CHRONIC MYELOID LEUKEMIA HISTORICAL PERESPECTIVE

D MANAL BESSAM MD HEMATOLOGY, ALEXANDRIA UNIVERSITY , EGYPT

Claim of priorityIt is generally agreed that Alfred Velpeau in France had the first

detailed description of what must have been leukemia in 1827 with

clinical observations of 63-years old lemonade salesman who

presented with gross hepatosplenomegaly and was noted to have

“globules of pus” in his blood.

The precise diagnosis, however, remained elusive.

Velpeau A. Rev Med. 1827;2:216.

In 1841 David Craigie in Glasgow saw a

patient with fever, splenomegaly, and leukocytosis;

he saw a second similar patient 3 years later and

this led his colleague John Bennett, a physician

and pathologist, to perform an autopsy and to

describe his findings in 1845 in the Edinburgh

Medical and Surgical Journal.

Cover of the Edinburgh Medical and Surgical Journalwhere the cases of Craigie and Bennett were first reported.

Edinburgh Med Surg J. 1845;64:413–23.

Simultaneously, Rudolph Virchow saw a similar patient in Berlin.

The patient died 4 months later and he noted at autopsy

enlargement of the spleen.

Virchow R. Weisses Blut. Frorieps Notizen. 1845;36:151–6.

Although one cannot know for sure, these two patients probably

represent the first descriptions of the disease that later became

known as chronic myeloid leukemia (CML).

While Bennet thought that the patient had an infection, Virchow

suspected a neoplastic disorder that he soon called white blood

disease or leukemia.

An important development occurred in 1872 when Ernst Neumann

recognized that the leukemia originated in the bone marrow.Bennett JH. Edinburgh: Sutherland and Knox; 1852.

A real quantum leap, however, was in 1960,

the discovery by Philadelphia cytogeneticists,

Peter Nowel and David Hungerford of an

abnormally small G-group chromosome that we

now call the Philadelphia chromosome

(Ph).

This was a seminal step, as for the first time in

the history of Medicine, the association

between a chromosome abnormality and a

malignant disease was described.Nowell PC, et al. Science. 1960;132:1497.

Thirteen years later; Janet Rowley, MD,

discovered the missing piece of chromosome

number 22 attached to chromosome number 9,

thereby identifying the first known reciprocal

chromosomal translocation (9;22) translocation

found in the leukemic cells of more than 95% of

patients with CML.

Rowley JD. Nature. 1973; 243:290–3.

As the field of genetics grew, it was

discovered that the gene abl (pronounced

"able"), normally located on chromosome 9,

had attached itself to the gene bcr

(pronounced "b-c-r") on chromosome 22.

The bcr-abl fusion gene encodes a

protein p210 (called tyrosine kinase),

de Klein A, et al. Blood. 1986;68:1369–75

The milestone of unravelling the biology of CML

Goldman JM ,Seminars in Hematology, 2010, pp 302–311

Treatment of CML Historical perspectives

Initial Efforts aimed to control the symptoms attributed to CML

It began with the use of arsenicals by Thomas Fowler in 1865, and Arthur Doylein in

1882,

and continued in the first half of the 20th century with:

Radiation therapy to the spleen in 1902,

Antileukocyte sera in 1932,

Benzene in 1935,

Urethane in 1950 and

Leukapheresis in the 1960s John M. Goldman .Semin Hematol 2010 ,47:302–311.

Busulfan Busulfan, an alkylating agent, was introduced by David

Galton in London in 1953. Galton then carried out the first

prospective randomized study in CML, comparing busulfan

and splenic radiation, and showed improved survival in

the busulfan cohort.

Galton DA. Lancet. 1953;264:208–13.

Hydroxycarbamide (hydroxyurea)

In the mid-1960s, busulfan was replaced by hydroxycarbamide

(previously hydroxyurea), a ribonucleotide reductase inhibitor,

following recognition that busulfan is mutagenic, and a randomized

study confirming the superiority of hydroxycarbamide, though neither

drug was able to reduce the proportion of Ph positive cells or prolong

overall survival.

Goldman JM, et al. leukaemia. Lancet. 1982;2:623–5.

A breakthrough was achieved in the mid 1970s when the Seattle group

reported the disappearance of the Ph chromosome in CML patients who

underwent allotransplant.

Allo-BMT representing the first curative modality, with a transplant-related

mortality of 10% to 20% at one year and five-year survival of approximately 60%.

As from 1990, AHSCT became the treatment of choice for CP patients less than

50 years old, and IFN, whether in combination with cytarabine or not, was

reserved for patients not eligible for AHSCT

Allogeneic SCT

Goldman JM, et al. leukaemia. Lancet. 1982;2:623–5.

John Goldman originally made seminal contributions to the use of

autologous and allogeneic stem cell transplantation from the late

1970s onwards.

Then, in collaboration with Brian Druker, he led efforts to develop

ABL1 tyrosine kinase inhibitors for the treatment of patients with

CML in the late 1990s.

He also led the global efforts to develop and harmonize

methodology for molecular monitoring.

Goldman JM, et al. J Clin Oncol. 2010;28: 1888–95.

