- Email: [email protected]
Treatment of Older Patients With Newly Diagnosed AML Unfit for Traditional Therapy
Review
Treatment of Older Patients With Newly Diagnosed AML Unfit for Traditional Therapy Alan K. Burnett Abstract Older patients with acute myeloid leukemia represent at least one half of those with the disease for whom randomized clinical trials of new treatments are in development. These patients represent an appropriate population in which to evaluate new treatments against the current standards of care, which could be azacitidine, decitabine, or low-dose cytarabine. However, despite the identification of treatments that can deliver a worthwhile increase in remission, none has yet delivered a survival superiority when assessed in a randomized setting, although some recent efforts provide encouragement. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Published by Elsevier Inc. Keywords: Chemotherapy, Non-intensive, Outcomes, Pick-a winner, Trials
Introduction Clinical trials of acute myeloid leukemia (AML) for the past 40 years have generally focused on younger patients or older patients clinically judged to be fit for intensive chemotherapy. However, the median age at diagnosis of AML is 68 to 70 years; thus, a large “trial-neglected” population exists, for whom therapeutic options have not been explored. The standard of care was palliation with supportive care and, if necessary, mild oral chemotherapy to control the white blood cell count, so-called best supportive care (BSC). However, physicians have not always unanimously agreed that it is correct to withhold chemotherapy from such patients; thus, some patients would have received standard chemotherapy into their ninth decade. In the past 15 years, interest has increased in developing better treatments for this population “considered unsuitable for intensive treatment,” however defined. However, it has been recognized that older patients will not do well even if they can tolerate intensive chemotherapy, which has led to a broader definition of “patients unlikely to benefit from intensive therapy.” Patients in the latter category will include, for example, those with adverse karyotypes or p53 mutations. No consensus has been reached in defining the former category; however, clearly, age and performance status can identify unsuitable patients.1,2 The latter group will also include patients who choose not receive intensive therapy, irrespective of their clinical status or the risk prediction of their AML. A
(Retired), Cardiff University Ty Mawr, Blackwaterfoot, United Kingdom Submitted: Jun 12, 2018; Accepted: Jun 26, 2018 Address for correspondence: Alan Burnett, MD, FMedSci, Cardiff University Ty Mawr, Blackwaterfoot, United Kingdom E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Published by Elsevier Inc. https://doi.org/10.1016/j.clml.2018.06.027
number of risk scores have been developed from the experience of recipients of intensive therapy or transplantation that can identify patients who are unlikely to do well.3-5 However, few have been prospectively validated in the context of a nonintensive approach.
Trials to Establish a Standard of Care Owing to investigator demand, 1 of the first randomized trials aimed at establishing a standard of care was the UK AML14 trial.6 This trial was aimed at patients aged > 60 years. If the treatment approach was uncertain, patients would be randomized to an intensive versus a nonintensive pathway. The intensive option was daunorubicin plus cytarabine (also known as Ara-C) with or without P-glycoprotein modulation with PSC-833 (valspodar). The nonintensive option was low-dose Ara-C (LDAC) versus BSC, each with or without all-trans retinoic acid. Although 1473 patients were recruited, only 8 were randomized. When a multivariate analysis was performed to define the factors associated with allocation to 1 or the other treatment approach, age, performance score, secondary disease, weight, and cardiac status occurred in that order of importance. However, when the name of the investigating physician was included as a variable, it became the third most important factor. Thus, little doubt exists that a doctor bias is present in treatment allocation. In the 208 patients randomized to LDAC (20 mg twice daily, subcutaneously on days 1-10 at 4- to 6-week intervals) or BSC, LDAC resulted in significantly better survival. Importantly, this benefit was not associated with extra cytopenia or supportive care requirements.7 However, the remission rate was only 18%, and none of the patients with adverse risk cytogenetics entered complete remission (CR), although the median duration of CR was 15
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Treatment of Older Unfit Patients With AML months. Also, no survival benefit was seen without CR. It was concluded that for future trial aspirations, CR should be a prerequisite for survival benefit. The next options to emerge were the demethylation agents, with azacitidine approved for myelodysplastic syndromes compared with “doctor’s choice” in the control arm.8 In that trial, each patient, before randomization, was given a choice of which treatment to receive if the patient had been randomized to “doctor’s choice.” The options were BSC, LDAC, or intensive therapy. At the time of the trial, the definition of myelodysplastic syndrome included patients with a presenting bone marrow blast percentage of 20% to 30%, which, in the subsequent definition revision, was classed as AML. When this subset was examined separately as a subset of AML, azacitidine delivered a survival benefit compared with doctor’s choice and led to approval for AML with 20% to 30% blasts.8 However, in this 113-patient subset, azacitidine was compared with BSC (36 vs. 27 patients) and produced a significant benefit (median survival, 19.1 vs. 13.4 months). However, only a trend was seen for the smaller number of patients in the LDAC comparison (14 vs. 20 patients), with no significant benefit realized (median, 24.5 vs. 17 months). What is of interest is the median survival of these patients receiving BSC, which, at 13.4 months, is not typical of patients with AML. The subsequent registration study of azacitidine was of broadly similar design but focused