CML paper summary - July 2024

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

Hochhaus A et al. NEJM, May 2024
ClinicalTrials.gov no. NCT04971226

Introduction

The study investigated the efficacy and safety of asciminib, a novel BCR::ABL1 inhibitor targeting the ABL myristoyl pocket, in patients newly diagnosed with chronic myeloid leukemia (CML). The objective was to determine if asciminib offered superior efficacy and safety compared to current first-line ATP-competitive tyrosine kinase inhibitors (TKIs), including imatinib and second-generation TKIs.

Trial Design

The trial enrolled a total of 405 patients, who were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or the investigator-selected TKI - one of the approved frontline TKIs, which included imatinib, nilotinib, dasatinib, or bosutinib.

Patients were stratified by European Treatment and Outcome Study long-term survival risk categories (low, intermediate, or high) and the TKI selected prior to randomization (imatinib or a second generation TKI).

Study endpoints

The primary endpoints were the major molecular response (MMR) at week 48, both for asciminib versus all TKIs collectively and specifically against imatinib.

Results
Patient Demographics and Follow-up:

• 201 patients received asciminib, and 204 received a TKI.
• Median follow-up was 16.3 months for asciminib and 15.7 months for TKIs.

Efficacy:

• At week 48, 67.7% of patients in the asciminib group achieved MMR, compared to 49.0% in the Investigator-selected TKI group (difference: 18.9 percentage points; 95% CI, 9.6 to 28.2; P<0.001).
• In the imatinib stratum (comparing only the patients where the investigator selected imatinib prior to randomization), 69.3% of asciminib-treated patients achieved MMR versus 40.2% in the imatinib group (difference: 29.6 percentage points; 95% CI, 16.9 to 42.2; P<0.001).
• In the second-generation TKI stratum, MMR was 66.0% with asciminib and 57.8% with second-generation TKIs (difference: 8.2 percentage points; 95% CI, −5.1 to 21.5).

Safety:

• Asciminib had a markedly favorable safety and tolerability profile, with fewer grade ≥3 AEs and AEs leading to treatment discontinuation vs all IS-TKIs

Discussion

The study demonstrated that asciminib significantly improved MMR rates compared to the investigator-selected TKI and to imatinib, in newly diagnosed CML patients. The safety profile of asciminib was also favourable, with a low rate of discontinuations due to side effects.

These results suggest that asciminib could become a preferred frontline therapy for CML,

Long-term follow-up is necessary to confirm the durability of these responses and the potential for treatment-free remission.

Professor Irina Dyagil (Kyiv, Ukraine)
Head of the Department of Radiation Oncohematology
National Scientific Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine
Kyiv (Ukraine)

Dr Kostyantyn Kotlyarchuk (Lviv, Ukraine)
Head of the Hematology Department
SI ‘Institute of Blood Pathology and Transfusion Medicine NAMS’,
Lviv (Ukraine)

Management of chronic myeloid leukemia (CML) improved dramatically over the last two decades. Introduction of imatinib and later other tyrosine kinase inhibitors (TKIs) changed prognostic expectations for these patients from quite poor to those approaching general population. However, availability of both therapeutic and diagnostic tools to achieve these results were and still are not the same in different countries around the world. Ukraine is one of the biggest countries in Europe with a total population of an estimated 40 million at the beginning of 2022. Already back then in relatively peaceful times, access to appropriate diagnostics and treatment for CML was quite challenging for Ukrainian patients and physicians. Now after almost two years of open war, this is a story of many struggles and losses and yet of many wins and successes.

In Ukraine, CML accounts for approximately 3500 patients according to the most recent analyses and the average age at diagnosis is 48 – younger than one would expect in the majority of other countries. Up to the year 2000, most of these patients would be treated either with interferon or hydroxyurea or in some occasional cases with busulfan. Bone marrow transplantation could be performed in even more rare situations. Diagnostic possibilities were limited to peripheral blood hematology test, bone marrow cytology and karyotyping. At the beginning of the TKI era, thanks to the enthusiasm of patients and physicians, first attempts to use imatinib were made already in 2003 - 2004 - sooner than in some countries with higher economical standards. This initiative evolved into even broader access to the medication within clinical trials and starting from 2008 – within a dedicated national program “Right to Live” with the ultimate goal to create ongoing access to life-saving therapy for CML patients and to implement International diagnostics and treatment of CML in Ukraine.

These efforts led to a gradual improvement of all aspects of medical service for this cohort of patients. Currently, in most of the cases CML diagnostic process in Ukraine - apart from the basic evaluations - includes also karyotyping and both quantitative and qualitative PCR-investigation. Patients can be treated with imatinib as well as the 2nd generation TKIs including nilotinib, dasatinib and bosutinib according to the indication. Thanks to these possibilities, 10-year overall survival for CML patients in Ukraine is estimated at 78%.

