- Email: [email protected]
How I treat chronic lymphocytic leukemia in older patients
JGO-00293; No. of pages: 8; 4C: J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
Available online at www.sciencedirect.com
ScienceDirect
Meet the Experts
How I treat chronic lymphocytic leukemia in older patients Bradley Heralya , Vicki A. Morrisona,b,⁎ a
University of Minnesota, Division of Hematology, Oncology, and Transplantation, 420 Delaware St SE, Minneapolis, MN 55455, USA Veterans Affairs Medical Center, One Veterans Dr, Minneapolis, MN 55417, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Chronic lymphocytic leukemia (CLL) is a disease predominantly of the elderly, with a median
Received 23 March 2015
age at diagnosis of 72 years. Although many advances have been made in the care of these
Received in revised form
patients with the addition of a variety of active drugs to the therapeutic armamentarium,
19 June 2015
treatment in the elderly remains complicated by factors as comorbidities, functional status,
Accepted 10 August 2015
and fitness, as well as underrepresentation in many clinical trials. We will review the data on initial CLL treatment approaches, as well as therapy in the relapsed/refractory disease setting,
Keywords:
with a focus on the elderly. We will also address the impact of comorbidities on treatment
Chronic lymphocytic leukemia
choices, and the importance of assessing the functional status and fitness of elderly patients
Elderly
when choosing appropriate therapies. Treatment recommendations for the older treatment
Functional status
naïve patient, both fit and less fit, as well as those receiving later therapies, will be summarized,
Geriatric assessment
with an emphasis not only on chronologic age, but also fitness for treatment.
Alkylators
Published by Elsevier Ltd.
Purine analogs Anti-CD20 monoclonal antibodies Immunomodulatory agents Bruton's tyrosine kinase inhibitors PI3 kinase inhibitors
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of Fitness and Comorbidity Burden for Treatment Consideration Initial Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. First Line Therapy in Healthy, Fit Patients Without del(17p) . . . . . . . 3.2. First Line Therapy in Frail, Unfit Patients Without del(17p) . . . . . . . 3.3. First Line Therapy in Patients With del(17p) . . . . . . . . . . . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
0 0 0 0 0 0
⁎ Corresponding author at: Section of Hematology/Oncology, 111E, VAMC, One Veterans Dr, Minneapolis, MN 55417. Tel.: + 1 612 467 4135; fax: +1 612 725 2149. E-mail address: [email protected] (V.A. Morrison).
http://dx.doi.org/10.1016/j.jgo.2015.08.003 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
2
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
4. Summary Recommendations for Initial Therapy (Table 2) 5. Therapy for Relapsed/Refractory Disease . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Significant progress has been made in the past two decades in the management of chronic lymphocytic leukemia (CLL), which is a disorder predominantly of the elderly, with median age at diagnosis of 72 years (yrs) [1–3]. At diagnosis, 30% of patients are aged 70–79 yrs, and 23% are >80 yrs of age [1]. A new diagnosis of CLL results in a shortened life expectancy in most patients [4–6]. Elderly patients have been underrepresented in prior treatment trials, with median ages of enrolled patients being > 10 yrs younger than the average age at diagnosis [7]. Many of these trials also excluded patients of poorer performance status (PS > 2) or significant comorbidities. Although select elderly individuals may be offered aggressive treatment approaches, fludarabine, cyclophosphamide, rituximab (FCR) cannot be tolerated by the majority of CLL patients with comorbidities who start therapy at age > 70 yrs [8]. Effective treatments are needed for these patients, as the majority will die of CLL or its complications [9]. In this review, we will address the evaluation of fitness in this elderly cohort, as well as recommendations for initial and later therapies based upon such assessments.
2. Assessment of Fitness and Comorbidity Burden for Treatment Consideration Indications for treatment initiation in elderly CLL patients are similar to those for younger patients [10] (Table 1). Factors that do not necessitate therapy initiation include the level of the absolute lymphocyte count, asymptomatic or slowly progressive lymphadenopathy, or frequent/recurrent infections. Chronologic age is not a surrogate for physiologic age or fitness. Comorbidities may be assessed by measures such as the Cumulative Index Rating Scale (CIRS) and the Charlson Comorbidity Index [11,12]. In one series, 89% of the newly diagnosed Table 1 – Indications for initiation of therapy in CLL patients. Evidence of progressive marrow failure (worsening anemia and/or thrombocytopenia) Massive and/or symptomatic splenomegaly Massive and/or symptomatic lymphadenopathy Progressive lymphocytosis, with >50% increase over two months, or lymphocyte doubling time <6 months Autoimmune anemia and/or thrombocytopenia with poor response to treatment Constitutional symptoms/signs, including: Unintentional weight loss 10% over 6 months Significant fatigue Fevers without infection Night sweats >1 month (Adapted from reference [10]).
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
0 0 0 0
CLL patients had at least one comorbidity, including 46% with >1 major comorbidity, such as vascular or pulmonary disease or diabetes [13]. Assessment of functional status is best done by measures such as the Comprehensive Geriatric Assessment (CGA), which includes consideration of functionality, coexisting health problems, social support, cognitive ability, nutritional status, and geriatric syndromes (dementia, delirium, falls, failure to thrive, depression, polypharmacy) [14–17]. Such assessments help to predict chemotherapy tolerance in the elderly [18,19]. Unfortunately, studies examining the interaction between comorbidities and CLL therapy are limited. In one large series, it was suggested that durable disease control was the most important factor in the outcome of CLL patients with comorbidities [20].
