Chronic Fatigue Syndrome

                    Englisch

Myalgische Enzephalomyelitis/das Chronic Fatigue Syndrome ME/CFS 

ME/CFS gehört zu den letzten großen Krankheiten, die kaum erforscht sind. Die Myalgische Enzephalomyelitis/das Chronic Fatigue Syndrome ist eine schwere neuroimmunologische Erkrankung, die oft zu einem hohen Grad körperlicher Behinderung führt. Weltweit sind etwa 17 Mio. Menschen betroffen. In Deutschland sind es geschätzt bis zu 240.000. Damit ist ME/CFS relativ weit verbreitet. Die WHO stuft ME/CFS seit 1969 als neurologische Erkrankung ein.

ME/CFS-Betroffene leiden neben einer schweren Fatigue (körperliche Schwäche), die das Aktivitätsniveau erheblich einschränkt, unter neurokognitiven, autonomen und immunologischen Symptomen.

Typisch für ME/CFS ist die Post-Exertional Malaise, eine ausgeprägte und anhaltende Verstärkung aller Symptome nach geringer körperlicher und geistiger Anstrengung. Die Post-Exertional Malaise führt zu ausgeprägter Schwäche, Muskelschmerzen, grippalen Symptomen und der Verschlechterung des allgemeinen Zustands. Sie tritt typischerweise schon nach geringer Belastung wie wenigen Schritten Gehen auf. Schon kleine Aktivitäten wie Zähneputzen, Duschen oder Kochen können zur Tortur werden; Besorgungen im Supermarkt anschließend zu tagelanger Bettruhe zwingen. Für Schwer- und Schwerstbetroffene kann die PEM bereits durch das Umdrehen im Bett oder die Anwesenheit einer weiteren Person im Raum ausgelöst werden.

Neben der Post-Exertional Malaise leiden die Betroffenen unter Symptomen des autonomen Nervensystems wie Herzrasen, Schwindel, Benommenheit und Blutdruckschwankungen. Viele Betroffene können dadurch nicht mehr für längere Zeit stehen oder sitzen. Medizinisch spricht man von der orthostatischen Intoleranz.

Dazu kommen immunologische Symptome wie ein starkes Krankheitsgefühl, schmerzhafte und geschwollene Lymphknoten, Halsschmerzen, Atemwegsinfekte und eine erhöhte Infektanfälligkeit.

Viele Betroffene leiden zudem unter ausgeprägten Schmerzen wie Muskel- und Gelenkschmerzen und Kopfschmerzen eines neuen Typus. Hinzu kommen Muskelzuckungen und -krämpfe, massive Schlafstörungen und neurokognitive Symptome wie Konzentrations-, Merk- und Wortfindungsstörungen (oft als »Brain Fog« bezeichnet) sowie die Überempfindlichkeit auf Sinnesreize. Schwerstbetroffene müssen deshalb oft in abgedunkelten Räumen liegen und können sich nur flüsternd mit Angehörigen verständigen.

Laut einer Studie der Aalborg Universität, 2015, ist die Lebensqualität von ME/CFS-Erkrankten oft niedriger als die von Multiple Sklerose-, Schlaganfall- oder Lungenkrebspatienten. Ein Viertel aller Patienten kann das Haus nicht mehr verlassen, viele sind bettlägerig und auf Pflege angewiesen. Schätzungsweise über 60 Prozent sind arbeitsunfähig.

Häufig beginnt die Krankheit akut nach einem schweren Infekt, aber auch schleichende Verläufe sind bekannt.

Die genauen Ursachen der Erkrankung sind bisher noch ungeklärt. Neuere Studien weisen auf eine mögliche Autoimmunerkrankung und eine schwere Störung des Energiestoffwechsels hin. Auch virale Infektionen, wie der Epstein-Barr-Virus, werden als Auslöser diskutiert.

Ein Biomarker zur eindeutigen Diagnose fehlt bisher. Die Diagnose wird daher nach Ausschluss anderer Krankheiten und anhand etablierter klinischer Kriterienkataloge gestellt. Für ME/CFS gibt es bisher keine zugelassene kurative Behandlung oder Heilung.

Symptome

Die folgende Auflistung orientiert sich in der Beschreibung der Symptomatik von ME/CFS an den Kanadischen Konsenskriterien für Kliniker (2005) und dem Bericht des Institute of Medicine (2015). Die Auflistung der Symptomatik erhebt nicht den Anspruch auf Vollständigkeit, sondern beschreibt die häufigsten Symptome. Nicht jeder ME/CFS-Betroffene hat alle aufgeführten Symptome. Vorkommen, Art und und Intensität der Symptome können von Betroffenem zu Betroffenem variieren.

 (1) Post-Exertional Malaise (PEM)
 (2) Chronische Fatigue
 (3) Orthostatische Intoleranz (OI)
 (4) Neurokognitive Symptome
 (5) Neurologische Symptome
 (6) Erhöhte Infektanfälligkeit
 (7) Immunologische Symptome
 (8) Schlafstörungen
 (9) Muskelschmerzen, Faszikulationen und Krämpfe
 (10) Kopfschmerzen
 (11) Sehstörungen

Verschiedene Bezeichnungen für ME/CFS

Chronic Fatigue Syndrome (CFS)
Die Bezeichnung wurde 1988 von den Centers of Disease Control and Prevention (CDC) eingeführt. Die amerikanische Gesundheitsbehörde untersuchte 1984 den Ausbruch einer chronischen grippeähnlichen Erkrankung  am Lake Tahoe in Nevada. Die Kommission brachte den Ausbruch mit dem Epstein-Barr-Virus in Verbindung. 1988 führte sie für das Chronische Epstein-Barr-Virus-Syndrom die Bezeichnung Chronic Fatigue Syndrome ein. In Deutschland werden auch die Begriffe Chronisches Erschöpfungssyndrom oder Chronisches Müdigkeitssyndrom  verwendet. Dies ist problematisch, da Fatigue in der Medizin eine krankhafte Erschöpfbarkeit bezeichnet und daher von Müdigkeit abzugrenzen ist. Der Name Chronic Fatigue Syndrome ist seit jeher unter Ärzten und Patienten umstritten, da er zur Stigmatisierung und Bagatellisierung von ME/CFS als einfache Müdigkeit und Erschöpfung beiträgt und die Schwere der Krankheit sowie die komplexe Symptomatik nicht beschreibt. CFS wird vor allem in den USA und Kontinentaleuropa verwendet.

Myalgische Enzephalomyelitis (ME)
Die Bezeichnung wurde vom britischen Arzt Melvin Ramsay nach einem Ausbruch am Royal Free Hospital in London geprägt. Ca. 300 Ärzte und Krankenschwestern entwickelten im Sommer 1955 über mehrere Monate schwere neurologische Symptome mit anhaltender Muskelschwäche. Der Name bedeutet auf Altgriechisch »Entzündung des Gehirns und Rückenmarks mit Muskelbeteiligung«. Viele Patienten  und Ärzte bevorzugen den Begriff, da er die Schwere der Symptomatik besser abbildet als CFS. Einige Studien geben zwar Hinweise auf Entzündungen im zentralen Nervensystem, allerdings steht bis heute der endgültige Beweis für eine umfassende Entzündung des zentralen Nervensystems aus. ME wird vor allem in Großbritannien und in den skandinavischen Ländern verwendet.

ME/CFS
In den letzten Jahren setzte sich unter einigen Wissenschaftlern und Ärzten, die ME/CFS biomedizinisch erforschen, der Hybridbegriff ME/CFS durch. Dieser wird vor allem verwendet, da die gängigen klinischen Kriterien von ME und CFS sich überschneiden.  Zudem gehen einige Ärzte davon aus, dass es sich bei ME und CFS um dieselbe Erkrankung handelt, da sich die Symptomatik stark ähnelt. Bis die Ätiopathologie geklärt ist, verwenden daher einige Wissenschaftler den Hybrid ME/CFS.

Systemic Exertion Intolerance Disease (SEID)
2015 schlug das amerikanische Institute of Medicine (heute National Academy of Medicine) den Namen SEID vor. Dieser steht für Systemic Exertion Intolerance Disease, auf Deutsch Systemische Belastungsintoleranz-Erkrankung. Das IOM wollte mit diesem Namen vor allem die ausgeprägte Belastungsintoleranz bzw. Post-Exertional Malaise von ME/CFS-Patienten betonen. Der Name hat sich allerdings bis heute in Wissenschaft und Praxis nicht durchgesetzt.

Chronic Fatigue Immune Dysfunction Syndrome (CFIDS)

Ein weiterer Name für ME/CFS, der auf die mit der Erkrankung einhergehenden Immundefekte hinweist. Die Bezeichnung war in den 90er Jahren in den USA gebräuchlich, hat sich aber klinisch nicht durchgesetzt. Wird heute kaum noch verwendet.

