Discontinuation Of Dasatinib Research Articles

Abstract 3993: A tunable safety switch for solid tumor CAR T-cell therapy

Abstract On-target off-tumor toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) are severe immune-related adverse events (irAEs) that are frequently associated with Chimeric Antigen Receptor (CAR) T-cell therapy. Current efforts to manage such therapy-related toxicities involve incorporation of an inducible suicide agent within CAR constructs, such as iCaspase-9 or herpes simplex virus type 1 thymidine kinase that can be selectively activated to produce toxic effects within CAR T cells and attenuate their activity. However, while activation of these agents helps to mitigate or overcome such unwarranted toxicities, the therapeutic benefit of CAR T cells anti-tumor activity is also compromised. Therefore, to continue maintenance of CAR T cells’ therapeutic function while minimizing irAEs, an ideal safety switch should 1) rapidly inhibit the activation and proliferation of CAR T cells exposed to the target antigen, 2) reversibly inhibit activity without inducing CAR T cell elimination and 3) be clinically translatable for safe application in patients. Our laboratory investigated one such safety switch to inhibit CAR T-cell activity while maintaining their therapeutic function. We showed that incorporating a mutant variant of c-KIT D816V (KITv) in the intracellular domain of mesothelin-targeting second-generation CAR T cells (M28z-KITv) improved efficacy in solid tumors with low antigen, or an immunosuppressive environment. Herein, we evaluate the use of Dasatinib, a clinically available multitarget (BCR, SRC, c-KIT) tyrosine kinase inhibitor (TKI), as a tunable safety switch to reversibly inhibit M28z-KITv CAR T-cell functional activity. In cohorts of mice established with lung adenocarcinoma, daily administration of Dasatinib starting on day 1 or day 3 after CAR T-cell administration stabilized tumor growth, which otherwise continued to regress in untreated mice, indicating inhibition of CAR T-cell functional activity. Upon discontinuation of Dasatinib, tumors regressed, indicating reversal of CAR T-cell functional activity. In an experiment conducted to investigate functional persistence of CAR T cells upon long-term exposure to Dasatinib (1 month), we noted uninhibited activity of CAR T cells to rechallenged tumors. Dasatinib, thus may act as a tunable safety switch to regulate M28z-KITv CAR T-cell activity without compromising its therapeutic function. Citation Format: Kyohei Misawa, Meriem Taleb, Srijita Banerjee, William-Ray Vista, Navin K. Chintala, Prasad S. Adusumilli. A tunable safety switch for solid tumor CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3993.

Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia

Patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy are expected to have long-term survival outcomes comparable to those of the general population. Many clinical trials have confirmed that some patients sustain molecular responses without continuing TKI therapy. Treatment-free remission (TFR) is a new goal in treating chronic CML. The safety and outcome of TFR were studied in clinical trials after discontinuing imatinib or the second-generation TKIs dasatinib or nilotinib. TFR was safe in approximately 50% of patients who achieved a deep molecular response to TKI therapy. Patients who relapsed after discontinuing TKI responded immediately to the reintroduction of TKI. The mechanism by which TFR increases the success rate still needs to be understood. The hypothesis that the modulation of immune function and targeting of leukemic stem cells could improve the TFR is under investigation. Despite the remaining questions, the TFR has become a routine consideration for clinicians in the practice of molecular remission in patients with CML.

A Dasatinib-Induced Chylothorax Persisting After the Discontinuation of Dasatinib

Dasatinib is a rare cause of chylothorax.Chylothorax should be included in the differential diagnosis in patients developing pleural effusions when treated with dasatinib.The cornerstone of the treatment is tapering the dose or discontinuing the dasatinib therapy and changing it to another tyrosine kinase inhibitor.

P700: TREATMENT-FREE REMISSION (TFR) AFTER DASATINIB IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) AND DEEP MOLECULAR RESPONSE (DMR): FINAL 5-YEAR RESULTS OF DASFREE