3. Initial Therapy 3.1. First Line Therapy in Healthy, Fit Patients Without del(17p) The approach to initial CLL therapy has evolved, with the introduction of the purine analogs, alemtuzumab, bendamustine, and more recently newer agents as ibrutinib, idelalisib, and obinutuzumab. Unfortunately, many of these trials are not of phase III design, and older patients have been underrepresented in the majority. Single agent chlorambucil is the comparator agent in many phase III trials based upon FDA guidance. Patients with a CIRS score <6 and preserved renal function can tolerate initial aggressive chemoimmunotherapy such as FCR, which is a standard of care in young/healthy individuals [21,22]. In the phase III trial comparing initial therapy with fludarabine plus cyclophosphamide (FC) to FCR in fit patients, FCR resulted in improved overall response rate (ORR) and progression-free survival (PFS), regardless of age [22]. The ORR (complete response (CR)) rates with FC and FCR were 79%(19%) versus 89%(45%), respectively (p < 0.001, p < 0.0001) in patients <65 yrs of age, and 83%(24%) versus 93%(43%) (p = 0.028 for ORR, p = 0.003 for CR) for those >65 yrs of age. Three-yr PFS was significantly prolonged with FCR in patients <65 yrs of age (46% versus 64% respectively, p < 0.0001), as well as those >65 yrs of age (43% versus 68% respectively, p = 0.001). A prolongation in overall survival (OS) was seen with FCR therapy as compared with FC (p = 0.017). However, this benefit was confined to those patients <65 yrs of age, and not those >65 yrs (p = 0.059 and 0.103, respectively). Although FCR was associated with more grade 3/4 neutropenia than FC (34% versus 21%, respectively, p < 0.0001), the incidence of severe infection was comparable with both regimens. Another option is FCR-lite, with low dose fludarabine and cyclophosphamide and high dose rituximab, including rituximab maintenance therapy [23,24]. In a phase II trial in patients (median age 58 yrs (range, 36–85 yrs)), ORR(CR) rates were 93%(73%), with median PFS of 5.8 yrs.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
Myelosuppression was less than with traditional FCR, with grade 3/4 neutropenia complicating 11% of FCR-lite cycles, and grade 3/4 infections occurring in 6% of patients. Cladribine has been combined with rituximab or cyclophosphamide for alternative purine analog-based combination trials including some elderly patients [25,26]. Bendamustine-based regimens are reasonably tolerated in the elderly [27–29]. In a phase II trial of initial bendamustine plus rituximab therapy (BR) in which half the patients were >65 yrs of age, ORR(CR) rates were 88%(23%), respectively, and median event-free survival was 33.9 months [28]. Grade 3/4 neutropenia, thrombocytopenia, and anemia each occurred in approximately 20% of patients. Initial therapy with bendamustine versus chlorambucil was compared in a randomized phase III trial, with ORR of 68% and 31%, respectively (p < 0.0001) [27,29]. More CRs occurred with bendamustine (21% versus 10.8%), and time to next treatment was prolonged (31.7 versus 10.1 months, p < 0.0001), as was median PFS (21.2 versus 8.8 months, p < 0.0001). Hypersensitivity reactions were more common with bendamustine than chlorambucil (5% versus 2%). Likewise, more grade 3/4 adverse events were seen with bendamustine than chlorambucil (40% versus 19%, respectively), including neutropenia and thrombocytopenia (23% versus 11%, and 12% versus 8%, respectively). In a preliminary analysis of the phase III trial comparison of BR versus FCR, higher CR rates (47% versus 38%, p = 0.031) and prolonged 2-yr PFS (85% versus 78%, p = 0.041) were seen with FCR as compared with BR, although no advantage in PFS was seen in patients >65 yrs of age [30]. However, significantly more grade 3–5 myelosuppression and infections occurred with FCR than BR, especially in the elderly cohort.
3.2. First Line Therapy in Frail, Unfit Patients Without del(17p) Patients with CIRS scores > 6 and/or compromised renal function do not tolerate aggressive chemoimmunotherapy as FCR, which may result in prolonged marrow suppression with concomitant morbidity/mortality. The substitution of pentostatin for fludarabine, in combination with rituximab alone (PR), or rituximab plus cyclophosphamide (PCR) may be better tolerated, with less myelosuppression and comparable ORR/CR rates and PFS [31,32]. Alternatively, extended PFS and OS were demonstrated with FR therapy in patients of median age 63 yrs (median 42 and 85 months, respectively) [33,34]. Chlorambucil remains a tolerable and efficacious agent for frail unfit patients. In a phase III trial, treatment-naïve patients >65 yrs of age (median, 70 yrs) were randomized to therapy with fludarabine or chlorambucil [9]. Two-thirds of the patients had >1 comorbidities. Fludarabine resulted in higher ORR and CR rates than chlorambucil (72% versus 51%, p = 0.003; 7% versus 0%, p = 0.011, respectively), and time to treatment failure (TTF) was prolonged (18 versus 11 months, p = 0.004). However, there were no differences in PFS and OS. Grade 3/4 leukopenia was more common with fludarabine (p < 0.001). Based upon these findings, it was concluded that initial fludarabine therapy in older patients does not result in major clinical benefit as compared with chlorambucil. In a subsequent phase II trial of chlorambucil plus rituximab in elderly patients (median age 70 yrs; median seven comorbidities), ORR(CR) rates were 84%(10%), with median PFS of 23.5 months [35]. Most
3
grade 3/4 toxicities were hematologic (41% grade 3/4 neutropenia). This is considered as a preferred initial regimen for unfit patients [36]. Several anti-CD20 antibodies have been studied in combination, some with chlorambucil, as initial CLL therapy [37–39]. Therapy with rituximab plus high dose methylprednisolone in patients (median age 65 yrs) resulted in ORR(CR) rates of 96%(32%), and median PFS of 30.3 months, with few grade 3/4 adverse events [37]. In a phase III trial in which patients (median age 69 yrs) were randomized to either ofatumumab plus chlorambucil or chlorambucil alone, median PFS as well as ORR(CR) rates were higher with combination therapy (22.4 versus 13.1 months, p < 0.001; 82 %(12%) versus 69%(1%), p < 0.001, respectively), as was grade > 3 neutropenia (26% versus 14%, respectively) [38]. Results of a phase III trial in which treatment naive CLL patients (median age 73 yrs) with a CIRS score > 6 and/or a creatinine clearance of 30–69 ml/min received chlorambucil, rituximab plus chlorambucil, or obinutuzumab plus chlorambucil, have recently been reported [39]. ORR(CR) rates were highest with obinutuzumab, compared to chlorambucil (77.3% versus 31.4%; 22.3% versus 0%, respectively, p < 0.001). Median PFS was longest with obinutuzumab plus chlorambucil, compared with rituximab plus chlorambucil (26.7 versus 16.3 months, p < 0.001, compared with 11.1 months with chlorambucil); higher CR (20.7% versus 7%, respectively) and molecular response rates were also found. Grade 3/4 infusion reactions and neutropenia were most common with obinutuzumab plus chlorambucil (21% and 35%, respectively). In updated analyses, treatment with either obinutuzumab or rituximab plus chlorambucil conferred an OS advantage over single agent chlorambucil (p = 0.0014 and 0.0242, respectively) [40]. Single agent lenalidomide has been studied as initial therapy for elderly CLL patients [41,42]. In one trial in patients >65 yrs of age, a 5 mg daily continuous dose of lenalidomide, with a dose escalation to 25 mg daily as tolerated, resulted in ORR(CR) rates of 65%(10%), and 2-yr PFS of 60% [41]. Grade 3/4 neutropenia and infections occurred in 34% of treatment cycles and 13% of patients, respectively; tumor flare is also a potential adverse event in such patients. With median followup of 4 yrs, median TTF had not been reached, 58% had a response lasting > 3 yrs, and OS was 82% [43]. A starting lenalidomide dose of 2.5 mg daily for 21 of 28 days, with a dose escalation to 10 mg daily, was utilized in another series, with ORR(CR) rates of 56%(0%), and grade 3/4 neutropenia in 72% of patients [42]. Data on lenalidomide plus rituximab combination therapy has also been reported [44]. However at present, lenalidomide is not available for CLL therapy outside of clinical trials.
