Medication-induced Pulmonary Injury: A Scenario- and Pattern-based Approach to a Perplexing Problem

Atypical Chronic Myeloid Leukemia: A Rare Disease With Poor Prognosis

Ongoing research is exploring new molecular targets and targeted therapies for this challenging disease.

Microscopic, photorealistic image of chronic myeloid leukemia (CML) cells - Generated with Adobe Firefly

Treating a patient with atypical chronic myeloid leukemia (aCML) is a challenge that stems from its rare incidence and limited curative therapies.1 Although it is still included in the heterogeneous group of myelodysplastic syndromes/ myeloproliferative neoplasms (MDS/MPN) by the World Health Organization, the last International Consensus Classification (ICC) renamed the disease as MDS/MPN with neutrophilia.2

Both classifications require a diagnosis of leukocytosis with more than 13 × 109/L, with greater than 10% of precursors and dysgranulopoiesis. Blasts in the peripheral blood and bone marrow should be no more than 20%, without monocytosis and basophilia. All the driver mutations that identified all Philadelphia chromosome (Ph)–positive (Ph+) and Ph-negative neoplasms should be absent, together with all tyrosine kinase gene fusions that identified the myeloid/ lymphoid neoplasms with eosinophilia.3

ICC classification also suggests the absence of peripheral eosinophilia and the possible appearance of cytopenia.2 aCML occurs in 1 in 100 cases of Ph+ CML, and is more evident in older male patients.4 No specific cytogenetic alterations are associated with the disease, but only some recurrent aberrations such as trisomy 8, deletion of 20q, and isochromosome 17q can occur. 5 In recent years, next-generation sequencing approaches have identified a clonal architecture in this disease: A mutational landscape has been proved with hierarchical progress. ASXL1 and ETNK1 appear to be ancestral mutations in this disease, followed by SETBP1, usually as a secondary event. In the progression and final leukemic stage, other mutations can be acquired, such as CUX1, RAS, and RUNX1.6

ETNK1 mutations are clustered in a small region of the kinase domain, in heterozygosity, and encode for the ethanolamine kinase, which allows the transformation of ethanolamine in phosphoethanolamine. The mutation reduces the enzyme's activity, increasing the mitochondrial activation with the production of reactive oxygen species and increased DNA damage.7,8

SETBP1 mutations have been identified in 25% to 33% of patients with aCML, so they are not unique in this disease and are associated with high leukocyte count and lower hemoglobin and platelet counts. SETBP1 interacts with SET, a negative regulator of the tumor suppressor protein phosphatase 2A, with consequent increased repression of cellular proliferation.9,10

Recently, it has been suggested that a close correlation exists between aCML and chronic neutrophilic leukemia (CNL); other than CSF3R being more commonly mutated in CNL, and EZH2 and TET2 more commonly mutated in aCML, no differences were detected in the remaining pathways affected, suggesting that the two diseases form a continuum.11 In response to this observation, the National Cancer Database was analyzed and, although the genomic data are missing, a difference in overall survival (OS) was found, with a median of 15 months for aCML and 23 months for CNL.12 The prognosis for aCML is poor: the median OS reported was 25 months with leukemic progression occurring in one-third of patients.3 Because of the rarity of the disease, only a few studies reported the possible prognostic factors associated with OS: being older than 65 years, being female, hemoglobin (Hb) less than 10 g/dL, and leukocytosis greater than 50 × 109/L with increased immature circulating precursors.4,6,13,14 Two different prognostic scores were also proposed, based on a small cohort of patients: the Modified MD Anderson Cancer Center score13 indicates being older than 65 years, Hb less than 10 g/dL, and white blood cell count greater than 50 × 109/L are possible predictive factors, whereas Mayo Clinic indicates being older than 67 years, an Hb less than 10 g/dL, and TET2 mutation are negative factors.5

No consensus document or risk-based treatment algorithm is available for treating aCML. Allogeneic stem cell transplant remains the only curative option: a European Society for Blood and Marrow Transplantation analysis reported an OS rate at 5 years of 51%, but contrasting results were reported in a small series of patients.15-17

Conservative treatment with hydroxyurea remains the mainstay of therapy, typically used to control the burden of disease.18 Interferon alpha has also been evaluated in some patients with complete or partial hematological control.19

Several cases treated with hypomethylating agents (HMAs), such as azacitidine or decitabine, have been reported: HMAs should be considered as a bridge to transplant in younger patients or as stand-alone therapy in patients without an option of care.20,21 Targeted therapy with ruxolitinib (Jakafi) was tested in single-case reports and a phase 2 trial (NCT01787487).

