Interview with Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany
NEW ORLEANS, USA—For your patients with acute myeloid leukemia (AML) the benefit of prompt allogeneic hematopoietic cell transplantation (alloHCT) extends to those whose disease has relapsed or is refractory to induction therapy, and should not be delayed in favor of further intensive chemotherapy in an attempt to achieve a complete remission. That’s according to conclusions from the randomized phase three ASAP (As Soon As Possible) Trial, reported by German researchers at the American Society of Hematology (ASH) 2022 Annual Meeting.
“Allogeneic stem cell transplantation is a very potent strategy which is curative for many patients,” said senior author of the study, Johannes Schetelig, Prof. Dr. med., at the University of Dresden in Germany. “Our study suggests that the international standard of bringing patients into remission first should be questioned, as it proves that allotransplant should be considered a standard treatment option even for patients with active disease.”
The new study was the first prospective randomized trial to assess whether or not high-dose “salvage chemotherapy” (to attempt to bring about a complete remission) made a difference in long-term outcomes after a stem cell transplant. Patients whose AML had relapsed or who did not respond to initial chemotherapy had similar outcomes when they proceeded directly to alloHCT compared with those who underwent intensive chemotherapy in the attempt to achieve complete remission first.
Retrospective data had established that having a complete remission prior to allogeneic hematopoietic cell transplantation was indeed a favorable risk factor for patients with AML. But the ASAP Trial had been the first to examine this relationship prospectively, the researchers noted.
“We were astonished. We never expected these results,” Schetelig said. “Patients did not gain additional benefit from salvage chemotherapy at all. It suggests we should think about starting the process of allotransplantation as soon as possible.”
In previous phase two trials the researchers had found transplanting patients who had active disease brought a benefit. “We had some good experience in the past where we were able to successfully treat patients with an allogeneic stem cell transplantation even in the setting of active disease,” said first author of the ASAP study, Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany.
Stelljes acknowledged that the majority of centers did not usually perform alloHCT in patients with relapsed or refractory AML with active disease. The new findings from ASAP, however, ran counter to the common practice of offering prompt transplantation only to patients who were in complete remission and clearly imply that many patients could skip the additional step of having salvage chemotherapy before receiving a transplant.
The study enrolled 281 patients treated for relapsed or refractory AML in Germany. Half of them were randomized to proceed directly to alloHCT and remaining half had salvage chemotherapy first. The median time from randomization to transplant was four weeks among those proceeding directly to a transplant and eight weeks among those receiving salvage chemotherapy first. Researchers tracked outcomes for a median of just over three years.
In the standard arm patients had salvage therapy with high dose cytarabine (ara-C) and mitoxantrone and then received an allogeneic transplant. This was either in subsequent remission or with active disease in those in whom no remission could be achieved, Stelljes told the Audio Journal of Oncology. “In the experimental arm we did not perform any salvage treatment. We just tried to get the patient as soon as possible to transplant. We were able to get most of the patients, without additional therapy, to allo transplant within three to four weeks,” he said.
The two study groups showed similar outcomes in all key endpoints. The primary endpoint of complete remission 56 days after transplant was achieved in 84.1 percent of patients in the direct-to-transplant arm and 81.3 percent of patients in the salvage chemotherapy arm. The groups also had similar rates of overall survival at one year (around 70 per cent). Just over half of them were alive three years after randomization.
In the experimental arm, patients were followed under a policy of “watchful waiting” which permitted some treatment while the search for a transplant donor was in progress, but not at doses aimed at achieving complete remission. Three quarters of them had transplants before any such treatment was needed, Stelljes noted.
Since transplantation could only take place if a donor was available, the search for a donor began at primary diagnosis, Stelljes said, and not at the time of relapse of refractory disease.
