Chronic myeloid leukemia

from Wikipedia, the free encyclopedia
Classification according to ICD-10
C92.1 Chronic myeloid leukemia
ICD-10 online (WHO version 2019)
Classification according to ICD-O-3
9863/3 Chronic myeloid leukemia NOS
ICD-O-3 first revision online
Detail of a blood smear with numerous precursors of the myeloid series (stained cells, unstained cells = erythrocytes; Pappenheim's panoptic staining )

Chronic myeloid leukemia (abbreviated to CML ), also known as chronic myeloid leukemia and (more rarely) chronic myelosis , is a chronic leukemia associated with a strong proliferation of leukocytes (white blood cells), especially granulocytes and their precursors, in the blood and in the blood-forming bone marrow . The disease is often asymptomatic in the early stages.

CML belongs to the group of myeloproliferative neoplasms (MPN), i.e. diseases that result from a (genetic) disorder of the hematopoietic stem cells found in the bone marrow . The disease described by Rudolf Virchow in 1845 and first given the name leukemia was most likely CML.

With the use of newer tumor-specific drugs, the so-called tyrosine kinase inhibitors , since around the turn of the millennium, the prognosis and the forms of treatment for CML have changed significantly, and in many cases the disease can be treated well and with relatively few side effects. Through this use of so- called targeted therapies , CML has almost become a model disease for the whole of hematology or tumor therapy in general.

epidemiology

Age -specific incidence of CML. Incidence is broadly similar worldwide, with no significant regional or ethnic differences.

CML has an incidence of about 1.6 new cases per 100,000 adults per year and accounts for about 20 percent of all leukemias. It is predominantly a disease of adulthood and shows a steady increase with age. Men are affected about 1.4 times more often than women. The diagnosis is made at an average age ( median ) of 65 years, about ten percent of the patients are younger than 35 years at the time of diagnosis. It is estimated that there are around 1,700 new cases per year in Germany, around 160 in Switzerland and around 175 in Austria.

causes and emergence

Philadelphia chromosome : In the course of cell division, chromosomes 9 and 22 randomly “break” into two pieces and are swapped and “reassembled” again.

The cause of the disease is the alteration and subsequent proliferation (multiplication) of a single multipotent hematopoietic progenitor cell . In almost all cases, the cause is found to be a reciprocal translocation between chromosomes 9 and 22 (written: t(9;22)(q34;q11), or abbreviated t(9;22)). In both chromosomes involved, the breakpoint is located on the longer arm (q-arm), closer to the end in chromosome 9 than in chromosome 22 .

The chromosome break is on both chromosomes in the region of genes, namely ABL (or ABL1 ) on chromosome 9 and BCR ( breakpoint cluster region ) on chromosome 22. The translocation leads to the formation of fusion genes: BCR-ABL on the altered chromosome 22 ( with the end of chromosome 9) and ABL-BCR on the altered chromosome 9 (with the end of chromosome 22). The chromosome translocation is cytogenetically visible as a shortened chromosome 22, as the so-called " Philadelphia chromosome ".

The ABL gene encodes a tyrosine kinase and plays an important role in cellular growth regulation. If the fusion gene BCR-ABL is formed , then the function of ABL is significantly disrupted and the tyrosine kinase activity is permanently activated. The BCR-ABL gene thus acts as an oncogene and leads to increased and uncontrolled proliferation of the affected cell. The translocation is acquired over the course of life and is not inherited or inheritable since the germ line cells are unaffected (as far as is known, only cells of the hematopoietic system are affected). Why it occurs is not understood. As with mutations in general, ionizing radiation or chemicals are discussed as risk factors for the occurrence of the change.

A Philadelphia chromosome is not detectable in all CML patients. In a large prospective study by the Medical Research Council , no Philadelphia chromosome could be detected cytogenetically in about 15 percent of cases. However, in two thirds of these Philadelphia chromosome negative patients the BCR-ABL oncogene was detectable and the clinical picture did not differ significantly from that of the Philadelphia chromosome positive patients. Some of these patients had complex chromosomal changes that masked the translocation t(9;22). In one third, that is about five percent of all CML patients, there was no evidence of the t(9;22) translocation or the BCR-ABL fusion. The clinical picture of this form differed more clearly from the "typical" CML and had a significantly poorer prognosis .

course

Classically, CML progresses through three disease phases, the chronic phase , the accelerated phase, and the blast crisis (or blast flare ). Before the advent of newer drugs and before the option of stem cell transplantation from cells from healthy donors was available, the course of the disease almost always followed this course. The blast crisis was the final stage of the disease and led to the death of the patient. Even today it is not possible to predict with certainty when the accelerated phase and when the blast crisis will occur in a patient. Individual cases of CML patients who have lived in the chronic phase for more than 20 years are known. In other patients, the accelerated phase and blast crisis occurred shortly after diagnosis. Today, blast crises have become rarer because there are good treatment options for the chronic phase. Occasionally, however, they are still diagnosed (often as the "first manifestation" of CML).

