Current Opinion in Hematology:
MYELOID DISEASE: Edited by Martin S. Tallman
Treatment for relapsed acute myeloid leukemia: what is new?
Ofran, Yishaia,b; Rowe, Jacob M.a,b
aDepartment of Hematology and Bone Marrow Transplantation, Rambam Healthcare Campus
bBruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Correspondence to Yishai Ofran, MD, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa 31096, Israel. Tel: +972 4 8542541; fax: +972 4 8542343; e-mail: firstname.lastname@example.org
Purpose of review: Despite enormous progress in the understanding of leukemia pathophysiology and novel transplantation protocols, the prognosis following acute myeloid leukemia (AML) relapse is still uniformly poor. In the current review, advances in risk stratification, protocols involving novel agents and allogeneic stem cell transplantation (ASCT) will be discussed in light of the vision of personalized therapy.
Recent findings: The role of ASCT in relapsed/refractory AML is well established and has been recently confirmed as mandatory for cure. Retrospective observations of different large cohorts categorized patients with early relapse, poor cytogenetics or fms-like tyrosine kinase receptor-3 internal tandem duplication mutation as the most challenging population. Multiple novel agents have been studied with various promising results; however, these agents can only serve as a bridge to transplantation. If ASCT is not an option, therapy should focus on prolongation of patient's life at its best possible quality. Accumulated molecular data open new horizons for personalizing therapy and assigning each patient to the drug or protocol from which the patient will benefit most.
Summary: Relapsed/refractory AML is a heterogeneous disease and no uniform protocol will provide cure to all patients. Molecular tests may contribute to future personalizing therapy resulting in improved outcome. Meanwhile, novel and more effective induction and postremission protocols are warranted to lower the relapse rate.
For acute myeloid leukemia (AML) patients who enter complete remission, maintaining remission is an imperative. The probability of relapse depends on the leukemia's molecular profile, patient's age and the type of postremission therapy administered. Moreover, with current intensive protocols, up to 20–30% of young and 40–50% of older AML patients will experience primary induction failure. Despite enormous progress in the understanding of leukemia pathophysiology, the prognosis following relapse is still uniformly poor and novel approaches are desired for the treatment of relapse.
Molecular and genetic methods enable the detection of scant leukemic cells reappearing in a morphologically normal bone marrow. The current review will discuss up-to-date therapies and how to interpret results of molecular tests in relapsed/refractory AML.
GOALS OF THERAPY AND PROGNOSTIC FACTORS IN RELAPSING ACUTE MYELOID LEUKEMIA
Only about 10% of patients survive after a relapse in AML [1,2]. For those select patients who have survived the relapse and responded to intensive reinduction therapy, AML may be curable by allogeneic stem cell transplantation (ASCT). However, physicians are often reluctant to administer aggressive therapy due to the unavoidable therapy-associated neutropenia and thrombocytopenia, especially in older patients. Nevertheless, susceptibility to infection and bleeding is often related to the nature of the disease per se. Of note is the fact that intensive chemotherapy goes together with and does not contraindicate palliative therapy ; alleviating suffering and symptoms is fundamental in any protocol, regardless of its curative intentions.
Prognostic factors predicting outcome following intensive chemotherapy for relapsed AML have been recently reported by two large retrospective studies of 1015 Japanese patients [4▪] and 138 patients from France and Israel [5▪]. An equivalent overall survival rate of 30% at 3 years and 36% at 2 years was reported. Patients were treated with cytarabine and anthracycline combinations and with addition of gemtuzumab ozogamicin in the French study. Early relapse (<1 year after complete remission 1) and unfavorable cytogenetics were poor prognostic markers in both series. The presence of fms-like tyrosine kinase receptor-3 (FLT3) mutation was evaluated only in the French study and was found to independently predict for a poor prognosis. Importantly, contrary to previous works [1,6], age was not a significant prognostic marker in both series. Those previous publications included patients younger than 60 years of age and within this group, younger patients did better. Recent works enrolled patients of all ages and demonstrated that patients younger or older than 60 years of age did as well with intensive chemotherapy. This must be very carefully considered, as the more common practice of many clinicians is to be aggressive with intensive chemotherapy for patients in their 50s, while hesitating in administering the same protocols to patients 10–15 years older. As in newly diagnosed AML [7,8], the data for relapsed AML suggest that although outcome of elderly patients is generally worse, some do benefit from intensive chemotherapy.
