Drugs Aging 2011; 28 (9): 749-764 1170-229X/11/0009-0749/$49.95/0
REVIEW ARTICLE
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Optimal Pharmacotherapeutic Management of Acute Lymphoblastic Leukaemia in the Elderly Philippe Rousselot1 and Andre´ Delannoy2 1 Department of Haematology, Hoˆpital Andre´ Mignot, Versailles, France 2 Department of Haematology, Hoˆpital de Jolimont, Haine-Saint-Paul, Belgium
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Information Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Clinical and Biological Characteristics of Elderly Patients with Acute Lymphoblastic Leukaemia (ALL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Reasons for Poor Prognosis of ALL in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Philadelphia Chromosome-Negative (Ph-) ALL in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Can the Prognosis be Improved? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Recommendations for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Philadelphia Chromosome/Breakpoint Cluster Region-Abelson Tyrosine Kinase-Positive (Ph/BCR-ABL+) ALL in the Elderly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Therapeutic Approaches to Ph/BCR-ABL+ ALL in the Elderly: the Revolution of Imatinib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Maintenance Therapy and CNS Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5 Management of Relapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
749 750 751 751 753 754 754 755 756 756 756 757 759 761 761
The main characteristic of acute lymphoblastic leukaemia (ALL) in the elderly is its dismal prognosis. However, other than a lower incidence of T-cell ALL and a greater likelihood of unfavourable chromosomal abnormalities, the clinical and biological characteristics of Philadelphia chromosomenegative (Ph-) ALL in the elderly at diagnosis are no different from those observed in younger adults, and do not account, per se, for its poor prognosis. Rather, the latter is explained to a large extent by a high rate of treatmentinduced mortality and/or by the use of less toxic but comparatively less effective drug regimens. Ph- ALL patients are offered treatments ranging from palliative care to intensive chemotherapy, but the survival of patients given palliative or minimally active chemotherapy is extremely poor. However, a valid comparison with patients given more intensive chemotherapy is lacking, as, in most cases, minimally active chemotherapy is used in patients
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with poor performance status at diagnosis. When more intensive chemotherapy is used, unacceptably high early mortality rates (up to 50%) have been reported, with complete-response rates ranging from 40% to 80% and 5-year survival consistently below 20%. Clearly, the results of therapy are unsatisfactory in Ph- ALL patients, which should encourage the development of innovative approaches, such as the use of new monoclonal antibodies. On the other hand, the availability of imatinib and second-generation tyrosine kinase inhibitors (TKIs) has improved the prognosis of Philadelphia-positive (Ph+) ALL in older patients. Impressive response rates have been reported, even in patients given imatinib and corticosteroids without additional chemotherapy, at the cost of manageable toxicity. Paradoxically, in the imatinib era, elderly patients with Ph+ leukaemia (which is clearly associated with an adverse prognosis in younger adults) seem to survive longer than Ph- elderly patients, although long-term survivors still remain relatively few. Whether new TKIs, such as dasatinib or nilotinib, will improve the prognosis of Ph+ ALL in the elderly is being prospectively assessed in several countries.
1. Introduction Although interest in acute lymphoblastic leukaemia (ALL) in the elderly has been growing during the last decade, papers and abstracts specifically devoted to ALL in the elderly remain relatively sparse,[1-23] at least compared with the information available on elderly patients with acute myeloblastic leukaemia (AML). ALL is a relatively common malignancy in children. Its incidence decreases dramatically in young adults and increases again in the elderly (figure 1). However, this phenomenon is much more pronounced in AML, with the incidence in the US reaching 15.9/100 000 in individuals aged >65 years compared with 1.5/100 000 in ALL.[24] Underrepresentation of elderly patients in reported cancer studies is a general phenomenon applying to all malignant disorders.[25] In the study by Taylor et al.,[3] the only populationbased study of ALL in the elderly, only 22 out of 49 patients were scheduled to receive a treatment with a curative intent, three of whom died before chemotherapy was started. Thus, only 19 out of 49 would have been eligible for protocol-based studies. In the single-institution study by Legrand et al.,[10] 21 out of 46 patients were not included in clinical studies because their general condition was poor or because their cardiac status contraindicated the use of anthracyclines. Overall, ª 2011 Adis Data Information BV. All rights reserved.
clinical trials in the elderly with ALL provide a far from realistic picture of ALL in the general population of elderly patients. Furthermore, there is no consensus on the definition of older patients. In most studies, elderly patients are defined on the basis of age, with a lower cutoff ranging from 50 to 65 years. In several treatment protocols, such as the French studies by the Leuce´mies Aigue¨s Lymphoblastiques de l’Adulte (Acute Lymphoblastic Leukaemia in Adults) [LALA] group and the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), some age overlap is permitted with younger adults’ treatment schedules, allowing fit older patients to be treated more intensively. However, the definitions of fitness and frailty may vary to a large extent. From the geriatrician’s point of view, fitness and frailty can be assessed on the basis of scoring systems that take into account, in addition to age, many parameters, including co-morbidities and functional status. From the haematologist’s point of view, the patient’s eligibility for optimal therapy, including intensive treatments such as allogeneic stem cell transplantation, is central to the definition of fitness. Accordingly, the definition of fitness is also driven by the therapies that are currently available, such as reduced-intensity conditioned stem cell transplantation and use of tyrosine kinase inhibitors (TKIs), a well tolerated Drugs Aging 2011; 28 (9)
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
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Incidence of ALL per 100 000 individuals in the US (2003−7)
8 7 6 5 4 3 2 1
4 −4 9 50 −5 4 55 −5 9 60 −6 4 65 −6 9 70 −7 4 75 −7 9 80 −8 4 45
9
−4 40
4
−3 35
9
−3 30
4
−2 25
9
−2 20
4
−1 15
9
−1 10
4
5−
1−
<1
0
Age (y) Fig. 1. Age-specific incidence of acute lymphoblastic leukaemia (ALL) per 100 000 individuals in the US in 2003–7. Source: Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Review,[24] 2003–7.
