Group on Hematology and Oncology (OSHO). Disclosures Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Burchert:Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria. Baerlocher:Novartis: Research Funding. Brümmendorf:Janssen: Consultancy; Ariad: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Heim:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Lange:Novartis: Research Funding. Fabarius:Novartis: Research Funding. Hänel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board; Roche: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Hasford:Novartis: Research Funding. Hehlmann:Novartis: Research Funding. Ernst:Novartis: Research Funding. OffLabel Disclosure: Combination of Nilotinib and PEG-IFN alpha is being tested is off-label and being tested in the TIGER study.

Ten-Year Follow-up of Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line: Final Results of the Gimema CML 0307 Trial

Ten-Year Follow-up of Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line: Final Results of the Gimema CML 0307 Trial

Long-Term Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Receiving Frontline Nilotinib Versus Imatinib: Enestnd 10-Year Analysis

Long-Term Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Receiving Frontline Nilotinib Versus Imatinib: Enestnd 10-Year Analysis

Experience of Generic Imatinib As a First Line Therapy for Patients with Chronic Myeloid Leukemia in a Single Reference Institution

Background: The treatment of chronic myeloid leukemia (CML) was revolutionized by the approval of Gleevec (imatinib mesylate) by the FDA in 2001. In low-middle-income countries, due to economic issues related to the high cost of this treatment, scientific governmental entities started to produce and release a generic imatinib in 2013. High quality data about the security profile and efficacy of generic imatinib treatment are still needed. Aims: We herein aimed to evaluate the 6 years follow up of CML patients treated with generic imatinib as first line therapy. Patients and Methods: We evaluated a retrospective cohort of 39 patients diagnosed with CML at a single institution, during the period between December 2001 and July 2019, that had used only generic formulation of imatinib since diagnosis; and analyzed their rate of response to treatment as a primary goal and adverse events and survival outcomes as secondary goals. Responses were evaluated according to ELN 2013. Event-free survival and overall survival were measured from starting date of treatment until: loss of molecular response or death from any cause, and until death from any cause or last seen, respectively. Results: The cohort of 39 patients treated with generic imatinib as first line therapy was composed of 23 men (59%) and 16 women (41%), with median age at diagnosis of 52 years (16-74). The median follow up time was 24 months (8-68), and the median duration of generic imatinib therapy was 19 months (5 - 68). Most of the patients were diagnosed at chronic phase (92%), with only 2 accelerated phase and 1 myeloid blast crisis. Risk stratification according to Eutos, Sokal and Hasford score was low in 92%, 67% and 80%; intermediate in 0%, 30% and 6% and high in 8%, 3% and 14%, respectively. Six different brands of generic imatinib were used (Cristalia, Instituto Vital Brasil, FURP, EMS, Fiocruz and Eurofarma); the most frequently used were Cristalia and Instituto Vital Brasil. The median number of brands used per patient was 2 (1-5). Patients received 400 mg of generic imatinib daily; the dose was increased to 600 mg in 4 patients due to sub-optimal response during follow up. The rate of hematologic response with treatment was 97% and median time to reach it was 1 month (1-7). The rate of response at 3, 6 and 12 months was 74%, 60%, and 92% for optimal cytogenetic response, and 69%, 61%, and 26% for optimal molecular response. The probability to reach deep molecular response at each year of follow up was 41% at 1st year, 52% at 2nd year, 46% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. The probability to reach a molecular response 4.5 at each year of follow up was 10% at 1st year, 23% at 2nd year, 30% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. Hematologic toxicities were frequent during the first three months of therapy. Reported non-hematologic adverse events were hypophosphatemia (62%), diarrhea (30%), cramps (30%), liver toxicity (28%), nausea (18%), bone pain (18%), edema (15%), rash (8%), and hypomagnesaemia (2.5%). Eight percent of patients evolved with deterioration of renal function during the treatment period, but its relationship with generic imatinib was not well established. Two patients (5%) needed a dose reduction because of adverse events. Eight (20.5%) patients switched to second line tyrosine-kinase inhibitors, five (13%) due to resistance and three (8%) due to side effects (severe hepatotoxicity, diarrhea, and rash). Three patients progressed after switching to another tyrosine kinase inhibitor. After a median follow up of 24 months, the event free survival rate was 80% and the overall survival rate was 100%. Conclusion: The rate of complete cytogenetic response, resistance, and intolerance after use of generic imatinib was not worse than the rates described in the long-term follow up of the IRIS trial (N Engl J Med 2017; 376:917-927). Deep molecular response rates seen in the cohort of patients on generic imatinib were inferior to the ones in the IRIS trial, but overall survival was not impacted. Hypophosphatemia was observed in a high percentage of patients, although it has not been reported in other cohorts on generic imatinib. Prospective randomized studies are needed to allow better conclusions regarding the comparative efficacy and safety of generic imatinib. Disclosures Figueiredo-Pontes: Novartis: Honoraria.