He highlighted the role of clonal selection of resistant cancer cells that can arise from the exposure patients have to cancer drugs. Prompt transplantation reduces the time during which patients are exposed to chemotherapy and should increase the success rate of transplantation in achieving long remissions, he noted. “The main message is: Contact your transplant center as soon as possible, and stay in contact with the transplant center.”
Study favors immediate progression to stem cell transplant for hard-to-treat AML even without achieving complete remission first
ABSTRACT 4, American Society of Hematology 2022 Annual Meeting, New Orleans, USA.
TITLE:In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial
ABSTRACT 4 ASH 2022:
In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial
Program: General Sessions
Session: Plenary Scientific Session
Hematology Disease Topics & Pathways:
MDS, clinical trials, AML, adult, Acute Myeloid Malignancies, Research, Clinical Research, Chronic Myeloid Malignancies, Diseases, therapy sequence, Therapies, Myeloid Malignancies, Human, Study Population
Sunday, December 11, 2022, 2:00 PM-4:00 PM
Matthias Stelljes, Prof. Dr. med.1, Jan Moritz Middeke, MD2*, Gesine Bug, MD3*, Eva-Maria Wagner, MD4*, Lutz Peter Mueller, MD5*, Schmid Christoph6*, Stefan W. Krause, MD7*, Wolfgang Bethge, MD8*, Edgar Jost9*, Uwe Platzbecker, MD10*, Stefan Klein, MD11, Jörg Schubert12*, Judith Niederland13*, Martin Kaufmann, MD14, Kerstin Schäfer-Eckart15*, Markus Schaich, MD16*, Henning Baldauf17*, Friedrich Stölzel18*, Cathleen Petzold, PhD17*, Christoph Röllig, MD, MSC19*, Nael Alakel, MD20*, Björn Steffen, MD21*, Beate Hauptrock22*, Christian Reicherts, MD23*, Christoph Schliemann, MD24*, Hubert Serve, MD21, Alexander H. Schmidt, MD, PhD25, Martin Bornhäuser, MD26*, Jan-Henrik Mikesch, PD, MD24* and Johannes Schetelig, MD, MSc17,20
1Department of Medicine / Hematology and Oncology, University of Muenster, Muenster, Germany
2Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
3Department of Medicine II, Hematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany
4Haematology and Oncology, University Medical Center, University Medicine Mainz, Mainz, Germany
5University Hospital, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Halle (Saale), Germany
6Augsburg University Hospital and Medical Faculty, Augsburg, Germany, Augsburg, Germany
7University Hospital Erlangen, Germany, Erlangen, Germany
8Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
9University Hospital Aachen, Germany, Aachen, Germany
10Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
11Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
12Elblandklinikum, Riesa, Germany, Riesa, Germany
13Helios Klinikum Berlin-Buch, Berlin, Germany, Berlin-Buch, Germany
14Medical Centre, Robert-Bosch-Hospital,, Stuttgart, Germany
15Department of Internal Medicine V, Nuremberg Hospital North, Paracelsus Medical University, Nuremberg, Germany
16Department of Hematology, Oncology and Palliative Care, Rems-Murr-Klinikum Winnenden, Germany, Winnenden, Germany
17Clinical Trials Unit, DKMS gGmbH, Dresden, Germany
18University Hospital, TU Dresden,Germany, Dresden, Germany
19University Hospital, TU Dresden, Germany, Dresden, Germany
20University Hospital TU Dresden, Germany, Dresden, Germany
21Department of Hematology and Oncology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany
22University Hospital Mainz, Germany, Mainz, Germany
23Department of Hematology, Oncolog and Pneumology, University of Münster, Muenster, Germany
24Department of Hematology, Oncolog and Pneumology, University of Münster, Münster, Germany
25DKMS gGmbH, Tubingen, Germany
26Department of Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
For patients (pts) with AML, a complete remission (CR) prior to allogeneic hematopoietic cell transplantation (alloHCT) is a favourable risk factor. However, whether pts with relapsed or refractory (r/r) AML benefit from an attempt to induce CR with intensive chemotherapy (CT) prior to alloHCT is unknown. Sequential conditioning within 12 days prior to alloHCT with high-dose cytarabine or melphalan followed by reduced intensity conditioning leads to good results as well. Therefore, we asked whether intensive remission induction CT prior to alloHCT really improves outcome compared to immediate alloHCT after sequential conditioning without attempt to induce a CR before transplantation.