and most effective class of drugs in patients with Philadelphia chromosome-positive (Ph+) ALL. Until the recent advent of TKIs, most studies devoted to the elderly with ALL made no distinction between Ph+ and Philadelphia chromosomenegative (Ph-) cases for many reasons, including the lack of cytogenetic data in many early studies, the equally poor patient survival irrespective of Ph status, and the absence of differentiated treatments based on the presence of the Ph chromosome.[26] The advent of TKIs has modified both the treatment and the prognosis of Ph+ ALL in the elderly. Accordingly, recent data on Ph+ elderly patients are considered separately in this review. 2. Information Sources Our previous overview of ALL in the elderly[26] is updated and modified in this review. To be included in this review, papers and abstracts were required to present data on the treatment and outcome of at least ten patients. We were able to identify 23 informative papers and abstracts devoted to ALL in the elderly, most of which dealt with mixed cases of Ph+ and Phpatients, the exceptions being studies by Sancho et al.[21] and Hunault-Berger et al.,[23] which were ª 2011 Adis Data Information BV. All rights reserved.
exclusively devoted to Ph- patients. Of these 23 data sources, three are available only as abstracts.[6,14,16] Only one study is a population-based report.[3] Nine of the remaining publications were devoted to a description of patients from a single hospital, or from a group of institutions, not treated homogeneously,[2,5,10,12,14,15,18,19,21] while 13 were protocol-based studies.[1,4,6-9,11,13,16,17,20,22,23] Although care was taken not to include duplicate cases, some patients may have been reported in several publications, for example, both in singleinstitution experience reports and in protocolbased studies. 3. Clinical and Biological Characteristics of Elderly Patients with Acute Lymphoblastic Leukaemia (ALL) The main features of the 23 selected studies are summarized in table I, and a comparison with younger adults is presented in table II. 1407 patients were included in the 23 data sources grouping patients with Ph+ and Ph- ALL, with a crude male/female ratio of 0.97, compared with a much higher sex ratio in younger adults, for example, 1.6 in 1002 patients in the large Medical Research Council/Eastern Cooperative Oncology Group study[32] and 1.6 in 257 patients in the Drugs Aging 2011; 28 (9)
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ª 2011 Adis Data Information BV. All rights reserved.
Table I. Main studies on acute lymphoblastic leukaemia (ALL) in the elderly, excluding Philadelphia chromosome-positive (Ph+) ALL specific studies Study
N
Age (median) [y]
WBC count >30 · 109/La (n/N)
Immunophenotype (B cell/T cell/ othersb)a [n]
CNSa involvement (n/N)
Ph+a (n/N)
Deaths during inductiona (n/N)
CR (%)
Median survival (moc)
Hussein et al.[1]
40
>50
NR
NR
NR
NR
20/40
35
1
Delannoy et al.[2]
18
>59 (69.5)
6/18
6/0/9
2/18
1/5
5/17
47
3
49
>59 (74)
NR
18/2/21
NR
3/20
3/19
31
1
Kantarjian et al.[4]
52
>59
NR
NR
NR
9/38
6/52
65
11d
Spa¨th-Schwalbe et al.[5]
29
>59 (65)
9/29
14/2/11
0/23
2/6
9/24
42
5
Mandelli et al.[6]
80
>60 (64.9)
NR
56/15/1
NR
7/18
32/77
46.5
19% at 2 years
Ferrari et al.[7]
49
>60 (68)
NR
17/4/8
3/25
NR
11/49
59
9
Taylor et al.
[3]
>59 (64)
NR
20/2/0
0/22
6/14
4/22
59
9.1
40
>54 (66.8)
6/40
29/3/1
3/40
8/26
3/40
85
14.2
[10]
Legrand et al.
46
>59 (67)
NR
85%/13%/0%
NR
11/30
8/46
43
10
Larson et al.[11]
41
>59
NR
NR
NR
NR
7/41
77
12
Nagura et al.[12]
20
>59 (68)
NR
13/2/1
NR
4/15
NR
55
7
Goekbuget et al.[13]
63
>65 (69)
NR
92%/8%/0%
NR
60% of ‘common ALL’
11/50
46
11
Onciu et al.[14]
33
>59 (65)
NR
23/4/6
NR
9/33
NR
81
NR
Pagano et al.[15]
37
>65 (69)
NR
29/1/1
1/33
2/20
9/37
68
7
Goekbuget et al.[16]
342
>55–65
NR
75%/12%/0%
NR
54% of B-cell ALL
24%
59
9
Delannoy et al.[17]
58
>54 (64.9)
NR
50/6/0
3/58
21/54
7/58
58
9.5
Thomas et al.
69
>59 (68)
NR
56/5/0
6/67
10/42
17/64
67
7
Robak et al.[19]
87
>60 (66)
NR
48/12/4
10/87
7/37
11/75
45
5
Offidani et al.[20]
17
>60 (69)
4/17
15/2/0
2/17
3/17
3/17
76
21
[21]
33
>55 (65)
NR
25/5/0
NR
NR
12/33
58
7
122
>60
34/122
NR
NR
33/122
12/122
84
14d
60
>55 (67)
10/60
51/7/2
2/60
0/60
5/60
82
10
[18]
Sancho et al.
