Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%–72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%–38%). TKI treatment for < 5 years and MR4.5 duration shorter than 4 years were both associated with higher incidence of molecular recurrence. No patient had disease progression. Response status at last control was: MR4.5 (n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.
Стремительное развитие биотехнологии и фармакологии наших дней так или иначе связано с целенаправленным поиском биологически активных веществ в тканях самых разных организмов, в том числе и антарктических морских гидробионтов. Данная группа организмов привлекает внимание исследователей за счет того, что является разумной альтернативой классическим видам сырья из-за своей дефицитности, а также наличия разнообразного белкового состава. Перспективным направлением является создание фармакологических препаратов на основе белков, выделенных из тканей антарктических гидробионтов. Особый интерес вызывает возможность получения молекул направленного действия-ферментов различной специфичности. В нашей работе представлена разработка методических подходов для выделения и тестирования фракции трипсиноподобных ферментов из тканей антарктического криля (Euphausia superba). Методичні підходи до отримання фракції трипсиноподібних ферментів з морських гідробіонтів (на прикладі антарктичного крилю). Д.В. Гладун, О.Н. Савчук, Л.І. Остапченко Реферат. Нинішній стрімкий розвиток біотехнології та фармакології так чи інакше пов'язаний з цілеспрямованим пошуком біологічно активних речовин у тканинах різноманітних організмів, у тому числі й антарктичних морських гідробіонтів. Дана група організмів привертає увагу дослідників за рахунок того, що є розумною альтернативою класичним видам сировини, а також завдяки наявності різноманітного білкового складу. Перспективним напрямком є створення фармакологічних препаратів на основі білків, виділених з тканин антарктичних гідробіонтів. Особливий інтерес викликає можливість отримання молекул спрямованої дії-ферментів різної специфічності. У нашій роботі представлено розробку методичних підходів до виділення і тестування фракції трипсиноподібних ферментів з тканин антарктичного крилю (Euphausia superba).
Background: There is a high unmet medical need for therapeutic options for patients suffering from myeloproliferative neoplasms (MPN), who have failed or are not eligible to available treatment options. Ropeginterferon-alfa-2b (P1101) is a novel, third generation pegylated interferon-alfa, recently approved by EMA to treat polycythemia vera (PV). Ropeginterferon-alfa-2b is also in the late stages of development in several countries for treatment of PV and other MPNs. Aims: Ropeginterferon-alfa-2b is a new and attractive treatment option for patients suffering from MPN who have exhausted all therapeutic options and require treatment. The Compassionate Use Program (CUP) was approved and initiated in Taiwan with the purpose of granting access to P1101 to patients with MPN disease with no therapeutic options who are not eligible to enroll in existing clinical trials for their disease. Methods: Patients were identified that had the potential to benefited from P1101 therapy and were eligible according to the protocol. Patients were treated at a starting dose of 250 ug with subsequent dose escalation every 2 weeks over a 6-week period to 350 ug, 450 ug and 500 ug. Dose adjustments were permitted based on tolerability and efficacy. Results: The CUP currently contains 15 patients from two academic hospitals: 9 with PV, 2 with post-PV myelofibrosis (MF), two with pre-fibrotic MF, one with primary MF, and one essential thrombocythemia patient. The driver mutation was JAK2 in 13 patients, CALR in one, and another one was triple negative. Pre-treatment with hydroxyurea and/or anagrelide was reported in 13 patients. P1101 was given for > 12 weeks to 14 patients (range 4 -64 weeks). The highest administered dose of P1101 was: 500 ug in 11 patients (time to highest dose -6 weeks in 9 patients, 10 weeks -in 1 and 20 weeks in another patient); 250 ug, 350 ug and 450 ug in three other patients. The need to decrease or temporarily interrupt P1101 therapy occurred in 4 patients, all due to transaminase(s) elevation. Notably, these events did not require permanent discontinuation of therapy and could be alleviated by appropriate dose modifications. The majority of observed adverse events were of grade 1 and included fatigue, arthralgia, myalgia, chills and dizziness. Grade 2 events included elevation of transaminases (in 3 patients), dizziness, pruritus and lower limbs pain (in 1 patient each). One patient developed elevation of transaminases of grade 3. Normalization of blood parameters within complete hematologic response range was observed in 3 PV and 2 post-PV MF patients. Two PV patients fulfilled the partial response criteria. In other patients, decrease of platelet count (even in previously treatment-resistant thrombocytosis) and symptomatic improvement were also observed. No major cardiovascular events were recorded. One pre-PMF patient transformed into MF (grade 5). No patients progressed to acute myelogenous leukemia (AML) during the observation. Summary/Conclusion: In this cohort of MPN patients, not amenable for establishe...
