Durable Treatment-free Remission Research Articles

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD.

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10-4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. 32/45 (71%) had U-MRD at the completion of venetoclax: 22/32 stopped ibrutinib; 10 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.

Outcomes with metastasis-directed therapy (MDT) and fixed-duration systemic therapy in oligometastatic hormone-sensitive prostate cancer (omHSPC).

178 Background: Intensification of systemic therapy beyond ADT, with use of novel hormonal agents (NHAs), and radiotherapy (RT) to the prostate have a proven survival benefit in mHSPC. MDT has shown benefit in delaying need for ADT in omHSPC in phase 2 trials. Combination of fixed-duration systemic therapy with MDT (and RT to the prostate in de novo mHSPC) may produce long-term remission and treatment-free survival in selected patients with omHSPC. Methods: Patients with de novo or recurrent omHSPC treated at our institution between 2010-2020 with MDT (+/- prostate RT if de novo) and a fixed duration of systemic therapy completed by September 2022 were identified. There was no limit on number of metastases as long as all sites could be treated with MDT in the view of the treating physician. Oligometastases were defined as bone or soft tissue lesions beyond the pelvic lymph nodes identified on conventional scans (CT, bone scan, MRI) or PET (fluciclovine or PSMA). The primary outcome was freedom from biochemical recurrence (BCR), defined as PSA of >0.02 (if the patient had undergone prior radical prostatectomy) or >2+nadir (if the patient underwent RT) after completion of systemic therapy. Testosterone recovery was defined as serum testosterone >150ng/dL attained after completion of systemic therapy. BCR-free survival after completion of systemic therapy was estimated using the Kaplan Meier method. Results: 32 patients were included. Median age at diagnosis of mHSPC was 67 (range 52-78). 12 patients (38%) had de novo mHSPC while 20 (63%) had oligorecurrent HSPC. Detection of omHSPC was by conventional scans in 23 patients (72%) and by PET only in 9 (28%), and median number of oligometastases was 1 (range 1-6). Median PSA at start of therapy for omHSPC was 8.2ng/mL (range 0.4-1244), with systemic therapy most commonly comprising of ADT and a NHA (abiraterone, enzalutamide, apalutamide, n=26 [82%]); 6 patients (19%) had ADT alone. Median duration of systemic therapy was 24 months (range 6-36), with 3 men (9%) having received prior systemic therapy for mHSPC. MDT consisted of external beam RT (EBRT, n=10, 31%), EBRT + stereotactic body radiotherapy (SBRT, n=8, 25%), or SBRT alone (n=14, 44%). At a median follow-up of 44 months (range 24-127) and 20 months (2-103) after start and completion of systemic therapy respectively, 9 patients (28%) had BCR and 23 (72%) remained free of BCR, of whom 13 (57%) had testosterone recovery. The estimated 2-year BCR-free survival after completion of systemic therapy was 73% (95% CI 51-86). Conclusions: In this carefully selected cohort of men with omHSPC, estimated 2-yr BCR-free survival after completion of therapy was >70% with ~2 years of ADT +/- NHA along with MDT +/- prostate RT (if de novo). Longer follow-up is needed to determine whether this translates to a durable treatment-free remission, and possibly cure, in these patients with omHSPC.

High Response and Prolonged Treatment-Free Remission after a Short-Course of Modified Intensive Chemotherapy and Venetoclax in Elderly AML: An Updated Analysis of the Caveat Trial

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia.

Simple SummaryLeukemic stem cells represent a rare subpopulation of leukemic cells, which not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. To achieve permanent cures and prevent relapse, eradication of leukemia stem cells is essential. Chronic myeloid leukemia is a myeloproliferative disorder, and tyrosine kinase inhibitors have dramatically improved long-term outcomes and quality of life for patients. Point mutations of the kinase domain of BCR-ABL1 lead to drug resistance, and as a result, several new generations of tyrosine kinase inhibitor have been introduced to the clinic. Some patients develop drug resistance without known mutations, however, and the presence of leukemia stem cells is believed to be at least partially associated with resistance development and disease relapse. The identification of specific markers distinguishing leukemia stem cells from healthy hematopoietic stem cells, and the potential contributions of the bone marrow microenvironment to leukemia pathogenesis, have also been explored. In this review, we revisit the current knowledge regarding the roles of leukemia stem cells in response to pharmacological treatment and explore how durable treatment-free remission may be achieved after discontinuing tyrosine kinase inhibitor treatment.Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.