Background: Patients (pts) with CML-CP who have a DMR are eligible to discontinue treatment (Tx) to attempt TFR. DASFREE (NCT01850004) is a single-arm, open-label, phase 2 trial evaluating dasatinib discontinuation in pts with a stable DMR. At the 2-year (y) follow-up, 46% of pts remained in TFR; in a multivariate analysis, longer duration of prior dasatinib, first-line (1L) dasatinib, and older age were significantly associated with TFR maintenance (Shah et al. Leuk Lymphoma 2019). Aims: To report the final 5-y results assessing TFR maintenance after dasatinib discontinuation. Methods: Eligible pts were aged ≥18 y, received dasatinib Tx as 1L or subsequent therapy for ≥2 y, and had a DMR (MR4.5 or BCR-ABL ≥0.0032% on the international scale, confirmed during pre-screening and with 2 central lab assessments 3 months [mo] apart) for ≥1 y prior to study entry. Pts discontinued dasatinib and were monitored for up to 5 y. All pts provided written informed consent. If loss of major molecular response (MMR) occurred, pts restarted dasatinib at the same dose as at enrollment. A univariate analysis was conducted to identify baseline correlates of maintaining TFR. Rate of TFR maintenance (event-free survival) in the extended follow-up, rate of MMR recapture after relapse, identification of predictive factors for TFR maintenance, and safety were all key secondary or exploratory endpoints. Results: A total of 84 pts discontinued dasatinib. At a minimum follow-up of 60 mo (database lock, Dec 2021), 44% (n=37) of pts remained in TFR and the remaining 56% (n=47) had lost MMR and restarted Tx. No relapses occurred later than 39 mo after discontinuation. Baseline characteristics were balanced between pts who remained in TFR versus those who restarted Tx, except for age (65% of pts who remained in TFR vs 85% who restarted Tx were aged <65 y). Among enrolled pts, 24 discontinued the study early (4 due to drug-related adverse events [AEs]; none due to death); 60 discontinued as planned per protocol (end of study). Patients who discontinued from the study were evaluated for response regained before discontinuation. All evaluable pts (n=46; one patient withdrew from the study 1 month after restarting Tx and did not undergo molecular assessment) who restarted Tx regained MMR and MR4.5 in a median (range) time of 1.9 mo (0.9–3.7) and 3.3 mo (1.5–29.6), respectively. The 5-y TFR rate was 43.8% (95% CI, 33.1–54.4; Figure). A univariate analysis of baseline correlates identified older age and 1L dasatinib as significantly associated with maintaining TFR. Musculoskeletal and connective tissue disorders (any grade) were experienced by 39% of pts (n=33). The most common any-grade AEs were arthralgia (18%) and hypertension (13%). There were no deaths due to CML. Withdrawal events (n=15) were experienced by 9 pts (11%) after a median (range) of 3.7 (<1–18) mo from dasatinib discontinuation, with no new events beyond 18 months of study follow-up; 10 events resolved in a median (range) of 5.98 (<1–70) mo. Image:Summary/Conclusion: Discontinuation of dasatinib after 1L therapy and beyond is a viable option for pts with CML-CP in sustained DMR. About half of the pts who discontinued dasatinib maintained TFR at 5 y. Re-treatment after relapse was successful; all evaluable pts who lost MMR regained MMR and MR4.5 after therapy was reinitiated. The overall safety profile was consistent with the known safety profile of dasatinib and with the 2-y results.

Dasatinib: A rare cause of recurrent cardiac tamponade

Dasatinib is one of the second-generation tyrosine kinase inhibitors (TKI) that used as the first line for the treatment of Philadelphia chromosome (Ph) positive chronic myeloid leukemia (CML). Several cardiovascular side effects such as pleural-pericardial effusion, pulmonary hypertension, prolonged QTc interval, and platelet dysfunction have been reported. A 59-year-old female with worsening dyspnoea was diagnosed with cardiac tamponade twice in six months period after initiation of Dasatinib 100 mg per day for CML. She was successfully treated with drainage of effusion percutaneously and discontinuation of Dasatinib. Recurrent cardiac tamponade is a rare complication related to the use of Dasatinib. It should be kept in mind that Dasatinib is a potential agent for pericardial effusion, especially when other possibilities are excluded.

Dasatinib-induced colitis: clinical, endoscopic and histological findings

Background Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with haematological malignancies. The main side effects of dasatinib are myelosuppression and pleural effusion; however, colitis, such as haemorrhagic colitis and cytomegalovirus (CMV) colitis, have been reported as rare side effects. There are only a few studies conducted on dasatinib-induced colitis. Aims This study aimed to clarify the clinical, endoscopic and pathological features of dasatinib-induced colitis. Methods This retrospective study included 51 consecutive patients who received dasatinib therapy between June 2009 and July 2020. Dasatinib-induced colitis was defined as the presence of colitis symptoms, exclusion of other diseases that could cause colitis, and improvement in symptoms after dasatinib withdrawal or dose reduction. CMV positivity was determined based on the positive result of CMV immunostaining. Results Dasatinib-induced colitis was diagnosed in nine of 51 patients (17.6%), and most of the symptoms were mild diarrhoea and bloody stools. The endoscopic findings were characterised by loss of vascular pattern (100%) and multiple small erosions (83.3%) which were mainly found in the transverse and descending colon. In a patient who underwent follow-up colonoscopy once a year while taking dasatinib, endoscopic findings changed from initial erythematous spots to multiple erosions, and finally to multiple small round elevations with erosion on the top that disappeared after discontinuation of dasatinib. Anti-CMV therapy was administered to one patient, but the treatment failed. All patients with dasatinib-induced colitis were cured after the discontinuation of dasatinib. Conclusion Physicians should consider CMV reactivation to manage dasatinib-induced colitis.