on patients presenting with > 30% blasts.9 Again, an overall benefit was seen in median survival (5.8 vs. 3.7 months; P ¼ .025) compared with BSC, with a nonsignificant trend (11.2 vs. 6.4 months; P ¼ .47) compared with LDAC. Thus, both trials achieved the objective of a survival benefit, although this was primarily when compared with BSC. To the best of our knowledge, no adequately powered study of azacitidine versus LDAC has been performed. Another candidate for this indication is the other demethylation agent, decitabine. In a large (n ¼ 485) straightforward trial design, patients were randomized to decitabine or doctor’s choice (ie, intensive therapy or LDAC).10 The LDAC schedule was 20 mg for 10 days but given only once daily. At the prespecified initial analysis, decitabine failed to produce a survival benefit (median, 7.7 vs. 5 months; P ¼ .108). However, during subsequent follow-up, a benefit did emerge. The once-daily LDAC schedule only delivered an 8% CR rate, which was less than expected. These trials resulted in approval of both azacitidine and decitabine in Europe but not in the United States. A characteristic of the demethylating drugs is that remissions can require several courses to emerge; thus, persistence is required. Also, even if remission is not obtained, hematologic stability can result in reasonable survival. Thus, 3 standards of care have emerged, which all have the inconvenience of parenteral administration, including twice daily for LDAC if the original schedule is followed. Although economical, LDAC has the additional criticism in that it failed in the original study to result in CRs in patients with an adverse karyotype.
Assessment of New Treatments
2
-
With the standards of care outlined, a number of issues emerge. It is not clear how to define a patient as unfit for intensive therapy, and much more use should be made of validated comorbidity scoring systems and the collection of information for every patient regarding why intensive treatment was not offered. In some cases,
Clinical Lymphoma, Myeloma & Leukemia Month 2018
the reason might be patient choice or the belief that it has little to offer; however, this does not always mean that the patient is “unfit.” The second issue, which is of more importance to this patient group, is the aspiration of treatment. The issues could be the same as for every other patient group (ie, improving survival). However, the convenience of treatment and quality of life might be larger issues. From a regulatory approval viewpoint, overall survival has generally been the required criterion. The original LDAC study showed that unless CR was achieved, no survival benefit would accrue. One of the traditional settings for new drug assessment in AML is relapsed or refractory disease; however, in older patients, the treatment outcome has been so poor, it is questionable whether it is ethical to introduce experimental therapy as first-line treatment. Finally, because the prognosis is so poor, the speed of the assessment of treatment options with sizeable benefits should be the aim. Because of these issues, the UK “Pick a Winner” program was developed.11 The aim was to simultaneously evaluate new treatments against a standard of care, which in this case was the 10-day twice daily schedule of LDAC. Several treatments can be tested at one time; however, they are not randomized against each other, only individually randomized against the standard of care. Although it might be a temptation to compare the novel study arms against each other, this would not be a legitimate choice, because each might not have the same eligibility requirements (eg, cardiac assessments). It could also have inhibited pharmaceutical companies’ cooperation in providing new drugs. Another key feature of the randomization is that only comparisons of contemporaneous randomizations are allowed. A novel aspect of the program is the inclusion of “Drug X,” both in the protocol and in the information given to patients. This allows for new options to be introduced as the trial progresses or if treatments under testing are withdrawn. This is appealing to investigators, who will have a sequence of new options to assess over time, and to trial organizers (potentially including pharmaceutical companies), who do not have the administrative burden of setting up multiple trials. The program was designed such that a “winner” would have to improve the remission rate and thereby survival. However, based on experience from the solid tumour field, this sort of design works most efficiently when many countable events occur, ideally occur early, and are surrogates for likely survival. In the early days, the remission rate fulfilled these criteria. Thus, the aim was to perform a formal assessment after w80 to 100 events (deaths or remissions) in the study arm compared with its contemporary control. If the independent monitoring committee believed the evidence pointed to an improved outcome, recruitment would continue (possibly with a further interim assessment for survival) to a conventionally powered study based on overall survival. If a novel arm seemed unlikely to meet the criterion, which was, initially, to double the remission rate, it could be withdrawn and a new treatment (“drug X”) introduced. This program was designed on the assumption that the achievement of CR was a strong surrogate for survival. Although this might be true for LDAC, it was undermined by the demethylation inhibitors, for which the remission rate has not been better, although longer survival without necessarily achieving remission has been realized. Although a “run-in” phase might be required for a novel combination, randomization is essential. The subsequent experience has borne this out. The outcomes of the
Alan K. Burnett Table 1 Outcome of Low-dose Ara-C Over Time Compared With Other Treatment Comparator, % Outcome CR
BSC
LDAC D GO
LDAC D Tipifarnib
LDAC D ATO
Clofarabine
Sapacitabine
Vosaroxin
Vosaroxin D LDAC
0
19
25
22
19
29
29
18
OS 1y
24
24
34
30
26
27
31
37
2y
7
12
13
15
13
10
10
NA
Abbreviations: ATO ¼ arsenic trioxide; BSC ¼ best supportive care; CR ¼ complete remission; GO ¼ gemtuzumab ozogamicin; LDAC ¼ low-dose Ara-C; NA ¼ not applicable; OS ¼ overall survival.