Quellen

1. Scheibenbogen et al. (2014), Chronisches Fatigue-Syndrom. Heutige Vorstellung zur Pathogenese, Diagnostik und Therapie, tägl. prax. 55, 567–574, Hans Marseille Verlag GmbH, München.
2. ICD-10 G.93.3.
3. Carruthers B , van de Sande M (2005), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners, An Overview of the Canadian Consensus Document, The National Library of Canada.
4. Siehe Fn. 1.
5. Siehe Fn. 3.
6. Institute of Medicine (2015), Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, National Academies Press, Washington, DC
7. Hvidberg et al. (2015), The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), PlosOne, DOI: 10.1371/journal.pone.0132421.
8. Siehe Fn. 6.
9. Bateman et al. (2014), Chronic fatigue syndrome and comorbid and consequent conditions: evidence from a multi-site clinical epidemiology study, Fatigue: Biomedicine, Health & Behavior, DOI:10.1080/21641846.2014.978109.
10. Fluge et al. (2015), B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with RTX Maintenance Treatment, PlosOne, DOI: 10.1371/journal.pone.0129898.
11. Bradley et al. (2012), Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls, Clinical and Experimental Immunology 172: 73–80, doi:10.1111/cei.12043.
12. Fluge Ø et al. (2017) Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome, JCI Insight. 2017;1(21):e89376. doi:10.1172/jci.insight.89376.
13. Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, et al. (2014), Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome, PLoS ONE 9(1): e85387, doi:10.1371/journal.pone.0085387.
14. Siehe Fn. 3 und 6.
15. https://www.cdc.gov/mmwr/preview/mmwrhtml/00000740.htm, abgerufen am 08. Oktober 2017.
16. Holmes et al. (1988), Chronic fatigue syndrome: a working case definition, Ann Intern Med. 1988 Mar;108(3):387-9, DOI: 10.7326/0003-4819-108-3-387.
17. Siehe Fn. 6.
18. Ramsey et al (1955), An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, Br Med J 1957;2:895, DOI:https://doi.org/10.1136/bmj.2.5050.895.
19. Carruthers et al (2011), Myalgic encephalomyelitis: International Consensus Criteria, J Intern Med. 2011 Oct;270(4):327-38, DOI: 10.1111/j.1365-2796.2011.02428.x.
20. Nakatomi et al (2014), Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study, J Nucl Med. 2014 Jun;55(6):945-50, DOI: 10.2967/jnumed.113.131045.
21. Abigail et al (2013), Contrasting Case Definitions: The ME International Consensus Criteria vs. the Fukuda et al. CFS Criteria, N Am J Psychol. 2013 Mar 1; 15(1): 103–120.
22. Siehe Fn. 6.
23. http://me-pedia.org/wiki/CFIDS, abgerufen am 08. Oktober 2017.

Ten tips for protection against cancer

Deutsch

Quit smoking

Smoking is the biggest preventable risk factor for cancer. Experts estimate that smoking is the cause of 25 to 30 percent of cancer deaths. It is not just about lung cancer, it also showed links between smoking and laryngeal, pancreatic, esophageal and bladder cancer. The risk of developing cancer increases with the number of cigarettes and the length of time that is already being smoked. Several dozen carcinogenic substances have been detected in cigarettes, along with nicotine, nitrosamines, benzene, formaldehyde, arsenic, nickel, cadmium and even radioactive molecules.

Reduce obesity

Not only the right food is important, but also the appropriate amount. Those who permanently consume more energy than they consume use fat. It has been scientifically proven that a body mass index (BMI) of 23 increases the risk of colon cancer. In women overweight after menopause can also lead to increased breast cancer. The most common overweight-prone cancers are also uterine, renal and esophageal cancers.

Avoid alcohol

Too much alcohol can harm almost any organ. It only counts the amount, but not the type of alcohol. Even beer and wine can - drunk in excess - increase the risk of cancer. After all, three percent of cancers are related to alcohol. The cause of the cancer is the acetaldehyde contained in it. Since alcohol is distributed throughout the body, it can damage all organs. Those who drink alcohol regularly increase their risk of breast, intestinal, laryngeal, liver, stomach, mouth and throat as well as esophageal and ovarian cancer.

According to the German Society for Nutrition (DGE) are for men at most 20 grams of alcohol a day tolerated by health, for women a maximum of 10 grams. 20 grams are just under half a liter of beer or a glass of wine.

Especially in connection with tobacco consumption, alcohol is considered a risk factor.

Protect yourself from solar radiation

Intense sunshine carries the greatest risk of skin cancer. The German Cancer Aid advises not to expose children to direct sunlight until the end of their first year of life. In the sun you should always wear sun-tight clothes and a headgear. Basically, the blazing midday sun between 11 and 15 o'clock should be avoided. It is indispensable to cream unprotected parts of the body with a sunscreen starting from SPF 20. "But beware: sunscreens do not protect against skin cancer," emphasizes the cancer aid. Incidentally, the artificial UV radiation in the solarium also damages the skin.

Move a lot

Sport not only protects against overweight and the consequences, but also directly reduces the risk of developing malignant tumors. Those who move regularly have a lower risk of developing colon cancer, breast cancer and uterine cancer. At least three times a week you should be active for half an hour.

Protect liver with hepatitis vaccine

In Europe, about ten percent of all cancers are due to chronic infections with viruses, bacteria, or parasites. This mainly affects cervix cancer, liver cell cancer and gastric cancer. Hepatocellular carcinoma often develops as a result of infection with hepatitis B or C. Especially in children who become infected with hepatitis, the risk increases later, to develop liver cancer. Therefore, the recommendation is to have children vaccinated against hepatitis B. This also makes sense for adults whose relatives are suffering from hepatitis B, who often have changing sexual partners and who work in medical professions.

Reduce cancer risks in the workplace

About four to eight percent of all cancers are due to harmful substances or radiation in the workplace. In order to optimally protect against such dangers, the regulations on the handling of such hazardous substances should be strictly observed and the recommendations of the Federal Office for Radiation Protection should be observed. A classification of hazardous substances and protective measures is contained in the German Hazardous Substances Ordinance.

Know hereditary risk

Ask specific questions about cancer in your family. The predisposition to pathological cell growth is hereditary. Those who know about their risk can be aware of possible changes in good time. Especially affected organs are eyes, intestines, breasts, ovaries and thyroid. In five percent of all cases, experts say, there are genetic factors.

Regular cancer screening

The sooner a cancer is detected, the better the chances of recovery. Use the statutory cancer screening program. These examinations are paid to the statutory health insurance companies:

- Skin cancer: Statutory insured persons over the age of 35 are entitled to a screening of the entire body surface every two years

- Colon cancer: from the 50th Age once a year test for hidden (occult) blood in the stool. From the age of 55 a colonoscopy (colonoscopy), one-time repetition after ten or more years or instead of the colonoscopy from 55 test for occult blood every two years.

- Cervical cancer: from 20 once a year examination of the genitals and smear examination of cervix and cervix.

- Breast cancer: from 30 once a year palpation of the breasts and armpits, instructions for breast self-examination; from 50 up to and including 69 biennial invitations to mammography.

- Prostate cancer: From age 45, once a year, scan the prostate from the rectum, examine the external genitalia and scan the lymph nodes in the groin.

In the case of a hereditary pre-exposure, early detection examinations can also be carried out at other times.

Healthy food/Nutrition

30 to 40 percent of all tumors go back to a wrong diet. According to new studies, the impact of fruits and vegetables is overestimated. It could not be proven that vegetables can prevent cancer. But you should not give up fruits and vegetables because it contains important nutrients for the body. Experts advise eating five servings of fruits and vegetables daily and eating less meat, sausage and fatty dairy products.

Other sources
European Code against Cancer: http://www.europeancancerleagues.org/european-code-against-cancer.html
Arnold, M. et al .: Global burden of cancer attributable to high body mass index in 2012: a population-based study. The Lancet Oncology, online pre-release on November 26, 2014, doi: 10.1016 / S1470-2045 (14) 71123-4
Baldur-Felskov, B. et al.: Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program. Cancer Causes and Control 2014, 25 (7): 915-922
Beuth, J .: Cancer prevention through lifestyle - what is guaranteed? best practice oncology 2013, 5 (8): 6-13
Chilian-Herrera, O.L. et al .: Passive smoking increases the risk of breast cancer among pre- and post-menopausal Mexican women. Presentation at the 3rd "The Science of Cancer Health Disparities" Conference of the American Association for Cancer Research 2010, Abstract A99
Drings, P .: Smoking and Cancer. In: The Oncologist 10 (2), (2004), pp. 156-165
Keum, N. et al .: Visceral Adiposity and Colorectal Adenomas: Dose Response Meta-Analysis of Observational Studies. Annals of Oncology, online pre-release on December 5, 2014, doi: 10.1093 / annonc / mdu563
Schmitz, K.H. et al .: American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors. In: Medicine & Science in Sports & Exercise 42 (7), (2010), pp. 1409-1426

Zehn Tipps zum Schutz vor Krebs

Englisch

Rauchen abgewöhnen

Rauchen ist der größte vermeidbare Risikofaktor für Krebs. Experten schätzen, dass Rauchen die Ursache für 25 bis 30 Prozent der Krebstodesfälle ist. Dabei geht es nicht nur um Lungenkrebs, nachgewiesen wurden auch Zusammenhänge zwischen Rauchen und Kehlkopf-, Bauchspeicheldrüsen-, Speiseröhren- und Blasenkrebs. Das Risiko an Krebs zu erkranken steigt mit der Anzahl der Zigaretten und der Länge der Zeit, über die bereits geraucht wird. Mehrere Dutzend krebserzeugende Substanzen wurden in Zigaretten nachgewiesen, neben Nikotin sind das Nitrosamine, Benzol, Formaldehyd, Arsen, Nickel, Cadmium und sogar radioaktive Moleküle.

Übergewicht abbauen

Nicht nur die richtige Kost ist wichtig, sondern auch die angemessene Menge. Wer dauerhaft mehr Energie aufnimmt, als er verbraucht, setzt Fett an. Wissenschaftlich erwiesen ist, dass ab einem Body-Mass-Index (BMI) von 23 das Dickdarmkrebsrisiko steigt. Bei Frauen kann Übergewicht nach den Wechseljahren auch vermehrt zu Brustkrebs führen. Die häufigsten durch Übergewicht begünstigten Krebsarten sind zudem Gebärmutter-, Nieren- und Speiseröhrenkrebs.

Alkohol abnehmen
Zu viel Alkohol kann nahezu jedem Organ schaden. Dabei zählt nur die Menge, nicht aber die Art des Alkohols. Auch Bier und Wein kann also - im Übermaß getrunken - das Krebsrisiko erhöhen. Immerhin drei Prozent der Krebserkrankungen stehen im Zusammenhang mit Alkohol. Als Krebsauslöser gilt das darin enthaltene Acetaldehyd. Da sich Alkohol im gesamten Körper verteilt, kann er alle Organe schädigen. Wer regelmäßig Alkohol trinkt, erhöht sein Risiko für Brust-, Darm-, Kehlkopf- ,Leber-, Magen-, Mund- und Rachen- sowie Speiseröhren- und Eierstockkrebs.