A randomized, phase II trial of adjuvant immunotherapy with durable TKI-free survival in patients with chronic phase CML

PurposeChronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation. MethodsTKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover. ResultsThirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFN⟶vaccine: n = 9, vaccine⟶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7–66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5–43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9–92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %–79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation. ConclusionAdjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early.

AML-212: Treatment Free Remission (TFR) After Ceasing Venetoclax-Based Therapy in Responding Patients with Acute Myeloid Leukemia

<h3>Context:</h3> Ph3 studies confirmed the benefit of adding venetoclax (VEN) to hypomethylating agents (HMA) or low-dose cytarabine (LDAC) in older/unfit patients with newly diagnosed AML with a median response duration of 12-18 months(mo). It is currently unknown whether patients should continue therapy until progression and whether elective therapy cessation could detrimentally impact outcomes. <h3>Objective:</h3> To compare the natural history of patients receiving ≥12mo of VEN-based therapy in first remission. <h3>Design, Setting and Patients:</h3> Retrospective analysis of patients with AML receiving VEN plus HMA or LDAC for ≥12mo and in sustained first remission from three institutions. Two treatment approaches were compared: elective therapy cessation in remission followed by monitoring (STOP) or continued therapy until relapse (CONT). <h3>Main Outcome Measures:</h3> Primary: treatment free remission (TFR), progression free survival (PFS). Secondary: overall survival (OS), molecular correlates of PFS. <h3>Results:</h3> 28 patients were identified: 14 in STOP, 14 in CONT. Median follow-up was 60.9mo. Treatments included VEN-HMA (68%) or VEN-LDAC (32%). Median time on therapy (TOT) was shorter in STOP (19.0mo <i>vs</i> 32.7mo) and fewer cycles were received in STOP (median 17 <i>vs</i> 30). In STOP, treatment cessations were due to patient request (43%) or medical (57%), with a median TFR of 45.8m (95%CI 9.5-not reached). 7/14(50%) have relapsed, with 3 relapsing >31mo of TFR. In CONT, 9/14(64%) have relapsed, with 6 relapsing >24mo of therapy. Cytogenetic evolution was more frequently observed at relapse in CONT (67% <i>vs</i> 43%). A landmark analysis was performed (landmarked at median TOT in STOP to exclude lead-time bias from early relapses in CONT), which revealed no significant difference in PFS (p=0.14) or OS (p=0.24). 10/15 patients with <i>NPM1</i> and/or <i>IDH2</i> mutations remain in remission (6/8 STOP, 4/7 CONT), of which 9/10 achieved undetectable MRD (by flow/qPCR). 1 had detectable <i>IDH2</i> mutation at pre-leukemic levels. Multivariate analysis showed that mutant <i>NPM1</i> is an independent predictor of OS (HR for death 0.002, p=0.037) and PFS (HR for relapse 0.012, p=0.024). <h3>Conclusion:</h3> Durable TFR is highest among patients with <i>NPM1/IDH2</i> mutations and MRD negative after ceasing >12 months of VEN-based treatment. A prospective, randomised, discontinuation study in pts in CR_MRDneg after 12 months of VEN-based therapy should be considered.

