Przewlekła białaczka szpikowa – Rokowania, prognozy i postęp choroby

Przewlekła białaczka szpikowa
Rokowania, prognozy i postęp choroby

Wprowadzenie inhibitorów kinazy tyrozynowej (TKI) zrewolucjonizowało leczenie przewlekłej białaczki szpikowej (CML), znacząco poprawiając rokowanie pacjentów, z 5-letnim przeżyciem sięgającym około 90%, a u osób poniżej 60 roku życia przekraczającym 90%. Pomimo tego, u części pacjentów dochodzi do progresji choroby do fazy akceleracji (AP) i blastycznej (BP), gdzie mediana przeżycia wynosi mniej niż rok, zwłaszcza bez możliwości allogenicznego przeszczepu komórek macierzystych. Kluczowe czynniki prognostyczne obejmują wiek, fazę choroby, status chromosomu Philadelphia, wielkość śledziony, liczbę płytek krwi, obecność dodatkowych aberracji chromosomowych (ACA) oraz poziom blastów i hemoglobiny. W praktyce klinicznej stosuje się wskaźniki prognostyczne, takie jak Sokal, EUTOS i ELTS, z których ELTS wykazuje najwyższą wartość prognostyczną, przewidując ryzyko zgonu związanego z CML na poziomie 2%, 15% i 40% dla niskiego, pośredniego i wysokiego ryzyka odpowiednio w ciągu 10 lat.

Prognosis w przewlekłej białaczce szpikowej

Wprowadzenie inhibitorów kinazy tyrozynowej (TKI) całkowicie zmieniło paradygmat leczenia przewlekłej białaczki szpikowej (CML), prowadząc do dramatycznej poprawy rokowania pacjentów, którzy obecnie mają niemal normalną oczekiwaną długość życia, a w wybranych przypadkach mogą nawet dążyć do ambitniejszego celu, jakim jest remisja wolna od leczenia (TFR)¹². Aktualne dane wskazują, że około 90% pacjentów z CML przeżywa co najmniej 5 lat od momentu diagnozy³⁴⁵. W przypadku osób młodszych niż 60 lat wskaźnik ten przekracza 90%, natomiast dla osób w wieku 60 lat i starszych wynosi około 80%³. Jest to ogromna poprawa w porównaniu z erą przed wprowadzeniem TKI, kiedy tylko około 22% pacjentów z CML przeżywało 5 lat od diagnozy⁵.

Pomimo znaczącego postępu w leczeniu, nadal istnieje mniejszość pacjentów, którzy nie odpowiadają na leczenie inhibitorami TKI i doświadczają progresji choroby z fazy przewlekłej (CP) do fazy akceleracji (AP) i fazy blastycznej (BP)¹⁶. W takich przypadkach rokowanie pozostaje stosunkowo niekorzystne, szczególnie u pacjentów niekwalifikujących się do allogenicznego przeszczepu komórek macierzystych (allo-SCT), gdzie mediana przeżycia zwykle wynosi mniej niż rok⁷⁶. Identyfikacja czynników predykcyjnych umożliwiających wczesne rozpoznanie pacjentów o wyższym ryzyku progresji pozostaje więc jednym z priorytetów w zakresie postępowania w CML⁷⁶.

Podstawowe czynniki prognostyczne

Rokowanie w CML zależy od wielu czynników, które można ocenić już w momencie diagnozy. Do najważniejszych z nich należą:

Wiek pacjenta – młodsi pacjenci mają lepsze rokowanie niż osoby starsze⁸³
Faza choroby w momencie diagnozy – CML w fazie akceleracji lub blastycznej ma mniej korzystne rokowanie niż CML rozpoznana w fazie przewlekłej⁹
Status chromosomu Philadelphia (Ph) – Ph+ CML ma bardziej korzystne rokowanie niż Ph- CML⁹
Wielkość śledziony – powiększona śledziona w momencie diagnozy wiąże się z gorszym rokowaniem. Im większa śledziona, tym mniej korzystne rokowanie⁹
Liczba płytek krwi – zarówno bardzo niska, jak i bardzo wysoka liczba płytek krwi w momencie diagnozy jest mniej korzystnym czynnikiem prognostycznym⁹
Obecność dodatkowych aberracji chromosomowych (ACA), szczególnie tych zaliczanych do „wysokiego ryzyka”⁶¹⁰
Poziom blastów we krwi obwodowej¹¹
Poziom hemoglobiny¹¹