chronic phase

The onset of the disease is slow and insidious and often goes unnoticed for years. The main symptoms of this phase are leukocytosis (increase in white blood cells) and splenomegaly (enlarged spleen). Splenomegaly is explained by the increasing displacement of healthy blood formation from the bone marrow, so that extramedullary blood formation occurs in the spleen and later also in the liver. The diagnosis is usually made at this stage and it is not uncommon for it to be an accidental diagnosis, for example based on a blood count that reveals leukocytosis. In the differential blood count , in addition to mature granulocytes , there are immature precursors of the myeloid series up to the myeloblasts (so-called pathological left shift ). However, the proportion of completely immature cells (blasts) is less than ten percent.

acceleration phase

The acceleration phase ( lat. accelerare = to speed up) is a transitional phase between the chronic phase and the blast attack, in which the disease gains momentum. It is characterized by increasing leukocytosis, anemia (low blood count), thrombocytopenia (lack of blood platelets ) and increasing swelling of the spleen. The differential blood count shows a proportion of blasts of ten to 30 percent. Cytogenetic analysis often shows new chromosomal abnormalities in addition to the Philadelphia chromosome (most commonly: isochromosome 17, a second Philadelphia chromosome, trisomy of chromosomes 8 or 19). The subjective general condition of the patient worsens. If the patient is undergoing chemotherapeutic treatment, the drug effect will decrease and dose increases will become necessary.

blast crisis

The blast crisis occurs relatively suddenly after the acceleration phase or directly from the chronic phase. In the blast crisis, the disease changes its character from a chronic, rather slow course to a course that corresponds to that of acute leukemia. The blast crisis is defined by:

  • Percentage of blast cells in the peripheral blood and/or in the bone marrow ≥ 30 percent (according to the criteria of the German CML Study Group) or ≥ 20 percent (according to the WHO definition), or/and
  • cytologically or histologically confirmed blastic infiltrates (accumulation of large amounts of CML cells in tissues) outside of the bone marrow, spleen or lymph nodes. Such infiltrates are also referred to as chloromas .

The blasts in about two-thirds of all blast crises show a myeloid or completely undifferentiated immune phenotype . The remaining third shows a lymphatic immune phenotype. In the latter case, the blast crisis is usually difficult or impossible to distinguish from Philadelphia chromosome-positive acute lymphocytic leukemia without knowledge of the history . Some clue is given by the different mRNA - BCR-ABL transcripts whose relative distribution is different in CML and ALL. If left untreated, the blast crisis stage ends fatally relatively quickly (within weeks).

diagnosis

a) Bone marrow cytology: CML is characterized by an increase in all four cell lines of myelopoiesis: thrombopoiesis (platelet formation), granulopoiesis (granulocyte formation), monopoiesis (monocyte formation) and erythropoiesis (erythrocyte formation). As a rule, a “full (i.e. cell-rich) bone marrow is shown. The granulocytopoiesis is the most increased and gains the upper hand in the late phase of the disease at the expense of the other cell lines. However, there are quantitative and qualitative changes with sometimes unusually small megakaryocytes ("micromegakaryocytes"), often also an increase in basophils and/or eosinophils .

b) Cytogenetics and molecular genetics: 95 percent detection of the Philadelphia chromosome and/or the BCR-ABL oncogene in the blood and bone marrow. A lack of these changes is prognostically unfavorable. Detection of BCR-ABL in a myeloproliferative disorder is conclusive for the diagnosis of CML. Sometimes the Philadelphia chromosome is also found in acute lymphocytic leukemia .

c) Blood count and clinical-chemical parameters of the blood: thrombocytosis (in the initial phase) in one third of the patients (risk of thrombosis!), neutrophilia with pronounced eosino- and basophilia and left shift (increase in immature precursors of granulocytes ) and moderate anemia . In contrast to acute myeloid leukemia, there are only a few blast cells in the chronic phase, despite the greatly increased number of leukocytes. With CML, leukocyte counts can reach over 500,000/µl (normal value < 10,000/µl). In addition, in contrast to the lymphocytic cells in chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL), for example, where high leukocyte counts are also reached in the blood, the CML cells tend to stick together (“stickiness”). Therefore, with such high values ​​there is an acute risk of leukostasis symptoms, i.e. the ability of the blood to flow is no longer guaranteed. As a result, thrombosis and circulatory disorders can occur at this stage (vein thrombosis of the retina , infarction of the spleen, painful priapism due to thrombosis of the erectile tissue , cerebral infarction , myocardial infarction ).

d) Cytochemistry: The ALP index as an expression of the activity of the alkaline leukocyte phosphatase in the neutrophils is usually reduced. Today, however, this provision has almost completely lost its meaning.

