**2. The advent of chemotherapy**

In 1948, based on the evidence that AL children receiving folic acid did worsen, Dr. Farber proposed the first rational treatment for AL [2, 5]. He correctly guessed


#### **Table 2.**

*Development of anti-leukemia treatments (adapted from Paul S. Gaynon, Toska J. Zomorodian, and Donald Pinkel. History of leukemia: Historical perspectives. In childhood Leukemias: Third edition, by Ching-hon Pui, Ed. Cambridge university press 978–0–521-19661-1).*

**5**

*Introductory Chapter: A Brief History of Acute Leukemias Treatment*

1873 Blood transfusion first applied to leukemic patients (*Callender*) 1901 First description of human blood groups (*Landsteiner*)

1968 First successful sibling donor bone marrow transplant (immunodeficiency) 1972 First successful matched sibling donor marrow transplantation (aplastic anemia)

1983 First successful haploidentical T-cell depleted bone marrow transplant

lymphoblastic leukemia in children and young adults.

1977 Evidence of survivals >1 for 18/110 patients with advanced leukemia transplanted from matched

1979 Report of Success >50% for matched sibling donor marrow transplantation for acute myeloid

2017 The FDA approves CD19-directed CAR T cells for the treatment of relapsed, refractory acute

1957 First successful syngeneic bone marrow transplantation

1974 Anthony Nolan Bone Marrow Donor Registry (UK)

1986 National Marrow Donor Registry Program (USA)

1989 First successful transplant using umbilical cord blood 1997 First reduced-intensity bone marrow transplantation

that blocking folic acid metabolism could on the contrary avoid leukemic cells growth. Based on that, he wrote "we may now with some justice hope that aminopterin, or some as yet unsynthesized substance related to it, will afford a substantial

Despite Farber intuition, the prognosis of AL patients remained very poor throughout the 1950s and the 1960s. When Boggs, Wintrobe, and Cartwright examined the overall outcome of AL patients treated with 6- mercaptopurine (6-MP) and methotrexate, they were discouraged, and concluded that, "*the possibility of spontaneous remission must be entertained whenever a patient with acute leukemia becomes apparently well yet, so far as known, practically all such patients subsequently died in relapse. Of the extremely rare case in which the patient did not die, it may be said* 

Conversely, in the pediatric setting, progressive and impressive improvements were seen starting in the 1960s, especially due to the big efforts of Don Pinkel and Colleagues at St. Jude Institute [7, 8]. Particularly, they systematically changed and improved their chemotherapy regimens, documenting a terrific improvement in a few decades in the prognosis of children affected by AL, an almost invariably fatal

By contrast, the prognosis remained dismal in adults. However, largely following pediatric studies, the treatment of lymphoid (ALL) and non-lymphoid (myeloid, AML) leukemias became progressively distinct. Eventually, in 1973, the combination of daunorubicin and cytarabine, administered according to the 3 + 7 scheme was documented to be effective in acute myeloid leukemia [9], while post-induction intensification was further developed for ALL (see a schematic timeline of anti-

In the 1950s, pre-clinical experiments led to the evidences that bone marrow engraftment after sub-lethal irradiation was associated to leukemia disappearance

basis for real hope in this now hopeless disease" [5].

*Evolution of transfusion services and stem cell transplantation.*

*that the original diagnosis was incorrect*" [2, 6].

leukemia treatments development in **Table 2**).

disease till then [7, 8].

*DOI: http://dx.doi.org/10.5772/intechopen.96439*

1954 Introduction of platelet transfusion

leukemia in first remission

2002 First generation CAR-T cells

**Table 3.**

**Date Development**

1937 First hospital blood bank

donors

*Introductory Chapter: A Brief History of Acute Leukemias Treatment DOI: http://dx.doi.org/10.5772/intechopen.96439*


#### **Table 3.**

*Acute Leukemias*

**Year Development**

leukemia

**2. The advent of chemotherapy**

transfusion 1943 Isolation of folic acid

 Prednisone licensed by FDA Dexamethasone licensed by FDA Cyclophosphamide licensed by FDA Vincristine licensed by FDA Cytarabine licensed by FDA

 Native L-asparaginase licensed by FDA Daunorubicin licensed by FDA Etoposide licensed by FDA Mitoxantrone licensed by FDA

1994 Pegylated L-asparaginase licensed by FDA

*\*During XXI century, several novel targeted agents were then approved.*

*Ed. Cambridge university press 978–0–521-19661-1).*

1995 All-trans-retinoic acid approved for acute promyelocytic leukemia 2000 Arsenic trioxide licensed for acute promyelocytic leukemia by FDA 2001 Imatinib licensed for chronic myelogenous leukemia by FDA\*

*Development of anti-leukemia treatments (adapted from Paul S. Gaynon, Toska J. Zomorodian, and Donald Pinkel. History of leukemia: Historical perspectives. In childhood Leukemias: Third edition, by Ching-hon Pui,* 

1865 *Heinrich Lissauer* administered potassium arsenite to a woman with chronic myelogenous

as the first stem cell transplant, rather than on anti-leukemic agents only.