Cumulative Incidence of Treatment-Free Remission (TFR) for Patients with Chronic Myeloid Leukemia (CML): The Adelaide Experience

Background: For patients (pts) meeting specific clinical criteria, a trial of tyrosine kinase inhibitor (TKI) cessation is a safe option if regular quantitative RT-PCR (qRT-PCR) monitoring is performed and TKI is promptly recommenced in the event of molecular relapse [Mahon, Lancet Oncology 2010; Ross, Blood 2013]. With expert opinions incorporating TKI cessation into global guidelines such as the National Comprehensive Cancer Network and an increasing number of clinical trials demonstrating its success with both first and second-generation agents, treatment-free remission (TFR) is steadily being adopted into mainstream practice. Aim: To determine the proportion of pts becoming eligible and achieving a TFR attempt in a single academic centre. Patients and Methods: Adult pts receiving their primary CML management at the Royal Adelaide Hospital were included. We excluded pts referred specifically for clinical trials, transplantation, second opinions, and those with incomplete data. Clinical and molecular data from the period January 2008 to July 2017 were analysed. Specific TKI therapy was not mandated. Minimum criteria for qualifying for a TFR attempt were ≥3 years of TKI therapy and ≥2 years of sustained deep molecular response (DMR, BCR-ABL1 Results: A total of 245 pts were included in our analysis with a median follow-up of 6 yrs (0.2-19.2 yrs). Forty-seven pts will never qualify for TFR by our institution criteria due to death, allogeneic stem cell transplantation, loss to follow up, development of a T315I mutation and presence of atypical BCR-ABL1 transcripts. In total, 103 pts became eligible for a TFR attempt with an increasing proportion of pts becoming eligible for TFR with longer duration of TKI exposure (Table 1, Figure 1), from 16% at 4 yrs compared to 61% at 14 yrs. Eighty-two pts (80% of eligible pts) attempted TFR. The median age at TFR attempt was 61 yrs (range 34-89 yrs) and 55% (n=45) were male. The proportion of pts attempting TFR rose with longer duration of TKI exposure from 3% at 4 yrs compared with 53% at 14 yrs. The median duration of TKI treatment prior to TFR was 7.45 yrs (range 3-15.7 yrs) and the median duration of MR4.5 prior to TKI cessation was 2.8 yrs (range 2-9.9 yrs). The TKI at the time of the first TFR attempt in decreasing order of frequency was imatinib (n=53, 65%); nilotinib (n=18, 22%), dasatinib (n=10, 12%) and bosutinib (n=1, 1%). Durable TFR was achieved in 33 pts (40%) on the first attempt with a minimum follow-up of 12 months; 10 pts have Conclusion: TFR in published literature is achieved in 40-50% of cessation attempts for pts who meet the qualification criteria and these figures are in line with our real-world experience. Many pts (40%) ceased TKI outside of a clinical trial with close medical supervision and monthly PCR monitoring to ensure timely TKI recommencement if TFR failure occurred. Duration of TKI exposure correlated with TFR success which is comparative to recent data presented by the EUROSKI study. With longer follow-up, the availability of second generation TKIs for pts not achieving DMR on imatinib and the potential role of second and third attempts at TFR, we have observed a steady increase in eligibility for TFR, TFR attempts and durable TFR. Disclosures Shanmuganathan: Bristol-Myers Squibb: Honoraria, Other: Travel Support; Novartis: Honoraria, Other: Travel Support. Branford: Qiagen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Yeung: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Yong: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Research Funding. Hughes: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

Impact of Treatment Cessation on Overall Disease Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Attempting Treatment-Free Remission (TFR): Findings from Enestfreedom and Enestop

Impact of Treatment Cessation on Overall Disease Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Attempting Treatment-Free Remission (TFR): Findings from Enestfreedom and Enestop

