Chronic myeloid leukemia (CML), also referred to as chronic myelogenous leukemia, is a somewhat rare clonal hematologic malignancy that is exemplified by proliferation of myeloid cells in the bone marrow. This condition, which typically results in elevated white blood cell counts, is more frequently found in older patients, with an average age of approximately 64 years at initial diagnosis. According to the American Cancer Society, approximately one in 526 in the U.S. will develop CML within their lifetime, and roughly half of these will be older than 65. In the west, CML accounts for roughly 15-25 percent of all adult leukemia cases.
CML is often divided into three separate phases: chronic phase, accelerated phase, and blast crisis phase. Between different institutions, there may be subtle variations between these phases, typically based on hematologic characteristics.
One frequent hallmark of this disease is the detected presence of the genetic anomaly known as the so-called Philadelphia chromosome, which arises from the fusion of the ABL1 gene (on chromosome 9) and the BCR gene (on chromosome 22). This gene fusion was first described in a 1960 publication co-authored by Peter Nowell, MD, from the University of Pennsylvania and David Hungerford, PhD, from Fox Chase Cancer Center (Science 1960;132:1497). This gene fusion then produces the constitutively activated protein kinase BCR-ABL.
The approval by the FDA in May 2001 of the tyrosine kinase inhibitor (TKI) imatinib for the treatment of patients with advanced stages of CML was a paradigm-shifting event for the treatment of this malignancy. Since then, a number of second- and third-generation TKIs have been approved by the FDA for the treatment of those with CML, although, currently patients must receive continuous treatment with these therapies to remain disease-free.
However effective these medications are at preventing the return of their disease, currently only allogeneic stem cell transplantation (alloSCT) is a curative treatment for this malignancy. In a recent publication, Aleksandar Radujkovic, MD, in the Department of Internal Medicine V at the University Hospital Heidelberg, Germany, and colleagues presented the findings from a multi-center retrospective study conducted among blast crisis phase CML alloSCT recipients in the European Society for Blood and Marrow Transplantation (EBMT) registry (Biol Blood Marrow Transplant 2019 doi: 10.1016/j.bbmt.2019.06.028).
“The main finding of the study is that survival of patients allografted for blast crisis CML in the current TKI era remains poor unless disease remission prior to transplant could be achieved,” Radujkovic noted. “However, the survival for patients allografted in remission of blast crisis CML is still far worse compared to those transplanted in first chronic phase (CP1).”
The majority of patients are at the chronic phase of CML when diagnosed with that disease. It is at this stage of the disease when there are the most successful treatment options. Currently, targeted molecular therapy using small molecule TKIs is now considered the standard first-line approach for newly diagnosed CML patients of all disease stages including advanced stages (which include both the accelerated phase and blast crisis phase of the disease). Consequently, there is considerable debate as to the role for and the optimal timing of alloSCT in CML. In addition, the patient populations receiving alloSCT have also changed.
“In the last 2 decades, the number of CML patients receiving alloSCT in CP1 has rapidly declined and, today, the majority of patients referred to alloSCT are high-risk patients (i.e., those at disease stages beyond CP1 or who experienced TKI treatment failure),” Radujkovic explained.
“The main challenge in the treatment of patients with CML in advanced phase is represented by the fact that response to TKI treatment is often transient, particularly in blast crisis CML. For this group of patients, alloSCT still represents the only curative treatment option and TKI treatment may provide a therapeutic window that permits allografting. Therefore, with regard to alloSCT, the optimal pre-transplant treatment strategies and patient selection (eligibility) are of major importance.”
“After the introduction of TKIs, the role and timing of alloSCT in CML, as well as the population of patients undergoing allografting, have changed. With the introduction of TKIs, we can now prevent blast crisis in the vast majority of patients,” Radukovic stated. “But in patients with blast crisis, response to TKI treatment is usually temporary and alloSCT still represents the only curative treatment option.”
When queried as to the reasons for performing this retrospective multicenter study, Radujkovic replied, “Data on transplant outcomes in patients with blast crisis CML in the current TKI era are scarce. Therefore, we conducted a retrospective, EBMT registry-based study to evaluate the outcome of patients allografted for blast crisis CML, focusing on patients with active disease at transplant and pre-transplant prognostic factors.”
For this study, the primary endpoints included both overall survival (OS, i.e., date of alloSCT to death of any cause) and leukemia-free survival (LFS, i.e., date of alloSCT to occurrence of disease relapse or death from any cause). Secondary endpoints included incidence of nonrelapse mortality (NRM, death in the absence of disease relapse), relapse, and the presence of graft-versus-host disease, all of which were calculated from the date of alloSCT. Surviving patients were censored at the date of last contact for all study endpoints.
From 2004 to 2016, a total of 170 patients were included in this study who had blast crisis phase CML at transplant (i.e., prior to initiating conditioning). All patients received at least one type of TKI therapy during the course of their disease prior to alloSCT. For 76 percent of study participants, the TKI was combined with polychemotherapy. A total of 39 patients had mutations to BCR-ABL1, while 18 patients were confirmed to have the T315I variant (a mutation which has been documented to confer resistance to some TKI therapies).
With regard to the primary endpoints, in entire cohort-based univariate analyses, only two characteristics—low Karnofsky performance status (KPS, 80% or lower) and active blast crisis at transplant—had statistically significant (p=.001) associations with worse OS [hazard ratio (HR) values of 1.96 (p=.001) and 2.00 (p=.001), respectively] and shorter LFS [HR values of 1.95 (p=.001) and 1.80 (p=.001), respectively] after alloSCT. In both instances the adverse impact on survival was trended toward higher risk or relapse instead of NRM.