O’Brien et al.[22] Drugs Aging 2011; 28 (9)
Hunault-Berger et al. a
[23]
Data are not available for all patients.
b
Includes biphenotypic, null-cell and mature B-cell phenotypes.
c
Except where stated otherwise.
d
Estimated from survival curves.
CR = complete response; NR = not reported; WBC = white blood cell.
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Delannoy et al.[9]
Bassan et al.
[8]
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
smaller HOVON (Stichting Hemato-Oncologie voor Volwassenen Nederland [Dutch-Belgian Cooperative Trial Group for Hematology Oncology]) study.[33] Such differences may be accounted for, at least to some extent, by the male/ female imbalance observed in older persons. The median age of this population was 66.7 years, with most studies reporting on patients aged 55–60 years or older. This median age should be compared with the median age of 74 years reported by Taylor et al.[3] in their populationbased study, which underscores that most published studies are biased towards inclusion of relatively young patients. Across all of the selected studies, a myelodysplastic syndrome was present in only six patients before ALL was diagnosed. A white blood cell (WBC) count higher than 30 · 109/L, which is associated with a poor prognosis in adults with ALL, was no more frequent in the elderly; 44 of 182 elderly patients (24%) presented with a high WBC count compared with 28% of 135 younger adults.[34] T-cell ALL is associated with a favourable outcome in the young adult and was observed less often in the elderly (13% vs 22% of a control population of Ph+ and Ph- younger adult patients[27]), which, to some extent, may be accounted for by a higher incidence of Ph+ ALL (a B-cell ALL) in the elderly (27% vs 18% in the large Houston study).[22] As discussed in section 1, in the pre-TKI era, the survival of elderly patients was unaffected by their Ph status. AcTable II. Comparison of clinical and biological characteristics in the elderly and younger adults with acute lymphoblastic leukaemia (ALL) Characteristics
Male/female ratio White blood cell count >30 · 10 /L (%) 9
Elderly (age ‡55 y)
Younger adults (age <55 y)
0.97
1.6[27]
24
28[28]
T-cell ALL (%)
13
22[29]
Ph+ ALL (%)
27
18[22]
CNS invasion at diagnosis (%)
7
5[30]
Early deaths (%)
21
4.8[27]
Complete responses (%)
59
91[27]
Median survival (mo)
8.8
20[31]
Ph+ = Philadelphia chromosome-positive.
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753
cordingly, the excess of Ph+ cases did not account on its own for the poor prognosis of older persons with ALL. Overt CNS malignant invasion at diagnosis is also associated with a poor prognosis, but is not more common in the elderly (7% vs 5% in younger adults).[35] A recently published population-based cytogenetic study including 124 patients aged ‡60 years reached the same conclusions reported earlier in this section.[28] That study confirmed a lower male/female ratio, similar WBC counts and a lower incidence of T-cell ALL in the elderly, compared with younger adults. In addition, an increased proportion of some unfavourable chromosome abnormalities, including complex karyotypes (11% in patients aged ‡60 years vs 6% in patients aged 30–59 years and 3% in patients aged 15–29 years) was reported at diagnosis. However, other karyotype abnormalities associated with a poor outcome were relatively underrepresented in older patients, such as t(4;11) and t(1;19). In the same study, an unexpected high incidence of mature B-cell ALL was reported in older patients (23% vs 10% in patients aged 30–59 years and <1% in patients aged 15–29 years). Such a finding had not been previously reported. However, the incidence of mature B-cell ALL is likely to have been underestimated since this variant is excluded from most modern treatment protocols. 4. Reasons for Poor Prognosis of ALL in the Elderly As discussed in the previous section, the clinical and biological characteristics of ALL at diagnosis are similar in elderly and younger adults with respect to WBC count, a major prognosticator in ALL, and CNS invasion. However, T-cell ALL is underrepresented and unfavourable chromosomal abnormalities are overrepresented in the elderly. The impact of the latter two characteristics on the prognosis of older patients cannot be precisely quantified. For instance, the favourable impact of T-cell ALL on prognosis in the younger adult, although widely acknowledged, is often modest even when statistically significant. As an example, in the largest reported Drugs Aging 2011; 28 (9)
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study in adults, the survival benefit in favour of T-cell ALL patients was marginal (overall survival 48% vs 42%; p = 0.07).[29] The negative impact of unfavourable chromosome abnormalities has been recently identified. In the largest study devoted to cytogenetics of ALL in the elderly, unfavourable chromosomal abnormalities – namely t(4;11), t(14;18), complex karyotypes and low hypodiploidy/near triploidy – were significantly more prevalent in patients aged >60 years (36% vs 19% in younger patients) and were associated with a lower rate of complete remission and with a shorter overall survival.[28] On the other hand, early mortality from treatment-induced and, less commonly, from disease-related complications is typical in the elderly treated with a curative intent. From the available literature, 190 of 904 elderly patients (21%) died early, during the induction or during the salvage phase of treatment, compared with 4.8% of younger adults.[26] Even after a complete response (CR) has been achieved, a fraction of patients will still die from postinduction treatment toxicity. Following treatment with the fractionated cyclophosphamide, vincristine, adriamycin (doxorubicin) and dexamethasone (hyper-CVAD) regimen, for instance, 34% of elderly ALL patients achieving a CR ultimately died, mainly from drug-induced toxicity, during consolidation or maintenance treatment while still in CR.[22] Early mortality is largely responsible for the relatively low CR rate observed in the elderly: 59% versus 91% in the younger adult.[26] This relatively poor CR rate added to post-induction toxicity-related mortality finally translates into a poor overall median survival (8.8 months vs 20 months in younger adults).[36] In the Houston study, when the outcome for elderly patients was compared with that for younger adults given the same type of chemotherapy (hyperCVAD with a lower dose of cytarabine in the elderly), the finding underscored the burden of toxicity-related death in the elderly (44% vs 9% in younger adults), with resistance of the disease to drug therapy not being a common cause of failure in the elderly (5% vs 2% in younger adults).[22] ª 2011 Adis Data Information BV. All rights reserved.