However, there are many issues yet to be solved. From the diagnostic perspective it is critical to improve access to PCR-monitoring of CML, which is currently limited to very few dedicated institutions. Conduction of conventional or next generation sequencing for resistant patients requiring detection of BCR-ABL1 mutations is still impossible in Ukraine. Regarding the spectrum of treatment options patients are lacking access to later generation TKIs capable of overcoming the resistant mutant clones including T315I mutation. Possibility to utilize allogeneic hematopoietic stem cell transplantation as potentially curative option for refractory patients is also limited to very few procedures per year. With the beginning of an open military intervention, in addition to the issues described above, the Ukrainian hematological community had to also face situations, in which even basic medical service could be unavailable for patients located in areas most affected by the war.

Taking into account all the obstacles, challenges and unfavorable circumstances, one would hardly expect medical service for CML in Ukraine to improve significantly. Nevertheless, certain solutions are found and some successes have been achieved. Progress is seen regarding improved availability of PCR monitoring for CML, which is probably the most important tool to understand the course of the disease. In addition to one centre in Kyiv, a dedicated institution in Lviv and later some private institutions started monitoring CML patients with this method. Apart from local efforts, the development of PCR monitoring in Lviv was possible thanks to the support from the iCMLf within its “ICMLf Diagnosis and Testing Program”. International cooperation in these turbulent times is one of the most powerful solutions also for other issues like for example assessment of BCR-ABL1 mutations. Samples of these patients are investigated with support of MLL Münchner Leukämielabor in Germany. Patients requiring 3^rd generation TKIs or treatments currently unavailable in Ukraine are either referred to hospitals in other countries or apply for medications within compassionate use program and other support programs including those by The Max Foundation.

Several years ago, transplantation activity in adult Ukrainian patients was limited only to autologous procedures. Despite obvious challenges, allogeneic transplantations for this cohort of patients were recently initiated.  The number of procedures performed in 2022 increased 7-fold as compared to 2021. These first steps are very promising and include not only the rising access to this critical treatment method but also the creation of the Ukrainian Association of Bone Marrow Transplantation and an active International cooperation within the Help for Ukrainian Hematology Patients (HUP) initiative in particular. Careful but visible restoration of clinical trial activity is also detected, which is a very important option not only in CML but in other malignant blood disorders as well.

Progress in providing better service for CML patients means not only achievements in diagnostics and treatment – there are many other aspects that are important. Patient organizations are becoming more and more active and influential in Ukraine initiating educational and social events, participating in governmental boards responsible for medical decisions on the national level, integrating in international patient organizations and activities etc. There are ongoing research projects dealing with pregnancy in CML, TKI toxicity, disease course prognosis, treatment-free remission and many other issues.

One of the main priorities for the development of hematology in Ukrainian and the management of CML in particular, is International cooperation. Ukrainian researchers are participating in cooperative groups and networks including European LeukemiaNet, are taking part in joint projects and publications, which lift the standards of care for CML patients in the country to higher levels.

In conclusion, despite many challenges every effort is made by the hematological community in Ukraine (patients, physicians, researchers etc.) to bring medical service for CML in accordance with modern standards. International cooperation has been and continues to be crucial to keep CML treatment and diagnostics on an acceptable level during troubled times and to prepare for a fast development in more peaceful time once a normal life has been restored.

Contact:

Professor Irina Dyagil
Head of the Department of Radiation Oncohematology
National Scientific Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv
leuk@ukr.net

Dr Kostyantyn Kotlyarchuk
Head of the Hematology Department
SI ‘Institute of Blood Pathology and Transfusion Medicine NAMS’, Lviv
hematology_k@yahoo.com

Professor François Guilhot (Poitiers, France)
Emeritus Professor of Hematology and the past Director of the Clinical Investigation Center
1402 INSERM in Poitiers (France)

When I began my research into the treatment of patients suffering from chronic myeloid leukaemia, there were few truly effective treatments available apart from haematopoietic stem cell transplantation, but the vital risk was high and, above all, few patients could be transplanted. As early as 1989, I had observed complete and lasting cytogenetic responses with the interferon + cytarabine combination, the only 2 drugs acting on leukemic stem cells at the time.

In 2003, following the initial phase 1 and 2 trials, we knew that imatinib had a particularly important anti-leukemic effect because it was targeted. But there was no proof of its efficacy as a first-line treatment, so a prospective phase 3 trial had to be set up in previously untreated patients.

The "IRIS" trial was therefore carried out, comparing imatinib at a dose of 400 mg per day with the interferon + cytarabine combination. This comparison arm was chosen because I had demonstrated that the interferon + cytarabine combination significantly increased survival and had become the gold standard for the treatment of CML. After including 1106 patients, we showed that imatinib was more effective, with a significant increase in molecular response. To demonstrate the effect on survival, we were able - thanks to an excellent collaboration with Novartis - to carry out a comparison between the historical arm of our CML 91 trial involving the combination of interferon + cytarabine and the imatinib arm of the IRIS trial: this is the one and only proof of the positive effect of imatinib on patient survival.