Nach Angaben der Deutschen Gesellschaft für Ernährung (DGE) sind für Männer höchstens 20 Gramm Alkohol am Tag gesundheitlich verträglich, für Frauen maximal 10 Gramm. 20 Gramm entsprechen knapp einem halben Liter Bier oder einem Glas Wein.

Insbesondere in Verbindung mit Tabakkonsum gilt Alkohol als Risikofaktor.

Vor Sonnenstrahlung schützen

Intensive Sonnenbestrahlung birgt das größte Hautkrebsrisiko. Die Deutsche Krebshilfe rät, Kinder bis Ende des ersten Lebensjahres überhaupt nicht der direkten Sonne auszusetzen. In der Sonne sollte man immer sonnendichte Kleidung und eine Kopfbedeckung tragen. Grundsätzlich sollte die pralle Mittagssonne zwischen 11 und 15 Uhr gemieden werden. Unverzichtbar ist es, ungeschützte Körperstellen mit einem Sonnenschutzmittel ab Lichtschutzfaktor 20 einzucremen. "Aber Achtung: Sonnenschutzmittel schützen nicht vor Hautkrebs", betont die Krebshilfe. Übrigens schadet auch die künstliche UV-Strahlung im Solarium der Haut.

Viel bewegen

Sport schützt nicht nur vor Übergewicht und den Folgen, sondern senkt auch direkt das Risiko, an bösartigen Geschwulsten zu erkranken. Wer sich regelmäßig bewegt, hat ein geringeres Risiko an Dickdarmkrebs, Brustkrebs und Krebs der Gebärmutter zu erkranken. Mindestens dreimal die Woche sollte man sich eine halbe Stunde sportlich betätigen.

Leber mit Hepatitis-Impfung schützen

In Europa gehen etwa zehn Prozent aller Krebserkrankungen auf chronische Infektionen mit Viren, Bakterien, oder Parasiten zurück. Das betrifft hauptsächlich den Gebärmutterhalskrebs, Leberzellkrebs und Magenkrebs. Leberzellkrebs entsteht häufig in Folge einer Infektion mit Hepatitis B oder C. Vor allem bei Kindern, die sich mit Hepatitis infizieren, steigt das Risiko, später an Leberkrebs zu erkranken. Deshalb gilt die Empfehlung, Kinder gegen Hepatitis B impfen zu lassen. Dies ist auch für Erwachsene sinnvoll, deren Angehörige an Hepatitis B erkrankt sind, die häufig wechselnde Sexualpartner haben und die in medizinischen Berufen arbeiten.

Krebsrisiken am Arbeitsplatz reduzieren

Ungefähr vier bis acht Prozent aller Krebserkrankungen gehen auf schädliche Substanzen oder Strahlen am Arbeitsplatz zurück. Um sich optimal vor solchen Gefahren zu schützen, sollten die Vorschriften über den Umgang mit solchen gefährlichen Stoffen genauestens eingehalten und die Empfehlungen des Bundesamtes für Strahlenschutz beachtet werden. Eine Klassifizierung gesundheitsgefährlicher Substanzen und Schutzmaßnahmen enthält die deutsche Gefahrstoffverordnung.

Erbliches Risiko kennen

Fragen Sie in Ihrer Familie gezielt nach Krebserkrankungen. Die Veranlagung zum krankhaften Zellwachstum ist erblich. Wer um sein Risiko weiß, kann rechtzeitig auf mögliche Veränderungen achten. Besonders betroffene Organe sind Augen, Darm, Brust, Eierstöcke und Schilddrüse. In fünf Prozent aller Fälle, so Experten, liegen genetisch bedingte Faktoren vor.

Regelmäßig zur Krebsvorsorge gehen

Je früher eine Krebserkrankung erkannt wird, desto besser stehen die Chancen einer Heilung. Nutzen Sie das gesetzliche Krebsfrüherkennungsprogramm. Diese Untersuchungen werden den gesetzlichen Krankenkassen bezahlt:

- Hautkrebs: Gesetzlich Versicherte ab dem 35. Lebensjahr haben alle zwei Jahre Anspruch auf ein Screening der gesamten Körperoberfläche

- Dickdarmkrebs: ab dem 50. Lebensjahr einmal jährlich Test auf verborgenes (okkultes) Blut im Stuhl. Ab 55 Jahren eine Dickdarmspiegelung (Koloskopie), einmalige Wiederholung nach zehn oder mehr Jahren oder anstelle der Koloskopie ab 55 Test auf okkultes Blut alle zwei Jahre.

- Gebärmutterhalskrebs: ab 20 einmal jährlich Untersuchung der Genitalien und Abstrichuntersuchung von Gebärmuttermund und Gebärmutterhals.

- Brustkrebs: ab 30 einmal jährlich Abtastung der Brüste und der Achselhöhlen, Anleitung zur Brustselbstuntersuchung; ab 50 bis einschließlich 69 alle zwei Jahre Einladung zur Mammographie.

- Prostatakrebs: ab 45 Jahren einmal jährlich Abtastung der Prostata vom Enddarm aus, Untersuchung der äußeren Genitalien und Abtastung der Lymphknoten in der Leiste.

Bei erblicher Vorbelastung können Früherkennungsuntersuchungen auch zu anderen Zeitpunkten durchgeführt werden.

Gesund ernähren

30 bis 40 Prozent aller Tumore gehen auf eine falsche Ernährung zurück. Neuen Studien zufolge wird die Wirkung von Obst und Gemüse überschätzt. Es konnte nicht nachgewiesen werden, dass Gemüse Krebs vorbeugen kann. Auf Obst und Gemüse verzichten sollte man aber nicht, denn es enthält wichtige Nährstoffe für den Körper. Experten raten, fünf Portionen Obst und Gemüse täglich zu sich zu nehmen und dafür weniger Fleisch, Wurst und fetthaltige Milchprodukte zu essen.

Weitere Quellen
European Code against Cancer: http://www.europeancancerleagues.org/european-code-against-cancer.html
Arnold, M. et al.: Global burden of cancer attributable to high body-mass index in 2012: a population-based study. The Lancet Oncology, Onlinevorabveröffentlichung am 26. November 2014, doi:10.1016/S1470-2045(14)71123-4
Baldur-Felskov, B. et al.: Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program. Cancer Causes and Control 2014, 25(7):915-922
Beuth, J.: Krebsprävention durch Lebensführung - was ist gesichert? best practice onkologie 2013, 5(8):6-13
Chilian-Herrera, O. L. et al.: Passive smoking increases the risk of breast cancer among pre- and post-menopausal Mexican women. Präsentation anlässlich der 3. „ The Science of Cancer Health Disparities“ Conference der American Association for Cancer Research 2010, Abstract A99
Drings, P.: Rauchen und Krebs. In: Der Onkologe 10(2), (2004), S. 156-165
Keum, N. et al.: Visceral Adiposity and Colorectal Adenomas: Dose-Response Meta-Analysis of Observational Studies. Annals of Oncology, Onlinevorabveröffentlichung am 5. Dezember 2014, doi: 10.1093/annonc/mdu563
Schmitz, K. H. et al.: American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors. In: Medicine & Science in Sports & Exercise 42(7), (2010), S.1409-1426

These are the most common cancer warning signs

Deutsch

Cancer: These are the most common tumor warning signs. If the cancer remains unrecognized, it can spread further in the body. Every fourth German dies of cancer. 25 percent of all those who died in 2013 died of cancer, as reported by the Federal Statistical Office in Wiesbaden. With almost 224,000 deaths, cancer was the second leading cause of death after cardiovascular disease. Regular screening and knowledge of some warning signs are therefore particularly important.

Men were most likely to die from digestive tract tumors such as gastric or colon cancer (38,987 deaths), followed by lung and bronchial cancers with 30,962 deaths. Among the women, cancers of the digestive organs also led to the highest number of deaths (31,012). In second place followed breast cancer with 17,853 deaths.

More women die from lung cancer

However, more and more women die of lung cancer: over the past 30 years, the number of deaths among women increased from 5491 in 1983 to 15,370 last. That was an increase of 180 percent. A trigger for lung and bronchial cancer is smoking. In men, however, deaths from liver and biliary cancers have increased dramatically over the past three decades (plus 152 percent).

Cancer patients get older

Meanwhile, the average age at death of cancer patients has been rising for years: in 2013, the mortality age was 73.4 years - the highest ever measured. Cancer is increasingly a disease that occurs only at an advanced age. The proportion of cancer patients who were 85 years or older was 17 percent in 2013. Thirty years earlier, this share was just over eight percent.

Bad habits increase the risk

In Germany, around 500,000 people are diagnosed with cancer every year. 51 percent of all men and 43 percent of women in this country have to expect in the course of their life to contract a malignant tumor. The number of cancer cases worldwide is also increasing. The reasons for this are complex: In addition to genetic influences, individual health behavior, environmental factors as well as living and working conditions play a role. Smoking, alcohol, lack of exercise and an unhealthy diet can also promote tumors.

Not every cancer expresses itself with symptoms. For example, the treacherous tumor on the pancreas usually remains unrecognized for a long time. However, those who regularly carry out check-ups have a good chance of being diagnosed with cancer at an early stage. Thus, for example, colon cancer can be detected by a colonoscopy at an earliest stage. Skin cancer screening and cancer screening at the gynecologist should also be taken seriously.

For bleeding and knots to the doctor

One of the most common cancer warning signs is bleeding from the anus or rectum area as well as blood in the urine. These signs should be quickly clarified by a doctor. Behind it could be intestinal or bladder cancer stuck. Gastric cancer, however, often indicates pain in the upper abdomen. Blood in coughing out is a warning sign for lung cancer. Early symptoms may include fatigue, shortness of breath and weight loss, as well as chest pain.