Incidence of Pleural Effusion with Dasatinib and the Effect of Switching Therapy to Bosutinib in Patients with Chronic Phase CML

Incidence of Pleural Effusion with Dasatinib and the Effect of Switching Therapy to Bosutinib in Patients with Chronic Phase CML

BILATERAL CHYLOTHORAX AND ANASARCA CAUSED BY DASATINIB IN A PATIENT WITH CHRONIC MYELOGENOUS LEUKEMIA

TOPIC: Disorders of the Pleura TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dasatinib is one of the tyrosine kinase inhibitors that is used in the treatment for Philadelphia positive Chronic Myeloid Leukemia (CML). Pleural effusion can occur in 10% of patients on dasatinib, but chylothorax was rarely reported as a side effect of dasatinib (1,2). CASE PRESENTATION: A 52 year-old male with medical history of CML presented with shortness of breath over the past 4months. Patient was diagnosed with CML 10 years ago. Initially he was started on imatinib which he did not tolerate secondary to headache and he was switched to dasatinib 100mg daily which he tolerated for 5 years. Bone marrow biopsy showed complete cytogenetic remission in 6-months and he achieved major molecular remission. Physical exam was remarkable for reduced air entry to both lungs, abdominal ascites, and lower extremities pitting edema up to the groins. Basic labs were within normal limits. Chest X-ray showed bilateral pleural effusions and confluent bibasilar infiltrates. Computed topography of the chest showed large bilateral effusions with passive atelectasis in the lower lobes (figure-1A and 1B). CT scan of the abdomen and pelvis showed diffuse body edema in the lower abdomen extending to both lower extremities. Large right hydrocele and moderate left hydrocele were also noticed (figure-1C). Imaging guided thoracentesis was performed on the right side and 1900 ml of milky fluid was drained. Pleural fluid analysis showed total protein of 4.6 g/dL (serum total protein:7.3 g/dL), glucose of 97 mg/dL (serum glucose: 84 mg/dL), elevated lactate dehydrogenase (116 U/L), elevated triglyceride (485 mg/dL), and elevated cholesterol (83 mg/dL). Based on that, Diagnosis of chylothorax was made and dasatinib was discontinued. Patient was started on short course of diuretics and oral prednisone. After one month of dasatinib discontinuation, patients SOB improved significantly. Abdominal and lower extremities swelling has improved too. Repeated CXR showed improved bilateral pleural effusion (figure-1D). We kept patient off dasatinib with monthly check of BCR/ABL by PCR with plan to restart dasatinib at 50 mg daily or switching to another treatment if he relapses. DISCUSSION: Pleural effusion is a known side effect of dasatinib and few reports of unilateral chylothorax have been reported. Bilateral chylothorax and anasarca are very rare side effects of dasatinib. In most of the cases, discontinuation of dasatinib can improve symptoms. In a previous case report, 63 year-old female presented with right sided dasatinib induced chylothorax which totally resolved after switching dasatinib to nilotinib (2). In another case report, the 71 year-old patient presented with dasatinib induced chylothorax that initially resolved and then recurred after re-initiation of dasatininb (3). CONCLUSIONS: Bilateral chylothorax after dasatinib is very rare. Most cases resolve completely with dasatinib discontinuation. REFERENCE #1: Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. doi: 10.1056/NEJMoa1002315. Epub 2010 Jun 5. PMID: 20525995. REFERENCE #2: Al-Abcha A, Iftikhar MH, Abu Rous F, et al. Chylothorax: complication attributed to dasatinib use. BMJ Case Rep. 2019 Dec 16;12(12):e231653. doi: 10.1136/bcr-2019-231653. PMID: 31848139; PMCID: PMC6936595. REFERENCE #3: Chen B, Wu Z, Wang Q, et al. Dasatinib-induced chylothorax: report of a case and review of the literature. Invest New Drugs. 2020 Oct;38(5):1627-1632. doi: 10.1007/s10637-020-00932-3. Epub 2020 Apr 4. PMID: 32248338. DISCLOSURES: No relevant relationships by hamed daw, source=Web Response No relevant relationships by Christopher Haddad, source=Web Response No relevant relationships by Tariq Kewan, source=Web Response No relevant relationships by Talha Saleem, source=Web Response

Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial

A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. Epidemiological and Clinical Research Information Network.