As an expression of the increased cell turnover, the activity of lactate dehydrogenase (LDH) and the uric acid level in the blood are usually increased.

therapy

General therapy goals

The aim of the therapy is to suppress the disease as far as possible with acceptable side effects. To measure the effectiveness of treatment, the following terms are used:

  • Hematological response (hematological response) , ie degree of normalization of the blood count and regression of splenomegaly; hematological response is determined by clinical examination and differential blood count;
  • cytogenetic response , d. H. Percentage of cells in which the Philadelphia chromosome Ph+ is cytogenetically detectable;
  • Molecular response (molecular response) , that is, the measurement of BCR-ABL mRNA using quantitative polymerase chain reaction (PCR)

The following terms are defined in international medical terminology:

Hematological Response

A complete hematological response ( CHR ) is defined as complete normalization of the blood count and clinical symptoms, i. H. Platelets below 450 × 10 9 /l, leukocytes below 10 × 10 9 /l, a differential blood count without immature granulocytic precursors (myelocytes, promyelocytes, myeloblasts) and with less than five percent basophils and no palpable splenomegaly.

Cytogenetic Response

Cytogenetic response is measured by cytogenetic testing. The percentage of metaphases with detectable Philadelphia translocation is determined.

  • Complete cytogenetic response ( CCyR ): Ph+ 0 percent
  • Partial cytogenetic response ( PCyR ): Ph+ 1–35 percent
  • Minor cytogenetic response ( MiCyR ): Ph+ 36-65 percent
  • Minimal cytogenetic response : Ph+ 66-95 percent
  • No cytogenetic response : Ph+ >95%

Molecular Response

The molecular response is measured using RT-PCR . An international scale (IS) was developed to ensure comparability between different laboratories.

  • Complete molecular response ( CMR ): BCR-ABL not detectable
  • Good molecular response ( major molecular response , MMR): BCR-ABL ≤ 0.10 IS

Put simply, the percentage of CML cells in the blood/bone marrow can be at most in the low double digits for a complete hematological response, at most in the low single digits for a complete cytogenetic response, and below for a complete molecular response of the alcohol range.

medication

hydroxycarbamide

The normalization of the leukocyte count can often already be achieved by using hydroxycarbamide (hydroxyurea, English: hydroxyurea, HU). This cytostatic has been on the market for a long time. It inhibits the conversion of ribonucleotides into deoxyribonucleotides and is also effective in the other myeloproliferative diseases mentioned above. Typical dosages are one tablet of 500 mg to about four tablets (= two grams) daily.

Side effects are rare, occasionally mild nausea, very rarely damage to the mucous membranes or liver toxicity . This therapy makes it possible to reduce the number of leukocytes in the blood to almost the normal range again (5,000 to 10,000/μl). However, this normalization is not associated with a lasting influence on the course of the disease. After an average of three years, the condition deteriorates further and the acceleration phase begins. The median survival of patients treated with hydroxycarbamide is slightly longer than that of completely untreated patients and was approximately 4½ years in historical therapy studies.

The use of hydroxycarbamide in CML only makes sense in certain situations today, for example when very high leukocyte counts are to be reduced in the initial phase of treatment, or when the use of TKIs (see below) is not possible due to intolerable side effects, or if the patient has a very short life expectancy due to other existing diseases (e.g. advanced cancer).

Interferon-α

Interferon alpha (α) (IFN-α) is a cytokine produced and released by leukocytes; it serves the immune response to viral and bacterial infections and induces, among other things, an inhibition of proliferation in the target cells, for example in the case of virus infection. It also increases the activity of cytotoxic T cells and macrophages . Interferon is usually injected subcutaneously 3 times a week . Typical dosages are 3×0.5 to 3×6 million units per week. It can be given either as monotherapy or in combination with other medications. Interferon-α is a drug that is often not very well tolerated. Flu-like symptoms can occur, but these depend on the dose. In many cases, interferon therapy affects the ability to concentrate and remember , depression can occur, as well as dizziness , confusion and polyneuropathies . In addition, the treatment affects the digestive tract and the liver .

Tyrosine Kinase Inhibitors (TKIs)

Specific therapy can be used in patients who are BCR-ABL positive. Drugs have been available since around the turn of the millennium that can specifically and competitively inhibit the tyrosine kinase enzyme activity of the ABL portion of BCR-ABL . These tyrosine kinase inhibitors have revolutionized the treatment of CML and dramatically improved patient outcomes. A distinction is made between first, second and third generation tyrosine kinase inhibitors (TKIs), which have come onto the market one after the other. The most important first-generation TKI is imatinib . The substance received approval for the treatment of CML in Europe and the United States in 2001 and 2003, respectively. Second generation TKIs are nilotinib and dasatinib , third generation TKIs are bosutinib and ponatinib .

Tyrosine kinase inhibitors are now considered the “ gold standard ” of CML treatment.