Rousselot & Delannoy
In summary, the characteristics of ALL in the elderly are no different from those observed in younger adults, with the exception of a lower rate of T-cell ALL and a higher proportion of unfavourable chromosomal abnormalities, which together do not account for the poor outcomes seen in elderly patients. The disease does not appear to be particularly drug resistant in the elderly. Toxicity-related mortality is probably the major factor accounting for the poor overall outcome in this group. Even when high-dose treatments are administered together with intensive supportive treatment, the long-term survival rate of elderly patients with ALL typically remains below 20%.[22] 5. Philadelphia Chromosome-Negative (Ph-) ALL in the Elderly 5.1 Can the Prognosis be Improved?
In addition to their poor outcome, older people with ALL belong to a category of patients whose survival has, comparatively, benefited little from therapeutic progress during the last 2 decades.[37] Historically, the first drugs used to treat elderly patients with ALL were prednisone and vincristine; anthracyclines with or without asparaginase were introduced subsequently. The impact of these regimens on outcomes is extremely difficult to analyse, especially as many studies are retrospective and present global results for a population treated with heterogeneous regimens. In the only population-based study,[3] the outcomes with supportive, palliative (mainly prednisone and vincristine) and curative regimens (mainly characterized by the addition of anthracyclines) were compared. Although the number of patients analysed was low, and frail patients were offered a palliative approach, the study was able to show that the few patients who survived 5 years (4%) had been offered a curative approach. In 1994, the vincristine, adriamycin (doxorubicin) and dexamethasone (VAD) regimen was shown to induce a CR in 65% of patients aged ‡60 years, but, again, with an overall 3-year survival of less than 10%.[4] A recent randomized study by the GRAALL group showed that a Drugs Aging 2011; 28 (9)
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
modified VAD regimen, which included the use of pegylated doxorubicin, failed to improve survival.[23] Of more recent studies that reported the best treatment results, only two studies in the preTKI era reported median survival durations of longer than 1 year.[9,22] Both were protocol-based studies and characterized by relatively intense treatments based on regimens used in younger adults, with some dose adaptation. Both studies confirmed that the only chance of curing a tiny percentage of elderly patients with ALL (probably less than 20%) is with use of relatively intensive therapies, even at the price of a high rate of toxic deaths; however, as discussed in section 1, it is important to remember that intensive protocol-based studies are probably very much biased in favour of inclusion of fit individuals. As toxic death remains the major problem for the elderly population, intensifying supportive therapy could theoretically improve overall outcome. In the Houston study, mortality during induction dropped from 15% to 5% after patients were offered intensive supportive care, including nursing in a protected environment.[22] However, as the intense phase of the hyper-CVAD regimen is repeated in patients in CR for up to eight courses, late toxicity-related mortality from consolidation with hyper-CVAD, and even from maintenance therapy, was seen in 35 of 102 patients. Infection is the major cause of death during induction and in patients in CR. Accordingly, the use of growth factors during the neutropenic phases of induction/consolidation therapy has gained wide acceptance. Indeed, some randomized studies performed in patients with ALL reported a shortened duration of neutropenia, sometimes associated with fewer infectious complications, shorter stay in hospital and a lower mortality during induction therapy in patients given granulocyte colony-stimulating factor; however, there was no impact on longterm overall survival.[11] The introduction of new drugs into ALL regimens could improve the quality of responses achieved with current protocols. As toxicity is a major concern in elderly patients with ALL, new drugs with a favourable toxicology profile, such as monoclonal antibodies, should be preferred. ª 2011 Adis Data Information BV. All rights reserved.