DASFREE: Treatment-Free Remission (TFR) After Discontinuation of Dasatinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

DASFREE: Treatment-Free Remission (TFR) After Discontinuation of Dasatinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

EXPRESS: Pulmonary hypertension with dasatinib and other tyrosine kinase inhibitors.

Dasatinib and other tyrosine kinase inhibitors are commonly utilized in the management of chronic myelogenous leukemia. Pulmonary hypertension is an important adverse event associated with dasatinib. Mechanisms for pulmonary hypertension include pulmonary endothelial injury, apoptosis, and increased susceptibility to other triggers for pulmonary hypertension. The diagnosis is suspected based on symptoms, suggested by echocardiographic findings, and confirmed with right heart catheterization. Management includes discontinuation of dasatinib and initiation of pulmonary vasodilators. Persistent pulmonary hypertension is present in up to one third of patients after cessation of dasatinib. Other tyrosine kinase inhibitors, including bosutinib, lapatinib, and ponatinib have also been implicated in pulmonary hypertension in small series, although evidence for causation is less robust. A high index of suspicion, continued vigilance for pulmonary hypertension with long-term use, and early therapy are important in optimizing outcomes in this population.

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report

BackgroundThere have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease.Case presentationA 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed.A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units.ConclusionsPatients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied.

Chronic myeloid leukemia complicated by pulmonary hypertension during dasatinib therapy: a single-center retrospective study

Pulmonary artery hypertension (PAH) has been reported to be a severe adverse event associated with dasatinib therapy. Among the 76 chronic myeloid patients who were treated with dasatinib at our hospital, six patients showed high estimated pulmonary arterial systolic pressure, as observed by echocardiography. PAH was confirmed using right heart catheterization in three (3.9%) patients with increased mean pulmonary artery pressure (mPAP). In one patient, although mPAP was higher than the normal range, it did not fulfill the criteria of pulmonary hypertension. After the discontinuation of dasatinib, BNP and dyspnea were improved in five patients. Therefore, it should be noted that dasatinib can cause PAH at higher rates than those reported previously, and if PAH is confirmed or suspected during dasatinib therapy, then dasatinib should be immediately discontinued.

Discontinuation of Dasatinib after Deep Molecular Response for over 2 Years in Patients with Chronic Myelogenous Leukemia and the Unique Profiles of Lymphocyte Subsets for Successful Discontinuation: A Prospective, Multicenter Japanese Trial (D-STOP Trial)

