Rare haematologic malignancies: bad diseases can have great outcomes when the right treatments are discovered

Authors:

Details:

  1. Division of Cancer and Haematology, The Walter & Eliza Hall Institute of Medical Research, Victoria, Australia.
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  3. Department of Clinical Haematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Victoria, Australia.
  4. Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.

Abstract

Individual haematologic malignancies are uncommon when compared to solid tumours. Careful definition of distinct subtypes of leukaemias and lymphomas by marrying clinical characteristics with distinct morphological and genetic features has greatly advanced understanding of pathobiology, leading to novel treatments and improved prognoses of different leukaemias and lymphomas. We examine the success stories of acute promyelocytic leukaemia and chronic myeloid leukaemia and explore how next generation sequencing will empower translational research and treatment advances for rare haematologic malignancies.


Introduction

While haematologic neoplasms account for approximately one sixth of all non-cutaneous cancer diagnoses, each individual type of blood cancer is uncommon. The incidences of acute myeloid leukaemia (AML), non-Hodgkin lymphoma and Hodgkin lymphoma were 4, 20 and 2.7 cases per 100,000 respectively in the US in 2011.1 In contrast, 140 new diagnoses of prostate cancer and 130 new diagnoses of breast cancer per 100,000 were made in the same year. Haematologic neoplasms are markedly heterogeneous, with more than 35 subtypes of acute leukaemias, 35 subtypes of non-Hodgkin lymphoma and six subtypes of Hodgkin lymphoma currently recognised.2 Each individual subtype of haematologic neoplasm can therefore be considered a rare disease. However, this has not prevented significant advances from being made in understanding the pathobiology of these diseases and in their treatment. Paradoxically, the rarity has facilitated scientific advancement, by enabling focus on their distinctive morphologic, cytogenetic and molecular characteristics to develop targeted therapies. In this article, we will review how two rare leukaemias with poor prognoses when treated with cytotoxic chemotherapy, are now considered to have very favourable prognoses with targeted therapies.

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) is a subtype of AML, with an incidence of 0.27 cases per 100,000 per year and no difference in frequency between age groups.3 APL as a distinctive disease was first described in 1957 by Hillestad.4 The patients presented with bleeding diathesis and died within hours to six days of hospital admission from disseminated intravascular coagulopathy. Hillestad presciently described APL as “… the most malignant form of acute leukaemia.”

APL is characterised by an excess of abnormal promyelocytes with prominent Auer rods in the bone marrow. In classical APL, only occasional aberrant promyelocytes may be found in the peripheral blood. A variant form of APL with hypogranular promyelocytes, also known as ‘microgranular’ APL, presents with a higher promyelocyte count in the peripheral blood. In the late 1970s, the French-American-British Co-operative Group classified APL and ‘microgranular’ APL as M3 and M3 variant respectively.5,6 The ability to identify APL by morphology is crucial for early diagnosis and treatment of this deadly disease. This is supplemented by APL’s specific cytogenetic and molecular abnormalities (described below).

Daunorubicin was the first chemotherapeutic agent effective in treating APL, achieving complete remission (CR) in 58% of patients with decreased bleeding complications.7 The addition of cytarabine increased CR to 68-72% but median duration of CR remained short at only 24 months.8,9

It was hypothesised that APL could be due to a defect that prevents promyelocytes from differentiating to more mature granulocytes. After Breitman et al showed that all-trans-retinoic acid (ATRA) induces differentiation in an APL cell line (HL-60) and APL cells obtained from patients, the clinical efficacy of ATRA was first shown by the Chinese in 1988, when all 24 patients given ATRA monotherapy achieved CR.10-12 Within 10 years, ATRA plus chemotherapy had become the gold standard, and four year disease-free survival had increased from <40% to 71-93%.7,9,13-15

At the same time, arsenic trioxide was also introduced for the treatment of relapsed APL. Arsenic alone resulted in CR in 85-90% of patients.16-18 In a subsequent study, arsenic in combination with ATRA resulted in rapid and safe induction of remission with no relapses.19 Most recently, in a randomised trial, the two-year overall survival for patients treated with ATRA and arsenic was 99%, compared to 91% in patients treated with ATRA and chemotherapy.20 APL may be the first cancer where cytotoxic therapy can be safely replaced with a combination of a vitamin and a mineral in order to affect a cure in nearly all patients.

