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Conclusions Chemoimmunotherapy has had a dramatic impact on the outcome of patients with CLL, has improved CR rates, eradicates minimal residual disease, and has resulted in improved survival. Remissions with frontline therapy last for years and data are now emerging that more effective frontline regimens are associated with improved overall survival in CLL. Studies are also assessing whether specific treatments are indicated for groups of patients with specific cytogenetic abnormalities. However, not all patients can tolerate aggressive chemo-immunotherapy regimens, and patients continue to relapse so new drugs are needed to effect cure in these patient populations. The encouraging array of ongoing clinical trials and investigational drugs, many of which have novel mechanisms of action, engender great optimism that cure of CLL may be accomplished within the next 20 years. References 1. Gribben JG. How I treat CLL up front. Blood. 2010 Jan 14;115 (2):187-97. 2. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol. 2011 Feb 10;29(5):544-50. 3. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. 4. Tam CS, O’Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long term results of the fludarabine, cyclophosphamide & rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Apr 14. 5. Wierda W, O’Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. 6. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. 7. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med. 2002 Aug 8;347(6):452-3. 8. Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. 9. Gandhi V, Burger JA. Bendamustine in B-Cell Malignancies: The New 46-Year-Old Kid on the Block. Clin Cancer Res. 2009 Dec 15;15(24):7456-61. 10. Fischer K, Cramer P, Stilgenbauer S. Bendamustine combined with rituximab (BR) in first-line therapy of advanced CLL: a multicenter phase II trial of the German CLL Study Group (GCLLSG). Blood. 2009;114:89. Abstract 205. 11. Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. 12. Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. 13. Wierda WG, Kipps TJ, Dürig J. Ofatumumab combined with fludarabine and cyclophosphamide (O-FC) shows high activity in patients with previously untreated chronic lymphocytic leukemia (CLL): results from a randomized, multicenter, international, two-dose, parallel group, phase II trial. Blood. 2009; 114:90. Abstract 207. London, United Kingdom, June 9-12, 2011 14. Contri A, Brunati AM, Trentin L, Cabrelle A, Miorin M, Cesaro L, et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005 Feb;115(2):369-78. 15. Amrein L, Hernandez TA, Ferrario C, Johnston J, Gibson SB, Panasci L, et al. Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol. 2008 Dec;143(5):698-706. 16. Amrein PC, Attar EC, Takvorian RW, Hochberg EP, Ballen KK, Leahy KM, et al. Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Clin Cancer Res. 2011 Mar 14. 17. Gobessi S, Laurenti L, Longo PG, Carsetti L, Berno V, Sica S, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia. 2009 Apr;23(4):686-97. 18. Suljagic M, Longo PG, Bennardo S, Perlas E, Leone G, Laurenti L, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood. 2010 Dec 2;116(23):4894-905. 19. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010 Apr 1;115(13): 2578-85. 20. Herman SEM, Gordon AL, Mahoney E, Jaglowski SM, Blum KA, Buggy J, et al. The Kinase Inhibitor, PCI-32765, Demonstrates Activity in Chronic Lymphcytic Leukemia Cells Independent of Microenvironmental Survival Signals. Blood. 2010;116: Abstract 1385. 21. Burger J, O’Brien S, Fowler N, Advani R, Sharman JP, Furman RR, et al. The Bruton’s Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphcytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies. Blood. 2010;116:Abstract 57. 22. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM, et al. A sustained activation of PI3K/NFkappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004 Aug;18(8):1391-400. 23. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110delta selective phosphatidyl - inositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011 Jan 13;117(2):591-4. 24. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010 Sep 23;116(12):2078-88. 25. Furman RR, Byrd JC, Brown JR, Coutre SE, Benson DMJ, Wagner-Johnston ND, et al. CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110d, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Blood. 2010;116:Abstract 55. 26. Flinn IW, Schreeder MT, Wagner-Johnson ND, Boccia RV, Leonard JP, Courte SE, et al. A Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110d, In Combination with Rituximab and/or Bendamustine In Patients with Relapsed or Refractory B-cell Malignancies. Blood. 2010;116:Abstract 2832. 27. Gribben JG, Hosing C, Maloney DG. Stem cell transplantation for indolent lymphoma and chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2011 Jan;17(1 Suppl):S63-70. 28. Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007 Jan;21(1):12-7. 29. Gribben JG. One step back but 2 steps forward. Blood. 2009 Oct 15;114(16):3359-60. 30. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al. First line therapy with fludarabine compared to chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009 Jul 15. 31. Tsimberidou AM, O’Brien S, Khouri I, Giles FJ, Kantarjian HM, Champlin R, et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol. 2006 May 20;24(15):2343-51. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 103 |
B. Eichhorst M. Hallek Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Germany Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:104-111 Chronic lymphocytic leukemia Treatment of chronic lymphocytic leukemia in the elderly patients Introduction The incidence of CLL is markedly increased in patients older than 65 years, with a median age at diagnosis of 72 years. 1 About three-quarters of all patients with CLL are older than 65 years. In sharp contrast, the age of patients enrolled to pivotal trials evaluating the first-line treatment of CLL has ranged between 58 and 66 years. 2-6 Patients treated within trials on (immuno)chemotherapy were even younger with 57 to 63 years on average. 7-10 Thus, elderly patients are frequently underrepresented in clinical trials. In contrast to that, recently published data show that age is one of the most important prognostic factors in CLL. 11 Therefore, it is unclear whether this patient group equally benefits from the introduction of new chemoimmunotherapy regimens and new drugs in a similar way to younger patients. One of the major problems in the treatment of elderly CLL patients is the increased incidence of comorbidities. This review highlights typical clinical problems and current treatment approaches in elderly CLL patients. Clinical aspects to be considered before treatment of elderly patients There are several clinical aspects to be considered during the treatment of elderly patients. Geriatric assessment of physical fitness and comorbidity might be a helpful tool for the evaluation of older cancer patients. The geriatric assessment should help to determine the functional and cognitive sta- A B S T R A C T Although elderly patients above the age of 70 years represent the largest group of CLL patients, they are heavily underrepresented in clinical trials. A careful assessment of the physical fitness and comorbidity should be performed before initiation of therapy. The burden of comorbidity has significant influence on the outcome of treatment in elderly cancer patients. Therefore, not only age, but also the incidence and burden of comorbidity influence the choice of treatment strategy for every patient. In trials of the German CLL study group, the cumulative illness rating scale (CIRS) has proven to be a reliable tool for measuring comorbidity and to distinguish between physically fit and non-fit patients. While chlorambucil seems to be the current standard for treating non-fit patients, chemoimmunotherapies, or bendamustine, alone or in combination with antibodies, are currently investigated within clinical trials for this patient group. Because fully dosed combination therapies might cause increased toxicity rates in relapse situation, dose-reduced combination therapies should be considered in this situation. An adequate supportive treatment is necessary for the prevention of toxicities, as well as for the improvement of health-related quality of life. tus and to assess depression, nutritional status, and all associated diseases. This assessment allows to identify “vulnerable” patients with different degrees of impairment. An individualized approach must be followed to provide optimal treatment. 