Multivariate analyses revealed that active blast crisis at transplant had statistically significant association with both decreased OS (HR 1.87; p=.010) and shorter LFS (HR 1.69; p=.017). Other variables that displayed associations with outcome were low KPS-decreased OS (HR 1.82, p=.019) and shorter LFS (HR 1.65, p=.029); year of transplant 2010 or earlier-higher risk of NRM (HR 2.59; p=0.005).
Accelerated Blast Crisis Treatments
When asked to comment on some of the therapies available for those patients with accelerated phase CML, Radujkovic stated, “Several approved TKIs (including next-generation agents) as monotherapy or in combination with standard chemotherapy currently represent the mainstay in the treatment of advanced phase CML. Besides TKI and subsequent alloSCT as consolidation, treatment options are limited.
“Several non ABL-directed inhibitors have been evaluated as single agents and in combination with TKIs in clinical trials, which was comprehensively covered in a review by Massimino, et al, (Mol Cancer 2018;17(1):56),” he noted. “However, although several approaches showed ability to overcome TKI resistance in primary CML cells or to eradicate leukemia stem cells in animal models, the efficacy in a clinical setting was rather modest.”
When discussing alternatives to TKI-based therapies for those with blast crisis phase CML, Radujkovic stated, “Non ABL-directed inhibitors evaluated in clinical studies for these patients included farnesyl transferase inhibitors (e.g. tipifarnib and lonafarnib), molecular target of rapamycin inhibitors (everolimus, temsirolimus), Hsp90 inhibitors (17-AAG and STA-9090), the histone de-acetylase inhibitor vorinostat, and several aurora kinase inhibitors. With most of the non ABL-directed inhibitors (as single agent or in combination with TKI) studied in clinical trials, unsatisfactory results were obtained, and for many agents, no final data were published (Mol Cancer 2018;17(1):56).”
Potential Blast Crisis Phase Treatments
When asked to comment on therapies that he thought might hold promise for patients with advanced CML, Radujkovic stated, “Besides several studies employing TKIs in combination with non ABL-directed inhibitors mentioned above, one promising treatment option may be asciminib (ABL001), which is an allosteric (i.e., non-active site-binding) inhibitor of the tyrosine kinase activity of BCR-ABL1 and which showed a favorable toxicity profile and clinical activity in patients with resistance towards more than 2 TKIs.
“However, only few data on patients with accelerated phase CML were available. Activity in patients with blast crisis CML was not evaluated and, in the ongoing trials, patients with advanced phase CML are excluded.”
Summarizing their findings, Radujkovic noted, “Due to the aggressiveness of blast crisis CML, which resembles acute myeloid leukemia (AML), immunological approaches and alternative strategies targeting leukemia stem cells currently seem far from reaching clinical relevance for blast crisis CML therapy. Therefore, in the near future, similar to the situation with high-risk AML, a consolidating alloSCT will likely remain the only curative treatment approach for eligible patients with blast crisis CML.
“For physicians following chronic phase CML patients under TKI therapy, it is of utmost importance to avoid disease progression and to consider alloSCT prior to overt disease progression. This means that patients under TKI should be referred early to a transplant center, particularly when there is evidence for molecular progression after two or three lines of TKI therapy,” he concluded.
Richard Simoneaux is a contributing writer.
Treatment of Pediatric Patients With Chronic Myeloid Leukemia
Recently, Oncology Times had a conversation with pediatric hematologist-oncologist Nobuko Hijiya, MD, from Columbia University Medical Center, about her treatment of pediatric patients with chronic myeloid leukemia (CML). This discussion was spurred by her recent article with Meinolf Suttorp, MD, titled “How I treat chronic myeloid leukemia in children and adolescents” (Blood 2019;133(22):2374-2384).
What are some of the challenges with treating pediatric patients with CML?
One of the most challenging aspects to deal with is the relative rarity of this disease in the pediatric age group. CML is primarily a disease of older adults, with an average age at diagnosis of roughly 64 years. CML makes up roughly 2-3 percent of all pediatric leukemias, so consequently, there are fewer opportunities to glean information about how to best treat these patients. Recognize that in order to meet FDA approval, clinical trials must include patients in the appropriate age groups to be deemed valid.
With regards to therapies, what are some of the challenges there, apart from the number of patients available for clinical studies?
One particularly important challenge is that we do not know what the long-term effects will be for chronic dosing of the standard tyrosine kinase inhibitor (TKI)-based therapies. Thus far, patients have had to continue taking these medications to remain disease-free. The first FDA approval for a compound of this class was imatinib in 2001 for adults and 2003 for pediatric patients. Since then, FDA approvals for the treatment of pediatric CML have come for the second-generation TKIs dasatinib (November 2017) and nilotinib (March 2018), so there is a relatively short history of these drugs being dosed in pediatric patients. With chronic dosing and maintained efficacy, these patients could be receiving these drugs for several decades.
Another important concern specific to pediatric patients is that they are still undergoing growth and development. With adult patients, growth has ceased; however, many pediatric patients are pre-pubescent, which requires rapidly reproducing cells (cells often targeted when treating malignancies). As a result, one significant potential concern is delayed onset of growth. In pediatric patients, varying degrees of growth delay have been reported (Pediatr Blood Cancer 2016;63(8):1332-1338).
Are there any attempts to see if continuous TKI dosing is necessary for disease prevention?
Recently, some studies in adults have shown feasibility for discontinuing TKI therapy and maintaining treatment-free remission when deep and sustained molecular remission is achieved. Clearly, studies need to be done in the pediatric population to determine if the potentially attractive strategy of TKI discontinuation is in fact a viable one.