Imatinib and the IRIS study

The effectiveness and superiority of imatinib compared to all other forms of drug treatment known to date became clear in a large international phase III therapy study with more than 1000 CML patients, the so-called IRIS study ( IRIS = International R andomized Study of Interferon and S TI571 ). The IRIS therapy study was originally planned as a two-arm comparative study , i. H. half of the patients should receive imatinib as treatment and the other half of the patients should receive the current standard of care consisting of interferon-α and cytarabine. However, the superiority of the imatinib treatment was already clear in the first interim analysis with a mean observation period of 18 months. Patients treated with imatinib had a good cytogenetic response (see definitions of terms above) of 87.1 percent and a complete cytogenetic response of 76.2 percent. In the interferon-α/cytarabine group, the corresponding figures were 34.7 percent and 14.5 percent. In the imatinib-treated patient group, 96.7 percent had no disease progression to the blast crisis/acceleration phase, compared to 91.5 percent in the interferon-α/cytarabine group. Overall, imatinib treatment was also better tolerated than treatment with interferon alpha/cytarabine.

These results meant that most patients in the interferon-α/cytarabine group crossed over to the treatment arm with imatinib (this cross-over was allowed in the IRIS study). In addition, the US Food and Drug Administration and the European Medicines Agency accelerated the approval of imatinib for the treatment of CML (mainly based on the results of the IRIS study), and as a result many patients who were included in the IRIS study with interferon-α/cytarabine left the study and continued off-study with imatinib. The IRIS study has therefore now practically changed from an initially two-armed study into a purely observational study for the treatment of CML patients with imatinib.

An update of the IRIS study data published in 2009 showed a progression-free survival of 92 percent of patients treated with imatinib from the start with a median observation period of eight years.

Imatinib became the drug of choice in CML treatment after the results of the IRIS study were announced. However, there is still no consensus on the optimal imatinib dose. The usual dose is 400 mg daily. The German CML IV therapy study examined whether a 800 mg daily dose was tolerated and produced better results. According to initial evaluations, it seems that older patients (≥ 65 years) with an 800 mg imatinib medication achieve remission much more quickly than with a 400 mg medication, which, however, also has to be paid for with higher side effects. The conclusion from this analysis was that the imatinib dose in patients ≥ 65 years should preferably be above 400 mg daily. It seems certain that the daily dose should generally not be significantly below 400 mg, as this promotes the development of resistance. In the meantime, however, the situation has changed as newer second- or third-generation tyrosine kinase inhibitors are available (see below). In the current guidelines, no specific TKI is explicitly recommended, only specifications are made for the therapy goals that are to be achieved.

Imatinib is usually relatively well tolerated. Side effects can include nausea and vomiting (rarely), edema , pleural and pericardial effusions (accumulation of fluid in the pleura or pericardium), transaminase increase , muscle cramps and skin rashes .

Nilotinib and dasatinib: second-generation TKIs

Despite the remarkable treatment successes with imatinib, about 20 to 25 percent of CML patients require an alternative therapy within 5 to 8 years of imatinib treatment. The reasons for this are primarily insufficient efficacy, a loss of effectiveness of imatinib, or imatinib intolerance. In this situation there are two main alternatives, one is to switch to a different tyrosine kinase inhibitor and the other is to perform an allogeneic stem cell or bone marrow transplant. The reason for the loss of effect can be a mutation in the tyrosine kinase domains of the BCR-ABL gene.

Two new second-generation tyrosine kinase inhibitors, dasatinib (tradename Sprycel ) and nilotinib (tradename Tasigna ), have been approved for the treatment of imatinib-resistant or intolerant CML. Both dasatinib and nilotinib are significantly more potent at inhibiting ABL kinase in vitro and are also effective in most imatinib resistances. Only in the case of the T315I mutation are both substances ineffective. There is a gene mutation that leads to the amino acid exchange threonine → isoleucine at position 315. Isoleucyl residues are significantly larger than threonyl residues and so may prevent binding of the drug to the specific binding site.

The German TIGER therapy study (TIGER = T asigna/ Interferon in Germany ) started in 2013 relies entirely on nilotinib (in some cases combined with interferon α in a later phase). In the context of this study, imatinib should only be given in the case of nilotinib intolerance, while dasatinib (or allogeneic stem cell transplantation) should be used if nilotinib resistance occurs.

Third generation TKI

Other newer TKIs include bosutinib ( Bosulif ) and ponatinib ( Iclusig ), both of which were approved in the United States in 2012 for the treatment of CML when other TKIs are intolerant or ineffective. A few months later it was also approved in Europe. Ponatinib in particular is of great interest as it is also active against the BCR-ABL T315I mutation.

Resistance to tyrosine kinase inhibitors
Sensitivity of different BCR-ABL mutations to imatinib, nilotinib and dasatinib (Example explanation: V299L denotes the amino acid exchange valine → leucine at position 299 of the BCR-ABL protein.)

In therapy with tyrosine kinase inhibitors, the phenomenon sometimes occurs that the effect of the drug becomes progressively weaker and eventually disappears altogether. The earliest indicator of this is an increase in the BCR-ABL level (which is usually measured in the blood every three months during therapy). If no further action is taken, the disease will spread again and take the course described above . In such cases, one speaks of resistance to the drug, for example imatinib resistance or nilotinib resistance.