Systemy oceny prognostycznej

W celu przewidywania przebiegu CML i odpowiedzi na leczenie stosuje się różne systemy oceny prognostycznej. Najważniejsze z nich to:

Wskaźnik Sokala – stworzony w latach 80. XX wieku, nadal stanowi punkt odniesienia do określania ryzyka progresji choroby w momencie diagnozy¹²¹³
Wskaźnik EUTOS (European Treatment and Outcome Study) – opiera się na procentowym udziale bazofili (rodzaju granulocytów) we krwi oraz wielkości śledziony⁹
- Niskie ryzyko oznacza 90% szansę na 5-letnie przeżycie wolne od progresji
- Wysokie ryzyko oznacza 82% szansę na 5-letnie przeżycie wolne od progresji
Wskaźnik ELTS (EUTOS Long-Term Survival) – może być stosowany do przewidywania odpowiedzi na leczenie imatynibem, prawdopodobieństwa osiągnięcia całkowitej odpowiedzi cytogenetycznej oraz długości przeżycia¹⁴¹⁵
- Niskie ryzyko oznacza 2% ryzyko zgonu związanego z CML w ciągu 10 lat
- Pośrednie ryzyko oznacza 15% ryzyko zgonu związanego z CML w ciągu 10 lat
- Wysokie ryzyko oznacza 40% ryzyko zgonu związanego z CML w ciągu 10 lat

Wskaźnik ELTS okazał się lepszy prognostycznie od innych wskaźników zarówno pod względem przeżycia specyficznego dla CML, jak i przeżycia całkowitego¹⁶. Jest obliczany na podstawie wieku, liczby płytek krwi, wielkości śledziony i odsetka blastów, ocenianych w momencie diagnozy¹⁵.

Dynamiczna ocena ryzyka

Obecnie zalecana strategia monitorowania w CML opiera się na testach molekularnych wykorzystujących standaryzowane, zwalidowane i szeroko stosowane testy RT-qPCR¹⁷¹⁸. Osiągnięcie określonych poziomów odpowiedzi molekularnej w konkretnych punktach czasowych (3, 6, 12 i >12 miesięcy), znanych jako kamienie milowe odpowiedzi molekularnej, wiąże się w przypadku „optymalnej” odpowiedzi z najlepszymi długoterminowymi wynikami, tj. przeżyciem specyficznym dla CML bliskim 100%¹⁸.

Szczególne znaczenie prognostyczne ma wczesna odpowiedź molekularna (EMR) po 3 miesiącach terapii TKI: brak osiągnięcia EMR, definiowanej jako poziom transkryptu BCR::ABL1 < 10% w skali międzynarodowej (IS) po 3 miesiącach, wiąże się ze znacznie gorszymi wskaźnikami odpowiedzi molekularnej i przeżycia całkowitego oraz ze zwiększonym ryzykiem progresji, niezależnie od zastosowanego TKI¹⁹. Wśród przypadków niespełniających standardowych kryteriów EMR, tempo spadku poziomu transkryptu BCR::ABL1 od indywidualnej wartości wyjściowej pacjenta, mierzone po 3 miesiącach, jest istotnym i niezależnym predyktorem wyniku, pozwalającym na identyfikację pacjentów o najgorszym rokowaniu¹⁹.

Wyższe tempo redukcji obciążenia nowotworem wiązało się z lepszymi wskaźnikami odpowiedzi molekularnej i długoterminowymi wynikami¹⁹. Pacjenci osiągający kamienie milowe odpowiedzi molekularnej w 3, 6 i 12 miesiącu mieli znaczącą przewagę w przeżyciu²⁰.

Molekularne mechanizmy oporności

Niepowodzenie w osiągnięciu kamieni milowych odpowiedzi definiuje „oporność pierwotną”, podczas gdy „oporność wtórna” określana jest jako utrata wcześniej osiągniętej odpowiedzi¹⁷¹⁹. Niepowodzenie leczenia/oporność stanowi „czerwoną flagę” wskazującą na konieczność zmiany leczenia w celu ograniczenia ryzyka progresji i śmierci¹⁷¹⁹.

Pojawienie się mutacji punktowych w domenie kinazy (KD) ABL1 jest najlepiej rozpoznanym mechanizmem oporności na TKI. Jednak około 40% przypadków oporności jest niezależnych od sygnalizacji BCR::ABL1 i może być mediowanych przez akumulację dodatkowych aberracji genomowych, wtórnych do niestabilności genetycznej indukowanej przez ciągłą, nieograniczoną ekspresję i aktywność kinazy BCR::ABL1¹⁷.