Likewise, knots and indurations should alert. Such in the breast may indicate breast cancer, in the testes they indicate testicular cancer. Permanent complaints when swallowing should also be clarified. Behind them can be a carcinoma stuck to the esophagus. Itchy liver spots or changes in the skin may indicate skin cancer.

Das sind die häufigsten Krebs-Warnzeichen

Englisch

Krebs: Das sind die häufigsten Tumor-Warnzeichen. Bleibt der Krebs unerkannt, kann es sich im Körper weiter ausbreiten. Jeder vierte Deutsche stirbt an Krebs. 25 Prozent aller im Jahr 2013 Verstorbenen erlagen einem Krebsleiden, wie das Statistische Bundesamt in Wiesbaden mitteilt. Mit fast 224.000 Sterbefällen war Krebs nach den Herz-Kreislauferkrankungen damit die zweithäufigste Todesursache. Regelmäßige Vorsorge-Untersuchungen und das Wissen über einige Warnzeichen sind deshalb besonders wichtig. Wir haben die wichtigsten Warnzeichen für Sie aufgelistet: Klicken Sie sich durch!

Männer starben am häufigsten an Tumoren der Verdauungsorgane wie Magen- oder Darmkrebs (38.987 Todesfälle), gefolgt von Lungen- und Bronchialkrebs mit 30.962 Sterbefällen. Auch bei den Frauen führten Krebserkrankungen der Verdauungsorgane zu den meisten Todesfällen (31.012). An zweiter Stelle folgten Brustkrebserkrankungen mit 17.853 Sterbefällen.

Mehr Frauen sterben an Lungenkrebs

Allerdings sterben immer mehr Frauen an Lungenkrebs: In den vergangenen 30 Jahren stieg die Zahl der Sterbefälle bei Frauen von 5491 im Jahr 1983 auf zuletzt 15.370. Das war ein Anstieg um 180 Prozent. Ein Auslöser für Lungen- und Bronchialkrebs ist das Rauchen. Bei Männern nahmen hingegen die Sterbefälle durch Leber- und Gallenkrebs in den vergangenen drei Jahrzehnten drastisch zu (plus 152 Prozent).

Krebskranke werden älter

Das durchschnittliche Sterbealter der Krebskranken steigt indes seit Jahren: 2013 lag das Sterbealter bei 73,4 Jahren - der bislang höchste gemessene Wert. Krebs ist zunehmend eine Erkrankung, die erst im fortgeschrittenen Alter auftritt. Der Anteil der an Krebs gestorbenen Patienten, die 85 Jahre und älter waren, lag 2013 bei 17 Prozent. 30 Jahre zuvor lag dieser Anteil erst bei etwas über acht Prozent.

Schlechte Lebensgewohnheiten steigern das Risiko

In Deutschland erkranken jährlich rund 500.000 Menschen neu an Krebs. 51 Prozent aller Männer und 43 Prozent aller Frauen müssen hierzulande damit rechnen, im Laufe ihres Lebens an einem bösartigen Tumor zu erkranken. Auch weltweit steigt die Zahl der Krebserkrankungen. Die Gründe dafür sind vielschichtig: Neben genetischen Einflüssen spielen das individuelle Gesundheitsverhalten, Umweltfaktoren sowie Lebens- und Arbeitsbedingungen eine Rolle. Auch Rauchen, Alkohol, Bewegungsmangel und eine ungesunde Ernährung können Tumore begünstigen.

Nicht jeder Krebs äußert sich mit Symptomen. So bleibt zum Beispiel der tückische Tumor an der Bauchspeicheldrüse meist lange unerkannt. Wer jedoch regelmäßig Vorsorgeuntersuchungen wahrnimmt, hat gute Chancen, dass ein Krebsleiden frühzeitig erkannt wird. So kann zum Beispiel Darmkrebs durch eine Darmspiegelung schon im frühsten Stadium entdeckt werden. Auch das Hautkrebsscreening und die Krebsvorsorge beim Frauenarzt sollten ernst genommen werden.

Bei Blutungen und Knoten zum Arzt

Zu einem der häufigsten Krebs-Warnzeichen zählen Blutungen aus dem Anus- oder Enddarmbereich sowie Blut im Urin. Diese Anzeichen sollten schnell von einem Arzt abgeklärt werden. Dahinter könnte Darm- oder Blasenkrebs stecken. Auf Magenkrebs deuten hingegen häufig Schmerzen im Oberbauch hin. Blut im Hustenauswurf ist hingegen ein Warnzeichen für Lungenkrebs. Frühe Symptome dafür können auch Abgeschlagenheit, Kurzatmigkeit und Gewichtsverlust sowie Schmerzen im Brustkorb sein.

Ebenso sollten Knoten und Verhärtungen wachsam machen. Solche in der Brust können auf Brustkrebs hinweisen, im Hoden deuten sie auf Hodenkrebs hin. Dauerhafte Beschwerden beim Schlucken sollten ebenfalls abgeklärt werden. Hinter ihnen kann ein Karzinom an der Speiseröhre stecken. Juckende Leberflecken oder Veränderungen einer Hautpartie können auf Hautkrebs hinweisen.

Krebs

Englisch

Krebs bezeichnet in der Medizin die unkontrollierte Vermehrung und das wuchernde Wachstum von Zellen, d. h. eine bösartige Gewebeneubildung (maligne Neoplasie) bzw. einen malignen (bösartigen) Tumor (Krebsgeschwulst, Malignom). Bösartig bedeutet, dass neben der Zellwucherung auch Absiedelung (Metastasierung) und Invasion in gesundes Gewebe stattfindet. Im engeren Sinn sind die malignen epithelialen Tumoren (Karzinome), dann auch die malignen mesenchymalen Tumoren (Sarkome) gemeint. Im weiteren Sinne werden auch die bösartigen Hämoblastosen als Krebs bezeichnet, wie beispielsweise Leukämie als „Blutkrebs“.

Alle sonstigen Tumoren, zu denen auch benigne (gutartige) Neoplasien zählen, werden in der modernen Medizin nicht als Krebs bezeichnet. Diese sind Gewebsvermehrungen oder Raumforderungen im Körper, die keine Metastasen bilden. Das betrifft sowohl die Schwellung bei einer Entzündung als auch gutartige Neoplasien (Neubildungen von Körpergewebe durch Fehlregulationen des Zellwachstums).

Gutartige Tumoren wie Muttermale und Fettgeschwülste (Lipome) werden in der Fachsprache nicht als Krebs bezeichnet, aber sie können trotzdem gefährlich werden, da sie entarten können oder lebenswichtige Organe in deren Funktion beeinträchtigen (etwa der Kleinhirn-Brückenwinkeltumor). Krebs ist im allgemeinen Sprachgebrauch ein Sammelbegriff für eine Vielzahl verwandter Krankheiten, bei denen Körperzellen unkontrolliert wachsen, sich teilen und gesundes Gewebe verdrängen und zerstören können. Dieses Phänomen ist nach aktuellem Stand des Wissens auf Plazenta-Säugetiere beschränkt, sofern man die Hämoblastosen außer Acht lässt. Krebs hat unterschiedliche Auslöser, die letztlich alle zu einer Störung des genetisch geregelten Gleichgewichts zwischen Zellzyklus (Wachstum und Teilung) und Zelltod (Apoptose) führen. Die sich dem Krebs widmende medizinische Fachdisziplin ist die Onkologie.

Vorkommen und Verlauf

Prinzipiell kann jedes Organ des menschlichen Körpers von Krebs befallen werden. Es gibt jedoch erhebliche Häufigkeitsunterschiede nach Alter, Geschlecht, kollektiver Zugehörigkeit, geographischer Region, Ernährungsgewohnheiten und ähnlichen Faktoren. Es gibt über 100 verschiedene Krebsformen. In Deutschland treten Krebserkrankungen gehäuft in Organen wie Brustdrüse (Frauen), Prostata (Männer), Lunge und Dickdarm auf.

Krebs (in Rot dargestellt) ist in Deutschland bei Männern und Frauen die zweithäufigste Todesursache (2012).

Krebs ist in Deutschland nach den Herz-Kreislauferkrankungen die zweithäufigste Todesursache. Dennoch ist nicht jeder Krebsverlauf tödlich, falls rechtzeitig eine Therapie begonnen wird oder ein langsam wachsender Krebs erst in so hohem Lebensalter auftritt, dass der Patient an einer anderen Todesursache verstirbt. Die aktuellen von der Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (GEKID) 2017 veröffentlichten relativen 5-Jahres-Überlebensraten über alle Krebsarten beziehen sich auf Patienten, die 2013 und 2014 erkrankten. Für Frauen lag der Wert bei 65 %, für Männer bei 59 %. In nordeuropäischen Ländern gibt es noch günstigere Werte. In Finnland lagen beispielsweise die 5-Jahres-Überlebensraten von Frauen und Männern, die 2014–2016 erkrankten, bei 68,6 % bzw. 66,3 %. Als geheilt wird in der Onkologie ein Patient bezeichnet, der mindestens fünf Jahre lang ohne Rückfall (Rezidiv) überlebt. Diese Definition von „geheilt“ ist problematisch, weil viele Rückfälle erst zu einem späteren Zeitpunkt erfolgen. Es fließen mithin Patienten in die Krebs-Erfolgsstatistik ein, die später an Krebs sterben. Allerdings nähert sich bei den meisten Krebsarten nach rezidivfrei überlebten fünf Jahren die durchschnittliche Lebenserwartung derjenigen von Gleichaltrigen an.

Eine Krebserkrankung äußert sich in verschiedenen Ausprägungen und Krankheitsbildern. Aus diesem Grund können keine generellen Aussagen bezüglich Lebenserwartung und Heilungschancen getroffen werden. Es sind gegenwärtig etwa 100 verschiedene Krebserkrankungen bekannt, die sich in Überlebenschance, Behandlungsmöglichkeiten und der Neigung zur Bildung von Metastasen teilweise stark unterscheiden.