Responses were observed in combination or a single agent in patients with CSF3R mutation at a low rate compared with patients with CNL who had the same mutation.22,23 In CSF3R truncated mutation, the possible role of dasatinib (Sprycel) has been explored, but only in vitro.24 Other pathways for targeted therapy have also been investigated, such as RAS. Trametinib (Mekinist), a MEK1/2 inhibitor, has been explored in single-case reports showing hematological control and transfusion independence.25,26 aCML remains an orphan disease with limited therapeutic choices. New molecular targets and specific drugs should be evaluated for this disease with a poor prognosis and a high rate of acute transformation.

REFERENCES: 1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. Doi:10.1038/s41375-022-01613-1 2. Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. Doi:10.1182/blood.2022015850 3. Breccia M. Atypical CML: diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2023;2023(1):476-482. Doi:10.1182/hematology.2023000448 4. Breccia M, Biondo F, Latagliata R, Carmosino I, Mandelli F, Alimena G. Identification of risk factors in atypical chronic myeloid leukemia. Haematologica. 2006;91(11):1566-1568. 5. Patnaik MM, Barraco D, Lasho TL, et al. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. Am J Hematol. 2017;92(6):542-548. Doi:10.1002/ajh.24722 6. Patnaik MM, Tefferi A. Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management. Am J Hematol. 2023;98(4):681-689. Doi:10.1002/ajh.26828 7. Fontana D, Mauri M, Renso R, et al. ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine. Nat Commun. 2020;11(1):5938. Doi:10.1038/s41467-020-19721-w 8. Fontana D, Gambacorti-Passerini C, Piazza R. Impact of ETNK1 somatic mutations on phosphoethanolamine synthesis, ROS production and DNA damage. Mol Cell Oncol. 2021;8(2):1877598. Doi:10.1080/23723556.2021.1877598 9. Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):18-24. Doi:10.1038/ng.2495 10. Meggendorfer M, Bacher U, Alpermann T, et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia. 2013;27(9):1852-1860. Doi:10.1038/leu.2013.133 11. Carreño-Tarragona G, Álvarez-Larrán A, Harrison C, et al. CNL and aCML should be considered as a single entity based on molecular profiles and outcomes. Blood Adv. 2023;7(9):1672. Doi:10.1182/bloodadvances.2022008204 12. Tremblay D, Sastow D, Mascarenhas J. CNL and aCML are prognostically distinct: a large National Cancer Database analysis. Blood Adv. 2023;7(16):4400-4402. Doi:10.1182/bloodadvances.2023010722 13. Onida F, Ball G, Kantarjian HM, et al. Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer. 2002;95(8):1673-1684. Doi:10.1002/cncr.10832 14. Wang SA, Hasserjian RP, Fox PS, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123(17):2645-2651. Doi:10.1182/blood-2014-02-553800 15. Onida F, de Wreede LC, van Biezen A, et al. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol. 2017;177(5):759-765. Doi:10.1111/bjh.14619 16. Koldehoff M, Steckel NK, Hegerfeldt Y, Ditschkowski M, Beelen DW, Elmaagacli AH. Clinical course and molecular features in 21 patients with atypical chronic myeloid leukemia. Int J Lab Hematol. 2012;34(1):e3-e5. Doi:10.1111/j.1751-553X.2011.01351.X 1 7. Mittal P, Saliba RM, Giralt SA, et al. Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadelphia-negative/BCR-ABL-negative chronic myelogenous leukemia. Bone Marrow Transplant. 2004;33(10):1005-1009. Doi:10.1038/sj.Bmt.1704472 18. Gotlib J, Maxson JE, George TI, Tyner JW. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood. 2013;122(10):1707-1711. Doi:10.1182/blood-2013-05-500959 19. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 2001;19(11):2915-2926. Doi:10.1200/ JCO.2001.19.11.2915 20. Tong X, Li J, Zhou Z, Zheng D, Liu J, Su C. Efficacy and side-effects of decitabine in treatment of atypical chronic myeloid leukemia. Leuk Lymphoma. 2015;56(6):1911-1913. Doi: 10.3109/10428194.2014.986477 21. Hausmann H, Bhatt VR, Yuan J, Maness LJ, Ganti AK. Activity of single-agent decitabine in atypical chronic myeloid leukemia. J Oncol Pharm Pract. 2016;22(6):790-794. Doi:10.1177/1078155215605662 22. Dao KH, Solti MB, Maxson JE, et al. Significant clinical response to JAK1/2 inhibition in a patient with CSF3R-T618I-positive atypical chronic myeloid leukemia. Leuk Res Rep. 2014;3(2):67-69. Doi:10.1016/j.Lrr.2014.07.002 23. Dao KH, Gotlib J, Deininger MMN, et al. Efficacy of ruxolitinib in patients with chronic neutrophilic leukemia and atypical chronic myeloid leukemia. J Clin Oncol. 2020;38(10):10061018. Doi:10.1200/JCO.19.00895 24. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19):1781-1790. Doi:10.1056/NEJMoa1214514 25. Khanna V, Pierce ST, Dao KH, et al. Durable disease control with MEK inhibition in a patient with NRAS-mutated atypical chronic myeloid leukemia. Cureus. 2015;7(12):e414. Doi:10.7759/cureus.414 26. Elsayed M, Harry S, Nanua S, Zaidi S, Habib MH, Raza S. Trametinib: could it be a promising drug to treat atypical chronic myeloid leukemia? Cureus. 2022;14(7):e26619. Doi:10.7759/cureus.26619