patients in the various control arms, who were all treated with LDAC, are listed in Table 1. A wide variation in outcomes was seen, which could be explained by the different eligibility requirements (eg, cardiac criteria for quizartinib), but warns of the danger of making conclusions from a nonrandomized experience for patients of this age group.
New Treatment Assessments in the “Pick a Winner” Program The Pick a Winner program is ongoing; however, the outcomes for the first 10 comparators (Table 2) are known. In most cases, the candidate drug was known to have activity in AML, usually as monotherapy. Of these 10, only 4 progressed to the second stage, which was based on survival. Options 1, 2, 5, 7, and 8 (tipifarnib plus LDAC12; arsenic trioxide plus LDAC13; spacitibine14; vosaroxin; and vosaroxin plus LDAC15) did not improve the remission rate and were discontinued. Option 9 (ganetespib plus LDAC) did not complete because the drug’s development was halted. However, options 3, 4, 6, and 10 (gemtuzumab ozogamicin [GO] plus LDAC16; clofarabine17; quizartinib plus LDAC; and tosedostat plus LDAC) have progressed to the full assessment. Both clofarabine and GO doubled the remission rate but did not improve survival. This was because when the remitters in the clofarabine or GO arm developed a relapse, their survival was poorer than that of the LDAC remitting patients with relapse. Clofarabine, GO, and tosedostat each moved to the full phase III randomization, and quizartinib is still recruiting in phase III. However, tosedostat did not improve survival. The program continues with LDAC as the control arm, because neither of the demethylation agents is reimbursed in the United Kingdom. The conclusion from this experience is that even of the drugs that have activity in AML, none of the included options improved survival. It could, however, be debated whether the treatments that cleared the first assessment but did not result in a survival benefit were really failures. This suggestion is based on the assumption that being in remission, rather than not, is of value to patients in this age group. If being in remission were better for patients, a treatment that could deliver more remission days, without necessarily delivering more survival, would be a qualified success, albeit inadequately measured by patient-reported outcomes.
Other Combination Studies Volasertib Plus LDAC Volasertib is a parenterally administered inhibitor of polo-like kinases, which play a role in cell division, where expression is
maximal during the G2/M phase of the cell cycle. The inhibitor disrupts spindle organization, leading to apoptosis, and has shown in vivo activity in disease models, including AML. In a dose-finding study, w20% of patients responded. A randomized phase II trial combined LDAC (20 mg twice daily for 10 days) with volasertib 350 mg intravenously on days 1 and 15. The trial focused on older patients (median age, 75 years; range, 57-86 years).18 Eighty-seven patients received treatment. An encouraging improved response rate was seen in the volasertib patients (31% vs. 13%). Remissions occurred after w2 months, and for responders, the median number of courses given was w8. The median event-free survival in the volasertib arm was 5.6 months, which was significantly better than that with LDAC alone (2.3 months; hazard ratio, 0.56; range, 0.35-0.92; P ¼ .021). The analysis of overall survival was underpowered and thus lacked conclusive proof of benefit. The promising randomized phase II trial led to a randomized phase III trial with overall survival as the primary endpoint. However, the trial did not show a survival benefit.
Pracinostat Plus Azacitidine Pracinostat is a histone deacetylase inhibitor that seems more effective than other agents in this class, which have been disappointing in AML. However, the results from an unrandomized phase II study in combination with azacitidine were interesting.19 Given 3 times weekly for 3 weeks every 28 days, combined with azacitidine, produced a 42% CR rate, with 6 additional patients achieving CR with incomplete hematologic recovery (CRi) or a
Table 2 Pick a Winner Trial Options Study Arm LDAC þ tipifarnib LDAC þ ATO LDAC þ GO Clofarabine Sapacitabine LDAC þ quizartinib Vosaroxin LDAC þ vosaroxin LDAC þ ganetespib LDAC þ tosedostat
Era
Stage 1 Success
Phase III Success
2006-2008 2007-2009 2006-2010 2006-2010 2010-2012 2012 2012-2013 2012-2013 2012-2014 2014-2017
No No Yes Yes No Yes No No No Yes
NA NA No No NA Unknown NA NA NA No
Abbreviations: ATO ¼ arsenic trioxide; GO ¼ gemtuzumab ozogamicin; LDAC ¼ low-dose Ara-C; NA ¼ not applicable.