PB1925 COMPARATIVE STUDY OF GLIVEC VERSUS STATE SPONSORED GENERIC IMATINIB MESYLATE AS FIRST LINE THERAPY IN CHRONIC MYELOID LEUKEMIA‐ CHRONIC PHASE

Background:In a developing economy like India, Imatinib usage has increased manifold after generic formulations were introduced. 25 brands of generic Imatinib are approved by the Drug Controller General of India. The efficacy and safety of these brands have been repeatedly questioned by different studies. In most of these studies, generic Imatinib were used as a switch from the innovator. Institute of Hematology and Transfusion Medicine (IHTM) in Medical College, Kolkata is state run institute where two generic brands of Imatinib (Veenat; Natco, and Imatinate; KLabs) are available free of cost to the patients. Also there are patients who were on Glivec from the GiPAP and Max foundation at either free of cost or reduced cost. We took this opportunity to initiate a study to compare the efficacy and safety of these generic brands with the innovator brand (GIG vs IIG).Aims:1. To study the response rates, hematologic and non‐hematologic toxicities, tolerance, compliance and drop out rates of patients on generic Imatinib (GIG)2. To compare the above parameters in patients on innovator Imatinib (IIG)Methods:68 treatment naive CML‐CP patients who were started on generic Imatinib 400 mg/d from July 2015 to April 2016 were enrolled in the study. They were followed up for a median period of 30 months. The results were compared with 70 patients treated in our institute since Jan, 2014 on GiPAP program. Cytogenetic responses were assessed by FISH on bone marrow aspirates on 6 and 12months, and molecular responses were assessed by standardised qT‐ PCR on 3, 6, 12, and 18months of therapy to a resolution of 1 in 10‐4. Patients who were non‐compliant to therapy, response assessment and who failed hematologic response at 3 months were excluded from the analysisResults:Among the 60 patients of GIG included in the analysis, 43 were on Imatinate @KLabs and 17 were on Veenat @Natco. In GIG, 41.6% and 66.6% achieved complete cytogenetic response (CCyR) at 6 and 12 months as compared to 46.2% and 72.1% in IIG (p &gt; 0.05). The rates of optimum molecular responses (ELN 2013) in GIG at 3 and 6 months were 90% and 80% as compared to 92% and 86% in the IIG (p &gt; 0.05). However, the rates of MMR at 12 months in GIG and IIG were 63.3% and 71.4% respectively (p &lt; 0.05). The rates of failure of response by 18 months in GIG and IIG were 33.3% and 17.4% (p &lt; 0.05). In a median follow up of 30 months, 9 patients in GIG progressed to accelerated or blast phase and 20 patients were switched to 2nd line agents. In the IIG, 4 patients progressed and 12 patients were switched to 2nd line TKIs (p &lt; 0.05). There were 3 deaths in GIG and 2 in IIG. Grade 1/2 hematologic toxicities occurred in 100% patients in IIG as compared to 94% in GIG. Grade 3/4 hematologic toxicities occurred in 30% of IIG and 26% in GIG (p &gt; 0.05). Among the non‐hematologic toxicities, skin hypo‐pigmentation, gastritis, muscle cramps and arthritis were most common occurring in 58%, 50%, 30% and 24% in IIG and 50%, 44%, 32% and 30% in GIG. The rates of intolerance and therapy withdrawal are 10% in GIG as compared to 15% in IIG (p &gt; 0.05).Summary/Conclusion:When compared to the innovator brand (Glivec @Novartis), early cytogenetic and molecular responses in patients on generic Imatinib were similar. However, responses at 12 months, rates of failure of Imatinib, and progression of disease are significantly inferior in the GIG and more patients in GIG were switched to 2nd line TKI. Assessment of Deep molecular response rates might yield more significant results. The groups were similar in toxicity profile and therapy discontinuation

Rates of deep molecular response by digital and conventional PCR with frontline nilotinib in newly diagnosed chronic myeloid leukemia: a landmark analysis

ENESTnext (NCT01227577) was a single-arm, multicenter trial evaluating the rate of deep molecular response by 2 years in patients with newly diagnosed (within 6 months) chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib 300 mg twice daily. Among 128 enrolled patients, 94 (73%) achieved major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) and 34 (27%) achieved confirmed MR4.5 (BCR-ABL1IS ≤0.0032% detectable or undetectable; primary endpoint) by 2 years. Three-month BCR-ABL1 levels were predictive of later responses. In exploratory analyses, digital polymerase chain reaction (PCR) detected BCR-ABL1 in 39.4% of samples from patients with confirmed MR4.5 and identified further decreases in BCR-ABL1 with continued nilotinib. Safety results, including cardiovascular events, were consistent with those in other nilotinib trials. These results further substantiate the molecular response rates associated with frontline nilotinib therapy and demonstrate the feasibility of monitoring very low BCR-ABL1 transcript levels using digital PCR.

Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring”

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression. Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI. Materials &amp; Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013. Results. Median follow-up after initiation of treatment was 46 months (range 12-74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively. Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts).AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts.METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events.RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%.The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y.SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. DisclosuresGugliotta:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial

Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission.

Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.