Chevallier et al.[5▪] went a step further and created a prognostic score and validated it in a different group of 111 patients. The score that contains only three adverse factors (early relapse, FLT3 mutation and poor cytogenetics) discriminates well between patients with 0–1 and those with 2–3 adverse factors. The 2-year overall survival (OS) following intensive chemotherapy was in the range of 23–58% for low-score and 0–12% for high-score patients. This scoring scale encourages prescribing intensive chemotherapy for patients with low scores but should be carefully interpreted when treating relapsing patients with high scores. In the above-mentioned Japanese study [4▪], achievement of second remission and salvage ASCT emerged as the most important factors predicting longer OS. In the validation French cohort, patients with high-score relapse had a grave prognosis following intensive chemotherapy. However, the portion of patients who achieved second remission and proceeded for ASCT was not reported and might be low, as the validation cohort came from the LAM (lamivudine)-2001 trial [5▪], which included patients with no matched siblings.
THE ROLE OF SECOND REMISSION
Complete remission is fundamental for cure in first-line therapy of AML [9▪▪]. Failure to achieve a second remission in relapsed AML was recently demonstrated to be associated with reduced OS (hazard ratio of 3.23) in a large retrospective study [4▪]. Most clinicians agree that intensive chemotherapy aiming at second remission is appropriate in patients with good performance status, late relapse, no adverse cytogenetic or genetic markers and significant bone marrow blast counts [10,11]. For patients with early relapse, especially if poor cytogenetics or FLT3 mutation are present, chances to enter second remission with intensive chemotherapy are as low as 20% [12▪]. Moreover, with different reinduction protocols the 30-day mortality rate is as high as 20% [4▪,13–15]. Therefore, in patients with high-score relapse, intensive chemotherapy targeting second remission may be considered futile.
What should be offered to patients in whom an attempt to reach second remission is not considered? If cure is aspired, ASCT must be considered mandatory. Otherwise, the goal of therapy may be prolonging life of the best quality possible.
BONE MARROW TRANSPLANTATION IN PATIENTS NOT IN COMPLETE REMISSION
Conditioning protocols and donor selection in relapsed AML have been recently reviewed . We will herein focus on patient selection for ASCT in the challenging clinical setting of relapsed AML when second remission has not been achieved. Scoring predicting transplantation success was developed in a retrospective survey of 1673 patients who underwent a myeloablative ASCT for AML in relapse. Patients with a very low score were demonstrated to experience a 3-year OS of up to 42% and those with a very high score had a dismal prognosis with only 6% alive at 3 years [17▪▪]. Unfortunately, the high score refers to the same group of patients in whom attempts to reinduce second remission are likely to fail. Patients with a short complete remission 1, poor cytogenetics, low performance status and/or circulating blasts present a major clinical challenge. These patients have a low OS rate when proceeding directly to ASCT, but chances to improve it by inducing second remission are also scarce and the impact of significant toxicity associated with induction regimens should not be underestimated. An interesting strategy of cytoreductive chemotherapy, followed by reduced-intensity conditioning (RIC) and prophylactic transfusion of donor lymphocytes in refractory and early relapse patients was created . This German protocol known as the FLAMSA (fludarabine, Ara-C, amsacrine)-RIC protocol was reported in a prospective multicenter study involving 103 patients. The study recruited patients with early relapse and primary induction failure. The median survival of 16.4 months and the 4-year estimated OS of 32% are promising. The concept of the FLAMSA-RIC protocol inspired similar other sequential cytoreduction followed by RIC transplantation protocols with encouraging results [19–21]. This approach requires an HLA-matched donor available just when relapse is diagnosed. Therefore, for AML patients in complete remission 1 even if allogeneic transplantation is not scheduled, a search for a matched donor should be initiated to enable sequential transplantation in case of early relapse.