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Treatment of Older Unfit Patients With AML morphologically leukemia-free state. Of importance is that durability seems possible, with a 12-month overall survival rate of 60%. These encouraging results, if confirmed in a randomized trial, would be an important advance. The phase III trial (ClinicalTrials.gov identifier, NCT03151408) will include patients aged >75 years, who are not considered suitable for intensive treatment, although younger patients who are considered unfit can also be included.
Pevonedistat Plus Azacitidine Pevonedistat is an inhibitor of the NEDD8 (neural cell developmentally downregulated 8) activating enzyme, which processes NEDD8 resulting, by complex action, in cullinering E3 ubiquitin ligase accumulation, which has antiproliferative effects. In preliminary studies as a single agent, parenteral administration 3 times weekly every 3 weeks resulted in response rate of 17%. The findings from preclinical studies suggested synergy with azacitidine. Good results were also seen with this combination of intravenous pevonedistat and standard administration of azacitidine.20 Of the 64 evaluable patients, 50% had a response (20 CR, 5 CRi, and 7 partial remission), with a duration of response of 8.3 months. Evidence showed that the CR patients maintained responses for longer than did the patients with CRi or partial remission (18.8 months vs. 8.3 months).
Venetoclax Plus Azacitidine or LDAC
Venetoclax is the first successful inhibitor of BCL2, which is establishing an important role in chronic lymphatic leukemia. BCL2 overexpression is a well-established adverse prognostic factor in AML and is more frequents in older patients. Initial studies of relapsed/refractory disease using venetoclax combined with a hypomethylating agent or LDAC showed a 21% response rate.21 This resulted in a more detailed assessment of the dose, which produced CR in 35 of 57 patients (61%) who had received venetoclax with either azacitidine or decitabine, which were given in standard doses. Of all the potential combinations referred to so far, none seems more encouraging than the combination of venetoclax with LDAC developed by the Melbourne group.22 In that study patients with a median age of 75 years (range, 66-87 years) and untreated disease were given venetoclax 600 mg/d combined with LDAC 20 mg/d for 10 days. Of the patients, 62% responded (26% CR, 36% CRi), which included a 47% response rate in patients with adverse cytogenetics. Unlike the experiences in the Pick a Winner program, the responses seemed to be of reasonable duration (13.2 months), with all 16 patients who achieved CR remaining in remission after 1 year. Also, 47% of the 16 patients who achieved CRi were stable at 12 months. This led to a breakthrough designation and a large phase III trial is underway.
Conclusion
4
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Older patients with AML constitute at least one half of those with the disease and have tended to be ignored by collaborative group studies until recent years. The challenge has been that older patients tend to have more adverse disease factors that are less amenable to conventional chemotherapy. However, these patients will also have, in many cases, accumulated comorbidities that make intensive chemotherapy unsafe. In addition, some patients’ aspirations do not include immortality but quality for such time as
Clinical Lymphoma, Myeloma & Leukemia Month 2018
remains. In that respect, focusing primarily on treatment evaluated by survival only might need to be rethought. Although little disagreement would ensue that being in remission is beneficial, quantifying that benefit might need more development such as a greater emphasis on patient-reported outcomes as a routine assessment of treatments. Finally, given that patient populations can differ substantially in response to, for example, LDAC in the Pick a Winner program, randomized studies must remain the only measure.
Disclosure The author has stated that he has no conflicts of interest.
References 1. Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006; 106: 1090-8. 2. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood 2006; 107:3481-5. 3. Sorror ML, Giralt S, Sandmaier BM, et al. Hematopoietic cell transplantationspecific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007; 110:4606-13. 4. Wheatley K, Brookes CL, Howman AJ, et al. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 2009; 145:598-605. 5. Krug U, Rollig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010; 376: 2000-8. 6. Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol 2009; 145:318-32. 7. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109:1114-24. 8. Fenaux P, Mufti GJ, Hellstrom-Liindberg E, et al. Azacytidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28:562-9. 9. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126:291-9. 10. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30:2670-7. 11. Hills RK, Burnett AK. Applicability of a “Pick a Winner” trial design to acute myeloid leukemia. Blood 2011; 118:2389-94. 12. Burnett AK, Russell NH, Culligan D, et al. The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br J Haematol 2012; 158:519-22. 13. Burnett AK, Hills RK, Hunter A, et al. The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome. Leukemia 2011; 25: 1122-7. 14. Burnett AK, Russell N, Hills RK, et al. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia 2015; 29:1312-9. 15. Dennis M, Russell N, Hills RK, et al. Vosaroxin and vosaroxin plus low-dose AraC (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood 2015; 125:2923-32. 16. Burnett AK, Hills RK, Hunter AE, et al, UK National Cancer Research Institute AML Working Group. The addition of gemtuzumab ozogamicin to low-dose AraC improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia 2013; 27:75-81. 17. Burnett AK, Russell NH, Hunter AE, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood 2013; 122:1384-94. 18. Döhner H, Lübbert M, Fiedler W, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 2014; 124:1426-33. 19. Garcia-Manero G, Atallah E, Khaled SK. Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). Blood 2015; 126:453.