3.3. First Line Therapy in Patients With del(17p) The subset of CLL patients with TP53 deletions, regardless of the presence of 17p deletion, has a poor prognosis, with lower response rates and decreased PFS/OS with fludarabine-based regimens [45–48]. The efficacy of high-dose methylprednisolone plus rituximab has been demonstrated in patients with these adverse features [37,49,50]. Updated results with three-yr safety data of therapy with ibrutinib, a Bruton's tyrosine kinase inhibitor, in 31 previously untreated CLL patients >65 (median,
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
4
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
71) yrs of age have recently been published, with ORR(CR) rates of 84%(23%) [51,52]. Most toxicities were grade 1/2, including diarrhea (the most common grade 3 toxicity, with a 16% incidence), nausea, fatigue, hypertension, and edema. Median PFS and OS had not yet been reached. The impact of ibrutinib for patients with TP53 deletions has recently been demonstrated [53,54]. In a phase 2 trial of ibrutinib plus rituximab including patients, many previously treated, with TP53 mutations or deletions in 17p or 11q, 18-month PFS was 72.4% in those with TP53 mutation or deletion 17p [53]. In another preliminary report of a phase II ibrutinib trial in patients with high-risk disease, ORR was 97% in treatment naïve patients and 80% in those previously treated [54]. Comparable responses were seen in patients with TP53 mutations, with median PFS of 28.1 months.
4. Summary Recommendations for Initial Therapy (Table 2) For older patients, especially those who are > 70 yrs of age, chlorambucil in combination with an anti-CD20 monoclonal antibody and bendamustine–rituximab are reasonable options. In addition, a variety of single agent treatment options may be considered. For patients with TP53 mutations or deletion 17p, initial ibrutinib therapy may be considered. For those with deletion 11q, inclusion of an alkylator in the treatment regimen, especially cyclophosphamide, is associated with superior response rates and prolonged PFS [55]. The use of appropriate supportive care measures, including myeloid growth factor support when indicated and prophylactic antimicrobial therapy, is especially important in this population [56,57].
5. Therapy for Relapsed/Refractory Disease There is no standard therapy for relapsed CLL, with treatment decisions based upon prior therapy, length of remission, age, fitness, and adverse prognostic factors (Table 3). For patients with > 2 yrs of response to initial purine analog therapy, retreatment may be considered, with regimens as PCR or low dose FCR [23,24,58,59]. Bendamustine plus rituximab is effective and safe in the relapsed/refractory setting, and is active in fludarabine-refractory patients [60]. Alemtuzumab alone or with high dose methylprednisolone or rituximab may be considered for more fit patients, especially those with 17p deletion or TP53 mutation, while high dose methylprednisolone plus rituximab may be utilized for less fit patients [61–64]. Monotherapy with rituximab, ofatumumab, or obinutuzumab, which tend to be well tolerated, may also be considered [65–68]. Lenalidomide, as a single agent or in combination with rituximab, has also been studied in clinical trials including elderly patients with favorable results [69–73]. Treatment data with two new novel agents in relapsed/ refractory patients have been recently reported. With a recent three-yr followup, ibrutinib therapy in relapsed/refractory patients, median age 64 yrs (34% > 70 yrs), ORR(CR) was 90%(7%), and the estimated 30-month PFS and OS were 69% and 79%, respectively [52,74]. The most common grade 3
Table 2 – Recommendations for initial therapy of chronic lymphocytic leukemia. Age <70 yrs and no significant comorbidities Purine analog-based therapy FCR FR PCR BR Age >70 yrs, or <70 yrs and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Bendamustine +/− rituximab Fludarabine +/− rituximab Single agent therapy Obinutuzumab Chlorambucil Rituximab Cladribine Frail patient and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Single agent therapy Obinutuzumab Rituximab Chlorambucil Pulse corticosteroids Presence of 17p deletion Ibrutinib High dose methylprednisolone + rituximab FCR FR Obinutuzumab + chlorambucil Alemtuzumab +/− rituximab Presence of 11q deletion: Age >70 yrs, or <70 yrs and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Bendamustine +/− rituximab Cyclophosphamide, prednisone, +/− rituximab Reduced dose FCR Chlorambucil Rituximab Age <70 yrs and no significant comorbidities Purine analog-based therapy FCR PCR Bendamustine +/− rituximab Obinutuzumab + chlorambucil Based upon the NCCN recommendations, Version 2.2015[80].
toxicities were pneumonia (25%), hypertension (20%), neutropenia (18%), and thrombocytopenia (10%). In a subsequent phase III trial in which patients (median age 67 yrs) were randomized to ibrutinib or ofatumumab, ORR was superior with ibrutinib (42.6 % versus 4.1%, p < 0.001), as was median PFS (with median followup of 9.4 months, not reached with ibrutinib, versus 8.1 months with ofatumumab) [75]. The PI3 kinase inhibitor idelalisib was studied in a phase I trial, with 72% ORR and median PFS of 15.8 months [76]. The most
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
Table 3 – Recommendations for therapy of relapsed/ refractory chronic lymphocytic leukemia. Age <70 yrs and no significant comorbidities Ibrutinib Idelalisib + rituximab Purine analog-based therapy FCR PCR Fludarabine + alemtuzumab R-CHOP Single agent therapy Ofatumumab Obinutuzumab Lenalidomide +/− rituximab Alemtuzumab +/− rituximab High dose methylprednisolone + rituximab Age >70 yrs, or <70 yrs and significant comorbidities Ibrutinib Idelalisib + rituximab Purine analog-based therapy (reduced dose FCR, reduced dose PCR) High dose methylprednisolone + rituximab Rituximab + chlorambucil Single agent therapy Bendamustine +/− rituximab Ofatumumab Obinutuzumab Lenalidomide +/− rituximab Alemtuzumab +/− rituximab Dose-dense rituximab Based upon the NCCN recommendations, Version 2.2015[80].
common grade > 3 toxicities were pneumonia (20%), febrile neutropenia (11%), and diarrhea (6%). In a subsequent phase III study, patients (median age 71 yrs) were randomized to idelalisib plus rituximab versus placebo plus rituximab [77]. Median PFS, ORR, and one-yr OS favored the idelalisib (PFS not reached versus 5.5 months; 81% versus 13%, p < 0.001; 92% versus 80%, p = 0.02, respectively). The most common grade > 3 adverse events in the idelalisib group were neutropenia (34%), thrombocytopenia (10%), anemia (5%), transaminase elevation (5%), and diarrhea (4%). Idelalisib was also active in patients with 17p or 11q deletion, or TP53 mutation [78,79].
6. Conclusions Chronic lymphocytic leukemia is predominantly a disease of the elderly, who commonly have comorbidities, potential decline in functional status, and underrepresentation in clinical trials. Choosing appropriate, tolerable therapy in these patients is thus complex. Supportive care measures and attention to quality of life are important in the care of such patients. The recent addition of new agents to the therapeutic armamentarium provides further treatment options for these patients. Ongoing prospective treatment trials are now including older patients, including some of which have formal comprehensive geriatric assessment as a component of the study. The results of these trials will provide a framework for future treatment approaches in the elderly CLL patient.