Utrata całkowitej odpowiedzi cytogenetycznej po odstawieniu nilotynibu

Osiągnięcie remisji wolnej od leczenia (TFR) stało się w kilku ostatnich latach nowym, ważnym celem terapii chorych na przewlekłą białaczkę szpikową (CML). Doprowadzenie do długotrwałej i głębokiej remisji molekularnej, a następnie próba odstawienia inhibitora kinaz tyrozynowych (TKI) jest strategią szczególnie atrakcyjną dla młodszych chorych oraz tych, u których stosowane TKI wywołują przewlekłe działania niepożądane znacząco obniżające jakość życia. Wyniki wielu badań klinicznych wskazują na możliwość uzyskania trwałej TFR u około 50% chorych. U pozostałych dochodzi do utraty większej odpowiedzi molekularnej (rzadziej do utraty całkowitej odpowiedzi cytogenetycznej [CCyR]), co stanowi wskazanie do ponownego wdrożenia leczenia. Procedurę uznaje się za całkowicie bezpieczną. W toku prowadzonych badań nie odnotowano progresji ani zgonu spowodowanego odstawieniem TKI. Poniżej zaprezentowano przypadek chorego, u którego doszło do utraty CCyR po odstawieniu nilotynibu. Ponowne wdrożenie tego leku szybko doprowadziło do odzyskania CCyR i DMR (MR4).

CML-110: Predictors of Durable Treatment-Free Remission After Frontline or Second-Line Nilotinib Treatment in Patients with Chronic Phase Chronic Myeloid Leukemia

Context While some patients with chronic myeloid leukemia in chronic phase who maintain a deep molecular response (DMR) with tyrosine kinase inhibitors (TKIs) can discontinue treatment and achieve treatment-free remission (TFR), variables that reliably predict TFR are unknown. Objective Identify clinical predictors of TFR using pooled data from long-term follow-up studies (ENESTfreedom and ENESTop) of TFR following front- or second-line nilotinib. Patients In ENESTfreedom, patients with MR4.5 and ≥2 years of frontline nilotinib were enrolled and entered a 1-year nilotinib consolidation phase, after which those who maintained DMR in 4 quarterly assessments could enter the TFR phase (n=190). In ENESTop, patients with >4 weeks of imatinib followed by ≥2 years of nilotinib (≥3 years of total TKI therapy) who achieved MR4.5 on nilotinib were enrolled; patients entered a 1-year nilotinib consolidation phase, and those with no loss of MR4.5 subsequently entered the TFR phase (n=126). Main outcome measures Data from all patients who entered the TFR phases of ENESTfreedom and ENESTop were pooled. Univariate and multivariate analyses were conducted to identify predictors of durable TFR (i.e., remaining in the TFR phase with MR4.5 at 24 weeks). Variables assessed as predictors were age, sex, time since MR4.5 achievement until TFR phase entry, and duration of nilotinib prior to TFR. Results Among all patients who entered the TFR phases of ENESTfreedom and ENESTop, 180/316 achieved durable TFR at 24 weeks. In the univariate analysis, time since MR4.5 achievement until TFR phase entry (P=0.0025) and duration of nilotinib prior to TFR phase entry (P=0.0008) were significantly associated with durable TFR. Duration of nilotinib prior to TFR phase entry was the only significant predictor (P=0.0333) found in the multivariate analysis, with a 1-month increase in the duration of nilotinib treatment being associated with a 3.6% increase in the odds of durable TFR. Conclusions Pooled analyses suggest that durable TFR at 24 weeks was associated with duration of nilotinib prior to TFR. These data could help physicians with patients who are considering attempting TFR. Study sponsored by Novartis Pharmaceuticals Corporation. This abstract was accepted and previously published at the 61st ASH® Annual Meeting and Exposition.

CML-083: Prognostic Factors of Durable Treatment-Free Remission in CML Patients Based on the Prospective Study RU-SKI

