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Funding Information: The authors would like to acknowledge the patients, study nurses, and other personnel in the clinical centers for their participation in this trial. The trial was supported by a grant from Bristol-Myers Squibb to the Norwegian University of Science and Technology (NTNU). In addition, this work was supported by the Nordic Cancer Union, Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Helsinki Institute of Life Science, Cancer Foundation Finland, the EUTOS project for CML 2018, ERA-Net ERACoSysMed JTC-2 project “prediCt,” the Relander Foundation, and the Finnish Cancer Institute. JH was supported by the Finnish Hematology Association, the Blood Disease Research Foundation, the Helsinki Institute for Life Science, the Biomedicum Helsinki Foundation, the Finnish Medical Foundation, the K. Albin Johansson Foundation, the Kaute Foundation, and the Emil Aaltonen Foundation. Funding Information: Authorship note: JH and MI contributed equally to this work. Conflict of interest: UOS has received honoraria from Incyte. PK has received honoraria from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. JR has received honoraria and research funding from Novartis and Bristol-Myers Squibb and honoraria from Incyte. KP has received honoraria and research funding from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. HHH has received honoraria from Novartis, Bristol-Myers Squibb, and Incyte. SM has received honoraria and research funding from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. Copyright: © 2022, Huuhtanen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: July 6, 2021; Accepted: July 7, 2022; Published: September 1, 2022. Reference information: J Clin Invest. 2022;132(17):e152585. https://doi.org/10.1172/JCI152585. Publisher Copyright: © 2022 American Society for Clinical Investigation. All rights reserved. In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.

Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort-study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002-2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near-complete nationwide coverage were utilized for data acquisition. Median follow-up was 6 (IQR, 3-10) years with a total follow-up of 8510 person-years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5-2.6), heart failure 2.6 (2.2-3.2), pneumonia 2.8 (2.3-3.5), and unspecified sepsis 3.5 (2.6-4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within-cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5-5.6) and chronic ischemic heart disease (2.2; 1.2-3.9), dasatinib for pleural effusion (11.6; 7.6-17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4-6.0). Our extensive real-world data reveal significant risk increases of severe morbidity in TKI-treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored. Funding Agencies|Karolinska InstitutetKarolinska Institutet; Region Stockholm (Clinical Research Appointment)

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity. Title in Web of Science: Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TKI resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score2 and reduced intensity conditioning, and for death, CP2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.

Objectives Translocations involving the Fibroblast growth factor receptor 1 (FGFR1) gene are associated with the 8p11 myeloproliferative syndrome (EMS), a rare neoplasm that following a usually short chronic phase progresses into acute myeloid or lymphoid leukemia. The treatment commonly involves chemotherapy and, if possible, allogeneic stem cell transplantation which is the only therapeutic option for long term survival. Given the aggressive course of EMS, we here evaluated tyrosine kinase inhibitors as treatment options to delay disease progression. Methods We described a new case of EMS and used chromosome analyses, PCR, and sequencing to investigate the underlying genetic aberrations. The sensitivity to several tyrosine kinase inhibitors were tested in vitro on the EMS cell line KG1 and on primary cells from the newly diagnosed EMS patient. Results A translocation involving chromosomes 8 and 22 was detected and a BCR/FGFR1 fusion gene was confirmed and characterized by sequencing. KG1 cells and primary EMS cells displayed distinct sensitivity to dovitinib, ponatinib and dasatinib as compared to normal bone marrow control cells. Conclusions These results suggest that treatment with tyrosine kinase inhibitors may be beneficial for EMS patients during the search for a suitable stem cell donor and for those not eligible for transplantation. This article is protected by copyright. All rights reserved.

The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

Background: In a recent, large population-based study we identified an increased risk of a second malignancy in patients following a diagnosis of Chronic Myeloid Leukemia (CML), as compared to an age- and gender-matched control cohort (Gunnarsson et al, Br J Haematol. 2015 Jun; 169(5): 683-8). If CML patients have an increased congenital or acquired susceptibility to develop any cancer, the prevalence of other prior malignancies would be expected to be increased already at the time of CML diagnosis. There is a known association between autoimmune disease (AD) or chronic inflammatory disease (CID) and the development of some hematological malignancies. However, to date, studies on the prevalence of AD or CID detected prior to the CML diagnosis are few and inconclusive. Our aim was to estimate the prevalence of other malignancies, AD or CID in CML patients at or before the time point of the CML diagnosis. Materials and methods: We used the population-based Swedish CML Register to identify patients diagnosed with CML in Sweden between 2002-2013. This cohort was linked to the Swedish Cancer Register to retrieve information about malignancies reported before the diagnosis of CML and the Swedish National Patient Register to retrieve information about AD and CID. For each of the 984 patients with CML, five age-, gender- and county of residence-matched controls were selected from the general population. All controls had to be free of CML and alive at the time of CML diagnosis for the corresponding case patient. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We excluded diagnoses registered during the year prior to the CML diagnosis to avoid detection bias. In separate steps, analyses were also performed based on diagnoses of AD, CID or cancer three years before the date of CML diagnosis. Results: A total of 984 CML patients were assessed with regard to a prior diagnosis of malignancy, AD or CID excluding the year immediately prior to their CML diagnosis, representing more than 45.000 person-years of follow-up. Compared to the matched population controls, the prevalence of prior malignancies and AD were elevated in CML patients: OR 1.47 (95%CI 1.20-1.82) and 1.55 (1.21-1.98), respectively. Breast-, gastrointestinal- and urinary tract cancers and melanomas were common cancer types and were all significantly more prevalent in the CML cohort, table I. After implementing a three-year exclusion period before the date of CML diagnosis, prior malignancies remained more prevalent in CML patients. Assessment of ADs was hampered by small numbers, sarcoidosis was the only AD with increased prevalence: OR 13.43; 95 % CI 3.56 - 50.73. No association was detected between CML and previous CID. Conclusions: Based on a large population-based cohort, our findings indicate that CML patients have an increased prevalence of other malignancies and AD prior to the diagnosis of CML, suggesting that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML. Table 1. Odds Ratios for malignancies prior to CML among 984 Swedish CML patients diagnosed between 2002 and 2013. Diagnoses of malignancy during the year immediately prior to CML diagnosis excluded to avoid detection bias. Participants Latency More Than 3 YearsBefore CML Diagnosis Variable CMLn=984 Controlsn = 4920 OR 95% CI CMLn=984 Controlsn = 4920 OR 95% CI Overall 128 453 1.47 1.20 - 1.82 113 381 1.55 1.24 - 1.93 Men 58 184 1.61 1.19 - 2.18 50 146 1.75 1.26 - 2.43 Women 70 269 1.32 1.01 - 1.74 63 235 1.36 1.02 - 1.82 Age Disclosures Richter: Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Sjalander:Novartis: Honoraria.

No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia : a population-based study in Sweden

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents. Funding Agencies|Nordic Cancer Union; Finnish Society of Hematology; Biomedicum Helsinki Foundation; Research Foundation of Blood Diseases in Finland; Academy of Finland; Finnish Cancer Organizations; Signe and Ane Gyllenberg Foundation; Finnish Cancer Institute; Doctoral Programme in Clinical Research in the University of Helsinki

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 μg/week and it increased to 25 μg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation © 2014 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd. 243 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made

Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100,000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (70 years) and 79% for older (80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.