5
REFERENCES
1. Tadmor T, Polliack A. Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices. Blood Rev 2012;26: 15–23. 2. Delgado J, Briones J, Sierra J. Emerging therapies for patients with advanced chronic lymphocytic leukemia. Blood Rev. 2009;23:217–224. 3. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013:158–167. 4. Abrisqueta P, Pereira A, Rozman C, Aymerich M, Gine E, Moreno C. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood 2009;114:2044–2050. 5. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood 2008;111:4916–4921. 6. Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer 2010;116:4777–4787. 7. Goede V, Hallek M. Optimal pharmacotherapeutic management of chronic lymphocytic leukaemia: considerations in the elderly. Drugs Aging 2011;28:163–176. 8. Ferrajoli A, O’Brien SM, Wierda W, et al. Treatment of patients with CLL 70 years old and older: a single center experience of 142 patients. Leuk Lymphoma 2005;46(Suppl):48 [S86]. 9. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382–3391. 10. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia: updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446–5456. 11. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992;41: 237–248. 12. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47: 1245–1251. 13. Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, et al. Cormorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:49–56. 14. Balducci L. ESH-SIOG International Conference on Haematological Malignancies in the Elderly. Expert Rev Hematol 2010;3:675–677. 15. Brunello A, Sandri R, Extermann M. Multidimensional geriatric evaluation for older cancer patients as a clinical and research tool. Cancer Treat Rev 2009;35:487–492. 16. Terret C. Management and geriatric assessment of cancer in the elderly. Expert Rev Anticancer Ther 2004;4:469–475. 17. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 2011;29: 1290–1296. 18. Freyer G, Geay JF, Touzet S, Provencal J, Weber B, Jacquin JP, et al. Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study. Ann Oncol 2005;16:1795–1800.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
6
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
19. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older patients with cancer: a prospective multicenter study. J Clin Oncol 2011;29: 3457–3465. 20. Goede V, Cramer P, Busch R, Bergmann M, Stauch M, Hopfinger G, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014;99:1095–1100. 21. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma 2009;50: 171–178. 22. 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;376:1164–1174. 23. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2008;27:498–502. 24. Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, et al. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood 2012;119:3184–3185. 25. Bertazzoni P, Rabascio C, Gigli F, Calabrese L, Radice D, Calleri A, et al. Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients. Leuk Lymphoma 2010;51:1485–1493. 26. Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, et al. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 study). J Clin Oncol 2010;28:1863–1869. 27. 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;27:4378–4384. 28. Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30: 3209–3216. 29. Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, et al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol 2012;159: 67–77. 30. Eichhorst B, Fink AM, Busch R, Lange E, Köppler H, Kiehl MG, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German Study Group (GCLLSG). Blood 2013;122(Suppl) [Abstract 526]. 31. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007;109: 405–411.
32. Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 2007;109:2291–2298. 33. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B study 9712 (CALGB 9712). Blood 2003;101:6–14. 34. Woyach JA, Ruppert AS, Heerma NA, Peterson BL, Gribben JG, Morrison VA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 2011;29: 1349–1355. 35. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: final analysis of an open-label phase II study. J Clin Oncol 2014;32:1236–1241. 36. Foa R, Giudice ID, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014;89: 480–486. 37. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia 2009;23:1779–1789. 38. Hillmen P, Robak T, Janssens A, Govindbabu K, Grosicki S, Mayer J, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study Complement 1 (OMB110911). Blood 2013;122 [Abstract 528]. 39. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370: 1101–1110. 40. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LFC, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015;1–3. 41. Badoux XC, Keating MJ, Wen S, Bang-Ning L, Sivina M, Reuben J, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011;118:3489–3498. 42. Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, et al. Single agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 2011;29: 1175–1181. 43. Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734–737. 44. James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium. J Clin Oncol 2014;32:2067–2073. 45. Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T, et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia 2010;24: 2072–2079. 46. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010;28:4473–4479. 47. Fink AM, Bottcher S, Ritgen M, Fischer K, Pflug N, Eichhorst B, et al. Prediction of poor outcome in CLL patient following
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
48.
49.
50.
51.
52.
53.
54.
55.
56. 57.
58.
59.
60.
61.
62.
first-line treatment with fludarabine, cyclophosphamide, and rituximab. Leukemia 2013;27:1949–1952. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123:3247–3254. Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene F, Sejoniene J, et al. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma 2011;52:1055–1065. Bowen DA, Call TG, Jenkins GD, Zent CS, Schwager SM, Van Dyke DL, et al. Methylprednisolone–rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma 2007;48:2412–2417. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15:48–58. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment-naıve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497–2506. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab with high-risk chronic lymphocytic leukemia: a single-arm phase 2 study. Lancet Oncol 2014;15: 1090–1099. O'Brien SM, Furman RR, Coutre SE, Flinn I, Burger JA, Blum KA, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol 2014;32:5s [Abstract 7014]. Ding W, Ferrajoli A. Evidence-based mini-review: the role of alkylating agents in the initial treatment of chronic lymphocytic leukemia patients with the 11q deletion. Hematology 2010;90–92. Morrison VA. Infections in patients with leukemia and lymphoma. Cancer Treat Res 2014;161:319–349. Morrison VA. Infectious complications of chronic lymphocytic leukemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol 2010;23:145–153. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2006;24:1575–1581. Gozzetti A, Candi V, Fabbri A, Schiattone L, Cencini E, Lauria F, et al. Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia. Leuk Res 2014;38:891–895. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559–3566. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554–3561. Cortelezzi A, Gritti G, Laurenti L, Cuneo A, Ciolli S, Di Renzo N, et al. An Italian retrospective study on the routine clinical use of low dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients. Brit J Haematol 2011;156: 481–489.
7
63. Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol 2012;130: 1647–1655. 64. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine-refractory high-risk chronic lymphocytic leukemia. Leukemia 2008;22: 2048–2053. 65. 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;28:1749–1755. 66. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008;111: 1094–1100. 67. Flynn JM, Byrd JC, Kipps TJ, Boxer M, Kolibaba KS, Tyson N, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in patients with chronic lymphocytic leukemia (CLL): results of the phase II GAGE (GAO4768g) trial [abstract]. J Clin Oncol 2014;32(Suppl):5s [Abstract 7083]. 68. Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 2014;124:2196–2202. 69. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 2006;24:5343–5349. 70. Ferrajoli A, Lee BN, Schlette EJ, O’Brien SM, Gao H, Wen S, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291–5297. 71. Wendtner CM, Hillmen P, Mahadevan D, Buhler A, Uharek L, Coutre S, et al. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 2012;53:417–423. 72. Buhler A, Wendtner C, Hallek M, Kipps TJ, Rassenti L, Fraser G, et al. TP53 mutation or deletion and efficacy with single-agent lenalidomide in relapsed or refractory chronic lymphocytic leukemia (CLL) (CC-5013-CLL-009 study). Blood 2013;122 [Abstract 1638]. 73. Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013;31:584–591. 74. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42. 75. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–223. 76. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390–3397. 77. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Eng J Med 2014;370:997–1007. 78. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Efficacy of idelalisib in CLL subpopulations
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
8
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
harboring del (17p) and other adverse prognostic factors: results from a phase 3, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2014;32:5s [Abstract 7011]. 79. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with
TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169–176. 80. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. J Natl Compr Canc Netw 2015;13:326–362.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
Available online at www.sciencedirect.com
ScienceDirect
Meet the Experts
How I treat chronic lymphocytic leukemia in older patients Bradley Heralya , Vicki A. Morrisona,b,⁎ a
University of Minnesota, Division of Hematology, Oncology, and Transplantation, 420 Delaware St SE, Minneapolis, MN 55455, USA Veterans Affairs Medical Center, One Veterans Dr, Minneapolis, MN 55417, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Chronic lymphocytic leukemia (CLL) is a disease predominantly of the elderly, with a median
Received 23 March 2015
age at diagnosis of 72 years. Although many advances have been made in the care of these
Received in revised form
patients with the addition of a variety of active drugs to the therapeutic armamentarium,
19 June 2015
treatment in the elderly remains complicated by factors as comorbidities, functional status,
Accepted 10 August 2015
and fitness, as well as underrepresentation in many clinical trials. We will review the data on initial CLL treatment approaches, as well as therapy in the relapsed/refractory disease setting,
Keywords:
with a focus on the elderly. We will also address the impact of comorbidities on treatment
Chronic lymphocytic leukemia
choices, and the importance of assessing the functional status and fitness of elderly patients
Elderly
when choosing appropriate therapies. Treatment recommendations for the older treatment
Functional status
naïve patient, both fit and less fit, as well as those receiving later therapies, will be summarized,
Geriatric assessment
with an emphasis not only on chronologic age, but also fitness for treatment.