Alan K. Burnett 20. Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood 2018; 131:1415-24. 21. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated
acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19:216-28. 22. Wei AH, Strickland SA, Roboz GJ, et al. Safety and efficacy of venetoclax plus lowdose cytarabine in treatment-naive patients aged 65 years with acute myeloid leukemia. Blood 2016; 128:102.
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Treatment of Older Patients With Newly Diagnosed AML Unfit for Traditional Therapy Alan K. Burnett Abstract Older patients with acute myeloid leukemia represent at least one half of those with the disease for whom randomized clinical trials of new treatments are in development. These patients represent an appropriate population in which to evaluate new treatments against the current standards of care, which could be azacitidine, decitabine, or low-dose cytarabine. However, despite the identification of treatments that can deliver a worthwhile increase in remission, none has yet delivered a survival superiority when assessed in a randomized setting, although some recent efforts provide encouragement. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Published by Elsevier Inc. Keywords: Chemotherapy, Non-intensive, Outcomes, Pick-a winner, Trials
Introduction Clinical trials of acute myeloid leukemia (AML) for the past 40 years have generally focused on younger patients or older patients clinically judged to be fit for intensive chemotherapy. However, the median age at diagnosis of AML is 68 to 70 years; thus, a large “trial-neglected” population exists, for whom therapeutic options have not been explored. The standard of care was palliation with supportive care and, if necessary, mild oral chemotherapy to control the white blood cell count, so-called best supportive care (BSC). However, physicians have not always unanimously agreed that it is correct to withhold chemotherapy from such patients; thus, some patients would have received standard chemotherapy into their ninth decade. In the past 15 years, interest has increased in developing better treatments for this population “considered unsuitable for intensive treatment,” however defined. However, it has been recognized that older patients will not do well even if they can tolerate intensive chemotherapy, which has led to a broader definition of “patients unlikely to benefit from intensive therapy.” Patients in the latter category will include, for example, those with adverse karyotypes or p53 mutations. No consensus has been reached in defining the former category; however, clearly, age and performance status can identify unsuitable patients.1,2 The latter group will also include patients who choose not receive intensive therapy, irrespective of their clinical status or the risk prediction of their AML. A
(Retired), Cardiff University Ty Mawr, Blackwaterfoot, United Kingdom Submitted: Jun 12, 2018; Accepted: Jun 26, 2018 Address for correspondence: Alan Burnett, MD, FMedSci, Cardiff University Ty Mawr, Blackwaterfoot, United Kingdom E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Published by Elsevier Inc. https://doi.org/10.1016/j.clml.2018.06.027
number of risk scores have been developed from the experience of recipients of intensive therapy or transplantation that can identify patients who are unlikely to do well.3-5 However, few have been prospectively validated in the context of a nonintensive approach.
Trials to Establish a Standard of Care Owing to investigator demand, 1 of the first randomized trials aimed at establishing a standard of care was the UK AML14 trial.6 This trial was aimed at patients aged > 60 years. If the treatment approach was uncertain, patients would be randomized to an intensive versus a nonintensive pathway. The intensive option was daunorubicin plus cytarabine (also known as Ara-C) with or without P-glycoprotein modulation with PSC-833 (valspodar). The nonintensive option was low-dose Ara-C (LDAC) versus BSC, each with or without all-trans retinoic acid. Although 1473 patients were recruited, only 8 were randomized. When a multivariate analysis was performed to define the factors associated with allocation to 1 or the other treatment approach, age, performance score, secondary disease, weight, and cardiac status occurred in that order of importance. However, when the name of the investigating physician was included as a variable, it became the third most important factor. Thus, little doubt exists that a doctor bias is present in treatment allocation. In the 208 patients randomized to LDAC (20 mg twice daily, subcutaneously on days 1-10 at 4- to 6-week intervals) or BSC, LDAC resulted in significantly better survival. Importantly, this benefit was not associated with extra cytopenia or supportive care requirements.7 However, the remission rate was only 18%, and none of the patients with adverse risk cytogenetics entered complete remission (CR), although the median duration of CR was 15
Clinical Lymphoma, Myeloma & Leukemia Month 2018
-1