PATIENTS NOT CANDIDATES FOR ALLOGENEIC TRANSPLANTATION
If no matched donor is available, cure may be accomplished by double umbilical cord or haploidentical ASCT, but with a very low success rate if transplanted not in remission [22▪], similar to the data when using matched unrelated donors . Select patients may be cured with intensive chemotherapy followed by an autologous transplant . In chemorefractory relapses when a matched donor is not available or the patient is unfit for ASCT, therapy should target prolongation of life instead of curing the disease. The ultimate objective of getting patients into remission should, therefore, be replaced by controlling leukemia and intensive chemotherapy by continuous chronic therapy with minimal side effects. For some patients such therapy will buy time until a suitable donor is available (bridge to transplantation). In other ‘unfit’ elderly patients, therapy that will yield significant prolongation of life of an acceptable quality will be favored.
Hydroxyurea, 6-mercaptopurine and low-dose Ara-C are old drugs with proven ability to control leukemia for a limited period of time. Novel agents and strategies in relapsed AML have been reviewed by Litzow . Herein we will update those agents that have been shown to be effective in controlling leukemia in recent years and discuss benefits and drawbacks of each agent.
NOVEL AGENTS AND THEIR ROLE IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA
Clofarabine is a novel purine nucleoside analogue structurally similar to fludarabine and cladribine, developed with the aim of avoiding the neurotoxicity that limits the maximal tolerated dose of old-generation purine analogues. The role of clofarabine as intensive chemotherapy has been evaluated in several successful phase I/II studies [26▪,27]. A phase III study (ECOG-E2906) comparing clofarabine with traditional 7+3 (daunorubicin and cytarabine) as induction in newly diagnosed older patients with AML is currently recruiting. The efficacy of single-agent low-dose clofarabine or combined with other drugs in controlling relapsed or refractory leukemia has been evaluated , but so far with no significant breakthrough.
Mutation in FLT3 is well known to be a poor prognostic marker in newly diagnosed and relapsed AML [5▪]. Specific inhibitors of FLT3 such as sorafenib, lestaurtinib (CEP-701) and quizartinib (AC220) have been studied in relapsed or refractory AML. The largest trial was a phase III randomized trial of salvage chemotherapy with or without lestaurtinib, which failed to demonstrate a general benefit from the addition of lestaurtinib . However, the target inhibition of FLT3 was achieved in only 58% of patients receiving lestaurtinib, although good inhibition did correlate with longer OS. Sorafenib was demonstrated to slow down disease progress in relapse but cannot induce second remission . Quizartinib (AC220) is probably the most effective FLT3 inhibitor and results of large-scale trials in relapsed AML are still pending . However, interim analysis of a phase I/II study has demonstrated that quizartinib provides clinically meaningful reductions in marrow blasts and successfully bridges to ASCT in a substantial proportion of patients .
Mammalian target of rapamycin (mTOR) was identified in vitro as an attractive target for therapy. Furthermore, gene expression analysis pointed to the AKT/mTOR signaling pathway as involved in Ara-C responsiveness . Preliminary encouraging results were reported with deforolimus, sirolimus or everolimus [33–35], alone or in combination with other drugs, but confirmation in large-scale studies is warranted.
Hypomethylating agents are active in high-risk meylodysplastic syndrome but to a lesser degree in highly proliferative AML. 5-Azacitidine was shown in one study to prolong OS in elderly AML patients with low proliferative disease [36▪], and hence has drawn attention as an agent that may control low proliferative relapses. Indeed, a small retrospective study of 26 patients demonstrated that absence of peripheral blood blasts is the strongest predictor for OS in patients relapsing after ASCT. Interestingly, bone marrow blast counts of more than 20% failed to predict response in both this and other trials . Responses, however, were observed in the minority of relapsing patients and were of short duration. If given with first signs of molecular relapse, azacitidine may delay relapse and allow some patients to proceed to ASCT .
Lenalinomide is an immunomodulatory agent with known activity in multiple myeloma. High-dose lenalinomide induced second remission in five of 31 (16%) patients, all of them with low proliferative relapse . Trials combining lenalinomide with chemotherapy or hypomethylation agents are ongoing.