Alkylators
Published by Elsevier Ltd.
Purine analogs Anti-CD20 monoclonal antibodies Immunomodulatory agents Bruton's tyrosine kinase inhibitors PI3 kinase inhibitors
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of Fitness and Comorbidity Burden for Treatment Consideration Initial Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. First Line Therapy in Healthy, Fit Patients Without del(17p) . . . . . . . 3.2. First Line Therapy in Frail, Unfit Patients Without del(17p) . . . . . . . 3.3. First Line Therapy in Patients With del(17p) . . . . . . . . . . . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
0 0 0 0 0 0
⁎ Corresponding author at: Section of Hematology/Oncology, 111E, VAMC, One Veterans Dr, Minneapolis, MN 55417. Tel.: + 1 612 467 4135; fax: +1 612 725 2149. E-mail address: [email protected] (V.A. Morrison).
http://dx.doi.org/10.1016/j.jgo.2015.08.003 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
2
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
4. Summary Recommendations for Initial Therapy (Table 2) 5. Therapy for Relapsed/Refractory Disease . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Significant progress has been made in the past two decades in the management of chronic lymphocytic leukemia (CLL), which is a disorder predominantly of the elderly, with median age at diagnosis of 72 years (yrs) [1–3]. At diagnosis, 30% of patients are aged 70–79 yrs, and 23% are >80 yrs of age [1]. A new diagnosis of CLL results in a shortened life expectancy in most patients [4–6]. Elderly patients have been underrepresented in prior treatment trials, with median ages of enrolled patients being > 10 yrs younger than the average age at diagnosis [7]. Many of these trials also excluded patients of poorer performance status (PS > 2) or significant comorbidities. Although select elderly individuals may be offered aggressive treatment approaches, fludarabine, cyclophosphamide, rituximab (FCR) cannot be tolerated by the majority of CLL patients with comorbidities who start therapy at age > 70 yrs [8]. Effective treatments are needed for these patients, as the majority will die of CLL or its complications [9]. In this review, we will address the evaluation of fitness in this elderly cohort, as well as recommendations for initial and later therapies based upon such assessments.
2. Assessment of Fitness and Comorbidity Burden for Treatment Consideration Indications for treatment initiation in elderly CLL patients are similar to those for younger patients [10] (Table 1). Factors that do not necessitate therapy initiation include the level of the absolute lymphocyte count, asymptomatic or slowly progressive lymphadenopathy, or frequent/recurrent infections. Chronologic age is not a surrogate for physiologic age or fitness. Comorbidities may be assessed by measures such as the Cumulative Index Rating Scale (CIRS) and the Charlson Comorbidity Index [11,12]. In one series, 89% of the newly diagnosed Table 1 – Indications for initiation of therapy in CLL patients. Evidence of progressive marrow failure (worsening anemia and/or thrombocytopenia) Massive and/or symptomatic splenomegaly Massive and/or symptomatic lymphadenopathy Progressive lymphocytosis, with >50% increase over two months, or lymphocyte doubling time <6 months Autoimmune anemia and/or thrombocytopenia with poor response to treatment Constitutional symptoms/signs, including: Unintentional weight loss 10% over 6 months Significant fatigue Fevers without infection Night sweats >1 month (Adapted from reference [10]).
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
. . . .
0 0 0 0
CLL patients had at least one comorbidity, including 46% with >1 major comorbidity, such as vascular or pulmonary disease or diabetes [13]. Assessment of functional status is best done by measures such as the Comprehensive Geriatric Assessment (CGA), which includes consideration of functionality, coexisting health problems, social support, cognitive ability, nutritional status, and geriatric syndromes (dementia, delirium, falls, failure to thrive, depression, polypharmacy) [14–17]. Such assessments help to predict chemotherapy tolerance in the elderly [18,19]. Unfortunately, studies examining the interaction between comorbidities and CLL therapy are limited. In one large series, it was suggested that durable disease control was the most important factor in the outcome of CLL patients with comorbidities [20].