Treatment of Older Unfit Patients With AML months. Also, no survival benefit was seen without CR. It was concluded that for future trial aspirations, CR should be a prerequisite for survival benefit. The next options to emerge were the demethylation agents, with azacitidine approved for myelodysplastic syndromes compared with “doctor’s choice” in the control arm.8 In that trial, each patient, before randomization, was given a choice of which treatment to receive if the patient had been randomized to “doctor’s choice.” The options were BSC, LDAC, or intensive therapy. At the time of the trial, the definition of myelodysplastic syndrome included patients with a presenting bone marrow blast percentage of 20% to 30%, which, in the subsequent definition revision, was classed as AML. When this subset was examined separately as a subset of AML, azacitidine delivered a survival benefit compared with doctor’s choice and led to approval for AML with 20% to 30% blasts.8 However, in this 113-patient subset, azacitidine was compared with BSC (36 vs. 27 patients) and produced a significant benefit (median survival, 19.1 vs. 13.4 months). However, only a trend was seen for the smaller number of patients in the LDAC comparison (14 vs. 20 patients), with no significant benefit realized (median, 24.5 vs. 17 months). What is of interest is the median survival of these patients receiving BSC, which, at 13.4 months, is not typical of patients with AML. The subsequent registration study of azacitidine was of broadly similar design but focused on patients presenting with > 30% blasts.9 Again, an overall benefit was seen in median survival (5.8 vs. 3.7 months; P ¼ .025) compared with BSC, with a nonsignificant trend (11.2 vs. 6.4 months; P ¼ .47) compared with LDAC. Thus, both trials achieved the objective of a survival benefit, although this was primarily when compared with BSC. To the best of our knowledge, no adequately powered study of azacitidine versus LDAC has been performed. Another candidate for this indication is the other demethylation agent, decitabine. In a large (n ¼ 485) straightforward trial design, patients were randomized to decitabine or doctor’s choice (ie, intensive therapy or LDAC).10 The LDAC schedule was 20 mg for 10 days but given only once daily. At the prespecified initial analysis, decitabine failed to produce a survival benefit (median, 7.7 vs. 5 months; P ¼ .108). However, during subsequent follow-up, a benefit did emerge. The once-daily LDAC schedule only delivered an 8% CR rate, which was less than expected. These trials resulted in approval of both azacitidine and decitabine in Europe but not in the United States. A characteristic of the demethylating drugs is that remissions can require several courses to emerge; thus, persistence is required. Also, even if remission is not obtained, hematologic stability can result in reasonable survival. Thus, 3 standards of care have emerged, which all have the inconvenience of parenteral administration, including twice daily for LDAC if the original schedule is followed. Although economical, LDAC has the additional criticism in that it failed in the original study to result in CRs in patients with an adverse karyotype.
Assessment of New Treatments
2
-
With the standards of care outlined, a number of issues emerge. It is not clear how to define a patient as unfit for intensive therapy, and much more use should be made of validated comorbidity scoring systems and the collection of information for every patient regarding why intensive treatment was not offered. In some cases,
Clinical Lymphoma, Myeloma & Leukemia Month 2018
the reason might be patient choice or the belief that it has little to offer; however, this does not always mean that the patient is “unfit.” The second issue, which is of more importance to this patient group, is the aspiration of treatment. The issues could be the same as for every other patient group (ie, improving survival). However, the convenience of treatment and quality of life might be larger issues. From a regulatory approval viewpoint, overall survival has generally been the required criterion. The original LDAC study showed that unless CR was achieved, no survival benefit would accrue. One of the traditional settings for new drug assessment in AML is relapsed or refractory disease; however, in older patients, the treatment outcome has been so poor, it is questionable whether it is ethical to introduce experimental therapy as first-line treatment. Finally, because the prognosis is so poor, the speed of the assessment of treatment options with sizeable benefits should be the aim. Because of these issues, the UK “Pick a Winner” program was developed.11 The aim was to simultaneously evaluate new treatments against a standard of care, which in this case was the 10-day twice daily schedule of LDAC. Several treatments can be tested at one time; however, they are not randomized against each other, only individually randomized against the standard of care. Although it might be a temptation to compare the novel study arms against each other, this would not be a legitimate choice, because each might not have the same eligibility requirements (eg, cardiac assessments). It could also have inhibited pharmaceutical companies’ cooperation in providing new drugs. Another key feature of the randomization is that only comparisons of contemporaneous randomizations are allowed. A novel aspect of the program is the inclusion of “Drug X,” both in the protocol and in the information given to patients. This allows for new options to be introduced as the trial progresses or if treatments under testing are withdrawn. This is appealing to investigators, who will have a sequence of new options to assess over time, and to trial organizers (potentially including pharmaceutical companies), who do not have the administrative burden of setting up multiple trials. The program was designed such that a “winner” would