Such resistances are often caused by nucleotide mutations in the BCR-ABL oncogene, which lead to amino acid substitutions. The drug is then no longer effective against the mutated BCR-ABL protein. It is now assumed that most of these mutations are already present in small amounts at the start of therapy and are then selected out by the therapy (only the mutated, i.e. resistant clone can grow). However, some of the mutations are likely to occur randomly during the course of the disease. Many BCR-ABL mutations have been characterized in recent years. Of clinical interest is the fact that some BCR-ABL mutations confer resistance to one tyrosine kinase inhibitor but are sensitive to others. In such cases, switching to a different tyrosine kinase inhibitor makes sense. In a consensus statement by a group of experts from the European LeukemiaNet from 2011, the following procedure was recommended when detecting mutations under imatinib therapy:

  • T315I : allogeneic transplantation or experimental therapy;
  • V299L , T315A , V517L/V/I/C : nilotinib rather than dasatinib;
  • Y253H , E255K/V , F359V/C/I : dasatinib rather than nilotinib;
  • any other mutation: higher-dose imatinib or dasatinib or nilotinib.

However, there is also the phenomenon of resistance without a BCR-ABL mutation being detected. This is obviously due to other genetic changes that are not well understood. In this situation, changing the tyrosine kinase inhibitor or increasing the dose of the previous one can also make sense.

Therapy goals in TKI therapy

In 2013, the expert committees formulated recommendations for the therapy goals to be achieved. No specific TKI (e.g. imatinib, nilotinib, dasatinib, etc.) was expressly recommended. The therapeutic goals in treatment with tyrosine kinase inhibitors are a complete hematological response (CHR) after three months at the latest, a complete cytogenetic response (CCyR) after six months at the latest, and an extensive molecular remission (MMR) after a maximum of 18 months. If there are warnings, it is recommended to carry out more frequent checks (e.g. BCR-ABL measurement up to once a month), if the therapy has failed, the therapy must be changed.

Criteria for evaluating the effectiveness of TKI therapy
time Optimal Warnings therapy failure
time of diagnosis not applicable High risk (see risk scores below),
additional chromosomal
aberrations in Ph+ cells 		not applicable
3 months after diagnosis BCR-ABL ≤ 10% and/or
Ph+ metaphases ≤ 35% 		BCR-ABL >10% and/or
Ph+ metaphases 35 to 95% 		no complete hematological
response (CHR) and/or
Ph+ metaphases > 95%
6 months after diagnosis BCR-ABL ≤ 1% and/or
Ph+ metaphases 0% 		BCR-ABL 1 to 10% and/or
Ph+ metaphases 1 to 35% 		BCR-ABL >10% and/or
Ph+ metaphases >35%
12 months after diagnosis BCR ABL ≤ 0.1% BCR-ABL 0.1% to 1% BCR-ABL > 1% and/or
Ph+ metaphases > 0%
at any later time BCR-ABL ≤ 0.1% (MMR) cytogenetic clonal aberrations Loss of complete cytogenetic response and/or
loss of hematological response and/or
confirmed (!) loss of extensive
molecular response (MMR) and/or
evidence of BCR-ABL mutations

Bone marrow or blood stem cell transplant

According to current knowledge, allogeneic stem cell transplantation (SZT) (rarely also bone marrow transplantation BMT) is the only form of therapy that can lead to complete healing . There are also isolated patients in whom therapy with tyrosine kinase inhibitors leads to the BCR-ABL fusion gene no longer being detectable . However, it is not clear whether this is a real cure or just a suppression of the disease below the detection limit. Since the prognosis is best the earlier the SZT/KMT is performed, a decision should be made as early as possible. The problem of this transplantation is the relatively high mortality due to complications (particularly severe infections) during the transplantation procedure and the possible occurrence of severe autoaggressive diseases after transplantation ( graft-versus-host disease , GvHD).

This effect can arise because all blood and immune cells in the body are formed from the stem cells of the bone marrow. So not only the blood formation is replaced, but essential parts of the immune system are transplanted. While a host-versus-graft effect ('recipient versus transplant'), i.e. a typical rejection reaction , can be observed in conventional transplants, the transplanted immune system is directed against the new body in this case. For this reason, SCT/BMT must also be preceded by highly aggressive chemotherapy in order to destroy the body's own immune system as completely as possible. The establishment of the new stem cells could be severely disturbed by a remaining immune system.

However, the graft-versus-host effect is not only disadvantageous for the patient: some of the transplant recipients may benefit from the new immune system fighting the remaining tumor cells. This effect is called the graft-versus-leukemia reaction (GvL reaction).