Adult pts with poor responsive non-favourable AML after first induction therapy (IT-1) or AML relapse, eligible for intensive CT and alloHCT, with either a matched sibling donor (MSD), an HLA-compatible (≥9/10) unrelated donor (UD) or ongoing donor search with two potential UD with ≥90% HLA-matching probability were enrolled. Patients were randomized 1:1 to a remission induction strategy (RIST-arm) with 3 g/m2 cytarabine (1 g/m2 for pts >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3-5 (HAM) and subsequent alloHCT (remission induction strategy, RIST-arm) or to disease control (DISC-arm) prior to sequential conditioning and alloHCT. In the DISC-arm watchful waiting (w&w) was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease-control. The primary endpoint was treatment success, defined as CR@day56 after alloHCT. Statistically, the goal was to show non-inferiority (NIF) for the DISC-arm with a NIF-margin of 5% and a one-sided alpha of 2.5%. Major secondary endpoints were overall survival from randomization and leukemia-free survival from CR@day56.
A total number of 281 pts (183 pts with poor response after IT-1 and 98 pts after relapse) were enrolled. The full analysis set comprised 276 pts after exclusion of five pts due to violation of inclusion criteria. Median age was 61 years (interquartile range [IQR] 52-66 years) and the HCT-CI was ≥3 in 37.3% of pts. At randomization, 39 pts had MSD, 133 pts had an HLA-compatible UD with confirmed HLA-typing, and 104 pts had ongoing UD searches. 272 pts were treated per protocol, 138 pts in the DISC- and 134 in the RIST-arm.
In the DISC-arm 105 of 138 pts (76%) were kept on w&w until start of sequential conditioning, while 33 pts (24%) needed disease-control measures. In the RIST-arm all pts received HAM. Sixty-two out of 134 pts (46%) achieved a CR. Five pts received a second course of intensive CT. The remaining pts proceeded to alloHCT without further attempts to induce a CR. The median time to alloHCT was 4 weeks in the DISC-arm and 8 weeks in the RIST arm. At 24 weeks from randomization 98% and 96% of pts had been transplanted in the DISC and RIST arm, respectively. Figure 1 A shows incidences of alloHCT and CR achievement in both arms. The primary endpoint CR@day56 after alloHCT was reached by 84.1% of pts in the DISC-arm and 81.3% of pts in the RIST-arm (test for non-inferiority, p=0.047). One-year leukemia-free survival from CR@day56 was 71.5% in the DISC-arm and 69.9% in the RIST-arm (z test, p=0.8).
The median follow-up from randomization is 37 months. According to the intention-to-treat, 1-year and 3-years overall survival from randomization was 69.1% (95%-CI, 60.6-76.1%) versus 71.9% (95%-CI, 63.3-78.9%) and 51.0% (95%-CI, 41.8-59.6%) versus 54.2% (95%-CI, 44.4-62.9%) in the DISC- versus RIST-arm, respectively (log-rank p=0.47) (Figure 1B).
This is the first randomized controlled trial, which questioned the benefit of intensive remission induction CT prior to alloHCT for pts with r/r AML. Chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate and did not confer a survival advantage. Watchful waiting followed by sequential conditioning and alloHCT resulted in comparable overall CR rates and survival. These data support sequential conditioning and alloHCT without prior remission induction CT whenever a stem cell donor is readily available. Finally, these results underline the importance of facilitating alloHCT as most effective anti-leukemic therapy in patients with r/r AML and stress the need for starting donor search at diagnosis.