have to improve the remission rate and thereby survival. However, based on experience from the solid tumour field, this sort of design works most efficiently when many countable events occur, ideally occur early, and are surrogates for likely survival. In the early days, the remission rate fulfilled these criteria. Thus, the aim was to perform a formal assessment after w80 to 100 events (deaths or remissions) in the study arm compared with its contemporary control. If the independent monitoring committee believed the evidence pointed to an improved outcome, recruitment would continue (possibly with a further interim assessment for survival) to a conventionally powered study based on overall survival. If a novel arm seemed unlikely to meet the criterion, which was, initially, to double the remission rate, it could be withdrawn and a new treatment (“drug X”) introduced. This program was designed on the assumption that the achievement of CR was a strong surrogate for survival. Although this might be true for LDAC, it was undermined by the demethylation inhibitors, for which the remission rate has not been better, although longer survival without necessarily achieving remission has been realized. Although a “run-in” phase might be required for a novel combination, randomization is essential. The subsequent experience has borne this out. The outcomes of the
Alan K. Burnett Table 1 Outcome of Low-dose Ara-C Over Time Compared With Other Treatment Comparator, % Outcome CR
BSC
LDAC D GO
LDAC D Tipifarnib
LDAC D ATO
Clofarabine
Sapacitabine
Vosaroxin
Vosaroxin D LDAC
0
19
25
22
19
29
29
18
OS 1y
24
24
34
30
26
27
31
37
2y
7
12
13
15
13
10
10
NA
Abbreviations: ATO ¼ arsenic trioxide; BSC ¼ best supportive care; CR ¼ complete remission; GO ¼ gemtuzumab ozogamicin; LDAC ¼ low-dose Ara-C; NA ¼ not applicable; OS ¼ overall survival.
patients in the various control arms, who were all treated with LDAC, are listed in Table 1. A wide variation in outcomes was seen, which could be explained by the different eligibility requirements (eg, cardiac criteria for quizartinib), but warns of the danger of making conclusions from a nonrandomized experience for patients of this age group.
New Treatment Assessments in the “Pick a Winner” Program The Pick a Winner program is ongoing; however, the outcomes for the first 10 comparators (Table 2) are known. In most cases, the candidate drug was known to have activity in AML, usually as monotherapy. Of these 10, only 4 progressed to the second stage, which was based on survival. Options 1, 2, 5, 7, and 8 (tipifarnib plus LDAC12; arsenic trioxide plus LDAC13; spacitibine14; vosaroxin; and vosaroxin plus LDAC15) did not improve the remission rate and were discontinued. Option 9 (ganetespib plus LDAC) did not complete because the drug’s development was halted. However, options 3, 4, 6, and 10 (gemtuzumab ozogamicin [GO] plus LDAC16; clofarabine17; quizartinib plus LDAC; and tosedostat plus LDAC) have progressed to the full assessment. Both clofarabine and GO doubled the remission rate but did not improve survival. This was because when the remitters in the clofarabine or GO arm developed a relapse, their survival was poorer than that of the LDAC remitting patients with relapse. Clofarabine, GO, and tosedostat each moved to the full phase III randomization, and quizartinib is still recruiting in phase III. However, tosedostat did not improve survival. The program continues with LDAC as the control arm, because neither of the demethylation agents is reimbursed in the United Kingdom. The conclusion from this experience is that even of the drugs that have activity in AML, none of the included options improved survival. It could, however, be debated whether the treatments that cleared the first assessment but did not result in a survival benefit were really failures. This suggestion is based on the assumption that being in remission, rather than not, is of value to patients in this age group. If being in remission were better for patients, a treatment that could deliver more remission days, without necessarily delivering more survival, would be a qualified success, albeit inadequately measured by patient-reported outcomes.
Other Combination Studies Volasertib Plus LDAC Volasertib is a parenterally administered inhibitor of polo-like kinases, which play a role in cell division, where expression is
maximal during the G2/M phase of the cell cycle. The inhibitor disrupts spindle organization, leading to apoptosis, and has shown in vivo activity in disease models, including AML. In a dose-finding study, w20% of patients responded. A randomized phase II trial combined LDAC (20 mg twice daily for 10 days) with volasertib 350 mg intravenously on days 1 and 15. The trial focused on older patients (median age, 75 years; range, 57-86 years).18 Eighty-seven patients received treatment. An encouraging improved response rate was seen in the volasertib patients (31% vs. 13%). Remissions occurred after w2 months, and for responders, the median number of courses given was w8. The median event-free survival in the volasertib arm was 5.6 months, which was significantly better than that with LDAC alone (2.3 months; hazard ratio, 0.56; range, 0.35-0.92; P ¼ .021). The analysis of overall survival was underpowered and thus lacked conclusive proof of benefit. The promising randomized phase II trial led to a randomized phase III trial with overall survival as the primary endpoint. However, the trial did not show a survival benefit.