In 1930, Dr. Gloor from the Naegeli's clinic in Zurich [3], described "*the case of an American businessman*" whose white blood cell count reached 100x109

with fever and anemia, a classical presentation of AL [2, 3]. He received radiation, arsenic, and mesothorium, and blood transfusion, achieving complete remission. Curiously (and possibly dramatically), when Dr. Gloor tried to publish this first successfully treated AL case, he lost his job and was outcasted in a small clinic in a peripheral canton, only a "fool or a knave" [2] possibly believing to cure AL. The patient, Eugene Metzger, died fifty years later, at the age of 102, in New York. Noteworthy, arsenic is nowadays a pillar of acute promyelocytic leukemia treatment, as established by Francesco Lo Coco and Colleagues [4]. A grapping hypothesis suggests that the curative effect might be due to the blood transfusion, acting

/L,

1930 *Walther Gloor* cured the first leukemic patient with arsenic trioxide, irradiation, mesothorium and

In 1948, based on the evidence that AL children receiving folic acid did worsen, Dr. Farber proposed the first rational treatment for AL [2, 5]. He correctly guessed

1948 Nitrogen mustard for Hodgkin disease; Antifols: aminopterin then amethopterin (methotrexate)

1951 Adrenocorticotropic hormone then prednisone for acute lymphoblastic leukemia

1895 Radiation therapy was administered with transient benefit

for acute lymphoblastic leukemia

1953 Mercaptopurine, methotrexate licensed by the FDA

**4**

**Table 2.**

*Evolution of transfusion services and stem cell transplantation.*

that blocking folic acid metabolism could on the contrary avoid leukemic cells growth. Based on that, he wrote "we may now with some justice hope that aminopterin, or some as yet unsynthesized substance related to it, will afford a substantial basis for real hope in this now hopeless disease" [5].

Despite Farber intuition, the prognosis of AL patients remained very poor throughout the 1950s and the 1960s. When Boggs, Wintrobe, and Cartwright examined the overall outcome of AL patients treated with 6- mercaptopurine (6-MP) and methotrexate, they were discouraged, and concluded that, "*the possibility of spontaneous remission must be entertained whenever a patient with acute leukemia becomes apparently well yet, so far as known, practically all such patients subsequently died in relapse. Of the extremely rare case in which the patient did not die, it may be said that the original diagnosis was incorrect*" [2, 6].

Conversely, in the pediatric setting, progressive and impressive improvements were seen starting in the 1960s, especially due to the big efforts of Don Pinkel and Colleagues at St. Jude Institute [7, 8]. Particularly, they systematically changed and improved their chemotherapy regimens, documenting a terrific improvement in a few decades in the prognosis of children affected by AL, an almost invariably fatal disease till then [7, 8].

By contrast, the prognosis remained dismal in adults. However, largely following pediatric studies, the treatment of lymphoid (ALL) and non-lymphoid (myeloid, AML) leukemias became progressively distinct. Eventually, in 1973, the combination of daunorubicin and cytarabine, administered according to the 3 + 7 scheme was documented to be effective in acute myeloid leukemia [9], while post-induction intensification was further developed for ALL (see a schematic timeline of antileukemia treatments development in **Table 2**).

In the 1950s, pre-clinical experiments led to the evidences that bone marrow engraftment after sub-lethal irradiation was associated to leukemia disappearance in mice [10]. This prompted further clinical research in humans and in 1957 Donald Thomas described the first intravenous infusion of bone marrow in humans [11]. In the following decades, tremendous progresses were made and successful bone marrow transplantations were recorded in acute leukemia patients, wither with relapsed/refractory disease and in complete remission [12–14]. By time, bone marrow transplantation evolved to stem cell transplantation, with different sources being available such as marrow, peripheral blood, and umbilical cord blood. At the same time, donation was not limited to siblings but extended to voluntary matched donors, the first registry being funded in UK in 1974, and even only partially compatible ones, in the so called haploidentical transplant (**Table 3**).

Overall, however, the success of anti-leukemic treatments was achieved not only by developing new drugs and schemes (**Table 2**) [15] but also by dramatically improving supportive cares (**Table 3**) [15], especially as far as blood and derivates transfusion as well as anti-microbe drugs were concerned. Particularly, after the first blood transfusion in a leukemic patient in 1873, the most significant advancement was represented by blood groups description in 1901 by Landsteiner et al. Eventually, in 1937 the first hospital blood bank was established and blood products such as platelets were successfully administered in 1954 [15].