3. Initial Therapy 3.1. First Line Therapy in Healthy, Fit Patients Without del(17p) The approach to initial CLL therapy has evolved, with the introduction of the purine analogs, alemtuzumab, bendamustine, and more recently newer agents as ibrutinib, idelalisib, and obinutuzumab. Unfortunately, many of these trials are not of phase III design, and older patients have been underrepresented in the majority. Single agent chlorambucil is the comparator agent in many phase III trials based upon FDA guidance. Patients with a CIRS score <6 and preserved renal function can tolerate initial aggressive chemoimmunotherapy such as FCR, which is a standard of care in young/healthy individuals [21,22]. In the phase III trial comparing initial therapy with fludarabine plus cyclophosphamide (FC) to FCR in fit patients, FCR resulted in improved overall response rate (ORR) and progression-free survival (PFS), regardless of age [22]. The ORR (complete response (CR)) rates with FC and FCR were 79%(19%) versus 89%(45%), respectively (p < 0.001, p < 0.0001) in patients <65 yrs of age, and 83%(24%) versus 93%(43%) (p = 0.028 for ORR, p = 0.003 for CR) for those >65 yrs of age. Three-yr PFS was significantly prolonged with FCR in patients <65 yrs of age (46% versus 64% respectively, p < 0.0001), as well as those >65 yrs of age (43% versus 68% respectively, p = 0.001). A prolongation in overall survival (OS) was seen with FCR therapy as compared with FC (p = 0.017). However, this benefit was confined to those patients <65 yrs of age, and not those >65 yrs (p = 0.059 and 0.103, respectively). Although FCR was associated with more grade 3/4 neutropenia than FC (34% versus 21%, respectively, p < 0.0001), the incidence of severe infection was comparable with both regimens. Another option is FCR-lite, with low dose fludarabine and cyclophosphamide and high dose rituximab, including rituximab maintenance therapy [23,24]. In a phase II trial in patients (median age 58 yrs (range, 36–85 yrs)), ORR(CR) rates were 93%(73%), with median PFS of 5.8 yrs.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
Myelosuppression was less than with traditional FCR, with grade 3/4 neutropenia complicating 11% of FCR-lite cycles, and grade 3/4 infections occurring in 6% of patients. Cladribine has been combined with rituximab or cyclophosphamide for alternative purine analog-based combination trials including some elderly patients [25,26]. Bendamustine-based regimens are reasonably tolerated in the elderly [27–29]. In a phase II trial of initial bendamustine plus rituximab therapy (BR) in which half the patients were >65 yrs of age, ORR(CR) rates were 88%(23%), respectively, and median event-free survival was 33.9 months [28]. Grade 3/4 neutropenia, thrombocytopenia, and anemia each occurred in approximately 20% of patients. Initial therapy with bendamustine versus chlorambucil was compared in a randomized phase III trial, with ORR of 68% and 31%, respectively (p < 0.0001) [27,29]. More CRs occurred with bendamustine (21% versus 10.8%), and time to next treatment was prolonged (31.7 versus 10.1 months, p < 0.0001), as was median PFS (21.2 versus 8.8 months, p < 0.0001). Hypersensitivity reactions were more common with bendamustine than chlorambucil (5% versus 2%). Likewise, more grade 3/4 adverse events were seen with bendamustine than chlorambucil (40% versus 19%, respectively), including neutropenia and thrombocytopenia (23% versus 11%, and 12% versus 8%, respectively). In a preliminary analysis of the phase III trial comparison of BR versus FCR, higher CR rates (47% versus 38%, p = 0.031) and prolonged 2-yr PFS (85% versus 78%, p = 0.041) were seen with FCR as compared with BR, although no advantage in PFS was seen in patients >65 yrs of age [30]. However, significantly more grade 3–5 myelosuppression and infections occurred with FCR than BR, especially in the elderly cohort.
3.2. First Line Therapy in Frail, Unfit Patients Without del(17p) Patients with CIRS scores > 6 and/or compromised renal function do not tolerate aggressive chemoimmunotherapy as FCR, which may result in prolonged marrow suppression with concomitant morbidity/mortality. The substitution of pentostatin for fludarabine, in combination with rituximab alone (PR), or rituximab plus cyclophosphamide (PCR) may be better tolerated, with less myelosuppression and comparable ORR/CR rates and PFS [31,32]. Alternatively, extended PFS and OS were demonstrated with FR therapy in patients of median age 63 yrs (median 42 and 85 months, respectively) [33,34]. Chlorambucil remains a tolerable and efficacious agent for frail unfit patients. In a phase III trial, treatment-naïve patients >65 yrs of age (median, 70 yrs) were randomized to therapy with fludarabine or chlorambucil [9]. Two-thirds of the patients had >1 comorbidities. Fludarabine resulted in higher ORR and CR rates than chlorambucil (72% versus 51%, p = 0.003; 7% versus 0%, p = 0.011, respectively), and time to treatment failure (TTF) was prolonged (18 versus 11 months, p = 0.004). However, there were no differences in PFS and OS. Grade 3/4 leukopenia was more common with fludarabine (p < 0.001). Based upon these findings, it was concluded that initial fludarabine therapy in older patients does not result in major clinical benefit as compared with chlorambucil. In a subsequent phase II trial of chlorambucil plus rituximab in elderly patients (median age 70 yrs; median seven comorbidities), ORR(CR) rates were 84%(10%), with median PFS of 23.5 months [35]. Most
3
grade 3/4 toxicities were hematologic (41% grade 3/4 neutropenia). This is considered as a preferred initial regimen for unfit patients [36]. Several anti-CD20 antibodies have been studied in combination, some with chlorambucil, as initial CLL therapy [37–39]. Therapy with rituximab plus high dose methylprednisolone in patients (median age 65 yrs) resulted in ORR(CR) rates of 96%(32%), and median PFS of 30.3 months, with few grade 3/4 adverse events [37]. In a phase III trial in which patients (median age 69 yrs) were randomized to either ofatumumab plus chlorambucil or chlorambucil alone, median PFS as well as ORR(CR) rates were higher with combination therapy (22.4 versus 13.1 months, p < 0.001; 82 %(12%) versus 69%(1%), p < 0.001, respectively), as was grade > 3 neutropenia (26% versus 14%, respectively) [38]. Results of a phase III trial in which treatment naive CLL patients (median age 73 yrs) with a CIRS score > 6 and/or a creatinine clearance of 30–69 ml/min received chlorambucil, rituximab plus chlorambucil, or obinutuzumab plus chlorambucil, have recently been reported [39]. ORR(CR) rates were highest with obinutuzumab, compared to chlorambucil (77.3% versus 31.4%; 22.3% versus 0%, respectively, p < 0.001). Median PFS was longest with obinutuzumab plus chlorambucil, compared with rituximab plus chlorambucil (26.7 versus 16.3 months, p < 0.001, compared with 11.1 months with chlorambucil); higher CR (20.7% versus 7%, respectively) and molecular response rates were also found. Grade 3/4 infusion reactions and neutropenia were most common with obinutuzumab plus chlorambucil (21% and 35%, respectively). In updated analyses, treatment with either obinutuzumab or rituximab plus chlorambucil conferred an OS advantage over single agent chlorambucil (p = 0.0014 and 0.0242, respectively) [40]. Single agent lenalidomide has been studied as initial therapy for elderly CLL patients [41,42]. In one trial in patients >65 yrs of age, a 5 mg daily continuous dose of lenalidomide, with a dose escalation to 25 mg daily as tolerated, resulted in ORR(CR) rates of 65%(10%), and 2-yr PFS of 60% [41]. Grade 3/4 neutropenia and infections occurred in 34% of treatment cycles and 13% of patients, respectively; tumor flare is also a potential adverse event in such patients. With median followup of 4 yrs, median TTF had not been reached, 58% had a response lasting > 3 yrs, and OS was 82% [43]. A starting lenalidomide dose of 2.5 mg daily for 21 of 28 days, with a dose escalation to 10 mg daily, was utilized in another series, with ORR(CR) rates of 56%(0%), and grade 3/4 neutropenia in 72% of patients [42]. Data on lenalidomide plus rituximab combination therapy has also been reported [44]. However at present, lenalidomide is not available for CLL therapy outside of clinical trials.