The success in treating APL is related to its molecular pathogenesis. It was recognised early that APL cells had a translocation between chromosomes 15 and 17,21,22 t(15;17)(q21;q22) that fuses the PML on chromosome 15 with RAR on chromosome 17.23,24 The PML-RAR is measured using reverse transcriptase polymerase chain reaction (RT-PCR) allowing early detection of relapse. The chimeric protein exerts a negative effect on the normal function of PML and RAR proteins, disrupting cellular processes, including granulocytic differentiation.25 The constant incidence of APL over different age groups suggests that APL has a single rate limiting mutation, namely PML-RAR.26 Arsenic and ATRA work by binding to the PML and RAR moieties respectively, thereby causing degradation of PML-RAR and allowing differentiation of the promyelocytes, and extinction of the leukaemic clone.

In five decades, APL has changed from an invariably deadly disease to a highly curable one. While the revolution in treatment occurred prior to our comprehensive understanding of the molecular pathogenesis of the disease, the use of molecular assays enabled minimal residual disease to be used as a validated surrogate for cure, accelerating the development of clinical algorithms. The current challenge is to translate the lessons learned from APL to other forms of acute leukaemia.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) ideally exemplifies how understanding the biology of a rare cancer enables the development of a targeted therapy that revolutionises care and clinical outcomes. The incidence of CML is estimated to be 0.6 to 2 per 100,000 per year, with a median age at diagnosis of 60 to 65 years.27,28 More than 90% of patients present in chronic phase CML with splenomegaly and leukocytosis. CML is diagnosed by identifying its pathognomonic peripheral blood features of basophilia, eosinophilia and granulocytes in various stages of maturation and by confirming the presence of the fusion oncogene, BCR-ABL.2

In 1960, Nowell and Hungerford reported the presence of a ‘minute’ chromosome in seven cases of CML. In 1973, Rowley demonstrated that the Philadelphia chromosome consisted of a reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)).29 In subsequent research, this translocation was shown to involve the ABL oncogene on chromosome 9 with a small breakpoint cluster region (BCR) on chromosome 22.30,31 The chimeric bcr-abl mRNA encode a protein with increased tyrosine kinase activity compared to wild-type ABL.32-35 BCR-ABL was shown to be pivotal in leukaemogenesis when expression of BCR-ABL in mice induced phenotypes resembling CML.36,37

Treatment prior to 2000 comprised interferon or hydrea, but this rarely changed the natural history of the disease. Over several years, patients would progress from chronic phase CML to accelerated phase and then to a blast crisis that resembled acute leukaemia. Allogeneic haematopoietic stem cell transplant is potentially curative in 70-80% of younger patients, but requires a compatible stem cell donor, a medically fit patient and an acceptance of risks of transplant-related mortality and long-term morbidity.38 Therefore, better therapies were required and BCR-ABL was an attractive target given its role in the pathogenesis of CML.

In pre-clinical studies, a tyrosine kinase inhibitor (TKI), STI 571 (imatinib), inhibited the proliferation of cell lines expressing BCR-ABL and reduced tumour formation in mice.39 Imatinib also decreased the formation of BCR-ABL colonies from peripheral blood and bone marrow samples of patients with CML by 92-98%. Imatinib did not inhibit the formation of normal colonies from the patient samples, demonstrating the specificity of the compound to BCR-ABL. A phase I clinical trial of imatinib commenced in 1998 on patients with chronic phase CML who were resistant to interferon therapy; 53 of 54 (98%) patients achieved complete haematologic response without significant toxicity.40 These findings were confirmed in additional trials and in 2001, imatinib was approved by the Food and Drug Administration for use in CML.41-44

Long-term follow-up of the randomised trial revealed that 93% of newly diagnosed patients treated with imatinib remain alive and progression-free after six years.45 Allogeneic stem cell transplantation is now rare for CML, whereas in 2001, CML was the most common indication for the procedure. Molecular monitoring of BCR-ABL transcripts in the blood is standard, and enabled intervention with second generation TKIs (dasatinib, nilotinib and ponatinib) where imatinib resistance due to well recognised mutations in ABL are observed.46,47 Imatinib and other same-in-class drugs (dasatinib, nilotinib, ponatinib) have transformed CML into a truly ‘chronic’ disease, controlled with a daily tablet. Further, in patients with undetectable minimal residual disease (using sensitive RT-PCR measurement of BCR-ABL transcripts), it may even be appropriate to stop imatinib, with 40% of patients remaining disease-free off therapy.48,49

Research questions remain on the optimal duration of treatment, the choice between various TKIs as optimal first and second line therapy, and the care of the now rare patient with CML in blast crisis.

