Evolution in leukemia diagnosis.
1. The early history
The first case of leukemia had been probably described by Velpeau in 1827 [1]. Literally, he described his patient as ‘
1600 BC | First written description of cancer in ancient Egypt |
1670* | Examination of the blood with the compound microscope |
1827 | First clinical description of leukemia by |
1847 | Term “leukemia” coined by |
1872 | |
1877 | |
1913 | Distinction of acute and chronic, lymphoid and myeloid leukemias |
1914 | |
1974 | FAB classification of leukemias based on cytology |
2008 | WHO classification of leukemia including molecular subtypes |
In 1930, Dr. Gloor from the Naegeli’s clinic in Zurich [3], described “
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 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, “
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 anti-leukemia treatments development in Table 2).
1865 | |
1895 | Radiation therapy was administered with transient benefit |
1930 | |
1943 | Isolation of folic acid |
1948 | Nitrogen mustard for Hodgkin disease; Antifols: aminopterin then amethopterin (methotrexate) for acute lymphoblastic leukemia |
1951 | Adrenocorticotropic hormone then prednisone for acute lymphoblastic leukemia |
1953 | Mercaptopurine, methotrexate licensed by the FDA |
1955 | Prednisone licensed by FDA |
1958 | Dexamethasone licensed by FDA |
1958 | Cyclophosphamide licensed by FDA |
1963 | Vincristine licensed by FDA |
1969 | Cytarabine licensed by FDA |
1978 | Native L-asparaginase licensed by FDA |
1979 | Daunorubicin licensed by FDA |
1983 | Etoposide licensed by FDA |
1987 | Mitoxantrone licensed by FDA |
1994 | Pegylated L-asparaginase licensed by FDA |
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* |
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, 13, 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).
1873 | Blood transfusion first applied to leukemic patients ( |
1901 | First description of human blood groups ( |
1937 | First hospital blood bank |
1954 | Introduction of platelet transfusion |
1957 | First successful syngeneic bone marrow transplantation |
1968 | First successful sibling donor bone marrow transplant (immunodeficiency) |
1972 | First successful matched sibling donor marrow transplantation (aplastic anemia) |
1974 | Anthony Nolan Bone Marrow Donor Registry (UK) |
1977 | Evidence of survivals >1 for 18/110 patients with advanced leukemia transplanted from matched donors |
1979 | Report of Success >50% for matched sibling donor marrow transplantation for acute myeloid leukemia in first remission |
1986 | National Marrow Donor Registry Program (USA) |
1983 | First successful haploidentical T-cell depleted bone marrow transplant |
1989 | First successful transplant using umbilical cord blood |
1997 | First reduced-intensity bone marrow transplantation |
2002 | First generation CAR-T cells |
2017 | The FDA approves CD19-directed CAR T cells for the treatment of relapsed, refractory acute lymphoblastic leukemia in children and young adults. |
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].
3. From chemotherapy to targeted drugs
The most recent advances, spanned across the last 3 decades, can be largely attributed to a terrific improvement in technology and a definitely better knowledge of leukemia biology (Table 4) [15]. Specifically, after the first recognition of recurrent genomic imbalances in the 1970s, patients’ risk of recurrence, and therefore the most appropriate treatment (more or less intensified), were defined by cytogenetic analyses [16, 17]. Subsequently, quantitative polymerase chain reaction (PCR) based techniques allowed an accurate and reliable quantitation of the residual disease, this becoming a major factor in determining the choice of treatment (more or less intensified chemotherapy, stem cell transplantation, and targeted drugs) especially in ALL [18]. Finally, next generation sequencing, the first AML genome studied in 2008 [19], quickly led to a refined molecular classification of both AML and ALL [20, 21], unveiling new therapeutic targets and hopefully nearing the new era of personalized medicine. Indeed, in the current century, a series of amazing new drugs have been licensed for acute leukemia treatment, including tyrosine kinase inhibitors, BCL2 inhibitors, IDH2 inhibitors, demethylating agents, and monoclonal antibodies including the novel bispecific T-cell engagers (Table 3). On the other hand, the latest frontier of cellular therapy relies on the chimeric antigen receptor T-cell therapies (CAR-T), firstly demonstrated to be effective in younger ALL patients [22].