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CD20 antigen is expressed in 32–47% of preB-cell ALL, making such cases amenable to treatment with anti-CD20 antibodies during induction and/or consolidation therapy in the hope of improving the poor prognosis of CD20positive (CD20+) ALL.[30,38] The preliminary experience with rituximab was encouraging, at least in young adults, but this agent failed to improve the overall survival of elderly patients compared with historical controls.[31] Blinatumomab belongs to a new class of monoclonal antibodies, the bi-specific T-cell engagers (BiTEs).[39] Blinatumomab combines two antigen-recognition sites: a CD3 site for T cells and a CD19 site for the target B cells. The drug works by linking these two cell types and activating the T cell to exert cytotoxic activity on the target cell. In 16 assessable patients with minimal residual disease resistant to conventional chemotherapy, a complete molecular response was achieved with use of blinatumomab (given as a single agent) in 13 cases, at the price of manageable toxicity.[39] Several other new agents are being assessed in adults with ALL. Nelarabine was found to be effective, especially in patients with T-cell ALL, which is relatively uncommon in the elderly.[40,41] Clofarabine is another purine analogue active in relapsing or refractory ALL, but its myelotoxicity will probably limit its use in older patients.[42] Vincristine sulfate liposomes have been assessed, in association with dexamethasone, in 101 patients with relapsing/refractory ALL.[43] CRs, including responses with incomplete haematological recovery, were achieved in 20% of cases with manageable toxicity, suggesting that vincristine sulfate liposomes are a possible candidate drug that could be incorporated into treatment schedules devised for the elderly.[43] Other drugs, including mammalian target of rapamycin (mTOR) inhibitors and forodesine, are being assessed in patients with relapsing or refractory ALL but are not yet sufficiently developed for use as first-line agents in the treatment of ALL outside clinical studies. 5.2 Recommendations for Treatment
As the prognosis of the elderly with Ph- ALL treated according to current protocols remains Drugs Aging 2011; 28 (9)
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poor, inclusion of a new patient in a clinical study should always be considered at diagnosis. Studies that offer an opportunity for the patient to benefit from use of less toxic agents, such as monoclonal antibodies, given in addition to classical chemotherapy, are a very reasonable option. Outside clinical studies, the treatment should be chosen, to a large extent, on the basis of the patient’s clinical condition, ideally assessed by comprehensive geriatric assessment techniques. In the fit patient, intensive chemotherapy derived from regimens in common use in the younger adult should be preferred, since, at the cost of considerable toxicity, intensive chemotherapy offers such patients an opportunity for long-term survival, even if the probability of 5-year survival is less than 20%. In the unfit patient, treatment, at this time, remains basically palliative, and includes corticosteroids, vincristine, transfusions and treatment of infections. 6. Philadelphia Chromosome/Breakpoint Cluster Region-Abelson Tyrosine KinasePositive (Ph/BCR-ABL+) ALL in the Elderly 6.1 Demographics
The Ph chromosome is the most frequent recurrent cytogenetic abnormality in the elderly with ALL.[44] Ph+ ALL is uncommon in children (2–3% of cases),[45] but its incidence has been found to increase with age to as high as approximately 50% of all cases of ALL in patients aged 60 years and, thereafter, to apparently decrease in frequency, at least in some studies.[17,44,46] In most if not all patients diagnosed with Ph+ ALL, the abnormality is considered to be a de novo feature of the disease.[47] No risk factor has been identified for developing Ph+ ALL, although secondary cases of Ph+ ALL have been reported following chemotherapy (for breast cancer, for example) or radiotherapy.[48] The frequency of Ph+ ALL is not significantly different in females compared with males. 6.2 Characteristics
The WBC count in patients with Ph+ ALL is variable at diagnosis. CNS leukaemia is inª 2011 Adis Data Information BV. All rights reserved.
frequent (5%), but there is an increased risk of developing meningeal leukaemia during the course of the disease. Spleen enlargement can be observed.[35,44] Ph+ ALL is a B-cell lineage ALL (B-ALL) with CD19+ and CD10+ antigen expression on the blast cells in most cases.[49] CD34 antigen is expressed in 89% of the cases, while 78.2% of the cases present with a common B-ALL immunophenotype (terminal deoxynucleotidyl transferase-positive [TdT+], CD19+, CD10+), 19.9% present with a pre-B immunophenotype (CD19+, CD10+, intracytoplasmic IgM+) and 1.9% present with a pro-B immunophenotype (CD19+, CD10-). The co-expression of a myeloid marker, such as CD13 antigen (20%) and CD33 antigen (15%), is common. Ph+ ALL is defined as ALL carrying the t(9;22) translocation on standard karyotype and/ or fluorescent in situ hybridization (FISH) analysis and/or presence of breakpoint cluster region/Abelson tyrosine kinase (BCR-ABL) fusion transcript detection by polymerase chain reaction (PCR) analysis.[50] The Ph chromosome results from the reciprocal translocation t(9;22) (q34;q11) that fuses the BCR gene from chromosome 22 to the ABL gene from chromosome 9. Additional chromosome aberrations were present in up to 79% of cases in a very large study of 209 patients and may be more frequent in the elderly.[46,51] In another study of 76 patients, additional aberrations, exceeding a frequency of 10%, comprised +der(22)t(9;22) abnormalities involving the short arm of chromosome 9, monosomy 7 and trisomy 8.[52] The presence of additional aberrations was significantly associated with shorter relapse-free survival and higher relapse rate, especially in cases with the +der(22)t(9;22) abnormality and abnormalities involving the short arm of chromosome 9. Overall, Ph+ ALL has been repeatedly associated with an adverse outcome. However, at least in the elderly, this dogma should be reconsidered since the advent of TKIs. The BCR-ABL fusion creates a constitutively active tyrosine kinase protein, bcr-abl. The location of the breakpoint within the BCR gene results in either the p190bcr-abl protein exclusively Drugs Aging 2011; 28 (9)
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
observed in Ph+ ALL (66.3% of the cases) or the p210bcr-abl protein common to patients with Ph+ ALL (31.2%) and nearly all patients with Ph+ chronic myelogenous leukaemia (CML).[44] The remaining cases present with both transcripts and/or with atypical transcripts. In addition, a recurrent deletion of Ikaros family zinc finger 1 (IKZF1) has been described in 83.7% of BCRABL ALL cases. These deletions result in a reduced activity of the Ikaros protein, which is involved in normal B lymphoid maturation, suggesting that Ikaros may directly contribute to the pathogenesis of BCR-ABL ALL.[53] Paired box 5 (PAX5), another gene involved in B-cell development, is also deleted in 50% of BCR-ABL ALL cases, with the majority harbouring, in addition, a deletion of IKZF1.[54] The main differential diagnosis workup is to rule out a CML in lymphoid blast crisis (LBC) [LBC-CML]. When a previous history of CML is lacking, LBC-CML could be suspected if myeloid hyperplasia and bone marrow basophilia are present. The finding of a major BCR-ABL fusion is not restricted to LBC-CML. 6.3 Therapeutic Approaches to Ph/BCRABL+ ALL in the Elderly: the Revolution of Imatinib
Imatinib was the first TKI targeted against BCR-ABL deregulated tyrosine kinase activity to be successfully tested in vivo and is now the gold standard for the treatment of de novo CML in the chronic phase.[55] Introduction of TKIs changed the clinical practice in relation to the treatment of adults with Ph+ ALL. The first evidence of clinical activity in relapsed or refractory Ph+ ALL was observed during the phase I study of imatinib, conducted in 1998–9 by Druker et al.[56] In this dose exploratory study, 20 patients with Ph+ ALL or LBC-CML were included. Fourteen patients (70%) obtained a haematological response, including four who had complete remissions. These unexpected results were confirmed in a further phase II study, in which 48 relapsed or refractory de novo Ph+ ALL patients were treated with imatinib 400–600 mg/day.[57] The complete haematological response rate was 19%, confirmª 2011 Adis Data Information BV. All rights reserved.