Living Well With CML: The Importance Of Vigilance, Monitoring, And Quality Care

Chronic Myeloid Leukemia (CML) is a type of cancer that originates in the blood-forming cells of the bone marrow and can invade the blood. CML stands out as one of the more manageable forms of cancer, largely thanks to revolutionary advancements in targeted therapies and regular monitoring. However, the perception that CML is 'good cancer', while understandable, can be misleading. CML remains a serious condition that demands vigilant management, careful monitoring, and timely medical interventions to ensure the disease does not progress into more aggressive stages.

Dr. AVS Suresh Senior Consultant Medical Oncologist & Hematologist at Continental Hospitals, Hyderabad, "In my experience I have observed although targeted therapies have revolutionized the treatment for CML, the important thing is to realize that this is a chronic disease and will be managed over the long term. The patient should come every three months for follow-up and evaluation of response to treatment. According to the ELN guidelines on CML, BCR-ABL levels represent a critical marker for outcomes of treatment. Testing will allow the patient and physician to understand if current therapy is effective and will provide an option to change it and alter it basis the patient's needs.

The Role of BCR-ABL Testing in CML Management

BCR-ABL testing is at the heart of CML monitoring. This test measures the levels of a specific abnormal protein created by the fusion of two genes, BCR and ABL. This protein is responsible for driving the uncontrolled growth of white blood cells seen in CML. Measuring the levels of BCR-ABL in the blood helps doctors assess how well the patient's treatment is working. Low levels of BCR-ABL indicate that the treatment is keeping the cancer under control, while rising levels could signal that the therapy is losing its effectiveness.

The Importance of Personalized Treatment

The treatment landscape for CML has changed drastically over the past few decades. In the early 2000s, the introduction of TKIs was a groundbreaking development. Before TKIs, treatment options for CML were limited and often involved more aggressive therapies such as chemotherapy or bone marrow transplants. Today, there are several different targeted therapies available, each with varying degrees of effectiveness and side effects. The key to managing CML effectively lies in finding the right treatment for each individual patient.

Understanding Resistance and Intolerance

Despite the success of TKIs, some patients may experience resistance or intolerance to these drugs. Resistance occurs when the leukemia cells no longer respond to the treatment, leading to an increase in BCR-ABL levels. Intolerance, on the other hand, refers to the development of side effects that make it difficult for patients to continue with their current treatment. Both resistance and intolerance are significant factors in determining whether a patient may need to switch to a different therapy or consider more aggressive interventions.

As patients progress through different lines of therapy, maintaining both efficacy and tolerability becomes a primary concern. In the later lines of CML treatment, newer drugs that go beyond TKIs may offer an enhanced balance between safety and efficacy, making it possible to manage the disease while still preserving a high quality of life (QoL).

Vigilance is Key

Living well with CML is not about assuming that the disease will always remain under control; it's about being proactive and vigilant. Regular BCR-ABL testing, personalized treatment plans, and consistent monitoring are the cornerstones of effective CML management. By staying ahead of the disease through timely interventions and maintaining an open dialogue with doctors about treatment goals, individuals with CML can continue to lead fulfilling lives while keeping the condition in check. Ultimately, quality care combined with vigilance allows for a more confident and empowered approach to living with CML.

Targeting AML: The Latest Advances

Sangeetha Venugopal, MD, MS, discussed the evolving landscape of acute myeloid leukemia treatment as well as unmet needs among these patients.

Sangeetha Venugopal, MD, MS

Patients with acute myeloid leukemia (AML) have benefited from recent advancements in treatment. The advent of drugs targeting specific genetic mutations, such as FLT3, IDH1, IDH2, NPM1, and KMT2A, as well as improved methods for genetic testing have changed the landscape for physicians and the patients they treat. Still, questions remain on how to best optimize treatment protocols.