Die Häufigkeit der meisten Krebserkrankungen nimmt mit dem Alter deutlich zu, so dass man Krebs auch als eine Alterserkrankung des Zellwachstums ansehen kann. Daneben sind das Rauchen, andere karzinogene Noxen, familiäre Disposition (Veranlagung) und Virusinfektionen die Hauptursachen für Krebserkrankungen. Der Nobelpreisträger Harald zur Hausen führt gut 20 Prozent aller Krebserkrankungen auf Infektionen zurück (Humane Papillomviren (HPV), Hepatitis B und C, Helicobacter pylori, EBV, Humanes Herpesvirus 8 (HHV-8), Humanes T-lymphotropes Virus 1 (HTLV-1), bestimmte Parasiten (Blasenkrebs im Nildelta) und Merkelzell-Polyoma-Virus). In Deutschland und den Vereinigten Staaten wird dieser Anteil als deutlich geringer eingeschätzt und mit etwa 5 Prozent angenommen. Der Umstand, ob eine Frau Kinder hat, führt zu einer Reduktion des Krebsrisikos um über 2/3 im Vergleich zu kinderlosen Frauen, bei Männern ist die Reduktion etwas geringer.

Durch Krebsvorbeugung und Früherkennung kann das Krebsrisiko unter bestimmten Umständen (abhängig vom Diagnosezeitpunkt, der Krebsart und einem dafür optimalen Alter des Patienten) deutlich verringert werden.

Krebs ist keinesfalls eine Erkrankung der Neuzeit. Es ist eine evolutionsgeschichtlich gesehen sehr alte Erkrankung, die prinzipiell zumindest alle Säugetiere betreffen kann. Krebs kommt im humanmedizinischen Sinne bei anderen Organismengruppen wie Pflanzen oder Reptilien (die ältesten Tumorbefunde liefern Saurierknochen) wahrscheinlich nicht vor; Gewebswucherungen sind hier eher als benigne Tumoren anzusprechen. Auch die unmittelbaren Vorfahren des Menschen (Homo), wie beispielsweise der Australopithecus (vor 2 bis 4,2 Millionen Jahren), hatten Krebs. Krebserkrankungen haben die Menschheit während der gesamten Evolution begleitet. Im Papyrus Ebers aus der Zeit 1550 vor Christus werden Krebserkrankungen erwähnt.

The world fights against Cancer

About the Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they can also have other causes. Over 100 types of cancers affect humans.

Cancers form a subset of neoplasms. A neoplasm or tumor is a group of cells that have undergone unregulated growth and will often form a mass or lump, but may be distributed diffusely.

All tumor cells show the six hallmarks of cancer. These characteristics are required to produce a malignant tumor. They include:
Cell growth and division absent the proper signals
Continuous growth and division even given contrary signals
Avoidance of programmed cell death
Limitless number of cell divisions
Promoting blood vessel construction
Invasion of tissue and formation of metastases.
The progression from normal cells to cells that can form a detectable mass to outright cancer involves multiple steps known as malignant progression.

Tobacco use is the cause of about 22% of cancer deaths. Another 10% are due to obesity, poor diet, lack of physical activity or excessive drinking of alcohol. Other factors include certain infections, exposure to ionizing radiation and environmental pollutants. In the developing world, 15% of cancers are due to infections such as Helicobacter pylori, hepatitis B, hepatitis C, human papillomavirus infection, Epstein–Barr virus and human immunodeficiency virus(HIV). These factors act, at least partly, by changing the genes of a cell. Typically, many genetic changes are required before cancer develops. Approximately 5–10% of cancers are due to inherited genetic defects from a person's parents. Cancer can be detected by certain signs and symptoms or screening tests. It is then typically further investigated by medical imaging and confirmed by biopsy.

Many cancers can be prevented by not smoking, maintaining a healthy weight, not drinking too much alcohol, eating plenty of vegetables, fruits and whole grains, vaccination against certain infectious diseases, not eating too much processed and red meat and avoiding too much sunlightexposure. Early detection through screening is useful for cervical and colorectal cancer. The benefits of screening in breast cancer are controversial. Cancer is often treated with some combination of radiation therapy, surgery, chemotherapy and targeted therapy. Pain and symptom management are an important part of care. Palliative careis particularly important in people with advanced disease. The chance of survival depends on the type of cancer and extent of disease at the start of treatment.[11] In children under 15 at diagnosis, the five-year survival rate in the developed world is on average 80%. For cancer in the United States, the average five-year survival rate is 66%.

In 2015, about 90.5 million people had cancer. About 14.1 million new cases occur a year (not including skin cancer other than melanoma). It caused about 8.8 million deaths (15.7% of deaths). The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer. In females, the most common types are breast cancer, colorectal cancer, lung cancer and cervical cancer. If skin cancer other than melanoma were included in total new cancer cases each year, it would account for around 40% of cases. In children, acute lymphoblastic leukemia and brain tumors are most common, except in Africa where non-Hodgkin lymphoma occurs more often. In 2012, about 165,000 children under 15 years of age were diagnosed with cancer. The risk of cancer increases significantly with age, and many cancers occur more commonly in developed countries. Rates are increasing as more people live to an old age and as lifestyle changes occur in the developing world. The financial costs of cancer were estimated at $1.16 trillion USD per year as of 2010.

Leukemia

Leukemia is a broad term for cancers of the blood cells. The type of leukemia depends on the type of blood cell that becomes cancer and whether it grows quickly or slowly. Leukemia occurs most often in adults older than 55, but it is also the most common cancer in children younger than 15.

Leukemia is a broad term for cancers of the blood cells. The type of leukemia depends on the type of blood cell that becomes cancer and whether it grows quickly or slowly. Leukemia occurs most often in adults older than 55, but it is also the most common cancer in children younger than 15. Explore the links on this page to learn more about the types of leukemia plus treatment, statistics, research, and clinical trials.

CAUSES & PREVENTION

We do not have PDQ evidence-based information about prevention of leukemia.

Adult Acute Lymphoblastic Leukemia Treatment 

• General Information About Adult Acute Lymphoblastic Leukemia (ALL)
• Cellular Classification of Adult ALL
• Stage Information for Adult ALL
• Treatment Option Overview for ALL
• Treatment for Untreated Adult ALL
• Treatment for Adult ALL in Remission
• Treatment for Recurrent Adult ALL
• Changes to This Summary (02/08/2019)
• About This PDQ Summary

General Information About Adult Acute Lymphoblastic Leukemia (ALL)

• Incidence and Mortality
• Anatomy
• Molecular Genetics
• Diagnosis
• Prognosis and Survival
• Late Effects of Treatment for Adult ALL
• Related Summaries

ALL (also called acute lymphocytic leukemia) is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous system (CNS), and other organs. Without treatment, ALL usually progresses quickly.

Signs and symptoms of ALL may include the following:

• Weakness or fatigue.
• Fever or night sweats.
• Bruises or bleeds easily (i.e., bleeding gums, purplish patches in the skin, or petechiae [flat, pinpoint spots under the skin]).
• Shortness of breath.
• Unexpected weight loss or anorexia.
• Pain in the bones or joints.
• Swollen lymph nodes, particularly lymph nodes in the neck, armpit, or groin, which are usually painless.
• Swelling or discomfort in the abdomen.
• Frequent infections.

ALL occurs in both children and adults. It is the most common type of cancer in children, and treatment results in a good chance for a cure. For adults, the prognosis is not as optimistic. This summary discusses ALL in adults. (Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for more information about ALL in children.)

Incidence and Mortality

Estimated new cases and deaths from ALL in the United States in 2019:[1]

• New cases: 5,930.
• Deaths: 1,500.

Anatomy

ALL presumably arises from malignant transformation of B- or T-cell progenitor cells.[2] It is more commonly seen in children, but can occur at any age. The disease is characterized by the accumulation of lymphoblasts in the marrow or in various extramedullary sites, frequently accompanied by suppression of normal hematopoiesis. B- and T-cell lymphoblastic leukemia cells express surface antigens that parallel their respective lineage developments. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear terminal deoxynucleotide transferase (TdT), while precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.

ENLARGE

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

Molecular Genetics

Some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1).[3] The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL.[4] In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Many patients who have molecular evidence of the BCR-ABL fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The BCR-ABL fusion gene may be detectable only by fluorescence in situ hybridization (FISH) or reverse-transcriptase polymerase chain reaction (RT-PCR) because many patients have a different fusion protein from the one found in CML (p190 vs. p210). These tests should be performed, whenever possible, in patients with ALL, especially in those with B-cell lineage disease.

L3 ALL is associated with a variety of translocations that involve translocation of the c-mycproto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).

Diagnosis

Patients with ALL may present with a variety of hematologic derangements ranging from pancytopenia to hyperleukocytosis. In addition to a history and physical, the initial workup should include:

• Complete blood count with differential.
• A chemistry panel (including uric acid, creatinine, blood urea nitrogen, potassium, phosphate, calcium, bilirubin, and hepatic transaminases).
• Fibrinogen and tests of coagulation as a screen for disseminated intravascular coagulation.
• A careful screen for evidence of active infection.

A bone marrow biopsy and aspirate are routinely performed even in T-cell ALL to determine the extent of marrow involvement. Malignant cells should be sent for conventional cytogenetic studies, as detection of the Ph1 t(9;22), myc gene rearrangements (in Burkitt leukemia), and MLL gene rearrangements add important prognostic information. Flow cytometry should be performed to characterize expression of lineage-defining antigens and allow determination of the specific ALL subtype. In addition, for B-cell disease, the malignant cells should be analyzed using RT-PCR and FISH for evidence of the BCR-ABL fusion gene. This last point is of utmost importance, as timely diagnosis of Ph1 ALL will significantly change the therapeutic approach.

Diagnostic confusion with AML, hairy cell leukemia, and malignant lymphoma is not uncommon. Proper diagnosis is crucial because of the difference in prognosis and treatment of ALL and AML. Immunophenotypic analysis is essential because leukemias that do not express myeloperoxidase include M0 AML, M7 AML, and ALL.