3.3. First Line Therapy in Patients With del(17p) The subset of CLL patients with TP53 deletions, regardless of the presence of 17p deletion, has a poor prognosis, with lower response rates and decreased PFS/OS with fludarabine-based regimens [45–48]. The efficacy of high-dose methylprednisolone plus rituximab has been demonstrated in patients with these adverse features [37,49,50]. Updated results with three-yr safety data of therapy with ibrutinib, a Bruton's tyrosine kinase inhibitor, in 31 previously untreated CLL patients >65 (median,
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
4
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
71) yrs of age have recently been published, with ORR(CR) rates of 84%(23%) [51,52]. Most toxicities were grade 1/2, including diarrhea (the most common grade 3 toxicity, with a 16% incidence), nausea, fatigue, hypertension, and edema. Median PFS and OS had not yet been reached. The impact of ibrutinib for patients with TP53 deletions has recently been demonstrated [53,54]. In a phase 2 trial of ibrutinib plus rituximab including patients, many previously treated, with TP53 mutations or deletions in 17p or 11q, 18-month PFS was 72.4% in those with TP53 mutation or deletion 17p [53]. In another preliminary report of a phase II ibrutinib trial in patients with high-risk disease, ORR was 97% in treatment naïve patients and 80% in those previously treated [54]. Comparable responses were seen in patients with TP53 mutations, with median PFS of 28.1 months.
4. Summary Recommendations for Initial Therapy (Table 2) For older patients, especially those who are > 70 yrs of age, chlorambucil in combination with an anti-CD20 monoclonal antibody and bendamustine–rituximab are reasonable options. In addition, a variety of single agent treatment options may be considered. For patients with TP53 mutations or deletion 17p, initial ibrutinib therapy may be considered. For those with deletion 11q, inclusion of an alkylator in the treatment regimen, especially cyclophosphamide, is associated with superior response rates and prolonged PFS [55]. The use of appropriate supportive care measures, including myeloid growth factor support when indicated and prophylactic antimicrobial therapy, is especially important in this population [56,57].
5. Therapy for Relapsed/Refractory Disease There is no standard therapy for relapsed CLL, with treatment decisions based upon prior therapy, length of remission, age, fitness, and adverse prognostic factors (Table 3). For patients with > 2 yrs of response to initial purine analog therapy, retreatment may be considered, with regimens as PCR or low dose FCR [23,24,58,59]. Bendamustine plus rituximab is effective and safe in the relapsed/refractory setting, and is active in fludarabine-refractory patients [60]. Alemtuzumab alone or with high dose methylprednisolone or rituximab may be considered for more fit patients, especially those with 17p deletion or TP53 mutation, while high dose methylprednisolone plus rituximab may be utilized for less fit patients [61–64]. Monotherapy with rituximab, ofatumumab, or obinutuzumab, which tend to be well tolerated, may also be considered [65–68]. Lenalidomide, as a single agent or in combination with rituximab, has also been studied in clinical trials including elderly patients with favorable results [69–73]. Treatment data with two new novel agents in relapsed/ refractory patients have been recently reported. With a recent three-yr followup, ibrutinib therapy in relapsed/refractory patients, median age 64 yrs (34% > 70 yrs), ORR(CR) was 90%(7%), and the estimated 30-month PFS and OS were 69% and 79%, respectively [52,74]. The most common grade 3
Table 2 – Recommendations for initial therapy of chronic lymphocytic leukemia. Age <70 yrs and no significant comorbidities Purine analog-based therapy FCR FR PCR BR Age >70 yrs, or <70 yrs and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Bendamustine +/− rituximab Fludarabine +/− rituximab Single agent therapy Obinutuzumab Chlorambucil Rituximab Cladribine Frail patient and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Single agent therapy Obinutuzumab Rituximab Chlorambucil Pulse corticosteroids Presence of 17p deletion Ibrutinib High dose methylprednisolone + rituximab FCR FR Obinutuzumab + chlorambucil Alemtuzumab +/− rituximab Presence of 11q deletion: Age >70 yrs, or <70 yrs and significant comorbidities Chlorambucil-based combination therapy Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Rituximab + chlorambucil Bendamustine +/− rituximab Cyclophosphamide, prednisone, +/− rituximab Reduced dose FCR Chlorambucil Rituximab Age <70 yrs and no significant comorbidities Purine analog-based therapy FCR PCR Bendamustine +/− rituximab Obinutuzumab + chlorambucil Based upon the NCCN recommendations, Version 2.2015[80].
toxicities were pneumonia (25%), hypertension (20%), neutropenia (18%), and thrombocytopenia (10%). In a subsequent phase III trial in which patients (median age 67 yrs) were randomized to ibrutinib or ofatumumab, ORR was superior with ibrutinib (42.6 % versus 4.1%, p < 0.001), as was median PFS (with median followup of 9.4 months, not reached with ibrutinib, versus 8.1 months with ofatumumab) [75]. The PI3 kinase inhibitor idelalisib was studied in a phase I trial, with 72% ORR and median PFS of 15.8 months [76]. The most
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
Table 3 – Recommendations for therapy of relapsed/ refractory chronic lymphocytic leukemia. Age <70 yrs and no significant comorbidities Ibrutinib Idelalisib + rituximab Purine analog-based therapy FCR PCR Fludarabine + alemtuzumab R-CHOP Single agent therapy Ofatumumab Obinutuzumab Lenalidomide +/− rituximab Alemtuzumab +/− rituximab High dose methylprednisolone + rituximab Age >70 yrs, or <70 yrs and significant comorbidities Ibrutinib Idelalisib + rituximab Purine analog-based therapy (reduced dose FCR, reduced dose PCR) High dose methylprednisolone + rituximab Rituximab + chlorambucil Single agent therapy Bendamustine +/− rituximab Ofatumumab Obinutuzumab Lenalidomide +/− rituximab Alemtuzumab +/− rituximab Dose-dense rituximab Based upon the NCCN recommendations, Version 2.2015[80].
common grade > 3 toxicities were pneumonia (20%), febrile neutropenia (11%), and diarrhea (6%). In a subsequent phase III study, patients (median age 71 yrs) were randomized to idelalisib plus rituximab versus placebo plus rituximab [77]. Median PFS, ORR, and one-yr OS favored the idelalisib (PFS not reached versus 5.5 months; 81% versus 13%, p < 0.001; 92% versus 80%, p = 0.02, respectively). The most common grade > 3 adverse events in the idelalisib group were neutropenia (34%), thrombocytopenia (10%), anemia (5%), transaminase elevation (5%), and diarrhea (4%). Idelalisib was also active in patients with 17p or 11q deletion, or TP53 mutation [78,79].
6. Conclusions Chronic lymphocytic leukemia is predominantly a disease of the elderly, who commonly have comorbidities, potential decline in functional status, and underrepresentation in clinical trials. Choosing appropriate, tolerable therapy in these patients is thus complex. Supportive care measures and attention to quality of life are important in the care of such patients. The recent addition of new agents to the therapeutic armamentarium provides further treatment options for these patients. Ongoing prospective treatment trials are now including older patients, including some of which have formal comprehensive geriatric assessment as a component of the study. The results of these trials will provide a framework for future treatment approaches in the elderly CLL patient.
