AML World Awareness Day 2020 | The evolution of AML treatment through clinical trials

On April 21, 2020, communities will unite on Acute Myeloid Leukemia (AML) World Awareness Day (WAD) to raise awareness of AML. Both scientific and patient communities will achieve this collective goal by sharing knowledge and advances in the prevention, management, and treatment of AML, worldwide. The AML Hub are proud to support AML WAD and have written a series of articles on key themes in AML to be shared in the lead-up to April 21. This article discusses the evolution of the treatment pathway in AML through key clinical trials.¹

Background

AML is a heterogenous disease, meaning that the success of given therapies depends significantly on an individual patient’s disease (i.e. genetic abnormalities at diagnosis) and characteristics, such as age and pre-existing comorbidities. The typical treatment pathway in AML consists of induction and consolidation therapy, which may be followed by hematopoietic stem cell transplant (HSCT), depending on the patient’s relapse risk and eligibility. Some patients will also receive subsequent maintenance therapy, which is currently restricted to patients with FLT3-mutated AML but is under investigation in other subtypes. There has been significant progress in the field of treatment options for AML in recent years following an increased understanding of the pathophysiology of AML, leading to the development of targeted agents alongside immunotherapies. To read more about clinical trials in AML, head to the AML Hub.

Induction therapy

The main aim of induction therapy is to decrease the number of leukemic cells to an undetectable level. Induction therapy for young or fit older patients is typically a ‘7 + 3’ regimen of cytarabine and an anthracycline, such as idarubicin, daunorubicin, or mitoxantrone. Important clinical trials in the induction setting that led, or may lead, to changes in clinical practice include 

• RATIFY study (NCT00651261), which compared induction and consolidation chemotherapy with cytarabine and daunorubicin, with or without midostaurin
• SORAML trial (NCT00893373), which evaluated the addition of sorafenib to standard induction therapy in patients with newly diagnosed (ND) AML who are less than 60 years old — results from the long term follow-up are available here
• VITAL (NCT02658487), which is testing vosaroxin with cytarabine in patients with untreated AML
• a phase III study (NCT01696084), comparing CPX-351 to 7 + 3 induction in patients aged 60–75 years old who have untreated high-risk AML. A recent subgroup analysis of patients who achieved remission is available here
• ALFA-701 (NCT00927498), which randomized patients aged 50–70 with ND AML to receive daunorubicin and cytarabine with or without gemtuzumab ozogamicin. Final results are available here

Maintenance

As relapse rates post-induction therapy remain high, maintenance therapy is considered as a therapeutic option to control leukemic regrowth. However, there is a lack of effective options for maintenance therapy in AML, and many clinical trials are ongoing in this setting.

One of the main clinical trials in the maintenance setting is the QUAZAR AML-001 study. This phase III study is investigating CC-486, an oral formulation of azacitidine, as maintenance in patients with AML who are not eligible for transplant and who are in first remission following induction chemotherapy (IC), with or without consolidation. Read the results of QUAZAR AML-001 here or watch Andrew Wei discuss them below.

Reducing the risks associated with allogeneic (allo) HSCT

The standard treatment strategy for many patients with high-risk AML who are in remission post-chemotherapy is allo-HSCT. Transplant eligibility is determined by the leukemic genetic-risk profile, scores that predict the risk of treatment-related death, and specific transplantation-associated factors in the patient. Despite its potential for curing AML, transplantation is associated with a high mortality, especially due to graft-versus-host disease (GvHD) and relapse.

Conditioning regimens

Some clinical trials have focused on elucidating the risk/benefit ratio of using reduced-intensity conditioning (RIC) compared to myeloablative conditioning (MAC) strategies. MAC strategies are typically associated with increased toxicity and treatment-related mortality. RIC allows more patients to undergo allo-HSCT, including older and less fit patients, although it may come with an increased risk of engraftment failure and late relapse.

One clinical trial investigating the difference between MAC and RIC approaches includes the MAvRIC trial. Long-term follow-up from this trial was recently published and concluded that, in fit patents with AML, MAC should be standard of care (SOC) instead of RIC. Table 1 summarizes other clinical trials in the HSCT setting.

Ongoing studies seeking to improve conditioning regimens include

• NCT01203722: This study will investigate low-dose, partially human leukocyte antigen (HLA)-mismatched bone marrow and peripheral blood allo-HSCT. Conditioning will be with fludarabine, cyclophosphamide, and total body irradiation, followed by allo-SCT and mycophenolate mofetil (MMF) and tacrolimus or sirolimus as immunosuppressive agents. It will enroll patients with AML arising from myelodysplastic syndrome or secondary AML (sAML), with FLT3­-ITD, poor risk cytogenetics, or primary refractory disease
• NCT02333162: A study of intensity-modulated total marrow irradiation, a type of radiation therapy, given with fludarabine phosphate and melphalan, in patients with AML undergoing second or higher HSCT

GvHD prophylaxis

GvHD is a potentially serious complication of allo-HSCT. Several studies are underway in patients with hematological malignancies that seek to identify GvHD prophylaxis strategies. Read more about GvHD prophylaxis options here. Some examples in AML include