The examination of bone marrow aspirates and/or biopsy specimens should be done by an experienced oncologist, hematologist, hematopathologist, or general pathologist who is capable of interpreting conventional and specially stained specimens.

Prognosis and Survival

Factors associated with prognosis in patients with ALL include the following:

• Age: Age, which is a significant factor in childhood ALL and AML, may be an important prognostic factor in adult ALL. In one study, overall, the prognosis was better in patients younger than 25 years; another study found a better prognosis in patients younger than 35 years. These findings may, in part, be related to the increased incidence of the Ph1 in older ALL patients, a subgroup associated with poor prognosis.[5,6]
• CNS involvement: As in childhood ALL, adult patients with ALL are at risk of developing CNS involvement during the course of their disease. This is particularly true for patients with L3 (Burkitt) morphology.[7] Both treatment and prognosis are influenced by this complication.
• Cellular morphology: Patients with L3 morphology showed improved outcomes, as evidenced in a completed Cancer and Leukemia Group B study (CLB-9251[NCT00002494]), when treated according to specific treatment algorithms.[8,9] This study found that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.[8,10,11]
• Chromosomal abnormalities: Chromosomal abnormalities, including aneuploidy and translocations, have been described and may correlate with prognosis.[12] In particular, patients with Ph1-positive t(9;22) ALL have a poor prognosis and represent more than 30% of adult cases. BCR-ABL-rearranged leukemias that do not demonstrate the classical Ph1 carry a poor prognosis that is similar to those that are Ph1-positive. Patients with Ph1-positive ALL are rarely cured with chemotherapy, although long-term survival is now being routinely reported when such patients are treated with combinations of chemotherapy and BCR-ABL tyrosine kinase inhibitors.
  Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the MLL gene and may be rearranged despite normal cytogenetics, and t(9;22). In addition to t(4;11) and t(9;22), compared with patients with a normal karyotype, patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years.[13] In a multivariate analysis, karyotype was the most important predictor of disease-free survival.[13][Level of evidence: 3iiDii]
• Late Effects of Treatment for Adult ALL
• Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of ALL or AML younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[14]

References

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online
   Exit Disclaimer
   . Last accessed January 23, 2019.
2. Pui CH, Jeha S: New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 6 (2): 149-65, 2007. [PUBMED Abstract]
3. Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976.
4. Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988. [PUBMED Abstract]
5. Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988. [PUBMED Abstract]
6. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988. [PUBMED Abstract]
7. Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988. [PUBMED Abstract]
8. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001. [PUBMED Abstract]
9. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
10. Fenaux P, Lai JL, Miaux O, et al.: Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol 71 (3): 371-6, 1989. [PUBMED Abstract]
11. Reiter A, Schrappe M, Ludwig WD, et al.: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80 (10): 2471-8, 1992. [PUBMED Abstract]
12. Chromosomal abnormalities and their clinical significance in acute lymphoblastic leukemia. Third International Workshop on Chromosomes in Leukemia. Cancer Res 43 (2): 868-73, 1983. [PUBMED Abstract]
13. Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999. [PUBMED Abstract]
14. Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001. [PUBMED Abstract]

Cellular Classification of Adult ALL

The following leukemic cell characteristics are important:

• Morphological features.
• Cytogenetic characteristics.
• Immunologic cell surface and biochemical markers.
• Cytochemistry.

In adults, French-American-British (FAB) L1 morphology (more mature-appearing lymphoblasts) is present in fewer than 50% of patients, and L2 morphology (more immature and pleomorphic) predominates.[1] L3 (Burkitt) acute lymphoblastic leukemia (ALL) is much less common than the other two FAB subtypes. It is characterized by blasts with cytoplasmic vacuolizations and surface expression of immunoglobulin, and the bone marrow often has an appearance described as a starry sky owing to the presence of numerous apoptotic cells. L3 ALL is associated with a variety of translocations that involve translocation of the c-myc proto-oncogene to the immunoglobulin gene locus t(2;8), t(8;12), and t(8;22).

Some patients presenting with acute leukemia may have a cytogenetic abnormality that is morphologically indistinguishable from the Philadelphia chromosome (Ph1).[2] The Ph1 occurs in only 1% to 2% of patients with acute myeloid leukemia (AML), but it occurs in about 20% of adults and a small percentage of children with ALL.[3] In the majority of children and in more than one-half of adults with Ph1-positive ALL, the molecular abnormality is different from that in Ph1-positive chronic myelogenous leukemia (CML).

Many patients who have molecular evidence of the BCR-ABL fusion gene, which characterizes the Ph1, have no evidence of the abnormal chromosome by cytogenetics. The BCR-ABL fusion gene may be detectable only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase chain reaction for the BCR-ABL fusion gene because many patients have a different fusion protein from the one found in CML (p190 vs. p210).

Using heteroantisera and monoclonal antibodies, ALL cells can be divided into several subtypes (see Table 1).[1,4-6]

Table 1. Frequency of Acute Lymphoblastic Leukemia (ALL) Cell Subtypes

Cell Subtype	Approximate Frequency
Early B-cell lineage	80%
T cells	10%–15%
B cells with surface immunoglobulins	<5%

About 95% of all types of ALL (except Burkitt, which usually has an L3 morphology by the FAB classification) have elevated terminal deoxynucleotidyl transferase (TdT) expression. This elevation is extremely useful in diagnosis; if concentrations of the enzyme are not elevated, the diagnosis of ALL is suspect. However, 20% of cases of AML may express TdT; therefore, its usefulness as a lineage marker is limited. Because Burkitt leukemias are managed according to different treatment algorithms, it is important to specifically identify these cases prospectively by their L3 morphology, absence of TdT, and expression of surface immunoglobulin. Patients with Burkitt leukemias will typically have one of the following three chromosomal translocations:

• t(8;14).
• t(2;8).
• t(8;22).

References

1. Brearley RL, Johnson SA, Lister TA: Acute lymphoblastic leukaemia in adults: clinicopathological correlations with the French-American-British (FAB) co-operative group classification. Eur J Cancer 15 (6): 909-14, 1979. [PUBMED Abstract]
2. Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976.
3. Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988. [PUBMED Abstract]
4. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988. [PUBMED Abstract]
5. Sobol RE, Royston I, LeBien TW, et al.: Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies. Blood 65 (3): 730-5, 1985. [PUBMED Abstract]
6. Foon KA, Billing RJ, Terasaki PI, et al.: Immunologic classification of acute lymphoblastic leukemia. Implications for normal lymphoid differentiation. Blood 56 (6): 1120-6, 1980. [PUBMED Abstract]

Stage Information for Adult ALL

There is no clear-cut staging system for this disease. This disease is classified as untreated, in remission, or recurrent.

Untreated Adult ALL

For a newly diagnosed patient with no prior treatment, untreated adult acute lymphoblastic leukemia (ALL) is defined by the following:

• Abnormal white blood cell count and differential.
• Abnormal hematocrit/hemoglobin and platelet counts.
• Abnormal bone marrow with more than 5% blasts.
• Signs and symptoms of the disease.

Adult ALL in Remission

A patient who has received remission-induction treatment of ALL is in remission if all of the following criteria are met:

• Bone marrow is normocellular with no more than 5% blasts.
• There are no signs or symptoms of the disease.
• There are no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.
• All of the following laboratory values are within normal limits:
  • White blood cell count and differential.
  • Hematocrit/hemoglobin level.
  • Platelet count.

Treatment Option Overview for ALL

Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease and the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS).[1,2] The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic therapy) and, in some cases, cranial radiation therapy.

Treatment is divided into the following three phases:

• Remission induction.
• CNS prophylaxis.
• Postremission (also called remission continuation or maintenance).

The average length of treatment for ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. Younger adults with ALL may be eligible for selected clinical trials for childhood ALL. (Refer to the Adolescents and Young Adults With ALL section in the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatmentfor more information.)

Entry into a clinical trial is highly desirable to assure adequate patient treatment and maximal information retrieval from the treatment of this highly responsive, but usually fatal, disease.

Table 2. Standard Treatment Options for Adult Acute Lymphoblastic Leukemia (ALL)

Disease Status	Standard Treatment Options
CNS = central nervous system.
Untreated ALL	Remission induction therapy
	CNS prophylaxis therapy
ALL in remission	Postremission therapy
	CNS prophylaxis therapy
Recurrent ALL	Reinduction chemotherapy followed by allogeneic bone marrow transplantation (alloBMT)
	Blinatumomab followed by alloBMT
	Inotuzumab ozogamicin followed by alloBMT
	Palliative radiation therapy
	Dasatinib

References

1. Clarkson BD, Gee T, Arlin ZA, et al.: Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature. Crit Rev Oncol Hematol 4 (3): 221-48, 1986. [PUBMED Abstract]
2. Hoelzer D, Gale RP: Acute lymphoblastic leukemia in adults: recent progress, future directions. Semin Hematol 24 (1): 27-39, 1987. [PUBMED Abstract]

Treatment for Untreated Adult ALL

• Standard Treatment Options for Untreated Adult ALL
  • Remission induction therapy
  • CNS prophylaxis therapy
• Special Considerations for B-Cell and T-Cell Adult ALL
• Current Clinical Trials

Standard Treatment Options for Untreated Adult ALL

Standard treatment options for untreated adult acute lymphoblastic leukemia (ALL) include the following:

1. Remission induction therapy, including the following:
   • Combination chemotherapy.
   • Imatinib mesylate (for patients with Philadelphia chromosome [Ph1]-positive ALL).
   • Imatinib mesylate combined with combination chemotherapy (for patients with Ph1-positive ALL)
   • Supportive care.
2. Central nervous system (CNS) prophylaxis therapy, including the following:
   • Cranial radiation therapy plus intrathecal (IT) methotrexate.
   • High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
   • IT chemotherapy alone.