▪IntroductionThe tyrosine kinase inhibitor (TKI), imatinib, dramatically improves the prognosis of chronic myelogenous leukemia (CML) by suppressing the function of BCR-ABL gene. It was shown that imatinib could be discontinued in a proportion of patients with CML who maintained deep molecular response (DMR) for at least 2 years. (Lancet Oncol. 2010; 11:p1029) Treatment with second generation TKI, dasatinib, after imatinib resistance/intolerance could also be discontinued after maintaining DMR for over 1 year in a proportion of patients with CML (Lancet Haematol. 2015; 2:p528). In this Japanese prospective multicenter trial (D-STOP trial by Shimousa Hematology and Kanto CML Study Groups, ClinicalTrials.gov Identifier: NCT01627132), we aimed to discontinue dasatinib in patients with CML who maintained DMR for over 2 years.Methods:Chronic phase CML patients treated with TKIs who had undetectable BCR-ABL1 mRNA were enrolled. After confirmation of undetectable BCR-ABL1 mRNA (International Scale <0.01%) using real-time quantitative polymerase chain reaction (RQ-PCR) in the central laboratory, the patient received additional dasatinib treatment for another 2 years as consolidation therapy. Patients who maintained DMR during the consolidation therapy proceeded to discontinue dasatinib. BCR-ABL1 mRNA was monitored every month in year 1 and every 3 months in year 2. Molecular relapse was defined as two successive positive RQ-PCRs for BCR-ABL1 within 1 month. The relapsed patients restarted dasatinib. The primary endpoint was treatment-free survival after 12 months of discontinuation. Lymphocyte subsets were analyzed using flow cytometry during and after the consolidation therapy.Results:Sixty-five patients received consolidation therapy, and 54 discontinued dasatinib treatment after maintenance of DMR for 2 years. Mean age of the patients was 54.2 (25-82) years, and median follow-up period after cessation of dasatinib was 16.2 (7-30) months. Twenty patients relapsed during the observation period. Using Kaplan-Meier analysis, the estimated overall treatment-free survival (TFS) was 62.9% (48.5-74.2) at 12 months (Fig.1). Most relapses occurred within 6 months after discontinuation of dasatinib. All relapsed patients responded again to dasatinib. There was no significant difference either in estimated TFS between males and females or Sokal scores at diagnosis. During the consolidation therapy, the proportion (%) of CD4+CD8−, CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells among total lymphocytes were monitored using flow cytometry in patients who could discontinue dasatinib during the observation periods (group A) and those who relapsed (group B). At the start of the consolidation therapy, there was no significant difference between groups A and B (CD4+CD8−%: 33.6 vs 34.0, p = 0.89, CD3−CD56+%: 24.3 vs 24.1, p = 0.95; CD16+CD56+%: 22.1 vs 23.9, p = 0.57; CD57+CD56+%: 19.7 vs 21.8, p = 0.51, respectively). In group B, the proportion of CD4+CD8− cells gradually decreased, whereas CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells gradually increased during the consolidation therapy. All four types of cells were relatively stable in group A. At the end of the consolidation therapy, there was a significant group difference in the proportion of these subsets (CD4+CD8−%: 29.6 vs 22.2, p = 0.018*; CD3−CD56+%: 25.9 vs 37.3, p < 0.01*; CD16+CD56+%: 23.2 vs 34.4, p < 0.01*; CD57+CD56+%: 21.9 vs 32.1, p < 0.001*; respectively). We concluded that patients with CD4+CD8− cells ≥23.1%, CD3−CD56+ cells ≤40.1%, CD16+CD56+ ≤35.6% or CD57+CD56+ ≤26.6% at the end of the consolidation therapy had significantly higher estimated overall TFS at 12 months than those without each condition (CD4+CD8−%: 84% vs 32%, p < 0.0001* (Fig.2); CD3−CD56+%: 77% vs 25%, p < 0.001* (Fig.3), CD16+CD56+%: 77% vs 25%, p < 0.0001*; CD57+CD56+%; 84% vs 46%, p < 0.01*, respectively). Although increased large granular lymphocytes and NK cells were reported to be associated with high responses to dasatinib (Int J Hematol. 2014; 99:p41), the unique profiles of lymphocyte subsets could predict successful discontinuation of dasatinib.Conclusion:Discontinuation of TKI in patients with chronic phase CML after consolidation therapy with dasatinib for 2 years was feasible with relatively high TFS. The unique profile of lymphocyte subsets might be able to predict successful discontinuation. [Display omitted] [Display omitted] [Display omitted] DisclosuresKumagai:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Nakaseko:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding. Nishiwaki:Novartis: Research Funding. Yoshida:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Morita:Bristol-Myers Squibb: Speakers Bureau. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Discontinuation of Nilotinib in Patients with Chronic Myeloid Leukemia Who Have Maintained Deep Molecular Responses for at Least 2 Years: A Multicenter Phase 2 Stop Nilotinib (Nilst) Trial

▪BackgroundSustained treatment-free remission (TFR) has been reported in 40-60% of patients with chronic myeloid leukemia-chronic phase (CML-CP) after discontinuation of imatinib or dasatinib following at least 1-2 years of deep molecular response (MR). We investigated safety and efficacy of discontinuing nilotinib treatment after 2 years of sustained MR4.5 (BCR-ABL1IS ≤ 0.0032%) on nilotinib in patient for whom MR4.5 was achieved by prior treatment with imatinib or nilotinib.MethodsThe Stop Nilotinib (NILSt) trial was a single-arm multicenter phase 2 study in Japan. CML-CP patients who obtained MR4.5 by treatment with imatinib or nilotinib were enrolled, and were further treated with nilotinib for 2 years. The patients who maintained MR4.5 during those 2 years were eligible for discontinuation of nilotinib. After treatment discontinuation, maintenance of MR4.5 was monitored by quantitative RT-PCR every month during the 1st year and every 2 months during the 2nd year. Nilotinib was reintroduced in patients who lost MR4.5. The primary endpoint was the proportion of patients who maintained MR4.5 at 1 year after the discontinuation. This study is registered, number UMIN000007141.Results112 patients were enrolled between April 11, 2012 and November 30, 2012, and were treated with nilotinib for 2 years. 90 of those patients maintained MR4.5 during the entire 2-year period and were eligible to discontinue treatment, among which 87 patients actually discontinued nilotinib to intend a treatment-free remission period. Median follow-up after the discontinuation was 13.4 months (range 4.8-20.1). At 1 year, 53 patients (58.9%, 90% CI 49.7-67.7) maintained MR4.5, whereas 34 patients experienced loss of MR4.5 mostly within 6 months after the discontinuation (Figure 1). Thirty-two of those 34 patients (94.1%) regained MR4.5 2.2 months (median, 95% CI 1.5-2.6) after reintroduction of nilotinib. The following parameters did not significantly predict the probability of MR4.5 at 1 year after the discontinuation: age, sex, Sokal, Hasford, EUTOS scores, history of IFN-a therapy, total duration of imatinib or nilotinib therapy, time to MR4.5, or trough concentrations of nilotinib in sera. Notably, the percentages of patients maintaining MR4.5 for one year without treatment did not improve significantly with longer duration of prior MR4.5 on treatment; even some patients with a duration of prior deep MR on treatment exceeding 10 years experienced loss of MR4.5 after treatment discontinuation (Table 1). The rates of all grade (grade 3/4 in parentheses) cardiovascular events were 5.5% (2.7%), fluid retention were 14.1% (0%), and musculoskeletal pain were 9.7% (1.8%) during the 2-year treatment periods.ConclusionNilotinib can be discontinued without relapse in more than half of the patients who maintained MR4.5 for at least 2 years. However, relapse occurred after the discontinuation following even more than 10 years of sustained deep MR in the rest of the patients. This suggests that the period of deep MR after which nilotinib can be discontinued without relapse is considerably long, if any, in a substantial proportion of patients. Biomarkers to detect such patients are awaited. Furthermore, additional strategies may be required to safely discontinue nilotinib as early as possible in such patients, in order to avoid serious adverse events caused by prolonged administration. [Display omitted] [Display omitted] DisclosuresKawaguchi:Novartis: Honoraria. Kuroda:Janssen: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Kanakura:Bristol Myers: Research Funding; Alexionpharma: Research Funding; Nippon Shinyaku: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Chugai Pharmaceutical: Research Funding; Shionogi: Research Funding; Kyowa Hakko Kirin: Research Funding; Fujimotoseiyaku: Research Funding; Toyama Chemical: Research Funding.