Akumulacja mutacji w innych genach oprócz BCR::ABL1 była związana z progresją choroby do faz zaawansowanych¹⁰. Pacjenci z wieloma mutacjami mają gorsze rokowanie niż ci bez mutacji lub z jedną mutacją, szczególnie ci z mutacjami złożonymi (definiowanymi jako występujące na tej samej cząsteczce BCR::ABL1), które nadają wyższe stopnie oporności obejmujące wiele TKI, w tym ponatynib¹⁰.

Ogólnie rzecz biorąc, pacjenci z jednoczesnym pojawieniem się dwóch lub więcej dodatkowych aberracji chromosomowych (ACA) mają gorsze przeżycie niż pacjenci z pojedynczymi ACA¹⁰. Jednoczesne występowanie ACA i hematologicznej fazy akceleracji (w zakresie zwiększonej liczby blastów) koreluje z dalszym zwiększonym ryzykiem transformacji blastycznej, szczególnie w przypadku ACA wysokiego ryzyka¹⁰.

Remisja wolna od leczenia

Remisja wolna od leczenia (TFR) jest nowym celem, który chcielibyśmy zapewnić coraz większej liczbie pacjentów¹²²¹. Około połowa pacjentów pozostaje w remisji wolnej od leczenia, podczas gdy druga połowa doświadcza nawrotu CML, zazwyczaj w ciągu 12 miesięcy po zaprzestaniu terapii²².

Sugeruje się, że mechanizmy immunologiczne są kluczowym czynnikiem determinującym wynik u konkretnego pacjenta²². Chociaż wiele badań sugerowało, że liczba i funkcja różnych typów komórek immunologicznych w momencie zaprzestania leczenia mogą służyć jako markery predykcyjne dla TFR, obecnie nie ma konsensusu w tej kwestii²².

Obecne strategie odstawienia TKI są nadal dalekie od optymalnych, ponieważ definicje „głębokiej” i „trwałej” odpowiedzi molekularnej są niepewne i niedokładne, a selekcja pacjentów jest przez to niewiarygodna²³²⁴. Posiadanie precyzyjnych i dokładnych metod pomiaru odpowiedzi molekularnej jest obowiązkowe dla lepszego projektowania przyszłych strategii, optymalizacji terapii CML i dopracowania postępowania z pacjentem²⁵.

Cyfrowy PCR (dPCR) może przezwyciężyć wewnętrzne ograniczenie RT-qPCR i jest jedynym praktycznym narzędziem w przypadku odstawienia TKI dla lepszej selekcji pacjentów z CML kwalifikujących się do przerwania leczenia²⁵. Dodatnia wartość predykcyjna dla dPCR waha się między 68 a 87%²⁴.

Czynniki niezwiązane z CML wpływające na rokowanie

W analizie wieloczynnikowej badania CML IV wykazano, że na przeżycie istotnie wpływały grupa ryzyka, aberracje chromosomowe głównego szlaku, choroby współistniejące, palenie tytoniu i ośrodek leczenia (akademicki vs inny), ale nie jakakolwiek forma optymalizacji leczenia²⁰. Przeżycie jest bardziej determinowane przez czynniki związane z pacjentem i chorobą niż przez początkowy wybór leczenia²⁶.

Brak różnic w przeżyciu między ramionami leczenia można wyjaśnić stosunkowo niewielką liczbą zdarzeń przypisywanych CML, biorąc pod uwagę ogólne 10-letnie przeżycie względne wynoszące 92%, co dobrze koresponduje z 10-letnią śmiertelnością z powodu CML wynoszącą zaledwie 6% i wskazuje na istotność przyczyn śmiertelności niezwiązanych z CML²⁶.

Dla pacjentów odpowiadających na leczenie, monoterapia imatynibem w dawce 400 mg zapewnia oczekiwaną długość życia zbliżoną do normalnej, niezależnie od czasu do odpowiedzi²⁰. Ponadto 90% pacjentów, którzy korzystnie odpowiadają na inhibitory kinazy tyrozynowej, takie jak imatynib, przeżywa bez powikłań przez co najmniej 5 lat od rozpoczęcia leczenia²⁷.