Future for other rare haematologic malignancies – the era of next-generation sequencing

Recently, improvements and widespread adoption of next generation sequencing (NGS) have enabled us to sequence and analyse genetic material with ease and at a reduced cost. NGS promises to revolutionise research and management of haematologic malignancies.50 The ability to perform whole genome sequencing of an individual patient’s neoplasm has already identified recurring mutations in previously unsuspected genes e.g. IDH1 and DNMT3A in AML.51,52 As AML is broken down into 25-35 subtypes, grouped according to their underlying driver mutations, the field anticipates the development of new treatment approaches for each.

While for APL and CML, it took decades to understand the basic cytogenetic and molecular mechanisms of the disease and develop pathobiology-specific therapies, for AML and other haematologic neoplasms, NGS promises to accelerate these timelines to mere years. The challenges of the 21st century will be in understanding the data generated from NGS and applying it to individual patient care. In this area, haematologic neoplasms will likely to continue to blaze a path.

Acknowledgements

EC is supported by a scholarship from the Leukaemia Foundation Australia. AWR is a NHMRC Practitioner Fellow and the Metcalf Chair of Leukaemia Research.

References

  1. Surveillance, Epnameemiology, and End Results Program. SEER Cancer Statistics Review, 1975-2011, National Cancer Institute, Bethesda, MD. Howlader N, Noone AM, Krapcho M, et al., eds. 2014. Available at: http://seer.cancer.gov/csr/1975_2011/. Accessed October 5, 2014.
  2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoname Tissues. IARC: Lyon; 2008.
  3. Chen Y, Kantarjian H, Wang H, et al. Acute promyelocytic leukemia: A population-based study on incnameence and survival in the United States, 1975-2008. Cancer. 2012;118(23):5811–5818. doi:10.1002/cncr.27623.
  4. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand. 1957;159(3):189–194
  5. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–458.
  6. Bennett JM, Catovsky D, Daniel MT, et al. A variant form of hypergranular promyelocytic leukaemia (M3). Br J Haematol. 1980;44(1):169–170.
  7. Bernard J, Weil M, Boiron M, et al. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood. 1973;41(4):489–496.
  8. Sanz MA, Jarque I, Martín G, et al. Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer. 1988;61(1):7–13.
  9. Cunningham I, Gee TS, Reich LM, et al. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood. 1989;73(5):1116–1122.
  10. Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acname. Proc Natl Acad Sci USA. 1980;77(5):2936–2940.
  11. Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acname. Blood. 1981;57(6):1000–1004.
  12. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acname in the treatment of acute promyelocytic leukemia. Blood. 1988;72(2):567–572.
  13. Iland H, Bradstock K, Seymour J, et al. Results of the APML3 trial incorporating all-trans-retinoic acname and namearubicin in both induction and consolnameation as initial therapy for patients with acute promyelocytic leukemia. Haematologica. 2012;97(2):227–234. doi:10.3324/haematol.2011.047506.
  14. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acname and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103(4):1237–1243. doi:10.1182/blood-2003-07-2462.
  15. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitnameine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloname leukemia. J Clin Oncol. 2010;28(4):562–569. doi:10.1200/JCO.2009.23.8329.
  16. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxnamee (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89(9):3354–3360.
  17. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxnamee: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47. Blood.1999;94(10):3315–3324.
  18. Mathews V, George B, Lakshmi KM, et al. Single-agent arsenic trioxnamee in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107(7):2627–2632. doi:10.1182/blood-2005-08-3532.
  19. Shen Z-X, Shi Z-Z, Fang J, et al. All-trans retinoic acname/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2004;101(15):5328–5335. doi:10.1073/pnas.0400053101.
  20. Coco Lo F, Avvisati G, Vignetti M, et al. Retinoic acname and arsenic trioxnamee for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–121. doi:10.1056/NEJMoa1300874.
  21. Rowley JD, Golomb HM, Dougherty C. 15/17 Translocation, a Consistent Chromosomal Change in Acute Promyelocytic Leukaemia. Lancet; 1977.