X-linked inhibitor of apoptosis protein (XIAP) inhibits caspases 3 and 9 and is overexpressed and promotes chemoresistance in AML. AEG-35156 is an antisense oligonucleotide that targets XIAP. AEG-35156 at a dose of 350 mg/m2 was well tolerated and effectively knocked down XIAP expression. Combination of XIAP with chemotherapy yielded complete remission/CRp in 91% of patients who had been refractory to a previous induction chemotherapy .
Immune therapy for AML has been reviewed elsewhere . We will herein discuss recent studies highlighting the immune therapy potential in relapsed AML. Vaccination with Wilm's tumor (WT)1 antigen-targeted dendritic cells induced complete remission 1 in two chemorefractory patients who achieved only partial response with induction protocol [42▪▪]. Adoptive transfer of T cells directed against different recipient minor antigens induced remission in seven AML patients relapsing after ASCT [43▪▪]. Most interesting is a study on infusion of HLA-mismatched stem cells that improves complete remission 1 and OS rates in elderly patients probably through an immune modulation mechanism [44▪].
RESPONDING TO MOLECULAR RELAPSING ACUTE MYELOID LEUKEMIA
With no consolidation therapy, all AML patients in complete remission 1 eventually relapse , suggesting that at least during the first months of therapy, undetectable minimal residual disease (MRD) exists in all patients. Traditional definition of chemorefractory AML requires the morphologic presence of 5% blasts in a bone marrow smear after recovering from conventional induction or reappearance of blasts in less than a year after achieving complete remission 1 . New sensitive molecular techniques allow detection of sparse malignant cells or DNA, but does detection of MRD always predict for refractory disease? Two debates should be addressed to create an updated clinically meaningful definition of refractory AML.
First, how long after induction are molecular signs of MRD permissible? Rapidity of MRD eradication is a good prognostic marker in acute lymphoblastic leukemia . In AML, rapid clearance of blasts and early reduction of WT1 transcripts from peripheral blood [48,49] predict for a good prognosis. The clinical challenge is how to consider patients who delayed but eventually attained complete remission. The presence of bone marrow blasts at day 14 of induction is definitely a surrogate marker for refractory AML. If reinduction was delayed until day 21 , prognosis is poor. Yet, with immediate reinduction, some patients will be rescued and OS for those who eventually attain complete remission is equal to those patients who obtained complete remission with single induction [51▪▪].
The second debate is whether any level of MRD justifies reinduction and ASCT [52▪]. The common wisdom is that leukemic cells should be completely eradicated. So, responding to any sign of molecular relapse should give patients a better chance for cure and a longer survival. This assumption probably will never be confirmed in prospective randomized trials because the ‘watch and wait’ approach ignoring molecular relapse may be considered unethical. A recent observation highlighted the contribution of a patient's own immune system to preventing relapse probably through its capacity to eradicate undetectable MRD. In 143 adult patients with AML in complete remission 1, adenine-adenine polymorphism in the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene was associated with higher incidence of leukemic relapse than the adenine-guanine polymorphism (56.4 vs. 35.6%, P = 0.004, respectively). This was translated to a lower overall survival at 3 years (39.4 vs. 68.4%, P = 0.004) [53▪▪]. One can speculate that some patients may be cured even if not all leukemic cells have been eradicated by chemotherapy.
Despite multiple novel agents available, prognosis of patients with relapsed AML remains poor. Progress in understanding molecular pathophysiology of AML may hold the key for future treatment approaches promoting proper assignment of patients to the most beneficial therapy. Advances in pharmacogenetics may in the future help identify such patients. This may direct clinical research into smaller trials focusing on genetically discriminated subgroups [32,54]. The above-mentioned CTLA4 polymorphism is an example of a potential path for personalizing therapy in AML. Immunotherapies may turn out to be more beneficial for patients with active CTLA4 polymorphism. Specific small molecules such as FLT3 inhibitors are only indicated in FLT3-positive AML and are most effective if significant FLT3 inhibition is achieved. Azacitidine is more likely to control disease in Ten-Eleven translocation 2 gene-mutated AML [55▪]. The personalized approach is promising but will bring about new challenges for treating physicians. Clinicians will have to switch their perspective from a general ‘best available’ protocol to sophisticated integration of multiple parameters. A meticulous workup will be mandatory to select the best protocol matching patient's condition, biological and genetic factors, and considering patient's wishes within a realistic context.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 127–128).
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