757
ing the phase I results, but the duration of response was short, with only three patients remaining in CR for more than 4 weeks and an estimated median survival of 4.9 months. These results led the investigators to combine imatinib with conventional chemotherapy in order to increase the CR rate and prolong the relapse-free interval. Several strategies have been tested to optimize the combination of imatinib and chemotherapy. For safety reasons, the first studies were based on schedules alternating imatinib (one or more courses) and chemotherapy. These protocols were followed by studies assessing various concurrent schedules in young patients (table III). Other groups addressed the question of a ‘more imatinib – less chemotherapy’ versus a ‘less imatinib – standard chemotherapy’ approach, particularly in the elderly. More selective prospective trials dedicated to elderly ALL patients have been conducted in recent years, with some having already been reported (table III). In the GRAALL AFR09 trial,[65] 30 ALL patients aged ‡55 years were treated with a corticosteroid-based regimen pre-phase, followed by a chemotherapy-based induction. Consolidation consisted of imatinib 600 mg/day and methylprednisolone. Patients in CR after consolidation were given ten maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Twenty-seven of 30 patients achieved a CR after either the first induction (72%) or after salvage imatinib or chemotherapy. The 1-year overall survival was 66%, with 58% disease-free survival. The median remission duration was 20 months. Both CR rates and survival were significantly improved compared with the historical controls treated according to the same regimen without imatinib. Over the long term, most patients in this study eventually relapsed with, at 5 years, only 10% of the patients being alive and relapse free, while overall survival was somewhat more encouraging (20% at 5 years), suggesting that some relapsing patients will survive for some years after their first relapse. The demonstration of the potential benefit of combining imatinib and chemotherapy in elderly patients was also shown by the GMALL (German Multi-Centre Drugs Aging 2011; 28 (9)
Study
Chemotherapy regimen/study identifier
Imatinib dosage (mg/d) induct. cons.
maint.
n
Results (%) CR relapse
DFS (y)
OS (y)
Hyper-CVAD
C (400)
C (400)
C (400)
39
92
14
83 (3)
55 (3)
Yanada et al.[60]
JALSG ALL202
C (600)
A (600)
C (600)
80
96
26
60 (1) 51 (2)
76 (1) 58 (2)
Lee et al.[61]
Modified from Linker et al.[62]
C (600)
C (400)
C (400)
20
95
32
62 (2)
59 (2)
Wassmann et al.[63]
GMALL A
None
C
None
A (400/600)
NR
47
NA
NR
52 (2)
36 (2)
C (600)
NR
45
NA
NR
61 (2)
43 (2)
GRAAPH-2003
None
C (600)
NR
45
96
19
51 (1.5)
65 (1.5)
Delannoy et al.[65]
GRAALL AFR09
None
C (600)
A (600)
30
72
60
58 (1)
66 (1)
Vignetti et al.[66]
GIMEMA
30
100
48
48 (1)
74 (1)
758
ª 2011 Adis Data Information BV. All rights reserved.
Table III. Imatinib-based chemotherapy regimens in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL). (Adapted with permission of American Society of Hematology, from Thomas;[58] permission conveyed through Copyright Clearance Center, Inc.)
Adults (all) Thomas et al.[59] Adults (age <65 years)
de Labarthe et al.[64] Elderly (age >55 years)
Ottmann et al.[67]
Only (800)
Only (800)
C (800)
C (800)
Chemotherapy
None
C (600)
C (600)
28
96
41
29 (1.5)
35 (1.5)
Imatinib
Only (600)
C (600)
C (600)
27
50
54
57 (1.5)
41 (1.5)
GRAALL AFR07 pilot
C (800)
C (600)
C (600)
31
90
NR
48 (1)
60 (1)
GMALL
A = alternating; C = concurrent; cons. = consolidation; CR = complete response; DFS = disease-free survival; GIMEMA = Gruppo Italiano Malattie EMatologiche dell’Adulto (Italian Group for Adult Hematologic Diseases); GMALL = German Multi-Centre Acute Lymphoblastic Leukaemia; GRAALL = Group for Research on Adult Acute Lymphoblastic Leukemia; GRAAPH = Group for Research on Adult Acute lymphoblastic leukemia Philadelphia positive; hyper-CVAD = fractionated cyclophosphamide, vincristine, adriamycin (doxorubicin), dexamethasone; induct. = induction; JALSG = Japan Adult Leukemia Study Group; maint. = maintenance; NA = not applicable; NR = not reported; OS = overall survival; Pred = prednisone.