5
REFERENCES
1. Tadmor T, Polliack A. Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices. Blood Rev 2012;26: 15–23. 2. Delgado J, Briones J, Sierra J. Emerging therapies for patients with advanced chronic lymphocytic leukemia. Blood Rev. 2009;23:217–224. 3. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013:158–167. 4. Abrisqueta P, Pereira A, Rozman C, Aymerich M, Gine E, Moreno C. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood 2009;114:2044–2050. 5. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood 2008;111:4916–4921. 6. Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer 2010;116:4777–4787. 7. Goede V, Hallek M. Optimal pharmacotherapeutic management of chronic lymphocytic leukaemia: considerations in the elderly. Drugs Aging 2011;28:163–176. 8. Ferrajoli A, O’Brien SM, Wierda W, et al. Treatment of patients with CLL 70 years old and older: a single center experience of 142 patients. Leuk Lymphoma 2005;46(Suppl):48 [S86]. 9. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382–3391. 10. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia: updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446–5456. 11. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992;41: 237–248. 12. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47: 1245–1251. 13. Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, et al. Cormorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:49–56. 14. Balducci L. ESH-SIOG International Conference on Haematological Malignancies in the Elderly. Expert Rev Hematol 2010;3:675–677. 15. Brunello A, Sandri R, Extermann M. Multidimensional geriatric evaluation for older cancer patients as a clinical and research tool. Cancer Treat Rev 2009;35:487–492. 16. Terret C. Management and geriatric assessment of cancer in the elderly. Expert Rev Anticancer Ther 2004;4:469–475. 17. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 2011;29: 1290–1296. 18. Freyer G, Geay JF, Touzet S, Provencal J, Weber B, Jacquin JP, et al. Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study. Ann Oncol 2005;16:1795–1800.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
6
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
19. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older patients with cancer: a prospective multicenter study. J Clin Oncol 2011;29: 3457–3465. 20. Goede V, Cramer P, Busch R, Bergmann M, Stauch M, Hopfinger G, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014;99:1095–1100. 21. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma 2009;50: 171–178. 22. 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;376:1164–1174. 23. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2008;27:498–502. 24. Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, et al. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood 2012;119:3184–3185. 25. Bertazzoni P, Rabascio C, Gigli F, Calabrese L, Radice D, Calleri A, et al. Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients. Leuk Lymphoma 2010;51:1485–1493. 26. Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, et al. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 study). J Clin Oncol 2010;28:1863–1869. 27. 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;27:4378–4384. 28. Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30: 3209–3216. 29. Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, et al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol 2012;159: 67–77. 30. Eichhorst B, Fink AM, Busch R, Lange E, Köppler H, Kiehl MG, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German Study Group (GCLLSG). Blood 2013;122(Suppl) [Abstract 526]. 31. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007;109: 405–411.
32. Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 2007;109:2291–2298. 33. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B study 9712 (CALGB 9712). Blood 2003;101:6–14. 34. Woyach JA, Ruppert AS, Heerma NA, Peterson BL, Gribben JG, Morrison VA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 2011;29: 1349–1355. 35. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: final analysis of an open-label phase II study. J Clin Oncol 2014;32:1236–1241. 36. Foa R, Giudice ID, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014;89: 480–486. 37. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia 2009;23:1779–1789. 38. Hillmen P, Robak T, Janssens A, Govindbabu K, Grosicki S, Mayer J, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study Complement 1 (OMB110911). Blood 2013;122 [Abstract 528]. 39. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370: 1101–1110. 40. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LFC, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015;1–3. 41. Badoux XC, Keating MJ, Wen S, Bang-Ning L, Sivina M, Reuben J, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011;118:3489–3498. 42. Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, et al. Single agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 2011;29: 1175–1181. 43. Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734–737. 44. James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium. J Clin Oncol 2014;32:2067–2073. 45. Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T, et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia 2010;24: 2072–2079. 46. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010;28:4473–4479. 47. Fink AM, Bottcher S, Ritgen M, Fischer K, Pflug N, Eichhorst B, et al. Prediction of poor outcome in CLL patient following
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X
48.
49.
50.
51.
52.
53.
54.
55.
56. 57.
58.
59.
60.
61.
62.
first-line treatment with fludarabine, cyclophosphamide, and rituximab. Leukemia 2013;27:1949–1952. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123:3247–3254. Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene F, Sejoniene J, et al. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma 2011;52:1055–1065. Bowen DA, Call TG, Jenkins GD, Zent CS, Schwager SM, Van Dyke DL, et al. Methylprednisolone–rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma 2007;48:2412–2417. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15:48–58. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment-naıve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497–2506. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab with high-risk chronic lymphocytic leukemia: a single-arm phase 2 study. Lancet Oncol 2014;15: 1090–1099. O'Brien SM, Furman RR, Coutre SE, Flinn I, Burger JA, Blum KA, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol 2014;32:5s [Abstract 7014]. Ding W, Ferrajoli A. Evidence-based mini-review: the role of alkylating agents in the initial treatment of chronic lymphocytic leukemia patients with the 11q deletion. Hematology 2010;90–92. Morrison VA. Infections in patients with leukemia and lymphoma. Cancer Treat Res 2014;161:319–349. Morrison VA. Infectious complications of chronic lymphocytic leukemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol 2010;23:145–153. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2006;24:1575–1581. Gozzetti A, Candi V, Fabbri A, Schiattone L, Cencini E, Lauria F, et al. Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia. Leuk Res 2014;38:891–895. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559–3566. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554–3561. Cortelezzi A, Gritti G, Laurenti L, Cuneo A, Ciolli S, Di Renzo N, et al. An Italian retrospective study on the routine clinical use of low dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients. Brit J Haematol 2011;156: 481–489.
7
63. Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol 2012;130: 1647–1655. 64. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine-refractory high-risk chronic lymphocytic leukemia. Leukemia 2008;22: 2048–2053. 65. 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;28:1749–1755. 66. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008;111: 1094–1100. 67. Flynn JM, Byrd JC, Kipps TJ, Boxer M, Kolibaba KS, Tyson N, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg in patients with chronic lymphocytic leukemia (CLL): results of the phase II GAGE (GAO4768g) trial [abstract]. J Clin Oncol 2014;32(Suppl):5s [Abstract 7083]. 68. Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 2014;124:2196–2202. 69. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 2006;24:5343–5349. 70. Ferrajoli A, Lee BN, Schlette EJ, O’Brien SM, Gao H, Wen S, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291–5297. 71. Wendtner CM, Hillmen P, Mahadevan D, Buhler A, Uharek L, Coutre S, et al. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 2012;53:417–423. 72. Buhler A, Wendtner C, Hallek M, Kipps TJ, Rassenti L, Fraser G, et al. TP53 mutation or deletion and efficacy with single-agent lenalidomide in relapsed or refractory chronic lymphocytic leukemia (CLL) (CC-5013-CLL-009 study). Blood 2013;122 [Abstract 1638]. 73. Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013;31:584–591. 74. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42. 75. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–223. 76. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390–3397. 77. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Eng J Med 2014;370:997–1007. 78. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Efficacy of idelalisib in CLL subpopulations
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003
8
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX
harboring del (17p) and other adverse prognostic factors: results from a phase 3, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2014;32:5s [Abstract 7011]. 79. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with
TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169–176. 80. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. J Natl Compr Canc Netw 2015;13:326–362.
Please cite this article as: Heraly B, Morrison VA., How I treat chronic lymphocytic leukemia in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/j.jgo.2015.08.003