Pracinostat Plus Azacitidine Pracinostat is a histone deacetylase inhibitor that seems more effective than other agents in this class, which have been disappointing in AML. However, the results from an unrandomized phase II study in combination with azacitidine were interesting.19 Given 3 times weekly for 3 weeks every 28 days, combined with azacitidine, produced a 42% CR rate, with 6 additional patients achieving CR with incomplete hematologic recovery (CRi) or a
Table 2 Pick a Winner Trial Options Study Arm LDAC þ tipifarnib LDAC þ ATO LDAC þ GO Clofarabine Sapacitabine LDAC þ quizartinib Vosaroxin LDAC þ vosaroxin LDAC þ ganetespib LDAC þ tosedostat
Era
Stage 1 Success
Phase III Success
2006-2008 2007-2009 2006-2010 2006-2010 2010-2012 2012 2012-2013 2012-2013 2012-2014 2014-2017
No No Yes Yes No Yes No No No Yes
NA NA No No NA Unknown NA NA NA No
Abbreviations: ATO ¼ arsenic trioxide; GO ¼ gemtuzumab ozogamicin; LDAC ¼ low-dose Ara-C; NA ¼ not applicable.
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Treatment of Older Unfit Patients With AML morphologically leukemia-free state. Of importance is that durability seems possible, with a 12-month overall survival rate of 60%. These encouraging results, if confirmed in a randomized trial, would be an important advance. The phase III trial (ClinicalTrials.gov identifier, NCT03151408) will include patients aged >75 years, who are not considered suitable for intensive treatment, although younger patients who are considered unfit can also be included.
Pevonedistat Plus Azacitidine Pevonedistat is an inhibitor of the NEDD8 (neural cell developmentally downregulated 8) activating enzyme, which processes NEDD8 resulting, by complex action, in cullinering E3 ubiquitin ligase accumulation, which has antiproliferative effects. In preliminary studies as a single agent, parenteral administration 3 times weekly every 3 weeks resulted in response rate of 17%. The findings from preclinical studies suggested synergy with azacitidine. Good results were also seen with this combination of intravenous pevonedistat and standard administration of azacitidine.20 Of the 64 evaluable patients, 50% had a response (20 CR, 5 CRi, and 7 partial remission), with a duration of response of 8.3 months. Evidence showed that the CR patients maintained responses for longer than did the patients with CRi or partial remission (18.8 months vs. 8.3 months).
Venetoclax Plus Azacitidine or LDAC
Venetoclax is the first successful inhibitor of BCL2, which is establishing an important role in chronic lymphatic leukemia. BCL2 overexpression is a well-established adverse prognostic factor in AML and is more frequents in older patients. Initial studies of relapsed/refractory disease using venetoclax combined with a hypomethylating agent or LDAC showed a 21% response rate.21 This resulted in a more detailed assessment of the dose, which produced CR in 35 of 57 patients (61%) who had received venetoclax with either azacitidine or decitabine, which were given in standard doses. Of all the potential combinations referred to so far, none seems more encouraging than the combination of venetoclax with LDAC developed by the Melbourne group.22 In that study patients with a median age of 75 years (range, 66-87 years) and untreated disease were given venetoclax 600 mg/d combined with LDAC 20 mg/d for 10 days. Of the patients, 62% responded (26% CR, 36% CRi), which included a 47% response rate in patients with adverse cytogenetics. Unlike the experiences in the Pick a Winner program, the responses seemed to be of reasonable duration (13.2 months), with all 16 patients who achieved CR remaining in remission after 1 year. Also, 47% of the 16 patients who achieved CRi were stable at 12 months. This led to a breakthrough designation and a large phase III trial is underway.
Conclusion
4
-
Older patients with AML constitute at least one half of those with the disease and have tended to be ignored by collaborative group studies until recent years. The challenge has been that older patients tend to have more adverse disease factors that are less amenable to conventional chemotherapy. However, these patients will also have, in many cases, accumulated comorbidities that make intensive chemotherapy unsafe. In addition, some patients’ aspirations do not include immortality but quality for such time as
Clinical Lymphoma, Myeloma & Leukemia Month 2018
remains. In that respect, focusing primarily on treatment evaluated by survival only might need to be rethought. Although little disagreement would ensue that being in remission is beneficial, quantifying that benefit might need more development such as a greater emphasis on patient-reported outcomes as a routine assessment of treatments. Finally, given that patient populations can differ substantially in response to, for example, LDAC in the Pick a Winner program, randomized studies must remain the only measure.
Disclosure The author has stated that he has no conflicts of interest.
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Alan K. Burnett 20. Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood 2018; 131:1415-24. 21. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated
acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19:216-28. 22. Wei AH, Strickland SA, Roboz GJ, et al. Safety and efficacy of venetoclax plus lowdose cytarabine in treatment-naive patients aged 65 years with acute myeloid leukemia. Blood 2016; 128:102.
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