Rousselot & Delannoy
Drugs Aging 2011; 28 (9)
Re´a et al.[68]
C (800) + Pred C (800) + Pred
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
Acute Lymphoblastic Leukaemia) Study Group.[67] In this study, 55 patients aged ‡55 years, ineligible for allogeneic haematopoietic stem cell transplantation, were randomly assigned to receive either induction therapy based on chemotherapy or imatinib alone at 600 mg/day for 4 weeks. The reported rate of complete molecular remission was 96% for imatinib compared with 50% in patients receiving chemotherapy-based induction. Of interest, tolerance of the induction schedule was also in favour of imatinib, with a more than 2-fold decrease in severe adverse events during induction. However, this improved efficacy and tolerability did not translate into significant improvements in disease-free survival or overall survival.[67] The GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto [Italian Group for Adult Hematologic Diseases]) proposed a study testing the use of corticosteroids combined with high-dose imatinib (800 mg/day), without additional chemotherapy, in 30 Ph+ ALL patients aged >60 years.[66] Patients in this study received a 7-day corticosteroid pre-treatment regimen (prednisone increasing from 10 to 40 mg/m2/day) followed by induction treatment with imatinib at the fixed dose of 800 mg/day together with prednisone 40 mg/m2/day from day 1 to day 45, which was then followed by maintenance therapy with imatinib in all responding patients until occurrence of relapse or excessive toxicity. Complete remission was obtained in the 29 assessable patients with minimal toxicity; however, the duration of remission was limited and the median survival from diagnosis was 20 months, a figure similar to that observed in previous studies.[65,67] The GRAALL AFR07 study assessed a low-intensity schedule (vincristine and dexamethasone [DIV regimen]) in combination with high-dose imatinib 800 mg/day in elderly patients aged >55 years.[68] In this pilot study, this combination showed promising results in relapsing and refractory Ph+ ALL, with a CR rate of 90%. Such non-toxic treatments can be administered to selected patients on an outpatient basis. Moreover, even the frailest patients can benefit from TKI-based therapy of this kind, such that, nowadays, elderly patients with Ph+ ALL are rarely denied access to a potentially curative treatment. ª 2011 Adis Data Information BV. All rights reserved.
759
From the experience of the above trials, it may be concluded that imatinib combined with corticosteroids is sufficient and safe for induction of remission, allowing CR achievement in almost all elderly Ph+ ALL patients, at the cost of limited toxicity. Imatinib-based consolidation and maintenance therapy appears to improve both remission duration and overall survival. Unfortunately, despite encouraging early results, the reported overall survival curves did not reach a plateau and therefore it remains questionable whether protocols based on imatinib alone or combined with chemotherapy have a real longterm curative potential. In the hope of improving patients’ long-term survival, new protocols that include second-generation TKIs have been designed. These agents may overcome most of the pre-existing kinase domain mutations and provide hope for an increased chance of curing elderly patients with Ph+ ALL. An international trial of the use of dasatinib in combination with chemotherapy (the common chemotherapeutic backbone for the elderly) has been proposed by the European Leukaemia Net European Working Group on Adult ALL (EWALL)-PH-01 study and is currently underway. An interim analysis showed a high rate of CR and acceptable toxicity.[51] The same chemotherapeutic schedule will be tested in combination with nilotinib (EWALL-PH-02 study) [figure 2]. 6.4 Maintenance Therapy and CNS Prophylaxis
There is no evidence-based recommendation for maintenance therapy in ALL patients not eligible for allogeneic bone marrow transplantation with myeloablative conditioning. Usually, such patients receive either imatinib alone until relapse or excessive toxicity, or imatinib combined with classical ALL maintenance, such as low-dose methotrexate and mercaptopurine. A promising approach, in which imatinib is combined with standard interferon or pegylated interferon, has been proposed by the GMALL and GRAALL groups.[69,70] Additional followup is needed to determine if this strategy will translate into a better relapse-free survival. The Drugs Aging 2011; 28 (9)
Rousselot & Delannoy
760
a Induction and consolidation therapy (first year) Induction Cons. I Cons. II Cons. III Cons. IV Cons. V Cons. IV
IDMTX HDAC IDMTX HDAC IDMTX HDAC VCR ASP ASP ASP DEXA
VCR DEXA
VCR DEXA
VCR DEXA
P Dasa 140
1
3
5
Dasa 100
7
Dasa 100
9 10 12 14
Dasa 100
Dasa 100 Dasa 100 Dasa 100 MP/MTX
17 19 21
Dasa 100
MP/MTX
Dasa 100
24 26 28 30 32 34 36 38 41 43 ~ Month 8 ~ Month 10
MP/MTX
48 51 52 week ~ Month 12
Maintenance therapy (second year) VCR DEXA
VCR DEXA
VCR DEXA
VCR DEXA
Dasa100 MP/MTX Dasa100 MP/MTX Dasa100 MP/MTX Dasa100 MP/MTX Dasa100 MP/MTX Dasa100
MP/MTX 15
18
21
24 months
PCR analysis b Induction and consolidation therapy (first year) Induction Cons. I Cons. II Cons. III Cons. IV Cons. V Cons. IV
VCR DEXA
IDMTX HDAC IDMTX HDAC IDMTX HDAC VCR ASP ASP ASP DEXA
P
1
VCR DEXA
MP/MTX
Nilo 400
Nilo 400
3
9 10 12 14
5
7
17 19 21
VCR DEXA
MP/MTX
MP/MTX
24 26 28 30 32 34 36 38 41 43 ~ Month 8 ~ Month 10
48 51 52 week ~ Month 12
Maintenance therapy (second year) VCR DEXA MP/MTX
VCR DEXA MP/MTX
MP/MTX
VCR DEXA MP/MTX
VCR DEXA MP/MTX
Nilo 400 MP/MTX 15
18
21
24 months
PCR analysis Fig. 2. Overview of European common protocol proposal for studies investigating the treatment of elderly patients (age ‡55 years) with de novo Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL): (a) EWALL-PH-01 (dasatinib [Dasa]) and (b) EWALL-PH-02 (nilotinib [Nilo]). Both are co-operative studies by the German Multi-Centre Acute Lymphoblastic Leukaemia (GMALL) Study Group, the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), the Northern Italy Leukemia Group (NILG), Programa para el Estudio de la Terape´utica en Hemopatı´a Maligna [Program for the Study and Treatment of Hematological Malignancies] (PETHEMA) and the Polish Adult Leukemia Group (PALG). All regimens of Dasa in the figure are once-daily doses expressed in milligrams; all doses of Nilo in the figure are twice-daily doses expressed in milligrams. ASP = asparaginase; Cons. = consolidation; DEXA = dexamethasone; EWALL = European Working Group on Adult ALL; HDAC = high-dose cytarabine; IDMTX = intermediate dose MTX, MP and folinic acid (leucovorin); MP = mercaptopurine; MTX = methotrexate; P = pre-phase; PCR = polymerase chain reaction; VCR = vincristine.