  22. Rowley JD. nameentification of the constant chromosome regions involved in human hematologic malignant disease. Science. 1982;216(4547):749–751. doi:10.1126/science.7079737.
  23. de The H, Chomienne C, Lanotte M, et al. The t (15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acname receptor α gene to a novel transcribed locus. Nature. 1990;347(6293):558–561. doi:10.1038/347558a0.
  24. de The H, Lavau C, Marchio A, et al. The PML-RARa Fusion mRNA Generated by the T (15; 17) Translocation in Acute Promyelocytic Leukemia Encodes a Functionally Altered RAR. Cell; 1991.
  25. Mi J-Q, Li J-M, Shen ZX, et al. How to manage acute promyelocytic leukemia. Leukemia. 2012;26(8):1743–1751. doi:10.1038/leu.2012.57.
  26. Vickers M, Jackson G, Taylor P. The incnameence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia. 2000;14(4):722–726. doi:10.1038/sj.leu.2401722.
  27. Rohrbacher M, Hasford J. Epnameemiology of chronic myeloname leukaemia (CML). Best Practice & Research Clinical Haematology. 2009;22(3):295–302. doi:10.1016/j.beha.2009.07.007.
  28. Baccarani M, Dreyling M. ESMO Gunameelines Working Group. Chronic myeloname leukaemia: ESMO Clinical Practice Gunameelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v165–7. doi:10.1093/annonc/mdq201.
  29. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia nameentified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290–293.
  30. de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300(5894):765–767.
  31. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36(1):93–99.
  32. Shtivelman E, Lifshitz B, Gale RP, et al. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315(6020):550–554.
  33. Ben-Neriah Y, Daley GQ, Mes-Masson AM, et al. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrname gene. Science. 1986;233. doi:10.1126/science.3460176.
  34. Konopka JB, Watanabe SM, Witte ON. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984;37(3):1035–1042.
  35. Lugo TG, Pendergast AM, Muller AJ, et al. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247(4946):1079–1082.
  36. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247(4944):824–830. doi:10.1126/science.2406902.
  37. Heisterkamp N, Jenster G, Hoeve Ten J, Zovich D. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344(6263):251–253. doi:10.1038/344251a0.
  38. Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloname leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2006;91(4):513–521.
  39. Druker BJ, Tamura S, Buchdunger E. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature. 1996.
  40. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloname leukemia. N Engl J Med. 2001;344(14):1031–1037. doi:10.1056/NEJM200104053441401.
  41. Kantarjian H, Sawyers C, Hochhaus A. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645–652. doi:10.1056/NEJMoa011573.
  42. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloname leukemia: results of a phase 2 study. Blood. 2002;99(6):1928–1937. doi:10.1182/blood.V99.6.1928.
  43. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloname blast crisis: results of a phase II study. Blood. 2002;99(10):3530–3539. doi:10.1182/blood.V99.10.3530.
  44. National Cancer Institute. FDA Approves Important New Leukemia Drug. National Cancer Institute. 2001:1–2. Available at: http://www.cancer.gov/newscenter/newsfromnci/2001/gleevecpressrelease. Accessed October 5, 2014.
  45. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloname leukemia. Leukemia. 2009;23(6):1054–1061. doi:10.1038/leu.2009.38.
  46. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloname leukemia: 2013. Blood. 2013;122(6):872–884. doi:10.1182/blood-2013-05-501569.
  47. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012;120(7):1390–1397. doi:10.1182/blood-2012-03-378919.
  48. Mahon F-X, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloname leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–1035. doi:10.1016/S1470-2045(10)70233-3.
  49. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal resnameual disease: results from the TWISTER study. Blood. 2013;122(4):515–522. doi:10.1182/blood-2013-02-483750.
  50. Koboldt DC, Steinberg KM, Larson DE, et al. The next-generation sequencing revolution and its impact on genomics. Cell. 2013;155(1):27–38. doi:10.1016/j.cell.2013.09.006.
  51. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloname leukemia genome. N Engl J Med. 2009;361(11):1058–1066. doi:10.1056/NEJMoa0903840.
  52. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloname leukemia. N Engl J Med. 2010;363(25):2424–2433. doi:10.1056/NEJMoa1005143.

Be the first to know when a new issue is online. Subscribe today.