Depth of Remission Is Key-and This Requires New Strategies

Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid progenitors that is more common among older adults, with a median age at diagnosis of nearly 70 years. Many AML patients have higher-risk disease, either due to the presence of adverse cytogenetic and molecular abnormalities that confer resistance to standard chemotherapy,[1] or due to concurrent comorbid conditions that limit a patient’s ability to receive standard treatment.

For decades, “7+3” chemotherapy (cytarabine plus an anthracycline) has remained the standard initial treatment for AML (excluding acute promyelocytic leukemia); indeed, this combination yields reasonable response rates, with approximately 70% of younger patients achieving an initial morphologic remission. The rates of remission in higher-risk disease are much lower, however, with only about 40% of patients achieving a first remission.[2] Modifications to the regimen, such as the use of higher doses of daunorubicin during induction, may improve the morphologic complete remission (CR) rate among high-risk AML patients to roughly 60%,[3] but have failed to improve the overall survival of high-risk patients-both those younger than age 60 with unfavorable cytogenetics[4] and those over age 60 without core binding factor abnormalities[3]; the survival rate at 5 years in both groups is only about 20%. With current standard therapies, a CR in high-risk disease may at best provide a tantalizing glimpse of response, only to be followed by relapse and limited salvage options for the majority of patients.

That such uninspiring regimens represent the standard initial treatment for AML patients is not for lack of trying. Initial therapy in AML seeks to achieve a CR, and no agents have convincingly supplanted 7+3, based on our current understanding of treatment efficacy. That said, even with risk-adapted consolidation strategies and expanded indications for allogeneic transplantation, relapse in high-risk AML is frequent and remains the primary cause of death.

A major development in AML is the discovery that early deep clearance of leukemic clones (ie, the achievement of negative minimal residual disease [MRD] status) provides valuable prognostic information and may largely inform the subsequent clinical course. Even in relatively chemosensitive disease, such as 

-mutated AML, detection of residual disease using reverse-transcriptase quantitative polymerase chain reaction was associated with a dismal 24% overall survival rate.[5,6] For patients with high-risk disease, standard therapy rarely clears MRD,[7] and the majority of these patients will relapse, even with allogeneic transplant.[8] Given what we are learning about the kinetics of subclonal response, it is critical that new initial treatment strategies be developed that can effectively and rapidly achieve MRD-negative status.

Perhaps even more challenging are those patients with high-risk AML who are not eligible for standard induction regimens, and who are relegated to lower-intensity regimens, such as DNA methyltransferase inhibitors or low-dose cytarabine. These regimens offer some advantages for certain patients, such as outpatient administration, but the responses to them are dismal, with fewer than 20% of patients achieving a CR.[9] Interestingly, some patients who have historically poor responses to 7+3 may have a more favorable response to treatment with epigenetic therapies; for instance, there are emerging data showing that decitabine may be effective in clearing a 

-mutated AML clone.[10] Nonetheless, even among responding patients, the current use of these agents is primarily palliative. In an era of new molecular targets and more tolerable therapies, it is difficult to consider the current lower-intensity options an adequate standard.

The standard of care for upfront AML therapy has remained 7+3 for decades. There is a degree of comfort with the combination, and with knowing that it can consistently provide the impression of good early responses; however, as we learn more about the biology of AML, it appears that this combination only rarely clears residual leukemic clones in patients with higher-risk disease. New therapies are needed that can target and eradicate resistant subclones early in the disease course; an example is the multikinase inhibitor midostaurin, which when added to 7+3 induction has been found to be of benefit in patients with 

-mutated AML, a subgroup associated with high rates of relapse and poor outcomes with standard therapy.[11] With more novel targets being identified, along with the evolving approach to MRD, the real standard of care for high-risk AML should be to consider novel therapeutic strategies whenever possible.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367-76.

 Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-5.

 LÃ¶wenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235-48.

 Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249-59.

 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422-33.

 Chen X, Xie H, Wood BL, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33:1258-64.

 Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA. 2015;314:811-22.

 Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease–based definition of complete remission? J Clin Oncol. 2015;34:329-36.

 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.

 Uy GL, Duncavage EJ, Chang GS, et al. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia. 2016 Nov 18. [Epub ahead of print]

 Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126:abstr 6.

Articles

As we learn more about the biology of AML, it appears that 7+3 only rarely clears residual leukemic clones in patients with higher-risk disease. New therapies are needed that can target and eradicate resistant subclones early in the disease course.