Interferon alpha (IFN-α) was introduced into the clinics in the mid-1980s and

proved popular, despite frequent side-effects such as flu-like symptoms and

fatigue.

In the early 1990s, several randomized studies comparing IFN-α with

hydroxycarbamide or busulfan were undertaken and demonstrated an

improvement in overall survival by about 2-3 years with IFN-α.

In addition, a French study testing the addition of cytarabine to IFN-2b found

this to result in an increased proportion of patients achieving a cytogenetic

Response.

Interferon

Talpaz M, et al. N Engl J Med. 1986;314:1065–9.

In 1992, Alexander Levitzki proposed the use of ABL inhibitors to treat leukemias driven by ABL

oncogenes.

At about the same time, scientists at Ciba-Geigy had synthesized a potent inhibitor of ABL that

was termed GCP57148B and is now known as imatinib.

Clinical trials initiated by Brian Druker, much against the skepticism of the manufacturer,

rapidly established the compound’s activity in patients with CML and revolutionized CML

therapy.

CML then became the first disease model of the so-called targeted therapy.

ABL inhibitors

Anafi M, et al. J Biol Chem. 1992;267:4518–23.

Imatinib was first used in 1998 to treat IFN-resistant patients.

The successful results of this small study led to the development of the IRIS study

(International Randomized Study of Interferon and STI 571), which demonstrated the

superiority of imatinib 400 mg/day in relation to the IFN and cytarabine combination,

regarding the rates of: Cytogenetic response (CyR), Event-free survival (EFS),

Progression-free survival(PFS) & Overall survival (OS).

After the year of 2000, imatinib, at 400 mg/day, became the first-choice treatment for patients

with CP CML.

Imatinib

Kantarjian H, et al. N Engl J Med. 2002;346(9):645 - 652.

Response Criteria to Imatinib Therapy

The next generation-TKI storyFurther research into the imatinib story has shown that only about 60% of CML patients

remain on the standard dosages of imatinib after six years, implying that about 40% have

required an alternative treatment or higher doses of imatinib.

In 2004, both nilotinib and dasatinib entered studies of patients who were resistant or

intolerant to imatinib at standard dosages.

The efficacy, but not the toxicity, of both drugs was fairly similar, with about 45% of the

imatinib-resistant patients achieving CCyR and a 4-year overall survival of 78%.

The results for the imatinib-intolerant group were slightly better for both drugsBradeen HA, et al. Blood. 2006;108(7):2332-2338.

The next generation-TKI story

Following these encouraging results, both nilotinib and dasatinib entered clinical trials for first-

line therapy of newly diagnosed patients in 2006.

Nilotinib at two dosages, either 300 mg BID or 400 mgBID, was tested against imatinib 400

mg/day in the “ Evaluating Nilotinib Efficacy and Safety in Newly Diagnosed Patients ” (ENESTnd) randomized study.

Dasatinib was tested at a dose of 100 mg/day in a trial known as “ Dasatinib versus

Imatinib Study in Treatment-Naïve CML Patients ” (DASISION).

Both drugs were licensed for first-line use in patients with CML in the chronic phase in 2010.Talpaz M, et al. N Engl J Med. 2006;354(24):2531-2541.Saglio G, et al.Engl J Med. 2010;362(24):2251-2259.

Bosutinib

The newest of the 2nd-generation TKIs, bosutinib, an oral

dual ABL1 and SRC inhibitor, the drug was approved in

2012 for the treatment of adult CML patients with chronic

phase or advanced phase disease who were resistant to

prior TKI therapy.

Kantarjian HM, et al. Blood. 2014;123(9):1309- 1318.

oPonatinib is a 3rd-generation TKI, It was developed initially for patients who were

considered to have become resistant to TKIs as a result of T315I subclone.

oThe drug was licensed in December 2012 for patients with CML in the chronic or advanced

phases resistant or intolerant to prior TKI therapy and Ph-chromosome positive ALL

resistant or intolerant to prior TKI therapy.

oThis approval constituted ponatinib to be the only licensed TKI with activity against the

T315I subclone.

Ponatinib

Lipton JH, et al. Blood. 2014;124(21): 519.

oUnfortunately, in October 2013, concerns about excessive arterial

vascular events led to the suspension of the drug.

oIn early 2014, despite these serious risks, ponatinib was re-licensed

exclusively for the treatment of adult patients with T315I-positive

CML in all phases.

Ponatinib

Lipton JH, et al. Blood. 2014;124(21): 519.

Survival with chronic myeloid leukemia over time (1993-2013): the German CML-

Study Group experience

Courtesy of Prof H Kantarjian; adapted, with permission, from Harrison’s Principles of Internal Medicine, 2014.

To concludeIt is clear now that though little progress was made in the 19th century,

tremendous advances were made in the last half of the 20th century in

unraveling the cytogenetic and molecular basis of the chronic phase of CML.

This progress led to the introduction of drugs that have dramatically

changed the prognosis for patients with newly diagnosed CML

To conclude:The CML story is richly studded with insight, innovation and

scientific breakthroughs.

However, there is much work to be done in order to continue the

story that was initiated by Janet Rowley and John Goldman.