• NCT02593123: A randomized study of early GvHD prophylaxis comparing MMF + sargramostim to MMF + filgrastim. This study will enroll patients with AML who are eligible for RIC allo-HSCT with a HLA-matched donor (related or unrelated) aged 40–74
• NCT02061800: A trial investigating T-cell depletion by selection of CD34⁺ stem cells. Patients undergoing allo-HSCT that have failed SOC or are unlikely to be cured with non-HSCT therapy are eligible, and will receive peripheral blood stem cells

Immunotherapy-based approaches in transplant

In specific scenarios, such as umbilical cord blood transplant (UCBT), natural killer (NK) cell therapy is being investigated. Results from a French study of NK cells after RIC UCBT in AML patients were previously reported here, with an ongoing study, NCT02727803, investigating personalized NK cell therapy after chemotherapy and UCBT. The latter study is enrolling patients with AML with myelodysplasia-related changes, AML with variant myeloid/lymphoid lineage (MLL) translocations, relapsed/refractory (R/R) AML, and sAML. Read more about NK cell therapy for patients with sAML or de novo AML here.

Other examples:

• Agents like panobinostat, in combination with decitabine, are also being investigated prior to donor lymphocyte infusion after allo-HSCT in the HOVON 116 trial
• In a phase III trial, HSV-Tk-engineered lymphocytes (genetically modified CD3 cells) are being compared to T-cell deplete and T-cell replete transplant strategies (NCT00914628)

Posttransplantation maintenance

An interesting study in the maintenance setting in AML is NCT02400255. This trial is testing crenolanib, a FLT3 inhibitor, as post-HSCT maintenance in patients with FLT3-positive AML who are in complete remission following HSCT. Gilteritinib is another FLT3­ inhibitor being investigated as maintenance post-allo-HSCT in patients with FLT3-internal tandem duplication (ITD) AML in the MORPHO study (NCT02997202). Additionally, the SORMAIN trial is a double-blind, placebo-controlled phase II trial to evaluate sorafenib maintenance therapy in patients with FLT3-ITD-positive AML in complete remission following allo-HSCT. Watch Andreas Burchert discuss the key highlights of SORMAIN here.

The AMADEUS study (NCT04173533) is comparing oral azacitidine to placebo in patients with AML following allo-HSCT, and the BATTLE study (NCT03154827) is evaluating BL-8040 and atezolizumab as maintenance for patients with AML who are aged 60 or older. Updated results from the E2906 trial of decitabine maintenance vs observation in patients aged 60 or older who were intensively treated were recently presented.

Treatment for patients with AML who are ineligible for intensive therapy

Older patients who are frail are typically considered unfit for intensive IC. There is no widely accepted treatment pathway for this patient population, though commonly used regimens include low-dose cytarabine, hypomethylating agents like azacitidine and decitabine, or best supportive care. This group of patients represents an unmet medical need, and therefore there is extensive effort in enrolling these patients in clinical trials in order to establish a standard of care.

The AGILE study is investigating the combination of ivosidenib (AG-120) with azacitidine in patients with ND AML who are ineligible for IC and have IDH1 mutations. Meanwhile, the phase III ASTRAL-1 study is comparing guadecitabine (SGI-110) to treatment of choice in patients with ND AML who are ineligible for IC. The results of ASTRAL-1 were recently presented and are summarized here.  The CULMINATE study (NCT04023526) is using a combination of cusatuzumab and azacitidine for maintenance in patients with ND AML who are ineligible for IC.

Meanwhile, the VIALE-A and VIALE-C trials are using venetoclax in combination with azacitidine and low-dose cytarabine, respectively, in patients with ND AML who are ineligible for standard IC.

R/R AML

Within 3 years of diagnosis, most patients with AML experience relapse. Again, there is no standard regimen for patients with R/R disease. Determinants of outcome after relapse include a short duration of remission, adverse genetic factors, prior allo-HSCT, older age, and poor general health status. It is important to identify patients who will benefit from salvage chemotherapy or who are candidates for clinical trials, so that more effective treatments can be found.

Clinical trials in AML are often conducted in the R/R AML population before potentially being moved into earlier lines of therapy. Many of the trials of novel agents are conducted in this group of patients.

In the R/R setting, older patients with HOX over-expression who are unfit for IC are being enrolled in a trial (NCT03513484) that is investigating nintedanib in combination with azacitidine as maintenance therapy. Bemcentinib (BGB324), a small molecule inhibitor of AXL, is being tested as monotherapy in patients with R/R AML following chemotherapy or treatment with a targeted agent, and as monotherapy or in combination with cytarabine or decitabine in patients with AML who are unsuitable for IC. Read the results of the phase II trial of bemcentinib in combination with cytarabine or decitabine here. Bemcentinib has already received fast track designation from the United States Food & Drug Administration.

Another important study in this population is NCT02670044. This trial is enrolling patients with R/R AML aged 60 years or older who are not eligible for cytotoxic therapy. The study will compare venetoclax, a BCL-2 inhibitor, plus cobimetinib, an MEK inhibitor, to venetoclax plus idasanutlin, an MDM2 inhibitor.

Conclusion

Increases in available treatment options for patients with AML have resulted from a variety of clinical trials in different patient settings. The contribution of each patient toward the development of improved treatment options cannot be underestimated and is appreciated by all in the field. The continued enrollment of patients into investigatory clinical trials will allow further, significant advances in therapeutic options.