Perspektywy na przyszłość

Obecna i przyszła terapia CML z zastosowaniem TKI powinna być naprawdę spersonalizowana i dostosowana do ryzyka choroby, wieku pacjentów, potencji i profilu toksyczności TKI oraz czasu opóźnienia odpowiedzi molekularnej²⁵²⁴.

U młodszych pacjentów z CML może być uzasadnione dążenie do strategii TFR poprzez stosowanie od początku bardziej potężnych TKI, mając na celu szybkie osiągnięcie głębokiej odpowiedzi molekularnej (DMR) w celu wcześniejszego przerwania leczenia²⁵.

W przyszłości terapia CML będzie musiała zmierzyć się z eradykacją komórek macierzystych Ph+ (Ph+ LSC)²⁴. Niestety, ani imatynib, ani bardziej potężne TKI drugiej generacji (np. nilotynib lub dazatynib) nie są w stanie wyeliminować Ph+ LSC i umożliwić „biologicznego wyleczenia” choroby¹³.

Wraz z rozwojem krajobrazu leczenia CML dzięki nowszym opcjom terapeutycznym, kluczowe jest dostosowanie modeli prognostycznych tak, aby odzwierciedlały nie tylko wskaźniki przeżycia, ale także inne ważne kamienie milowe kliniczne, takie jak remisja molekularna, przeżycie wolne od progresji i przeżycie związane z CML²⁸. Dalsze udoskonalanie tych narzędzi, wraz z międzynarodowymi wysiłkami walidacyjnymi, będzie niezbędne do zapewnienia klinicystom dokładniejszego i bardziej zindywidualizowanego prognozowania pacjentów, ostatecznie poprawiając podejmowanie decyzji terapeutycznych i wyniki pacjentów²⁸.