1670* | Examination of the blood with the compound microscope |
1877 | |
1934 | Flow cytometry |
1960* | Metaphase cytogenetics; |
1975 | Production of monoclonal antibodies |
1978 | Thiopurine methyltransferase polymorphisms related to response and toxicity |
1980 | Fluorescent in situ hybridization |
1985 | Polymerase chain reaction |
1996 | Gene expression arrays |
1998 | Minimal residual disease by the polymerase chain reaction |
2001 | Classification of AML risk based on cytogenetic features |
2008 | First whole genome sequencing in AML |
2016 | Genomic Classification and Prognosis in Acute Myeloid Leukemia |
2017 | Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia |
We may certainly expect that further improvements in our understanding of leukemogenesis will lead to later significant success in curing these still terrible diseases.
References
- 1.
Gunz FW. Leukemia in the past. In: Henderson ES, Lister TA (eds). Leukemia. WB Saunders Company: Philadelphia, 1990, pp 3-11 - 2.
Beutler E. The treatment of acute leukemia: past, present, and future. Leukemia (2001) 15, 658-661 - 3.
Gloor W. Ein fall von geheilter Myeloblasten leukamie. Munch Med Wochenschr 1930; 77: 1096-1098 - 4.
Lo Coco F, Avvisati G, Vignetti M, et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic LeukemiaN Engl J Med 2013; 369:111-121 - 5.
Farber S, Diamond LK, Mercer RD, Sylvester RF Jr, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). New Engl J Med 1948; 238: 787-793 - 6.
Boggs DR, Wintrobe MM, Cartwright GE. The acute leukemia. Analysis of 322 cases and review of the literature. Medicine (Baltimore) 1962; 41: 163-225 - 7.
Pui CH. Childhood leukemias. New Engl J Med 1995; 332: 1618-1630 - 8.
Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 354: 166-178 - 9.
Yates JW, Wallace HR, Ellison RR, Holland JF: Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 57:485, 1973 - 10.
Barnes, D.W.H., Corp, M.J., Loutit, J.F. & Neal, F.E. (1956) Treatment of murine leukaemia with X-rays and homologous bone marrow. British Medical Journal, ii, 626-627 - 11.
Thomas, E.D., Lochte, H.L., Jr, Lu, W.C. & Ferrebee, J.W. (1957). Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. New England Journal of Medicine, 257, 491-496 - 12.
Thomas, E.D., Buckner, C.D., Banaji, M., et al (1977) One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood, 49, 511-533 - 13.
Thomas, E.D., Buckner, C.D., Clift, R.A., et al (1979) Marrow transplantation for acute non-lymphoblastic leukemia in first remission. New England Journal of Medicine, 301, 597-599 - 14.
Thomas, E.D., Sanders, J.E., Flournoy, N., et al (1979) Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood, 54, 468-476 - 15.
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 - 16.
C.D. Bloomfield, L.M. Secker-Walker, A.I. Goldman, et al. Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia, Cancer Genetics and Cytogenetics, Volume 40, Issue 2, 1989, Pages 171-185 - 17.
Visani, G., Bernasconi, P., Boni, M. et al. The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia – analysis of 848 patients. Leukemia 15, 903-909 (2001) - 18.
Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med. 1998 Aug 27;339(9):591-8 - 19.
Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008 Nov 6;456(7218):66-72 - 20.
Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016 Jun 9;374(23):2209-2221 - 21.
Inaba H, Azzato EM, Mullighan CG. Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia with Targetable Lesions: The St. Jude Children’s Research Hospital Approach. Front Pediatr. 2017 Dec 4; 5:258 - 22.
Pehlivan KC, Duncan BB, Lee DW. CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: Transforming the Treatment of Relapsed and Refractory Disease. Curr Hematol Malig Rep. 2018 Oct;13(5):396-406