Dasatinib-Induced Colitis after Allogeneic Stem Cell Transplantation for Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

The tyrosine kinase inhibitor dasatinib is often used after allogeneic hematopoietic cell transplantation to treat minimal residual disease in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Colitis, sometimes hemorrhagic, has occasionally been described with the use of dasatinib for both chronic myeloid leukemia and Ph+ ALL. The pathogenesis of dasatinib-induced colitis is unclear but may be related to effects of dasatinib on immune function. We describe a series of 5 patients who had 7 episodes of colitis during dasatinib use. No patient had obvious large granular lymphocytosis in peripheral blood. The histopathologic and immunohistochemical features of these cases were indistinguishable from control cases of gut graft-versus-host disease (GVHD). In all patients symptoms resolved upon discontinuation of dasatinib in addition to therapy with local or low-dose systemic steroids. An additional 3 patients who developed cytomegalovirus (CMV) colitis while on dasatinib therapy were identified and studied. Dasatinib colitis may have an immune-mediated mechanism similar to GVHD, and dasatinib use may be associated with CMV colitis. Awareness of this association is important for avoiding unnecessary intensification of immunosuppression for suspected gut GVHD.

Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial

First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response. The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130. 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months. Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible. Epidemiological and Clinical Research Information Network (ECRIN).

Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056)