A transplant is only performed if:

  • Patients who are ineffective on treatment with imatinib or newer tyrosine kinase inhibitors
  • younger patients and
  • Patients for whom a compatible donor is found (family or unrelated donor).

therapy costs

Approximate therapy costs (as of 01/22)
drug Typical
dosage
per day 		daily
therapy costs
Glivec 400 mg €116
Tasigna 600 mg €131
Sprycel 100 mg €169
Roferon A 3× 6 million IU
(per week)		 €31
litalir 1g €4.52
Note: This table is not intended to suggest that the drugs listed are equivalent in effect. Only the therapy costs are compared here. There are big differences in terms of effectiveness.

The standard drug imatinib is available in tablet form in dosages of 100 mg or 400 mg. The standard dosage is 400 mg imatinib daily. The German pharmacy price (manufacturer's recommendation) for the pack of Gleevec with 90 tablets of 400 mg each was €10,434.48 (as of 01/2022, corresponds to €116 per tablet). Sprycel packs of 30 tablets of 100 mg each cost €5063.05, which corresponds to a daily therapy price of €169 for the usual 100 mg daily dose. Tasigna was available in a strength of 150 mg (112 capsules) at a price of approx. €3938.56, which, with the usual daily dose of 600 mg, entails daily therapy costs of €131. The drug costs for a CML patient were therefore between around €41,369 ( Gleevec ), €61.727 ( Sprycel ) and €48,848 ( Tasigna ) per year.

For comparison: treatment with hydroxycarbamide (hydroxyurea, e.g. Litalir ) with a daily dose of 1 g causes annual therapy costs of approx. 1650 €, with interferon alpha ( e.g. Roferon 3 × 6 million IU weekly) annual costs of approx. 11,500 € .

The fact that five different, highly effective tyrosine kinase inhibitors from different manufacturers are now on the market (as of July 2013: Novartis 's imatinib and nilotinib, Bristol-Myers Squibb's dasatinib , Pfizer 's bosutinib, Ariad Pharmaceuticals ' ponatinib ) was criticized. but the costs of therapy remain exorbitantly high and are even increasing. In an article published in May 2013 in the respected American journal Blood , an international collective of more than 100 experts clearly criticized the high prices of modern tumor medicine, especially using the example of CML, and pointed out that such prices are not sustainable for any healthcare system in the long term be. Even in highly developed countries such as the United States or Sweden, there would be a significant number of patients who could not afford this therapy due to the high cost of medication and would therefore have poorer survival. Of the approximately 1.2 to 1.5 million CML sufferers worldwide, only around 235,000 to 250,000, i.e. 20 to 25%, are treated with the standard drug imatinib, which is mainly due to the high therapy costs. It was also pointed out that there are significant price differences between different countries. The annual treatment costs of imatinib were given for different countries (in US$ 1,000): USA 92, Germany 54, Great Britain 34, France 40, Italy 31, South Korea 29, Japan 43, Russia 24. The main reason for the extremely different costs was the different Legislative requirements identified, which led to different freedoms in the manufacturer's pricing.

The lawsuit between Novartis and India regarding the validity of patent protection for Gleevec (Imatinib) in India also attracted considerable international interest. Finally, on April 1, 2013, Novartis lost the final instance before the Supreme Court in India , with the result that imatinib is also available in India as a generic drug from other manufacturers.

The costs for an allogeneic stem cell transplantation, including the follow-up treatment, are estimated at a flat rate of around €150,000, whereby this figure only refers to the immediate follow-up treatment. If complications arise later, such as chronic graft-versus-host disease, the actual total costs can be much higher. It is not uncommon for transplanted patients to also lose their ability to work and/or work, so that the overall "economic" costs are significantly higher.

forecast

Risk scores for CML
score
clinical and
blood parameters taken into account		 Web link for
calculation
EUTOS score Spleen size
basophils		 eutos.org
Sokal-Hasford Score Age Spleen size Platelets Basophils Eosinophils
Myeloblasts



 leukemia-net.org

Historical overview of survival rates

Before drugs were available, CML was the myeloproliferative neoplasm (MPN) disease with the worst prognosis. The median survival of CML patients without treatment was only about three to four years. Hydroxycarbamide resulted in a small improvement in median survival to approximately 4½ years and interferon subsequently resulted in a further improvement in median survival to approximately 5½ years.

Today, five-year survival rates with imatinib treatment are about 90 percent or even higher. Even with a follow-up period of more than 10 years for imatinib-treated patients, the “endpoint mean survival” has not yet been reached.

Stem cell transplantation in CML

The ten-year survival of patients treated with imatinib is significantly higher than after stem cell transplantation , where survival rates historically have been around 55 percent at ten years (see table of risk scores). After stem cell transplantation, a significant proportion of patients die as a result of the intensive treatment, severe infections or graft-versus-host disease . The surviving patients after stem cell transplantation often have to contend with the problem of chronic graft-versus-host disease, so that although they no longer have to take imatinib, they do have to take other drugs against the GvH disease.