Introduction: Over half of patients with chronic myeloid leukemia (CML) in sustained deep molecular remission do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in controlled clinical trials, but there is scarce information on its applicability in the real-life setting. We aimed to assess if treatment cessation was feasible in clinical practice in a large nationwide series of CML patients from Spain. Methods: This retrospective study comprised a series of 236 patients in chronic-phase CML who discontinued TKI treatment outside of clinical trials between April 2009 and February 2018 in 33 Spanish institutions. Inclusion criteria were: a) TKI treatment duration >3 years; b) sustained MR4.5 in >4 consecutive determinations (one single point in MR4 was acceptable) during >2 years; c) molecular monitoring in a reference laboratory expressing the results on the International Scale (IS). Patients who had undergone allogeneic hematopoietic stem-cell transplantation were excluded. Molecular relapse was defined as consecutively detectable BCR-ABL1 transcripts showing a ≥1 log increase or loss of MMR in any single sample. Treatment-free remission (TFR) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of restarting therapy for any reason or, if treatment was not restarted, the date of last contact. Incidence of molecular relapse was calculated using the cumulative incidence function with resumption of TKI treatment in the absence of molecular relapse and death in MMR as competing events. Analysis of factors predicting molecular relapse was done by the method of Fine and Gray. Results: Table 1 shows the main characteristics of the series. Median follow-up from treatment discontinuation was 21.5 months, and 5 patients died in MMR due to CML unrelated causes. TKI therapy was reinitiated due to molecular relapse (MMR loss: n=52, increase >1 log in BCR-ABL transcript level at two consecutive assessments without losing MMR: n=12), patient preference (n=2), and severe withdrawal syndrome (n=1). One additional patient lost MMR after 20 months from treatment cessation but decided not to be retreated, with spontaneous recovery of MMR. The probability of TFR at 4 years was 64% (95% Confidence Interval [CI]: 55%-72%)(Figure 1). The cumulative incidence of molecular recurrence was 33% (95% CI: 26%-38%) at 3 years (Figure 2). Forty-nine relapses (75% of total) occurred in the first 6 months. The latest MMR loss was detected 30 months after treatment stop. One patient restarted treatment 44 months after TKI discontinuation due to ≥1 log increase in BCR-ABL1 transcripts in two consecutive samples without losing MMR. In univariate analysis, duration of TKI treatment of less than 5 years (P=0.005) and time in RM4.5 shorter than 4 years before TKI discontinuation (P=0.003) were both significantly associated with a higher incidence of molecular recurrence. No patient progressed to the advanced phases of CML. At the time of restarting treatment, the median BCR-ABL1 IS was 0.3%, with this value being >5% in only 7 instances. Most patients (81%) received the same TKI that they were taking before the trial of treatment cessation. Median follow-up after treatment resumption was 20 months. Among the 64 patients who restarted treatment due to molecular relapse, 46 of 52 cases regained MMR after a median time of 3 months, and 47 of 64 regained MR4.5 after a median time of 5 months. Response status at last control was: MR4.5 (n=196), MR4 (n=15), MMR (n=14), complete cytogenetic response (n=10), and other (n=1). Fifty-one patients (22%) developed musculoskeletal or joint pain after treatment cessation. In patients stopping imatinib, a significant increase in Hb levels, leukocyte counts, total lymphocyte counts, platelet counts, and cholesterol levels was observed. At 6 months, an increase in Hb level >2 g/dL was observed in 47% of patients with anemia. By contrast, nilotinib discontinuation was not followed by any relevant change in laboratory values. Conclusions: Our results confirm that treatment discontinuation is feasible and safe in clinical practice in Spain. Duration of TKI treatment of less than 5 years and a time in RM4.5 shorter than 4 years before TKI discontinuation were significantly associated with a higher incidence of molecular recurrence. Disclosures Hernandez Boluda: Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ferrer Marin:Incyte: Consultancy; Novartis: Consultancy, Research Funding. Cervantes:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment.
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