▪Background: The randomized, phase 3 DASISION trial demonstrated improved efficacy with dasatinib compared with imatinib in treatment-naïve CML-CP patients (pts). Dasatinib was also well tolerated, and demonstrated a faster response at 3 months. Here, we report the results of the final, 5-year analysis of DASISION.Methods: Pts with newly diagnosed CML-CP were randomized to receive dasatinib 100 mg once daily (n=259) or imatinib 400 mg once daily (n=260) as previously reported. The primary endpoint was confirmed complete cytogenetic response (cCCyR) by 12 months. Long-term efficacy and safety data from pts with the predefined minimum 5 years of study treatment are presented.Results: Sixty-one percent of dasatinib-treated pts and 63% of imatinib-treated pts were still on their initial study therapy at study end. Cytogenetic and molecular response rates continued to be higher for dasatinib compared with imatinib (intent-to-treat population). Specifically, the rate of cCCyR by 5 years was higher with dasatinib versus imatinib (83% vs 78%, P=.187), as were the rates of major molecular response (MMR; BCR-ABL ≤0.1%; 76% vs 64%, P=.002) and MR4.5 (BCR-ABL ≤0.0032% IS; 42% vs 33%, P=.025) by 5 years. Time to cCCyR (hazard ratio [95% confidence interval]=1.46 [1.20–1.77], P=.0001) and MMR (hazard ratio [95% confidence interval]=1.54 [1.25–1.89], P<.0001) in all randomized pts were faster with dasatinib (Figure 1). Transformations to both accelerated (AP) and blast phase (BP) CML were reported on study or after discontinuation with fewer cases overall for dasatinib (n=12/259; 4.6%) compared with imatinib (n=19/260; 7.3%). Five-year progression-free survival (PFS) and overall survival (OS) rates were similar across treatment arms (PFS: 85% [dasatinib], 86% [imatinib]; OS: 91% [dasatinib], 90% [imatinib]). A higher proportion of pts on dasatinib achieved BCR-ABL ≤10% at 3 months (84%) compared with those on imatinib (64%). For pts who achieved BCR-ABL ≤10% versus >10% at 3 months, improved PFS, OS, and lower rates of transformation to AP/BP have been previously reported and were maintained at 5 years for dasatinib (PFS: 89% vs 72%, P=.0014; OS: 94% vs 81%, P=.0028; transformation n=6/198 [3%] vs n=5/37 [14%]) and imatinib (PFS: 93% vs 72%, P<.0001; OS: 95% vs 81%, P=.0003; transformation: n=5/154 [3%] vs n=13/85 [15%]). Between 4 and 5 years, the number of mutations increased slightly in dasatinib-treated pts (12 pts at 4 years; 15 pts at 5 years), and the spectrum remained the same. No new, unexpected safety events were identified in either treatment arm at 5 years. However, the total incidence of pleural effusion continued to increase each year in dasatinib-treated pts (29% overall). Most cases of pleural effusion were grade 1/2 (n=67/74), and the median time to first grade 1/2 pleural effusion was 114 weeks (range, 4–299 weeks). Discontinuation of dasatinib due to pleural effusion occurred in only 15 pts (6% overall; 20% of pts who experienced a pleural effusion). Arterial ischemic events overall were not common, occurring in 12 pts (5%) on dasatinib and 6 pts (2%) on imatinib. Cardiovascular (CV) ischemic events and transient ischemic attack were reported in 10 and 2 dasatinib-treated pts, respectively. CV ischemic and peripheral arterial occlusive events were reported in 4 and 2 imatinib-treated pts, respectively. Of the pts with overall arterial ischemic events, 8 pts on dasatinib and 3 pts on imatinib had a history and/or risk factors for atherosclerosis. Fourteen dasatinib-treated pts experienced pulmonary hypertension by 2D echocardiogram, with right heart catheterization (RHC) performed in 1; 6 discontinued therapy. No pts were diagnosed with World Health Organization Group 1 pulmonary arterial hypertension (confirmed by RHC).Conclusion: At 5 years, dasatinib 100 mg once daily has demonstrated superior outcome compared to imatinib 400 mg once daily as initial therapy for CML. This is manifested by a faster time to cytogenetic and molecular responses, with more pts achieving BCR-ABL ≤10% at 3 months, sustained higher cumulative rates of response, and a lower rate of transformation. The 5-year rates of PFS and OS were equal in both arms. After 5 years, no new safety signals have been reported. These consistent results suggest that dasatinib offers meaningful advantages for pts with newly diagnosed CML-CP and remains a standard of care in this setting. [Display omitted] DisclosuresCortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Baccarani:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Mayer:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment. Manos:Bristol-Myers Squibb: Employment. Hochhaus:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Discontinuation Of Dasatinib In Patients With CML Who Have Maintained Complete Molecular Response For At Least One Year: Results From a Prospective Discontinuation (DADI) Trial