In an interview with Targeted OncologyTM for Leukemia and Lymphoma Awareness Month, Sangeetha Venugopal, MD, MS, assistant professor of medicine in the leukemia program, the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, discussed the evolving landscape of AML treatment as well as unmet needs among these patients.

Targeted Oncology: What are some of the unmet needs among patients with AML?

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku - stock.Adobe.Com

Venugopal: AML [is mainly] an older age group [of] patients. The median age of diagnosis is 69 years, but that does not mean that it does not occur in younger patients. The treatment that revolutionized the survival outcomes in older patients is hypomethylating agents in combination with venetoclax [Venclexta]. We can give this treatment indefinitely, meaning there is no stopping point. What I would like to know, and most of the patients would like to know, is if there is a stopping point for this treatment? And if that is the case, what are the subgroups where we can stop treatment? I am sure it is a selected subgroup of patients who with whom we can stop treatment.

How has the treatment of AML evolved in the last 10 or so years?

I started my fellowship in 2017, and 2017 was the first year that saw the approval of midostaurin [Rydapt], which targets FLT3 mutations. Since then, we have had several drugs approved for special molecular subsets, and that has changed the treatment landscape of AML immeasurably.

Especially for FLT3, we now have now 3 drugs that target the mutation because it is one of the most common molecular subgroups. Those are midostaurin, which targets both FLT3 [internal tandem duplication (ITD)] and [tyrosine kinase domain (TKD)], gilteritinib [Xospata], which targets the FLT3 ITD and TKD, and quizartinib [Vanflyta], which targets FLT3 ITD.

We have a couple of other [targets], including IDH1, and we have 2 medications to that target the IDH1 mutation. One is ivosidenib [Tibsovo], and the other is olutasidenib [Rezlidhia], which was approved recently. For IDH2, we have enasidenib [Idhifa].

The other exciting aspect that I am looking forward is that we have a new kid in the block, which is a Menin inhibitor, and that targets against NPM1 mutation and KMT2A rearrangements. I am looking forward to how this is going to play out for Menin inhibitors.

How do you go about assessing the best course of treatment for a patient? At what point does molecular testing come into the process?

The molecular landscape of AML is dynamic, so we do genetic testing at diagnosis, because we incorporate FLT3 inhibitors on day 8. We need to know the genetic makeup of the AML before we decide on whether we are going to add a FLT3 inhibitor or not, and FLT3 inhibitors are added in frontline treatments. We [do molecular testing] at diagnosis to incorporate the molecularly targeted treatment, and we do it at remission, which is treatment assessment of the bone marrow at the end of the first cycle of treatment, to know if the molecular aberration is still present or absent. That would help us decide how the how the prognosis is going to be, because some of these patients may be going to transplant. In those patients, we want to make sure that they do not have any of these molecular aberrations left to give a best possible outcome for transplant. After that, we do molecular testing at any time the AML relapses in a patient, mainly because we need to know the dominant clone that is driving this leukemia. Was this the same molecular aberration that was present at diagnosis, or is this something new that will affect the management?

What role does measurable residual disease [MRD] play in determining treatment?

We measure the residual disease by 2 ways. One is through flow cytometry, and the other is specific testing for molecular subgroups. Looking at the measurable residual disease, we want to look at a deeper level than the morphology and the pulse sequencing. The measurable residual disease needs a depth of at least 10-5.

The reason why we are looking at measurable residual disease is because it predicts the outcomes in long-term outcomes. For example, in a patient with core binding factor leukemia, if we track the measurable residual disease by, especially for the [inversion 16] and RUNX1-RUNX1T1 translocation, and when we track it, we can find if, at some point, they lose that response. For example, all along it is negative, and suddenly we see something like popping up which is positive, even though it is low-level positive. Then we increase the frequency to see if we can intervene before there is a frank morphological relapse. Right now, we do not intervene if it is just molecular relapse; however, we monitor the MRD more frequently than usual if we see that the level of MRD is rising.

Who do you consider referring for transplant with AML?

All patients must be referred for evaluation for hematopoietic cell transplant, regardless of the age, because sometimes the biological age may not matter. Sometimes, the biological age may be lesser than the chronological age. I do think that all patients would benefit from referral for hematopoietic cell transplant.

REFERENCE: Venugopal S, Sekeres MA. Contemporary management of acute myeloid leukemia: a review. JAMA Oncol. Published online August 8, 2024. Doi:10.1001/jamaoncol.2024.2662

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