Aim To define the prognostic factors for molecular relapse-free survival (MRFS) after TKI discontinuation in the Russian CML population. Methods The base for the analysis was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in patients (pts) with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic-phase, TKI therapy for at least three years and a stable DMR (BCR-ABL Results Three-year MRFS rate was 51%. Baseline pts characteristics: male - 50%; median (Me) age at TKI cessation 46 years (range, 22 to 80); Me duration of TKI therapy 8.3 years (range, 3 to 16.2); Me duration of DMR 3.2 years (range, 2 to 10.7). Therapy before treatment cessation: imatinib in 67 (68.4%) pts, second-generation (2G) TKI in 31 (31.6%) pts. Me follow-up time after TKI cessation was 40 mo (range, 28 to 57). Probability of MRFS (1st stop) was 53% after 36 mo of follow-up. Length of DMR, duration of therapy and depth of molecular response were found to be significant factors with p ≤ 0.05. We have found that the duration of TKI therapy, and not the duration of DMR, has an independent prognostic value for the Russian CML population due to the lack of molecular monitoring data at early stages of the disease. No difference in 36 months MRFS was observed in 1st-line imatinib (55%) compared with 1st-line 2G TKI (70%; p=0.26) and 2nd-line 2G TKI (39%; p=0,09) groups. However, significantly shorter treatment duration was observed in pts treated with 1st-line 2G TKI (Me=41.5 mo) vs imatinib (Me=96.4 mo), p Conclusion Longer treatment duration and depth of DMR before cancellation at least MR 4.5 are associated with durable TFR. Our study showed that the MRFS rate is not significantly improved with the use of 1st-line 2G TKI in comparison with 1st-line imatinib.

Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib

Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib

Nilotinib in the treatment of chronic myeloid leukemia.

Nilotinib, a second-generation tyrosine kinase inhibitor, was designed to overcome resistance of a wide range of BCR-ABL mutants to imatinib. When used in the first-line treatment in newly diagnosed chronic myeloid leukemia (CML), it induces faster and deeper molecular responses in higher than imatinib percentage of patients. Treatment-free remission after achievement of sustained deep molecular response represents an emerging treatment goal for a proportion of patients with CML in chronic phase. The pharmacologic properties, and the role of nilotinib in the current treatment of CML in the context of considered optimal end point of therapy including the discontinuation trial and durable treatment-free remission achievement is discussed in the article.

Evaluation and Significance of CD25 Expression in Hematopoietic Stem/Progenitor Cell Fraction of Bone Marrow Cells in Chronic Myelogenous Leukemia Patients

Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myelogenous leukemia (CML). The treatment with TKIs maintain the depth of response; however, the life-long use of TKI has also been associated with late complications such as cardiovascular events and huge financial burden impairing their quality of life. To overcome these issues, investigators have been attempting to discontinue TKIs after durable molecular remission. However, the optimal timing to stop TKIs remains to be elucidated. We previously demonstrated that CD25 was highly expressed in murine and human CML-leukemia initiating cells (LICs) (Kobayashi CI et al., Blood, 2014). In this study we tried to clarify whether the proportion of CD25-positive cells in hematopoietic stem/progenitor cell fraction of bone marrow cells in CML patients treated with TKIs is associated with their molecular response and could serve as a novel surrogate marker to select patients who are likely to obtain durable treatment-free remission after stopping TKIs.Methods: Bone marrow samples were obtained from the patients with CML in chronic phase who were treated solely with TKIs at Keio University Hospital (Tokyo, Japan). This study was approved by the institutional ethical committee and informed consent was obtained from each patient. Both quantitative and qualitative PCR of BCR-ABL1 was performed using bone marrow mononuclear cells (BMMNCs). The proportion of CD25-positive cells in bone marrow hematopoietic stem/progenitor cell (HSPC; CD34+CD38-) fraction (%CD25+) was evaluated by flow cytometry. The response to TKIs at the time of analysis was determined according to as follows: complete cytogenetic remission (CCyR) defined as Philadelphia chromosome undetectable and quantitative PCR copy numbers >731 among BMMNCs; major molecular remission (MMR) as quantitative PCR copy numbers ≤731, and complete molecular remission (CMR) as undetectable BCR-ABL1 by quantitative and qualitative PCR.Results: Bone marrow samples obtained from 109 patients were evaluated (median age, 52 years; male/female, 76/33). Analysis was performed prior to TKI exposure in 26 patients and under TKI therapy in 64 patients (imatinib, 22; dasatinib, 33; nilotinib, 9). Remaining 19 patients were treatment free because they were enrolled into a clinical trial of TKI discontinuation. At diagnosis (n=26), %CD25+ were significantly correlated with hemoglobin level and platelet count (Table). The %CD25+ was significantly lower in patients with post TKI exposure than those at diagnosis without TKIs (p<0.00001). In nine patients with available samples before and after TKI therapy, the %CD25+ at diagnosis was significantly higher than after TKI therapy (Mean 34.7%, SD 24.8% vs. Mean 4.96%, SD 4.17%, p<0.01, Fig.a). In addition, %CD25+ was significantly correlated with copy number of BCR/ABL1 (P<0.001, Fig.b).Conclusion: We confirmed that the expression of CD25 in HSPC fraction of CML patients was significantly correlated with the disease status, and may be useful as a LIC minimal residual disease marker. [Display omitted] DisclosuresKasahara:Chugai: Research Funding. Sakurai:Bristol-Myers Squibb K.K.: Speakers Bureau. Kikuchi:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Ono: Speakers Bureau. Shimizu:Bristol-Myers Squibb K.K: Honoraria. Mori:Astella Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Novartis Pharma: Research Funding; MSD: Research Funding; MSD: Honoraria; Janssen: Honoraria; SHIONOGI: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Celgene: Honoraria; Ono: Honoraria; Eisai: Honoraria; Novartis Pharma: Honoraria; Shire Japan: Honoraria; CHUGAI: Honoraria; Asahi Kasei: Research Funding; Japan Blood Products Organization: Honoraria; Pfizer: Honoraria. Okamoto:Pfizer Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co.,Ltd.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Teijin Pharma Limited: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.:: Research Funding; Nippon Shinyaku Co., Ltd: Research Funding; Shionogi & Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Asahi Kasei Pharma Corp.:: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study

PurposeENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.MethodsAttempting TFR required ≥ 3 years of nilotinib, a molecular response of MR4.5 [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1IS)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1IS ≤ 0.1%).ResultsNinety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR4.5 by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR4.5 during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR4.5 during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR4.5, MR4 (BCR-ABL1IS ≤ 0.01%) but not MR4.5, and MMR but not MR4 at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.ConclusionsThese results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.

ENESTfreedom and ENESTop Update: Durable Treatment-Free Remission (TFR) at 96 Weeks after Nilotinib Treatment Cessation in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

ENESTfreedom and ENESTop Update: Durable Treatment-Free Remission (TFR) at 96 Weeks after Nilotinib Treatment Cessation in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients’ immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38− cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.

Chronic Myeloid Leukemia: What Every Practitioner Needs to Know in 2017.

The prognosis of chronic phase chronic myeloid leukemia (CML) has improved so that life expectancy for patients responding to tyrosine kinase inhibitors (TKIs) is now equivalent to age-matched controls. Attention should be paid to comorbidities that impact survival. The success of TKI therapy can be easily and reliably assessed at well-accepted time points using quantitative polymerase chain reaction (PCR) standardized to the international scale. Patient-reported outcome (PRO) tools are readily available for use in the clinic and provide complementary information on the tolerance of TKIs. Effectively managing adverse events of TKIs can improve compliance and quality of life. Discontinuation of TKIs is the next frontier in CML. In select patients with sustained deep molecular remission, a discontinuation of TKI is associated with a durable treatment-free remission in approximately 50%. Patient engagement in their discontinuation can be achieved through a provider multi-team coaching, is complementary to the available guidelines, and may provide an additional safety net so that these discontinuations remain safe when applied in general practices.

Chronic Myeloid Leukemia: What Every Practitioner Needs to Know in 2017

The prognosis of chronic phase chronic myeloid leukemia (CML) has improved so that life expectancy for patients responding to tyrosine kinase inhibitors (TKIs) is now equivalent to age-matched controls. Attention should be paid to comorbidities that impact survival. The success of TKI therapy can be easily and reliably assessed at well-accepted time points using quantitative polymerase chain reaction (PCR) standardized to the international scale. Patient-reported outcome (PRO) tools are readily available for use in the clinic and provide complementary information on the tolerance of TKIs. Effectively managing adverse events of TKIs can improve compliance and quality of life. Discontinuation of TKIs is the next frontier in CML. In select patients with sustained deep molecular remission, a discontinuation of TKI is associated with a durable treatment-free remission in approximately 50%. Patient engagement in their discontinuation can be achieved through a provider multi-team coaching, is complementary to the available guidelines, and may provide an additional safety net so that these discontinuations remain safe when applied in general practices.