PurposeIt has been proposed that imatinib can be discontinued without molecular relapse at least in some CML patients. But little is known about whether the assumption could be exploitable for the second-generation ABL-tyrosine kinase inhibitors. Here we conducted a prospective, multicenter clinical trial to assess whether dasatinib can be discontinued without occurrence of molecular relapse in CML patients in complete molecular response (CMR). MethodsIn our Dasatinib Discontinuation (DADI) trial (Japan Primary Registries Network #UMIN000005130, http://rctportal.niph.go.jp/), main eligibility criteria for pre-registration were; CML patients in chronic phase, 15 years and older, undergoing dasatinib treatment used as a second-line therapy after confirmation of resistance or intolerance to imatinib treatment. Previous treatments with interferon-α (IFN-α) or nilotinib were allowed. In this trial, CMR was defined as “No detectable BCR-ABL transcript determined by international scale (IS)-based RQ-PCR at a single central laboratory (BML Inc., Tokyo, Japan, which obtains conversion factor (CF) 0.87).” Patients in CMR status confirmed by RQ-PCR at the central laboratory were pre-registered before the full enrollment for the discontinuation. The pre-registration period was between April 1, 2011, and March 31, 2012. The levels of BCR-ABL transcripts were monitored every 3 months throughout the pre-registration period during the dasatinib treatment. Patients with sustained CMR for one-year duration were then enrolled for the dasatinib-discontinuation stage. In order to detect molecular relapse after the dasatinib-discontinuation, RQ-PCR was performed monthly for the first 12 months, and then every 3 months for the subsequent follow-up. Molecular relapse was defined as positivity of BCR-ABL transcript by RQ-PCR even at one analysis point. Dasatinib was immediately reintroduced in patients who showed molecular relapse during the discontinuation period. After the relapse, RQ-PCR monitoring was performed 1 month, 3 months, 6 months, and 12 months after the reintroduction of dasatinib. Primary endpoint of this study was “Molecular relapse-free survival (MoRFS) rate at 6 months after discontinuation of dasatinib.” Total follow-up duration was set to be 36 months after the discontinuation. In addition to the molecular assessment of the BCR-ABL transcript level, increase of large granular lymphocytes (LGL) in the peripheral blood, in combination with flow cytometry analysis, was also investigated. ResultsIn total, 88 patients were pre-registered at 41 participating institutions in Japan. Among them, a total of 63 patients who maintained stable CMR for one year after pre-registration were enrolled for the dasatinib-discontinuation stage. All of these 63 patients (42 male, 21 female) had been treated with imatinib before the start of the dasatinib treatments. Among these 63, 14 were imatinib-resistant, and 35 were imatinib-intolerant. Other previous treatments were; IFN-α (n=12), nilotinib (n=4), IFN-α and nilotinib (n=1). Median age was 59.5 years (range 24-84). Sokal scores were; low 70%, intermediate 15%, and high 15%. In this interim analysis with a data cut-off date of 31 July 2013, 27 patients out of 88 pre-registered patients were over the observation period of 6 months after the dasatinib-discontinuation. Among 27, 12 patients achieved 6 months-sustained CMR after dasatinib-discontinuation. The estimated MoRFS at 6 months determined by Kaplan-Meier method was 44 % (95%CI 26-62). Reintroduction of dasatinib to the relapsed patients showed rapid molecular responses in all of them. Among the 15 patients who lost CMR after dasatinib-discontinuation, 13 patients were available for the evaluation of reintroduction to CMR. 12 out of 13 patients (92%) returned to CMR again within 3 months (7 patients at 1 month, and 5 patients at 3 months) after the reintroduction, and all these patients have sustained CMR up to now. The remaining one patient out of 13 also showed a marked reduction of the BCR-ABL transcript level at 3 months. ConclusionDasatinib could be safely discontinued in a proportion of CML patients with stable CMR for at least one year, provided that frequent molecular monitoring is performed. Patients who lost CMR after dasatinib-discontinuation still maintained good sensitivity to the reintroduction of dasatinib. Disclosures:Nakamae:Novartis: Honoraria, Speakers Bureau, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; BMS.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other. Kimura:Bristol-Myers: Honoraria, Research Funding.

Transitory dasatinib-resistant states in KITmut t(8;21) acute myeloid leukemia cells correlate with altered KIT expression

KIT inhibition with dasatinib represents a promising approach to targeted therapy in t(8;21) acute myeloid leukemia (AML) and clinical trials are currently evaluating its clinical relevance. However, data on continuous long-term dasatinib exposure of AML cells are limited and the potential effects on KIT inhibition and dasatinib sensitivity are unexplored. Treatment-related resistance ultimately limits clinical efficacy of tyrosine kinase inhibitors (TKI), which could similarly apply to dasatinib in t(8;21) AML. In this study, we used the dasatinib-sensitive KIT(mut) t(8;21) AML cell line Kasumi-1 to model, in a confined and controllable way, molecular effects upon continuous dasatinib treatment. Long-term dasatinib exposure at clinically relevant levels resulted in markedly decreased drug-sensitivity of KIT(mut) t(8;21) AML cells. Notably, all dasatinib-resistant clones lacked secondary KIT-mutations. Instead, persistent growth correlated with alterations in KIT expression levels-that is, either KIT overexpression with maintained downstream signaling or KIT downregulation with concomitant activation of alternate pathways. Although KIT overexpression was associated with retained receptor activity and STAT3 activation, KIT downregulation correlated with decreased STAT3 levels and increased ERK-signaling. Importantly, brief discontinuation of dasatinib restored dasatinib-sensitivity associated with reversal of signaling signatures similar to treatment-naive, dasatinib-sensitive cells. The observed desensitization of KIT(mut) t(8;21) AML cells upon continuous dasatinib exposure suggests that therapy-related acquisition of resistance could pose significant limitations on therapeutic efficiency. Notably, we identified TKI-resistant states of transient nature that correlate with alterations in KIT expression and can be reversed upon brief inhibitor withdrawal. These findings indicate that discontinuing treatment maintains dasatinib sensitivity in KIT(mut) AML cells.