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Materiały źródłowe

#1 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://pmc.ncbi.nlm.nih.gov/articles/PMC10341256/
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). […] However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. […] The significant expansion of our knowledge of the biological mechanisms that underlie the disease evolution has helped to refine treatment decisions and response monitoring, contributing to the dramatic improvement of the outcome of CML patients, who currently have a life expectancy approaching that of the general population.
#2 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC7357035/
Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). […] The cure of CML can only pass through the abrogation of the Ph+ clone. […] Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFN) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. […] Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. […] The prolongation of survival is the most important end point which should be guaranteed to all patients.
#3 Survival for chronic myeloid leukaemia (CML) | Cancer Research UK
https://www.cancerresearchuk.org/about-cancer/chronic-myeloid-leukaemia-cml/survival
Chronic myeloid leukaemia (CML) is usually a slowly developing condition and treatment can keep it under control for many years. Doctors think that most people can expect to have a normal length of life. […] Survival depends on many factors. No one can tell you exactly how long you will live. […] Generally for all people with CML: around 90 out of 100 people (around 90%) will survive their leukaemia for 5 years or more after being diagnosed. […] For those younger than 60: more than 90 out of 100 (more than 90%) will survive their leukaemia for 5 years or more after diagnosis. […] For those who are 60 or older: 80 out of 100 (80%) will survive their leukaemia for 5 years or more after diagnosis. […] Your outlook depends on how well the treatment works, and how well your body copes with the treatment side effects. It also depends on your general health and whether you have any other illnesses. […] Several factors can affect your outlook (prognosis). These are called prognostic factors. Doctors can look at these prognostic factors to predict how you might respond to treatment. These factors include: your age – younger people have a better prognosis.
#4 Survival statistics for chronic myeloid leukemia | Canadian Cancer Society
https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival/survival-statistics
Survival statistics for chronic myeloid leukemia (CML) are very general estimates and must be interpreted very carefully. Because these statistics are based on the experience of groups of people, they cannot be used to predict a particular persons chances of survival. […] Since the development of tyrosine kinase inhibitors (TKIs) to treat CML, most people with this disease reach the average life expectancy. […] In Canada, the 5-year net survival for CML is between 57% and 63%. This means that between 57% and 63% of people diagnosed with CML will survive for at least 5 years. […] Some studies show that 5-year net survival may be closer to 90% when people take TKIs correctly. […] The 5-year relative survival for CML is 90%. This means that, on average, people with CML are 90% as likely to survive 5 or more years after diagnosis as people of the same age and sex in the general population. […] Doctors use the risk category to predict the percentage of people who are likely to die from CML or complications related to the disease. […] Your healthcare team is familiar with these factors and can put all of this information together with survival statistics to arrive at a prognosis.
#5 Chronic Myeloid Leukemia (CML): Symptoms, Treatment & Prognosis
https://my.clevelandclinic.org/health/diseases/21845-chronic-myelogenous-leukemia-cml
Chronic myeloid leukemia (CML) is blood cancer that starts in the blood-forming myeloid cells or stem cells in your bone marrow. Many people with CML may have normal life spans, thanks to therapy that has turned the condition from a life-threatening illness into a chronic illness that medication can manage. […] Without treatment, chronic myeloid leukemia can become a life-threatening illness within three to four years. […] TKIs have made a huge difference for people with chronic myeloid leukemia. Before TKIs, only about 20% of people with the condition were alive five years after diagnosis. TKIs changed that outcome for people with early (chronic) CML. […] Overall, 90% of people with CML are alive five years after diagnosis. (Before TKI, only 22% of people with CML were alive at the five-year mark.)
#6 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://www.mdpi.com/2073-4409/12/13/1703
The significant expansion of our knowledge of the biological mechanisms that underlie the disease evolution has helped to refine treatment decisions and response monitoring, contributing to the dramatic improvement of the outcome of CML patients, who currently have a life expectancy approaching that of the general population. […] However, there is still a minority of cases who fail TKI treatment and progress from CP to advanced disease, requiring a more aggressive therapeutic approach where allogeneic stem-cell transplantation (allo-SCT) still has a fundamental role; prognosis of transplant-ineligible patients remains particularly dismal, with a median survival usually less than one year. […] To this end, the early recognition of the risk of treatment failure and progression in patients with non-advanced phase CML is extremely relevant.
#6 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://www.mdpi.com/2073-4409/12/13/1703
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. […] The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at âhigh-riskâ.
#7 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://pmc.ncbi.nlm.nih.gov/articles/PMC10341256/
However, there is still a minority of cases who fail TKI treatment and progress from CP to advanced disease, requiring a more aggressive therapeutic approach where allogeneic stem-cell transplantation (allo-SCT) still has a fundamental role; prognosis of transplant-ineligible patients remains particularly dismal, with a median survival usually less than one year. […] To this end, the early recognition of the risk of treatment failure and progression in patients with non-advanced phase CML is extremely relevant. […] In this review we will summarize the prognostic factors in CML, some well-known and well-established and others more recently identified and not fully validated, potentially useful for a customized therapeutic approach, aimed at selecting the most appropriate TKI taking into account the profile and aggressiveness of each CP-CML patients disease.