It is therefore no longer justified, as it used to be, to send CML patients to a transplant immediately after diagnosis. However, it may make sense to carry out a transplantation in individual high-risk patients during the course of the disease if, for example, they show no response to treatment with imatinib or other tyrosine kinase inhibitors and are otherwise in good general condition. After ten years, 40 percent are still alive on interferon-α therapy, and only 20 percent of the high-risk groups.

Complete healing without stem cell transplantation?

A complete cure in the sense of a complete disappearance of the BCR-ABL oncogene was, according to the prevailing expert opinion for a long time, generally not achievable either with the previous tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) or with interferon-α. There are patients in whom imatinib or nilotinib work so well that the BCR-ABL oncogene can no longer be detected, even with the most sensitive measurement methods. It is unclear in individual cases whether these patients can be considered cured or whether the measuring sensitivity of the examination method is simply not sufficient to detect the few remaining CML cells. For this reason, it is currently not recommended in these cases to omit the medication uncontrolled, as there is a risk of the disease recurring.

Clinical studies are ongoing in which, among other things, it is being investigated whether the last remaining CML stem cells can be eliminated with such a BCR-ABL negativity as described above using immunotherapeutic approaches (e.g. interferon) and thus the patient can be completely cured. The German TIGER therapy study mentioned above, which started in 2013, examines this therapy approach. The plan here is to treat patients primarily with nilotinib (and in some cases also with interferon). In patients who achieve a complete molecular response that lasts longer than 2 years, a complete cessation attempt should be made - with further continuous molecular monitoring, of course - to see whether the patients are permanently cured.

literature

  • Bubnoff, Nikolas von; Duyster, Justus: Chronic myeloid leukemia: therapy and monitoring . In: Dtsch Arztebl Int . No. 107(7) , 2010, p. 114–121 ( Abstracts ).
  • Ludwig Heilmeyer , Herbert Begemann: Blood and blood diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer Verlag, Berlin/Goettingen/Heidelberg 1955; 2nd edition ibid 1961, pp. 376-449, here: pp. 424-426: Chronic myeloid leukemia (chronic leukemic myelosis).