ª 2011 Adis Data Information BV. All rights reserved.
Drugs Aging 2011; 28 (9)
Treatment of Acute Lymphoblastic Leukaemia in the Elderly
use of reduced-intensity allogeneic haematopoietic stem cell transplantation should always be considered in fit elderly patients with an appropriate donor, even if the benefits from such transplants remain to be demonstrated. Irrespective of treatment schedule, the prognostic value of the molecular response (quantification of the BCR-ABL messenger RNA by quantitative reverse transcriptase [qRT]-PCR), its use for monitoring and altering treatment intensity, and the long-term benefit of TKIs remain open questions. The long-term outcome for patients treated with TKIs also remains a matter of debate, although there is no doubt that a minority of patients can survive without treatment for years, which was practically unknown in the preimatinib era in patients not offered a transplant. In contrast with dasatinib, imatinib does not cross the blood-brain barrier to an appreciable extent, and levels in the cerebrospinal fluid have been shown to reach approximately 1–2% of serum concentrations.[71] Therefore, active CNSdirected prophylactic therapy is mandatory in all patients with Ph+ ALL treated with an imatinibbased regimen.[71] 6.5 Management of Relapses
Most relapses observed after the use of TKIs alone or in combination with chemotherapy are associated with point mutations of the BCR-ABL kinase domain.[72] The pattern of mutations may be driven by the selectivity of the TKI against the BCR-ABL kinase domain. P-loop domain mutations or the T315I mutation are associated with imatinib or nilotinib failures, while dasatinib may elicit the appearance of T315I or F317L mutations.[51] Intensive chemotherapy is not recommended in the relapsing elderly patient. The choice of a second-line TKI should be driven by the pattern of mutation observed at relapse. Promising results have been reported with new TKIs, such as AP-24534 (ponatinib).[73] Ponatinib is a TKI with activity against all imatinibresistant forms of BCR-ABL ALL, including those with the T315I mutation. Preliminary data have confirmed the activity of ponatinib in vivo, and the drug has manageable toxicity consisting ª 2011 Adis Data Information BV. All rights reserved.
761
mainly of thrombocytopenia, headaches, nausea, arthralgia, fatigue, anaemia, increased lipase, muscle spasms, rash, myalgia and pancreatitis. The use of immunotherapy such as BiTE antibodies has recently been developed to transiently engage cytotoxic T cells for lysis of selected target cells, and may be an interesting agent for treating Ph+ ALL, especially in the elderly.[39] 7. Conclusions TKIs have changed the outcome for Ph+ ALL elderly patients. Paradoxically, the outcome of elderly patients with ALL is now better in Ph+ cases, as compared with Ph- patients. As TKIs should be used early during the course of induction treatment, the best initial approach is to use a ‘prephase’ therapy in new patients, which should allow TKIs to be started, if appropriate, 3–7 days later. The standard treatment of de novo Ph+ ALL in elderly patients is based on the combination of high-dose imatinib (600–800 mg/day) with corticosteroids or reduced-intensity chemotherapy. Despite high CR rates, only a few patients remain relapse free after 24 months. The ideal maintenance schedule remains to be determined, the most promising options being new TKIs and immunotherapy, while stem cell transplantation with reduced-intensity conditioning should be considered in selected patients or in the context of a study treatment protocol.[74] CNS prophylaxis remains mandatory, at least in imatinib-based regimens. Acknowledgements Philippe Rousselot has acted as a consultant to and received honoraria from Bristol-Myers Squibb and Novartis, and has been granted a research fund by Bristol-Myers Squibb. Andre´ Delannoy has no conflicts of interest that are directly relevant to the content of this review. The authors warmly thank Dr Katrina Rack, Institut de Pathologie et de Ge´ne´tique, Gosselies, Belgium, for her careful review of the manuscript.
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Correspondence: Professor Andre´ Delannoy, Hoˆpital de Jolimont, Service d’He´matologie, Rue Ferrer, 159, 7100 Haine-Saint-Paul, Belgium. E-mail:
[email protected]
Drugs Aging 2011; 28 (9)