COUNTERPOINT: Standard vs Investigational Agents as Upfront Treatment for High-Risk AML

‘7+3’ Still Remains the Best Option for Most Patients

Acute myeloid leukemia (AML) is a heterogeneous disorder, with subgroups best classified by discrete mutations detectable by cytogenetic or molecular genetic techniques (the latter most informative in patients with normal karyotypes). For decades, the standard therapy has been initial treatment with cytarabine and an anthracycline, the so-called “7+3” regimen, followed by higher doses of cytarabine as consolidation. This approach is curative in ~40% of younger patients overall, with patients in some of the more favorable subgroups enjoying cure rates of ~60%. Many manipulations of this regimen, including dose intensification and the addition of other agents, have failed to improve on these results, suggesting an inherent mechanism of resistance to cytotoxic agents in some patients, who will likely require innovative, noncytotoxic strategies to improve outcomes. It is probable that some of the mechanisms of resistance are exaggerations of defenses against environmental toxins that allow normal hematopoietic stem cells and stem cells in other organs to survive. Interestingly, although countless in vitro studies have attempted to identify mechanisms of resistance, there is virtually no understanding of why certain subtypes of AML are sensitive to, and other subtypes develop resistance to, the same cytotoxic drugs.

That is the relatively good news. However, a significant fraction of patients either fail to achieve remission or relapse quickly and succumb to their AML. Although some can be salvaged with allogeneic stem cell transplantation in first or second remission, the relapse rate posttransplant is much higher in AML patients with genetic findings associated with resistance to chemotherapy, and even in those with minimal residual leukemia detected pretransplantation using very sensitive techniques.[1,2] In addition, the outcomes are worst in older patients, who represent the majority of individuals with AML, as well as in those whose AML either evolved from a prior diagnosis of myelodysplastic syndrome (MDS) or in whom the AML has morphologic or genetic features that resemble the features of MDS. In older patients, the long-term disease-free survival rate is at best 10% to 15%, and most are not candidates for transplantation.

Hence the sentiment to want to try totally new treatments instead of 7+3. This would certainly be appealing if promising therapies were available-and indeed, pharmaceutical companies have pounced on this “unmet medical need,” reasoning that it should be easy to improve on current outcomes in older patients. Not surprisingly, however, this has turned out not to be so easy; biologically resistant disease continues to be a tough egg to crack. A number of both phase II and randomized phase III trials have been conducted in older patients considered to be unsuitable for intensive chemotherapy, sometimes using straw men such as low-dose cytarabine or supportive care as controls, usually with overall survival as an endpoint.[3,4]

Apart from the difficulties in reproducibly defining the patient population to be targeted, these trials, many of which used putatively “gentler” therapy with hypomethylating agents and/or histone deacetylase inhibitors (so-called “epigenetic modifiers”), have demonstrated modest benefit, with few long-term responses.[4] Even for those who view the results of these trials more favorably than I do, the overall results are certainly disappointing, yielding little evidence that the agents studied provide cogent clues to future solutions for these patients.

Further complicating the interpretation of these trials and their impact on patient management, AML in older, higher-risk patients comes in two general “flavors”: a disease with lower blast counts that more resembles advanced MDS, or a true proliferative leukemia with hypercellular marrows and high blast counts. The latter often requires immediate intensive chemotherapy, and as a result, such patients have been infrequently enrolled in the trials mentioned previously. Advances in supportive care have permitted 7+3–like approaches in most older patients, with a 1-month mortality rate of < 10%[5]; 7+3 should thus be the initial consideration for all such patients.[6,7] Although complete remission rates with 7+3 vary from 30% to 50%, with median durations of remission of 6 to 12 months, in part depending on patient selection, patients clearly benefit clinically from complete remission-and even from a partial remission, with incomplete count recovery-and they should be afforded this opportunity.

That said, I am certainly supportive of testing investigational agents in all AML patients, particularly if there are encouraging data from studies in patients with more advanced disease, or with approaches that target specific driver mutations. There are few such “druggable” candidates at this time, although oral inhibitors of mutated 

,[9] qualify as sufficiently promising. It is already clear, however, that these agents will have to be added to chemotherapy to achieve maximal benefit. In the absence of such agents or of thoughtful clinical trials powered to detect important improvements in outcome, patients should not be denied therapy that has been proven to be of clinical value, albeit not often curative.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735-41.

 Sekeres MA, Steensma DP. Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia. J Clin Oncol. 2012;30:4061-3.

 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.

 Yang J, Schiffer CA. The artful management of older patients with acute myeloid leukemia. Expert Rev Hematol. 2016;9:425-32.

 Schiffer CA. “I am older, not elderly,” said the patient with acute myeloid leukemia. J Clin Oncol. 2010;28:521-3.

 Grunwald MR, Levis MJ. FLT3 tyrosine kinase inhibition as a paradigm for targeted drug development in acute myeloid leukemia. Semin Hematol. 2015;52:193-9.

 Stein EM. IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol. 2015;28:112-5.

Oncology Vol 31 No 3

COUNTERPOINT: Standard vs Investigational Agents as Upfront Treatment for High-Risk AML

POINT: Standard vs Investigational Agents as Upfront Treatment for High-Risk AML