#8 Prognosis and survival for chronic myeloid leukemia | Canadian Cancer Society
https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival
People with chronic myeloid leukemia (CML) may have questions about their prognosis and survival. Prognosis and survival depend on many factors. Only a doctor familiar with a persons medical history, type of cancer, stage, characteristics of the cancer, treatments chosen and response to treatment can put all of this information together with survival statistics to arrive at a prognosis. […] A prognosis is the doctors best estimate of how cancer will affect a person, and how it will respond to treatment. […] CML is treated with tyrosine kinase inhibitors (TKIs). Taking these medicines as prescribed is called compliance. When TKIs are taken correctly, CML has a favourable prognosis. […] People who are older than 60 years of age have a less favourable prognosis than people younger than 60.
#9 Prognosis and survival for chronic myeloid leukemia | Canadian Cancer Society
https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival
CML that is in the accelerated or blast phase at the time of diagnosis has a less favourable prognosis than CML that is diagnosed in the chronic phase. […] Ph+ CML has a more favourable prognosis than Ph CML. […] If the spleen is larger than normal at diagnosis, the prognosis is less favourable. The larger the spleen is, the less favourable the prognosis. […] Having a very low or a very high platelet count at diagnosis is a less favourable prognostic factor. […] Doctors use different scoring systems to help them determine a prognosis and estimate survival for CML. […] The European Treatment and Outcome Study (EUTOS) score is based on the percentage of basophils (a type of granulocyte) in the blood and the size of the spleen. […] A low-risk score means there is a 90% chance of 5-year progression-free survival.
#10 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://pmc.ncbi.nlm.nih.gov/articles/PMC10341256/
The accumulation of mutations in other genes in addition to BCR::ABL1 has been associated with the disease progression to advanced phases. […] Patients with multiple mutations have a worse prognosis than those with no or one mutation, especially those with compound mutations (as defined when they occur on the same BCR::ABL1 molecule) conferring higher degrees of resistance involving multiple TKIs, including ponatinib. […] Overall, patients with emergence of two or more ACAs simultaneously have a worse survival than patients with single ACAs. […] The concurrent presence of ACAs and hematologic AP (in terms of increased blast count) correlates with a further increased risk of blastic transformation, significantly with higher-risk ACAs. […] The presence of Y as the only CCA/Ph was associated with survival rates lower than the control group without ACAs, though not statistically significant.
#11
https://link.springer.com/article/10.1007/s00277-013-1937-4
Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV […] We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome. […] AYAs in our study presented features of a more aggressive disease, with higher levels of WBC and blasts in the peripheral blood, lower hemoglobin, larger spleen size, and more frequent organomegaly-related symptoms. […] Although a worse outcome was expected in our group of 120 AYAs, no differences in cumulative incidence of CCR, MMR, and MR4 were observed in comparison to the other three groups. […] We conclude that AYAs with CML show features of a more aggressive disease indicating possible biological differences of younger patients that need to be investigated. Also, the higher transcript level at 3 months suggests a worse prognosis of AYAs. Nevertheless, younger patients do well in spite of poorer prognostic indicators.
#12 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC7357035/
The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. […] The cure remains the main objective of CML therapy. […] The risk of disease progression is not the same in all newly diagnosed patients and intensification of therapy through transplantation or testing new therapeutic approaches had to be primarily reserved for patients with high-risk disease or negative prognostic factors, able to predict earlier blastic transformation. […] The Sokal score, generated in the 1980s, still represents the reference for defining the risk of disease progression at diagnosis. […] The evidence of a potential eradication of the Ph+ clone was a great success, but the overall benefit for CML patients was limited. […] Several criticisms persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs.
#13 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://www.mdpi.com/2077-0383/9/6/1709
The Sokal score, generated in the 1980s, still represents the reference for defining the risk of disease progression at diagnosis. […] The advent of TKIs in the 2000s radically changed the fate of CML, since imatinib (IM), before, and nilotinib (NIL), dasatinib (DAS) or bosutinib (BOS), after, showed to be able to prevent the disease blastic transformation and significantly prolong the survival. […] Several criticisms persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. […] The other 50% of CML patients are older than 60 years. […] Therefore, for different reasons, it is clear that a long-term therapy with TKIs is not easily sustainable for the great majority of patients. […] Unfortunately, neither IM nor the more potent second-generation TKIs (e.g., NIL or DAS) are able to eradicate the Ph+ leukemic stem cells (Ph+ LSC) and allow a âbiological cureâ of the disease.
#14 Prognosis and survival for chronic myeloid leukemia | Canadian Cancer Society
https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival
A high-risk score means there is an 82% chance of 5-year progression-free survival. […] The EUTOS long-term survival (ELTS) score can be used to predict how well a person will respond to treatment with imatinib, how likely they are to have a complete cytogenetic response and how long they will survive. […] A low-risk score means there is a 2% risk of a CML-related death in 10 years. […] An intermediate-risk score means there is a 15% risk of a CML-related death in 10 years. […] A high-risk score means there is a 40% risk of a CML-related death in 10 years. […] Survival statistics for chronic myeloid leukemia (CML) are very general estimates. Survival has improved with newer treatments.