Remission induction therapy

Sixty percent to 80% of adults with ALL usually achieve a complete remission status following appropriate induction therapy. Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and an anthracycline, with or without asparaginase, results in a complete response rate of up to 80%. In patients with Ph1-positive ALL, the remission rate is generally greater than 90% when standard induction regimens are combined with BCR-ABL tyrosine kinase inhibitors. In the largest study published to date of Ph1-positive ALL patients, overall survival (OS) for 1,913 adult ALL patients was 39% at 5 years.[1]

Patients who experience a relapse after remission usually die within 1 year, even if a second complete remission is achieved. If there are appropriate available donors and if the patient is younger than 55 years, bone marrow transplantation may be a consideration in the management of this disease.[2] Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.[3] If allogeneic transplant is considered, a recommendation is that transfusions with blood products from a potential donor be avoided, if possible. [4-10]

Combination chemotherapy

Most current induction regimens for patients with adult ALL include combination chemotherapy with prednisone, vincristine, and an anthracycline. Some regimens, including those used in a Cancer and Leukemia Group B (CALGB) study (CLB-8811), also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.[1,4,5,11,12]

Imatinib mesylate

Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in Ph1-positive ALL.[13,14][Level of evidence: 3iiiDiv] More commonly, particularly in younger patients, imatinib is incorporated into combination chemotherapy regimens. There are several published single-arm studies in which the complete response rate and survival are compared with historical controls.

Evidence (imatinib mesylate):

Several studies have suggested that the addition of imatinib to conventional combination chemotherapy induction regimens results in complete response rates, event-free survival rates, and OS rates that are higher than those in historical controls.[15-17] At the present time, no conclusions can be drawn regarding the optimal imatinib dose or schedule.

1. In a study of imatinib combined with chemotherapy from the Northern Italy Leukemia Group, patients with newly diagnosed, untreated Ph1-positive ALL were treated with an induction regimen containing idarubicin, vincristine, prednisone, and L-asparaginase.[18] After accrual of an initial cohort, the study was modified to include the use of imatinib (600 mg qd from days 15 to 21). In consolidation, patients received imatinib (600 mg qd for 7 days) beginning 3 days before the start of each course of chemotherapy.
   • For all patients who achieved remission, the intent was to proceed to allogeneic transplant when and if an HLA-matched donor could be identified. Patients lacking a donor received an autologous transplant. After completion of chemotherapy and transplant, all patients were to receive maintenance imatinib for as long as tolerated. After 20 patients had accrued to the imatinib arm, L-asparaginase was omitted from the induction regimen from both arms because of toxicity.
   • Outcomes for the first cohort of 35 patients (imatinib-free) were compared with those of the subsequent cohort of 59 (imatinib-treated) patients. For patients treated with imatinib, OS probability was 38% at 5 years (median, 3.1 year) versus 23% in the imatinib-free group (median, 1.1 year; P = .009).[18][Level of evidence: 3iii]
   • The drawbacks of this nonrandomized study are the small sample size (94 total patients) and the change in the treatment regimen (omission of L-asparaginase) midway through the study. However, the results suggest that inclusion of imatinib into a relatively standard chemotherapy regimen for newly diagnosed adult patients with Ph1-positive ALL may provide a significant survival advantage.
2. In another study, ten patients with Ph1-positive ALL and ten patients with chronic myelogenous leukemia in lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1,000 mg per day.[13] Of these 20 patients, four had complete hematologic remission and ten had marrow responses. Responses were short lived, with the majority of these patients relapsing at a median of 58 days after the start of therapy.
3. In another study, 48 patients with Ph1-positive ALL were treated with 400 mg to 800 mg of imatinib per day.[14] The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a complete remission. The responses again were short, with a median duration of 2.2 months.

In each of these studies, common toxicities were nausea and liver enzyme abnormalities, which necessitated interruption and/or dose reduction of imatinib.[13,14] (Refer to the PDQ summary on Treatment-Related Nausea and Vomiting for more information.) Subsequent allogeneic transplant does not appear to be adversely affected by the addition of imatinib to the treatment regimen.

Imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL because of the responses observed in monotherapy trials. If a suitable donor is available, allogeneic bone marrow transplantation should be considered because remissions are generally short with conventional ALL chemotherapy clinical trials.

Supportive care

Since myelosuppression is an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support and for the treatment of infectious complications.

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions, when appropriate.[19,20]

Evidence (supportive care):

1. Randomized clinical trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than at a level of 20,000/mm3.[21]
2. The incidence of platelet alloimmunization was similar among groups randomly assigned to receive one of the following from random donors:[22]
   • Pooled platelet concentrates.
   • Filtered, pooled platelet concentrates.
   • Ultraviolet B-irradiated, pooled platelet concentrates.
   • Filtered platelets obtained by apheresis.

Empiric broad-spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[23,24] Careful instruction in personal hygiene and dental care and in recognizing early signs of infection are appropriate for all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization, are not routinely indicated but may benefit transplant patients.[25,26]

Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.[27] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks), though further studies are necessary.[28] Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms in these patients.

As suggested in a CALGB study (CLB-9111), the use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.[29,30]

CNS prophylaxis therapy

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.

Special Considerations for B-Cell and T-Cell Adult ALL

Two additional subtypes of adult ALL require special consideration. B-cell ALL, which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22), is not usually cured with typical ALL regimens. Aggressive brief-duration high-intensity regimens, including those previously used in CLB-9251 (NCT00002494), that are similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% complete response; 40% failure-free survival).[31-33] Similarly, T-cell ALL, including lymphoblastic lymphoma, has shown high cure rates when treated with cyclophosphamide-containing regimens.[4]

Whenever possible, patients with B-cell or T-cell ALL should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma and Lymphoblastic lymphomasections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008. [PUBMED Abstract]
2. Bortin MM, Horowitz MM, Gale RP, et al.: Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 268 (5): 607-12, 1992. [PUBMED Abstract]
3. Horowitz MM, Przepiorka D, Champlin RE, et al.: Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 79 (10): 2771-4, 1992. [PUBMED Abstract]
4. Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995. [PUBMED Abstract]
5. Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991. [PUBMED Abstract]
6. Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989. [PUBMED Abstract]
7. Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983. [PUBMED Abstract]
8. Jacobs AD, Gale RP: Recent advances in the biology and treatment of acute lymphoblastic leukemia in adults. N Engl J Med 311 (19): 1219-31, 1984. [PUBMED Abstract]
9. Doney K, Buckner CD, Kopecky KJ, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission. Bone Marrow Transplant 2 (4): 355-63, 1987. [PUBMED Abstract]
10. Vernant JP, Marit G, Maraninchi D, et al.: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6 (2): 227-31, 1988. [PUBMED Abstract]
11. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988. [PUBMED Abstract]
12. Kantarjian H, Thomas D, O'Brien S, et al.: Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 101 (12): 2788-801, 2004. [PUBMED Abstract]
13. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001. [PUBMED Abstract]
14. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002. [PUBMED Abstract]
15. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004. [PUBMED Abstract]
16. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006. [PUBMED Abstract]
17. Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006. [PUBMED Abstract]
18. Bassan R, Rossi G, Pogliani EM, et al.: Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol 28 (22): 3644-52, 2010. [PUBMED Abstract]
19. Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980. [PUBMED Abstract]
20. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986. [PUBMED Abstract]
21. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997. [PUBMED Abstract]
22. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997. [PUBMED Abstract]
23. Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990. [PUBMED Abstract]
24. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988. [PUBMED Abstract]
25. Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984. [PUBMED Abstract]
26. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987. [PUBMED Abstract]
27. Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990. [PUBMED Abstract]
28. Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981. [PUBMED Abstract]
29. Scherrer R, Geissler K, Kyrle PA, et al.: Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL). Ann Hematol 66 (6): 283-9, 1993. [PUBMED Abstract]
30. Larson RA, Dodge RK, Linker CA, et al.: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92 (5): 1556-64, 1998. [PUBMED Abstract]
31. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
32. Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001. [PUBMED Abstract]
33. Thomas DA, Cortes J, O'Brien S, et al.: Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol 17 (8): 2461-70, 1999. [PUBMED Abstract]

Treatment for Adult ALL in Remission

• Standard Treatment Options for Adult ALL in Remission
• Postremission therapy
• CNS prophylaxis therapy
• Current Clinical Trials

Standard Treatment Options for Adult ALL in Remission

Standard treatment options for adult acute lymphoblastic leukemia (ALL) in remission include the following:

1. Postremission therapy, including the following:
   • Chemotherapy.
   • Ongoing treatment with a BCR-ABL tyrosine kinase inhibitor, such as imatinib, nilotinib, or dasatinib.
   • Autologous or allogeneic bone marrow transplant (BMT).
2. Central nervous system (CNS) prophylaxis therapy, including the following:
   • Cranial radiation therapy plus intrathecal (IT) methotrexate.
   • High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
   • IT chemotherapy alone.

Postremission therapy

Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:

• Longer-term therapy at lower doses (maintenance therapy).
• Allogeneic bone marrow transplant.

Because the optimal postremission therapy for patients with ALL is still unclear, a consideration is participation in clinical trials. (Refer to the B-cell [Burkitt] lymphoma] section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Evidence (chemotherapy):

1. Several trials, including studies from the Cancer and Leukemia Group B (CLB-8811) and the completed European Cooperative Oncology Group (ECOG-2993[NCT00002514]), of aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.[1-7]
   • In two series,[4,5] especially good prognoses were found for patients with T-cell lineage ALL, with DFS rates of 50% to 70% for patients receiving postremission therapy.
   • These series represent a significant improvement in DFS rates over previous, less intensive chemotherapeutic approaches.
2. In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11).

Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications are necessary. Studies in which continuation or maintenance chemotherapy was eliminated had outcomes inferior to those with extended treatment durations.[8,9] Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.[10-12]

Evidence (allogeneic and autologous BMT):

AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.[13]

1. The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high-risk or Ph1-positive ALL.[14-17] This was confirmed in the ECOG-2993(NCT01505699) study.[7]
   • The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decade.
   • The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.
2. Following on the results of earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively; patients were accrued from 1993 to 2006.[7] Patients with Ph1-negative ALL between the ages of 15 years and 59 years received identical multiagent induction therapy resembling previously published regimens.[1-3] Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation therapy. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS); event-free survival, relapse rate, and nonrelapse mortality were secondary outcomes. A total of 1,929 patients were registered and stratified according to age, white blood cell (WBC) count, and time to remission. High-risk patients were defined as those having a high WBC count at presentation or those older than 35 years.
   1. Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 had an HLA-identical sibling, 310 of whom underwent an alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT.
   2. By donor-to-no-donor analysis, standard-risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01).
   3. In a subgroup analysis, the advantage for patients with standard-risk ALL who had donors remained significant (OS = 62% vs. 52%; P = .02).
      • For patients with high-risk disease (older than 35 years or high WBC count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2).
      • Relapse rates were significantly lower (P < .00005) for both standard- and high-risk patients with HLA-matched donors.
   4. In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-year OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03).
   5. The results of this trial suggest the existence of a graft-versus-leukemia effect for adult Ph1-negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long-term survival for patients with standard-risk adult ALL in first remission.[7][Level of evidence: 2A]
   6. The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[7][Level of evidence: 2A]

The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, it is reserved for patients in second remission or beyond. The dose of total-body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[18][Level of evidence: 3iiB]

Evidence (B-cell ALL):

Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged DFS for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).[19]

1. Retrospectively reviewing three sequential cooperative group trials from Germany, one group of investigators found the following:[19]
   • A marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in two subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months.

CNS prophylaxis therapy

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.[20]

Aggressive CNS prophylaxis remains a prominent component of treatment.[19] This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin and L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype, but unusual cytogenetic features, were not cured with this approach. A WBC count of less than 50,000 per microliter predicted improved leukemia-free survival in a univariate analysis.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. 

References

1. Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988. [PUBMED Abstract]
2. Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988. [PUBMED Abstract]
3. Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991. [PUBMED Abstract]
4. Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995. [PUBMED Abstract]
5. Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995. [PUBMED Abstract]
6. Kantarjian H, Thomas D, O'Brien S, et al.: Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 101 (12): 2788-801, 2004. [PUBMED Abstract]
7. Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008. [PUBMED Abstract]
8. Cuttner J, Mick R, Budman DR, et al.: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia 5 (5): 425-31, 1991. [PUBMED Abstract]
9. Dekker AW, van't Veer MB, Sizoo W, et al.: Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol 15 (2): 476-82, 1997. [PUBMED Abstract]
10. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004. [PUBMED Abstract]
11. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006. [PUBMED Abstract]
12. Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006. [PUBMED Abstract]
13. Finiewicz KJ, Larson RA: Dose-intensive therapy for adult acute lymphoblastic leukemia. Semin Oncol 26 (1): 6-20, 1999. [PUBMED Abstract]
14. Horowitz MM, Messerer D, Hoelzer D, et al.: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115 (1): 13-8, 1991. [PUBMED Abstract]
15. Sebban C, Lepage E, Vernant JP, et al.: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 12 (12): 2580-7, 1994. [PUBMED Abstract]
16. Forman SJ, O'Donnell MR, Nademanee AP, et al.: Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 70 (2): 587-8, 1987. [PUBMED Abstract]
17. Fière D, Lepage E, Sebban C, et al.: Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11 (10): 1990-2001, 1993. [PUBMED Abstract]
18. Corvò R, Paoli G, Barra S, et al.: Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys 43 (3): 497-503, 1999. [PUBMED Abstract]
19. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
20. Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988. [PUBMED Abstract]

Treatment for Recurrent Adult ALL

• Standard Treatment Options for Recurrent Adult ALL
  • Inotuzumab ozogamicin followed by alloBMT
  • Palliative radiation therapy
  • Dasatinib
• Blinatumomab followed by alloBMT
• Reinduction chemotherapy followed by alloBMT
• Treatment Options Under Clinical Evaluation for Recurrent Adult ALL
• Current Clinical Trials

Standard Treatment Options for Recurrent Adult ALL

Standard treatment options for recurrent adult acute lymphoblastic leukemia (ALL) include the following:

1. Reinduction chemotherapy followed by allogeneic bone marrow transplantation (alloBMT).
2. Blinatumomab followed by alloBMT.
3. Inotuzumab ozogamicin followed by alloBMT.
4. Palliative radiation therapy (for patients with symptomatic recurrence).
5. Dasatinib (for patients with Philadelphia chromosome [Ph1]-positive ALL).

Reinduction chemotherapy followed by alloBMT

Patients with ALL who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by alloBMT.

Blinatumomab followed by alloBMT

Blinatumomab is a bispecific antibody targeting CD19 and CD3 with approval by the U.S. Food and Drug Administration (FDA) for use in patients with relapsed or refractory B-cell ALL.

Evidence (blinatumomab):

1. A randomized phase III study of blinatumomab versus one of four standard reinduction regimens was conducted in patients with primary refractory disease, which was refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.[1] The four regimens included the following: fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline; a high-dose cytosine arabinoside–based regimen; a high-dose methotrexate-based regimen; or a clofarabine-based regimen.
   • Remission rates were 43.9% for the blinatumomab-treated group versus 24.6% in the standard-treatment group (odds ratio, 2.40; 95% confidence interval [CI], 1.51–3.80).
   • Overall survival (OS) was superior in the blinatumomab-treated group (7.7 months vs. 4.0 months in the standard-treatment group) with a hazard ratio (HR) of .71 (95% CI, 0.55–0.93), favoring blinatumomab.
   • Adverse events occurred at similar rates in both groups, and the only unique side effect of blinatumomab was cytokine-release syndrome, which was seen in 4.9% of patients.

Blinatumomab should be considered as an option for reinduction therapy for patients with primary refractory disease, which is refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.[1][Level of evidence: 1iiA]

Inotuzumab ozogamicin followed by alloBMT

Inotuzumab ozogamicin is an antibody-drug conjugate targeting CD22, which contains a conjugated toxin, calicheamicin. Inotuzumab ozogamicin is approved by the FDA for use in patients with relapsed or refractory B-cell ALL with CD22 expression.

Evidence (inotuzumab ozogamicin):

1. A randomized phase III study of inotuzumab ozogamicin versus one of three standard reinduction regimens was conducted with 218 patients, age 18 or older, who had relapsed or refractory disease and were to receive their first or second salvage regimen.[2] The three standard regimens consisted of fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG), cytarabine and mitoxantrone, or high dose cytarabine.
   • Complete remission or complete remission with incomplete count recovery rates were 80.7% (95% CI, 72.1%–87.7%) for the inotuzumab group versus 29.4% (95% CI, 21.0%–38.8%) in the standard-treatment group (P < .001).
   • Progression-free survival was superior in the inotuzumab-treated group (5.0 months vs. 1.8 months in the standard-treatment group) with an HR of 0.45 (97.5 CI, 0.34–0.61; P < .001).
   • Duration of remission was short in both groups; duration in the inotuzumab group was 4.6 months (95% CI, 3.9–5.4) and duration in the standard chemotherapy group was 3.1 months (95% CI, 1.4–4.9).
   • Of the 48 patients in the inotuzumab arm who proceeded to transplantation after therapy, 10 developed veno-occlusive disease. Of the 20 patients who proceeded to transplantation after remission on the standard chemotherapy arm, 1 developed veno-occlusive disease after transplantation.
   • OS was not statistically prolonged in the inotuzumab group (7.7 months in the inotuzumab group vs. 6.7 months in the standard-treatment group) (HR, 0.77; 97.5% CI, 0.58–1.03; P = .04) because of a failure to meet a study-prespecified boundary of P = .0208.
   • Adverse events (≥grade 3) involving the liver were higher in the inotuzumab group with 11% of patients experiencing veno-occlusive disease of the liver compared with 1% in the standard-treatment group.

Inotuzumab ozogamicin should be considered as an option for reinduction for patients with relapsed or refractory CD22-positive ALL.[2][Level of evidence: 1iiD]

Palliative radiation therapy

Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.[3]

Dasatinib

Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR-ABL mutations, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leukemia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL.

Evidence (dasatinib):

1. In one study, ten patients were treated with dose-escalated dasatinib.[4] Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood cell counts), three of whom had a complete cytogenetic response.
   • The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%).
   • Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.

Treatment Options Under Clinical Evaluation for Recurrent Adult ALL

Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying the following:[5-11]

1. Autologous transplantation.
2. Immunomodulation.
3. Chimeric antigen receptor (CAR) T-cell therapy.[12]
4. Novel chemotherapeutic or biological agents.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Kantarjian H, Stein A, Gökbuget N, et al.: Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med 376 (9): 836-847, 2017. [PUBMED Abstract]
2. Kantarjian HM, DeAngelo DJ, Stelljes M, et al.: Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 375 (8): 740-53, 2016. [PUBMED Abstract]
3. Gray JR, Wallner KE: Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. Int J Radiat Oncol Biol Phys 19 (2): 439-44, 1990. [PUBMED Abstract]
4. Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006. [PUBMED Abstract]
5. Herzig RH, Bortin MM, Barrett AJ, et al.: Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1 (8536): 786-9, 1987. [PUBMED Abstract]
6. Thomas ED, Sanders JE, Flournoy N, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up. Blood 62 (5): 1139-41, 1983. [PUBMED Abstract]
7. Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989. [PUBMED Abstract]
8. Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983. [PUBMED Abstract]
9. Sallan SE, Niemeyer CM, Billett AL, et al.: Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 7 (11): 1594-601, 1989. [PUBMED Abstract]
10. Paciucci PA, Keaveney C, Cuttner J, et al.: Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia. Cancer Res 47 (19): 5234-7, 1987. [PUBMED Abstract]
11. Biggs JC, Horowitz MM, Gale RP, et al.: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80 (4): 1090-3, 1992. [PUBMED Abstract]
12. Maude SL, Frey N, Shaw PA, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371 (16): 1507-17, 2014. [PUBMED Abstract]