Following the IRIS trial, a number of unresolved questions remained. For example, was the 400 mg dose of imatinib sufficient and was there any point in testing combinations such as combining imatinib with interferon or cytarabine? With Brian Druker, Steve O'Brien and Joëlle Guilhot (my wife!), we wrote a clinical trial project, the 'SPIRIT' trial, which was to be conducted in the USA, the UK and France; but only France finally enrolled patients and published the results. This trial had four arms: Two arms with doses of 400 mg and 600 mg of imatinib, one arm with the imatinib-cytarabine combination, and one arm with the imatinib-pegylated interferon combination.

We demonstrated that the combination of imatinib and interferon significantly increased the molecular response, but survival at 15 years was the same for all four arms, at 80-85%, which is still very remarkable. We observed that if patients could continue interferon for at least one year, they had a high probability of being able to stop their treatment without risk.

In conclusion, it should be remembered that the immune system plays an important role in CML, and that interferon has had a remarkable effect in some patients who have been able to tolerate it long enough. However, its toxicity and its use by injection are difficult for patients to accept.

Contact:

Emeritus Professor of Hematology
Past Director of the Clinical Investigation Center
Centre d’Investigation Clinique
Inserm CIC 0802
CHU de Poitiers
f.guilhot@chu-poitiers.fr

Professor Jerry Radich (Seattle, USA)
Director of the Radich Laboratory and the Molecular Oncology Laboratory at the Fred Hutchinson Cancer Center in Seattle (USA)

I am honored beyond measure to receive the Rowley Prize in 2023. Dr. Janet Rowley was a remarkable physician, scientist, and (most of all), human. For me to be mentioned in the same sentence as Janet is both humbling and mindboggling, especially since I readily confess to drafting behind the wake of brilliance of others before me (many who have won this award in previous years).

I have been remarkably lucky. I got interested in CML because my first boss, Nobel Laureate, E. Donnall Thomas, had a special interest in it, and encouraged my participation in clinical transplantation and lab work focused on CML. I worked in the lab of Steve Collins, who was one of the first to study the molecular biology of CML progression, added by the then novel technique of PCR (done at first in water baths. An aside: we had the first automated PCR machine in the city of Seattle. I broke it in its inaugural run…). My good fortune continued when I was brought into the IRIS trial by my friend and colleague Brian Druker. From then on, I was off on an academic joy ride, meeting the most remarkable band of colleagues and friends that any worker, in any field, could ever ask for.

With our remarkable success in CML, many in the cancer field - especially funding agencies - wonder if CML is essential “done.” How much better can our therapies be? What new translatable knowledge can CML provide that will continue to guide the field (CML is, after all, the first and foremost example of the “precision medicine” movement)?

I would argue, a lot.

I think there are three essential questions we are still dealing with in CML, and all of them are important models to other cancers:

1. Who responds to therapy?
2. Who loses response (relapse/progression)?
3. Who can have their treatment discontinued?

Who responds to therapy? It is remarkable that in CML we can fairly predict outcomes based on a relatively short-term series of response landmarks. We have leveraged this into using BCR-ABL as a rapid surrogate for drug approval trials - a remarkable accomplishment that is the envy, and goal, of virtually all other malignancies. Indeed, in the U.S., there is large, funded effort in AML to perfect and standardize measurable residual disease to both guide therapy, and be used as an early endpoint for drug development - all based and guided by our work in CML. Moreover, work in CML has shown the huge importance of the immune system in influencing and maintaining disease response, and these findings are spurring work in other hematological and solid malignancies.

Who loses response? CML is the classic model of disease progression, as without intervention with TKI or transplant, all patients will eventually march from chronic phase to accelerated and blast phase. The biologic “clock” is still being investigated, but several lines of work have shown the similarities of outright progression and resistance. This work will likely inevitably map to other liquid diseases where progression occurs (MPN, MDS) as well as potentially solid tumors (prostate and colon cancer being good candidates).

Who can have their disease discontinued?  The amazing finding that a good proportion of CML patients can eventually discontinue therapy has spawned an industry of creative clinical trials and biological methodology to better predict and succeed treatment free remissions. The work has shown the biological importance in immune mechanisms in TFR, and the power of innovative technical measures such as duplex sequencing, digital PCR, and single cell ‘omics to predict outcomes. As treatments advance in other hematological malignancies, a few diseases are vying for the honor of “the next CML”, where considerations of treatment discontinuations pioneered in CML are promoted as the future models of therapy (looking at you, CLL).

Lastly, I had the honor of winning the iCMLf Prize in 2017 for work developing CML diagnostics for low- and middle-income countries. With the advent of new oral agents for other malignancies, those experimental strategies found to work for CML should be adaptable for new targets, allowing all patients in low resource areas to enjoy the same benefits of the cancer treatment revolution as those who live in richer countries.

Many, many thanks for all your past, present, and continued support. Anything I accomplished was done with you, and so I thankfully share this honor with you all.

Contact:

Jerald Radich, MD
Translational Science & Therapeutics Division
Kurt Enslein Endowed Chair
Fred Hutchinson Cancer Center
jradich@fredhutch.org