#15 Prognostic scoring systems in chronic myeloid leukaemia | Leukemia
https://www.nature.com/articles/s41375-025-02606-6
Compared to the current situation, the prognosis for CML was historically very poor. […] The advent of targeted therapies, specifically tyrosine kinase inhibitors (TKIs), has brought remarkable improvements over the past two decades. […] In clinical trial settings, CML patients now generally have a life expectancy close to that of the general population. […] Today, most CML patients are expected to die from causes unrelated to their leukaemia. […] Given that more CML patients are dying from causes unrelated to CML, recent studies have taken the opposite approach by focusing on CML-related survival. […] The ELTS score categorizes patients into three risk groups and is calculated based on age, platelet count, spleen size, and blast percentage, all of which are assessed at the time of diagnosis.
#16 Prognostic scoring systems in chronic myeloid leukaemia | Leukemia
https://www.nature.com/articles/s41375-025-02606-6
The ELTS score proved prognostically superior to the other three scores in terms of both CML-specific and overall survival. […] The creators of the ELTS score stated that it would also perform with respect to OS probabilities considering any type of death. […] However, it should no longer be employed for the prognostic classification of patients diagnosed in 2025. […] The EUTOS score represents a unique case. […] Regarding treatment-free survival with TKIs, Zhang et al. demonstrated the superiority of their score compared to the ELTS and Sokal scores. […] It will be interesting to see what developments emerge in the future for prognostic research in CML.
#17 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://pmc.ncbi.nlm.nih.gov/articles/PMC10341256/
The current recommended monitoring strategy in CML is based on molecular tests using standardized, validated and widely used RT-qPCR assays. Evidence supports the importance of the achievement of well-defined molecular response levels at specific time-points (3, 6, 12 and 12 months), regarded as molecular milestones, associated in cases of optimal response to the best long-term outcome, which is a CML-specific survival close to 100%. […] A treatment failure/resistance is a red flag entailing a treatment switch is warranted to limit the risk of progression and death. […] Failure to achieve milestone responses defines the primary resistance, whereas a secondary resistance is defined by the loss of a previously achieved response. […] The emergence of point mutations within the kinase domain (KD) of ABL1 is the most well-recognized mechanism of TKI resistance. However, approximately 40% of resistant cases are independent of BCR::ABL1 signaling and could be mediated by the accumulation of additional genomic aberrations, secondary to the genetic instability induced by the continuous unrestrained expression and activity of BCR::ABL1 kinase.
#18 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://www.mdpi.com/2073-4409/12/13/1703
In this review we will summarize the prognostic factors in CML, some well-known and well-established and others more recently identified and not fully validated, potentially useful for a customized therapeutic approach, aimed at selecting the most appropriate TKI taking into account the profile and aggressiveness of each CP-CML patientâs disease. […] The early recognition of the risk of treatment failure and progression in patients with non-advanced phase CML is extremely relevant. […] The current recommended monitoring strategy in CML is based on molecular tests using standardized, validated and widely used RT-qPCR assays. Evidence supports the importance of the achievement of well-defined molecular response levels at specific time-points (3, 6, 12 and >12 months), regarded as molecular milestones, associated in cases of âoptimalâ response to the best long-term outcome, which is a CML-specific survival close to 100%.
#19 Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
https://www.mdpi.com/2073-4409/12/13/1703
A âtreatment failure/resistanceâ is a âred flagâ entailing a treatment switch is warranted to limit the risk of progression and death. […] Failure to achieve milestone responses defines the âprimary resistanceâ, whereas a âsecondary resistanceâ is defined by the loss of a previously achieved response. […] In particular, the initial molecular response after 3 months of TKI therapy has been reported to have a prognostic significance: a failure to attain an early molecular response (EMR), defined by a BCR::ABL1 transcript level < 10% on the International Scale (IS) at 3 months, is associated with significantly inferior molecular response rates and OS and with an increased progression risk, irrespective of the TKI used. [...] Among cases who fail to meet standard EMR criteria, the rate of decline in BCR::ABL1 transcript level from the individual patient baseline value when measured at 3 months is a significant and independent predictor of outcome, allowing the discrimination of the poorest-risk patients. Higher velocity of tumoral burden reduction has been associated with superior molecular response rates and long-term outcomes.
#20 Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants | Leukemia
https://www.nature.com/articles/leu2017253
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). […] After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. […] In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. […] Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. […] For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response.
#21 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://www.mdpi.com/2077-0383/9/6/1709
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). […] The cure of CML can only pass through the abrogation of the Ph+ clone. […] Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. […] The prolongation of survival is the most important end point which should be guaranteed to all patients. […] The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. […] The risk of disease progression is not the same in all newly diagnosed patients and intensification of therapy through transplantation or testing new therapeutic approaches had to be primarily reserved for patients with high-risk disease or negative prognostic factors, able to predict earlier blastic transformation.