12 Older patients show stronger cognitive impairments, including verbal learning, word fluency, and memory after start of chemotherapy than younger cancer patients. 13 Patients with cognitive impairment may have problems remembering signs and symptoms of cancer therapy, as well as appointments. An impairment of activity in daily living (ADL) increases the risk of mortality 14 and chemotherapy-associated toxicities. 15 Social support also has a significant impact on the outcome of elderly patients after chemotherapy. A study showed that in geriatric patients receiving outpatient chemotherapy social support was found to be crucial in coping with fatigue. 16 Most importantly, the associated diseases, which increase with the patients’ age, have a significant impact on the tolerability and outcome of chemotherapy. A negative correlation between the burden of concomitant illness and the survival of cancer patients has been demonstrated for many malignancies. 17 Thus, the burden of comorbidity has been shown to have a significant impact on the outcome of CLL. An analysis of 554 patients with advanced CLL who received chlorambucil, fludarabine, or fludarabine plus cyclophosphamide within the CLL4 and CLL5 trial of the GCLLSG revealed a trend towards inferior survival in CLL patients suffering from concomitant diseases. 18 Survival was significantly impaired in CLL patients | 104 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Page 82 and 83: J.G. Gilles Center for Molecular an
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Page 94 and 95: leed. These issues are especially i
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Page 100 and 101: J.A. Burger Department of Leukemia,
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Page 108 and 109: TE, Nowakowski GS, et al. CD49d exp
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Page 120 and 121: 34. Ferrajoli A. The combination of
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Page 130 and 131: alive after 10 years. 11 Hence, CCy
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Page 136 and 137: H. Kantarjian J. Cortes Leukemia De
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Page 150 and 151: demonstrated that changes in osteob
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Page 156 and 157: ization. In WASP deficiency, lympho
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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myelodysplastic syndromes is associ
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ubiquitous chaperone that promotes
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was thought that they are linked to
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pathologic induction of miR-28 in M
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STATs. Second, levels of HP1 alpha
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72. Irandoust MI, Aarts LH, Roovers
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A.M. Vannucchi Section of Hematolog
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2,559 patients with a diagnosis of
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tant use of aspirin should be caref
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sions at this regard. Based on thes
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in bcr-abl-negative myeloproliferat
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Table 1. Prognostic scoring systems
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Figure 1. Current inhibitors of JAK
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Table 4. A risk-based approach to d
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the flexibility to be adjusted as t
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A. Vacca 1 D. Ribatti 2 1 Departmen
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neovessel building together with MM
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Mevastatin, a specific inhibitor of
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egression of tumor vessels, and app
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diagnosis does not require genetic
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Genetics prognostic tools should be
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sone induction improves outcome of
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Table 1. Conventional chemotherapy
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Novel agents given as consolidation
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dence of peripheral neuropathy, gas
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31. Barlogie B, Tricot G, Anaissie
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Table 1. Major differences between
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first line therapy have shown survi
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transplantation, 7,91 and generally
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
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Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
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Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
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stitution but even with optimal sub
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T.M. Hackeng Department of Biochemi
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and inhibits FVIIa, and that the se
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Figure 4. Regulation of coagulation
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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compared with 3.5% in patients with
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49. Hron G, Kollars M, Binder BR, E
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Women receiving vitamin K antagonis
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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the HOD construct. Furthermore, the
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Goals of future murine studies incl
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F. Noizat-Pirenne C. Tournamille Et
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phenotype. 26 In 2010, we investiga
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ody has been involved in DHTR. 37 T
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antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
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We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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