Correlation of Expression of CD25 in Hematopoietic Stem/Progenitor Cell Fraction of Bone Marrow Cells with Response to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Patients

Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myelogenous leukemia (CML). The treatment with TKIs continues to improve the depth of response and overall survival of CML patients, but the life-long use of TKI is known to be associated with late complications such as cardiovascular events as well as heavy financial burden, and thus impairs the quality of life. To overcome these issues, many studies evaluating the possibility of TKI discontinuation have been ongoing worldwide. In order to achieve durable treatment-free remission, it is crucial to understand the dynamics of CML-leukemia initiating cells (LICs). We previously reported that CD25 was highly expressed in murine and human CML-LICs (Kobayashi CI et al., Blood, 2014). The aim of this study was to assess whether the proportion of CD25 positive cells in hematopoietic stem/progenitor cell fraction of bone marrow cells in CML patients treated with TKIs is associated with their molecular response and could serve as a novel surrogate marker to stop TKI therapy.Methods: Bone marrow samples were obtained from patients with CML in chronic phase who were diagnosed and have been treated solely with TKIs at Keio University Hospital (Tokyo, Japan). This study was approved by the institutional ethical committee and informed consent was obtained from each patient. Both quantitative and qualitative PCR of BCR-ABL was performed using bone marrow mononuclear cells (BMMNCs). The proportion of CD25 positive cells in bone marrow hematopoietic stem/progenitor cell (HSPC; CD34+CD38-) fraction was evaluated by flow cytometry using FITC-labeled anti-CD34, PE- labeled anti-CD38 and APC-labeled anti-CD25 antibodies. The response to TKIs at the time of evaluation was determined according to the previous report (Yoshida C et al., Int J Clin Oncol, 2012): complete cytogenetic remission (CCyR) defined as Philadelphia chromosome undetectable and quantitative PCR copy numbers >731 among BMMNCs; major molecular remission (MMR) as quantitative PCR copy numbers ≤731, and complete molecular remission (CMR) as undetectable BCR-ABL by quantitative and qualitative PCR.Results: Bone marrow samples obtained from 95 patients were evaluated (median age 53 years old; male/female, 67/28). Analysis was performed prior to TKI exposure in nine patients and under TKI therapy including 2nd generation TKI in 64 patients (imatinib, 22; dasatinib, 33; nilotinib, 9). Remaining 22 patients were treatment free because they enrolled in a clinical trial of TKI discontinuation. The proportion of CD25 positive cells in HSPC fraction significantly decreased in patients with prior TKI exposure relative to patients at diagnosis (n=86; Mean 4.2%, SD 7.0% vs n=9; Mean 22.4%, SD 11.3%, P<0.01). In addition, the proportion of CD25 positive cells in HSPC fraction significantly correlated the level of quantitative PCR (Figure, P<0.0001), and MMR was also dividable from CMR by the proportion of CD25 positive cells (MMR; n=29, Mean 4.6%, SD 4.8% vs CMR; n=49, Mean 2.6%, SD 2.5%, P<0.05). The expression of CD25 was still detected in the majority of patients who achieved CMR, including those who sustained CMR after the discontinuation of TKIs.Conclusion: We confirmed that the expression of CD25 in HSPC fraction of CML patients was significantly correlated with the response to TKI therapy, and may serve as an asset to select patients who are likely to achieve durable treatment-free survival. [Display omitted] DisclosuresKarigane:Celgene: Honoraria. Sakurai:Celgene: Honoraria. Matsuki:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Nippon Shinyaku: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Mitsuhashi:LSI Medience: Consultancy. Okamoto:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Astellas Pharma Inc.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Teijin Pharma Limited: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.