web links

itemizations

  1. ↑ Chronic myeloid leukemia guideline. German Society for Hematology and Oncology (DGHO), September 2013, accessed March 19, 2016 .
  2. ↑ Junia V Melo, David J Barnes: Chronic myeloid leukemia as a model of disease evolution in human cancer . In: Nature Reviews Cancer . tape 7 , 2007, p. 441–453 , PMID 17522713 ( nature.com [accessed 8 August 2011]).
  3. ^ a b SEER Stat Fact Sheets: Chronic Myeloid Leukemia. Surveillance, Epidemiology and End Results (SEER), accessed 2 June 2011 (from data 2004-2008).
  4. ↑ CA Schiffer: BCR-ABL Tyrosine kinase inihitors for chronic myelogenous leukemia. In: N Engl J Med . 2007; 357, pp. 258-265. PMID 17634461
  5. ↑ The figures for Germany are based on estimates by the Competence Network for Acute and Chronic Leukemia weblink , the figures for Austria and Switzerland are estimated in proportion to the German figures
  6. ↑ a b c A. High rise: Chronic myeloid leukemia (CML). In: S. Seeber, J. Schütte (eds.): Therapy concepts oncology . Springer-Verlag, Heidelberg 2007, ISBN 978-3-540-28588-5 , p. 293.
  7. ↑ a b DG Savage et al.: Clinical features at diagnosis in 430 patients with chronic myeloid leukemia seen at a referral center over a 16-year period. In: Br J Haematol . 1997;96, pp. 111-116. PMID 9012696 .
  8. ↑ from Ancient Greek χλωρός chlōrós "pale/light green, green-yellow". The infiltrates appear slightly greenish when processed by the pathologist.
  9. ↑ European LeukemiaNet: CML recommendations
  10. ↑ a b c R Hehlmann, H Heimpel, J Hasford, HJ Kolb, H Pralle, DK Hossfeld, W Queisser, H Löffler, A Hochhaus, B Heinze et al.: Randomized comparison of interferon-alpha with Busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. In: Blood. 1994;84(12), pp. 4064-4077. PMID 7994025 .
  11. ↑ a b SG O'Brien, F Guilhot, RA Larson, I Gathmann, M Baccarani, F Cervantes, JJ Cornelissen, T Fischer, A Hochhaus, T Hughes, K Lechner, JL Nielsen, P Rousselot, Reiffers, J, Saglio, G, Shepherd, J, Simonsson, B, Gratwohl, A., Goldman, JM, Kantarjian, H, Taylor, K, Verhoef, G, Bolton, AE, Capdeville, R, Druker, BJ; IRIS Investigators: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. In: N Engl J Med. 2003; 348, pp. 994-1004. PMID 12637609
  12. ↑ FDA infopage Gleevec (Imatinib Mesylate) , specifically Regulatory history including approval letters and reviews from Drugs@FDA
  13. ↑ European public assessment report (EPAR): Glivec from the European Medicines Agency (pdf)
  14. ↑ M Baccarani, J Cortes, F Pane, D Niederwieser, G Saglio, J Apperley, F Cervantes, M Deininger, A Gratwohl, F Guilhot, A Hochhaus, M Horowitz, T Hughes, H Kantarjian, R Larson, J Radich, B Simonsson, RT Silver, J Goldman, R Hehlmann; European LeukemiaNet: Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol . 2009;27(35), pp. 6041-6051. PMID 19884523
  15. ↑ U. Proetel, N. Pletsch, M. Lauseker, M. Müller, B. Hanfstein, SW Krause, L. Kalmanti, A. Schreiber, D. Heim, GM Baerlocher, WK Hofmann, E. Lange, H. Einsele, M Wernli, S. Kremers, R. Schlag, L. Müller, M. Hänel, H. Link, B. Hertenstein, M. Pfirrman, A. Hochhaus, J. Hasford, R. Hehlmann, S. Saußele; German Chronic Myeloid Leukemia Study Group; Swiss Association for Clinical Cancer Research (SAKK): Older patients with chronic myeloid leukemia (≥65 years) benefit more from higher doses of imatinib than younger patients: a subanalysis of the randomized CML-Study IV. In: Ann Hematol. 2014 Jul;93(7), pp. 1167-1176. PMID 24658964 .
  16. ↑ a b c Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen, Hughes TP, HM Kantarjian, DW Kim, RA Larson, JH Lipton, JH Mahon, G Martinelli, J Mayer, MC Müller, D Niederwieser, F Pane, JP Radich, P Rousselot, G Saglio, S Saussele, C Schiffer, R Silver, B Simonsson, JL Steegmann, JM Goldman, R Hehlmann: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. In: Blood. 2013;122(6), pp. 872-884. doi:10.1182/blood-2013-05-501569 . PMID 23803709 .
  17. ↑ De Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. In: J Clin Oncol. 2008 Jul 10;26(20) pp. 3358-3363. PMID 18519952
  18. ↑ M. Talpaz et al: Dasatinib in Imatinib-Resistant Philadelphia Chromosome-Positive Leukemias. In: N Engl J Med. 2006;354, pp. 2531-2541. PMID 16775234
  19. ↑ H. Kantarjian et al: Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome-positive ALL. In: N Engl J Med. 2006; 354, pp. 2542-2551. PMID 17715389
  20. ↑ a b A. Hochhaus, T. Ernst, J, Ziermann, E. Eigendorff, P. La Rose: Chronic myeloid leukemia. In: Oncologist. 2012; 18, pp. 1108-1114. Springer-Verlag
  21. ↑ Ponatinib: a pan-BCR-ABL inhibitor. ( Memento of November 26, 2012 at the Internet Archive )
  22. ↑ O'Hare T, Eide CA, Deininger MW: Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. In: Blood. 2007 Oct 1;110(7), pp. 2242-2249. PMID 17496200
  23. ↑ S Branford, JV Melo, TP Hughes: Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? In: Blood. 2009 Dec 24;114(27), pp. 5426-5435. PMID 19880502
  24. ↑ O'Hare T, Eide CA, Deininger MWN: Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. In: Blood. 2007;110(7), pp. 2242-2249. PMID 17496200
  25. ↑ S Redaelli, R Piazza, R Rostagno et al: Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. In: J Clin Oncol. 2009;27(3), pp. 469-471. PMID 19075254
  26. ↑ S Soverini, A Hochhaus, FE Nicolini, F Gruber, T Lange, G Saglio, F Pane, MC Müller, T Ernst, G Rosti, K Porkka, M Baccarani, NC Cross, G. Martinelli: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. In: Blood. 2011;118(5), pp. 1208-1215. doi:10.1182/blood-2010-12-326405 . PMID 21562040 .
  27. ↑ a b c d Glivec 400 mg film-coated tablets. Retrieved January 22, 2022 .
  28. ↑ a b "Primum non nocere" and the pharmaceutical industry's pursuit of profit - an irreconcilable contradiction in oncology? In: The Medicines Letter Volume 46, No. 5, May 2013.
  29. ↑ a b Experts in Chronic Myeloid Leukemia: The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. In: Blood. 2013;121(22), pp. 4439-4442. PMID 23620577
  30. ↑ Gleevec patent case in India. Retrieved on April 3, 2014 (English, presentation of the case from the point of view of Novartis).
  31. ↑ CIVIL APPEAL Nos. 2706-2716 OF 2013. (No longer available online.) Supreme Court of India, April 1, 2013, archived from the original on April 7, 2014 ; Retrieved April 3, 2014 (English).
  32. ↑ Burchert A, Müller MC, Kostrewa P, Erben P, Bostel T, Liebler S, Hehlmann R, Neubauer A, Hochhaus A: Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. In: J Clin Oncol. 2010;28(8), pp. 1429-1435. PMID 20142590 .