#22 Predicting treatment-free remission outcomes in Chronic Myeloid Leukemia patients using an integrated model of tumor-immune dynamics | bioRxiv
https://www.biorxiv.org/content/10.1101/2024.10.10.617526v2.full-text
The interactions between tumor and the immune system are main factors in determining cancer treatment outcomes. In Chronic Myeloid Leukemia (CML), considerable evidence shows that the dynamics between residual leukemia and the patientâs immune system can result in either sustained disease control, leading to treatment-free remission (TFR), or disease recurrence. […] About half of the patients remain in treatment free remission (TFR) while the other half presents with CML recurrence usually within 12 months after therapy stop. […] It has been suggested that immunological mechanisms are a central determinant to account for the particular patient outcome. […] While a number of studies have suggested that the number and function of various immune cell types at the time of treatment cessation may serve as predictive markers for TFR, there is currently no consensus on this question.
#23 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC7357035/
The adherence and tolerance to chronic treatment, the onset of late and unexpected side effects, the worsening of quality of life, and the high costs of therapy are still open questions. […] The most recent recommendations on the CML management highlight to achieve the treatment discontinuation (TD) and maintain TFR but, at the same time, they do not clarify if TFR is a cost-effective strategy and right for all CML patients. […] The current TKI discontinuation strategies are still too far from being considered optimal because the definitions of deep and durable MR are uncertain and inaccurate and the selection of patients is thus not reliable. […] Despite all the strategies mentioned above, it is crucial to remember that the main goal in CML is still to avoid potential progressions to advanced phases.
#24 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://www.mdpi.com/2077-0383/9/6/1709
The most recent recommendations on the CML management highlight to achieve the treatment discontinuation (TD) and maintain TFR but, at the same time, they do not clarify if TFR is a cost-effective strategy and right for all CML patients. […] However, the current TKI discontinuation strategies are still too far from being considered optimal because the definitions of âdeepâ and âdurableâ MR are uncertain and inaccurate and the selection of patients is thus not reliable. […] The positive predictive value for dPCR ranges between 68 and 87%. […] In the future, CML therapy will have to face the eradication of Ph+ LSC. […] The current and the future CML therapy with TKIs would be really personalized and adapted to the risk of the disease, the patientsâ age, the TKIsâ potency and toxic profile, and the latency of the molecular response.
#25 Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC7357035/
The current and the future CML therapy with TKIs would be really personalized and adapted to the risk of the disease, the patients age, the TKIs potency and toxic profile, and the latency of the molecular response. […] In the younger CML patients, it could be reasonable to pursue a TFR strategy by employing upfront the more potent TKIs, aiming to quickly achieve a DMR for discontinuing the treatment earlier. […] Having a precise and accurate methods for MR measurement is mandatory to better design the future strategies, to optimize the CML therapy and to refine patient management. […] Digital PCR (dPCR) may overcome this intrinsic limit of RT-qPCR and is the only feasible tool in the event of stopping TKIs for a better selection of CML patients eligible to treatment discontinuation.
#26 Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants | Leukemia
https://www.nature.com/articles/leu2017253
Survival is more determined by patients and disease factors than by initial treatment selection. […] Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival. […] The study further demonstrates that with regard to survival none of the experimental treatments is superior to IM400mg. […] The lack of survival differences between treatment arms may be explained by relatively few events attributable to CML, considering an overall 10-year relative survival of 92%, matching well with the 10-year CML mortality of just 6% and pointing to the relevance of non-CML causes of mortality. […] Survival as shown by multivariate analysis was influenced more by disease biology, patients demographics and microeconomic elements than by initial treatment selection indicating that more attention has to be paid to non-CML factors in order to improve outcome of CML-patients. […] In conclusion, the results show that monotherapy with IM400mg achieved a survival not much different from that of the general population, and that survival with CML is currently more determined by patients and disease factors than by initial treatment selection.
#27 Azthena logo with the word Azthena
https://www.news-medical.net/health/Chronic-Myelogenous-Leukemia-Prognosis.aspx
It is not clear if these systems are wholly effective in predicting outcome after the advent of more targeted and effective therapies with drugs like Imatinib. […] However, 90% of those patients who respond favourably to tyrosine kinase inhibitors like Imatinib have been seen to survive without complications for at least 5 years after treatment commencement. Most of these patients had normal white blood cell counts at 5 years.
#28 Prognostic scoring systems in chronic myeloid leukaemia | Leukemia
https://www.nature.com/articles/s41375-025-02606-6
Prognostic scores are an important tool in medical statistics. In chronic myeloid leukaemia (CML), prognostic models have existed for many years, enabling the classification of patients into groups that can be clearly differentiated in terms of their prognosis. […] As the landscape of CML treatment evolves with newer therapeutic options, it is crucial to adapt prognostic models to reflect not only survival rates but also other important clinical milestones such as molecular remission, progression-free survival, and CML-related survival. The continued refinement of these tools, alongside international validation efforts, will be essential in providing clinicians with more accurate and individualized patient prognostication, ultimately improving therapeutic decision-making and patient outcomes.