2. Claim of priority
It 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.
3. 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 Journal
where the cases of Craigie and Bennett were first reported.
Edinburgh Med Surg J. 1845;64:413–23.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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
9. The milestone of unravelling the
biology of CML
Goldman JM ,Seminars in Hematology, 2010, pp 302–311
11. 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.
12. 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.
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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
20. The next generation-TKI story
Further 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 drugs
Bradeen HA, et al. Blood. 2006;108(7):2332-2338.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. To conclude
It 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
27. 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.
