Opinion statement
Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40–50% of younger and the great majority of elderly patients. The prognosis in relapsed ...AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (
IDH
) 1/
2
–mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30–40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with
IDH1/2
mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (
FLT3)
mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for
IDH1/2-
and
FLT3
-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.
The development and approval of novel substances have resulted in substantial improvements in the treatment of acute myeloid leukemia (AML). In the current era of novel treatment options, genetic and ...molecular testing at the time of diagnosis and relapse becomes increasingly relevant. Midostaurin in combination with intensive chemotherapy is the standard of care as upfront therapy in younger AML patients with mutated fms-related tyrosine kinase 3 (FLT3). Gilteritinib, a second- generation FLT3 inhibitor, represents a key drug for relapsed/refractory (R/R) FLT3-mutated AML patients. Targeted therapy has also been developed for patients with mutated isocitrate dehydrogenase 1 (IDH1) and IDH2. The US Food and Drug Administration (FDA) approved ivosidenib as a monotherapy for newly diagnosed older adult IDH1-mutated patients and enasidenib for R/R IDH2-mutated AML patients. CPX-351, a liposomal formulation of daunorubicin and cytarabine, has become an important upfront treatment strategy for fit patients with therapy-related AML or AML with myelodysplasia-related changes that are generally challenging to treat. The antibody drug conjugate gemtuzumab ozogamicin was approved in combination with intensive therapy for patients with newly diagnosed (FDA/European Medicines Agency EMA) as well as R/R CD33+ AML. The combination of venetoclax, an oral selective B-cell leukemia/lymphoma-2 inhibitor, with hypomethylating agents or low-dose AraC (LDAC) has changed the treatment landscape and prognosis for older adult patients very favorably. The addition of glasdegib, a small-molecule hedgehog inhibitor, to LDAC is another example of novel options in older patients. Further substances have shown promising results in early clinical trials.
The authors identify 11 discrete genetic subsets of acute myeloid leukemia on the basis of the expression and coexpression of particular mutations. Prospective studies may elucidate distinct ...approaches to their management.
Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. Although many patients with AML have a response to induction chemotherapy, refractory disease is common, and relapse represents the major cause of treatment failure.
1
Cancer develops from somatically acquired driver mutations, which account for the myriad biologic and clinical complexities of the disease. A classification of cancers that is based on causality is likely to be durable, reproducible, and clinically relevant. This is already evident in the case of AML, for which there has been a progressive shift from . . .
Between 10% and 40% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy and are therefore categorized as primary ...refractory or resistant. Few of these patients can be cured with conventional salvage therapy. They need to be evaluated regarding eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) as this is currently the treatment with the highest probability of cure. To reduce the leukemia burden prior to transplantation, salvage chemotherapy regimens need to be employed. Whenever possible, refractory/relapsed patients should be enrolled in clinical trials as we do not have highly effective and standardized treatments for this situation. Novel therapies include tyrosine kinase inhibitors, small-molecule inhibitors (eg, for Polo-like kinase 1 and aminopeptidase), inhibitors of mutated isocitrate dehydrogenase (IDH) 1 and IDH2, antibody-based therapies, and cell-based therapies. Although the majority of these therapies are still under evaluation, they are likely to enter clinical practice rapidly as a bridge to transplant and/or in older, unfit patients who are not candidates for allogeneic HSCT. In this review, we describe our approach to refractory/early relapsed AML, and we discuss treatment options for patients with regard to different clinical conditions and molecular profiles.
Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell ...transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high‐dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms‐related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR‐246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural‐precursor‐cell‐expressed developmentally down‐regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.
Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1
) AML, ...we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1
samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1
loss (n = 11). To better understand these NPM1
loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1
loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1
are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1
loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.
Allogeneic hematopoietic stem cell transplantation is curative in myelofibrosis, and current prognostic scoring systems aim to select patients for transplantation. Here, we aimed to develop a ...prognostic score to determine prognosis after transplantation itself, using clinical, molecular, and transplant-specific information from a total of 361 patients with myelofibrosis. Of these, 205 patients were used as a training cohort to create a clinical-molecular myelofibrosis transplant scoring system (MTSS), which was then externally validated in a cohort of 156 patients. Multivariable analysis on survival identified age at least 57 years, Karnofsky performance status lower than 90%, platelet count lower than 150 × 109/L, leukocyte count higher than 25 × 109/L before transplantation, HLA-mismatched unrelated donor, ASXL1 mutation, and non-CALR/MPL driver mutation genotype being independent predictors of outcome. The uncorrected concordance index for the final survival model was 0.723, and bias-corrected indices were similar. Risk factors were incorporated into a 4-level MTSS: low (score, 0-2), intermediate (score, 3-4), high (score, 5), and very high (score, >5). The 5-year survival according to risk groups in the validation cohort was 83% (95% confidence interval CI, 71%-95%), 64% (95% CI, 53%-75%), 37% (95% CI, 17%-57%), and 22% (95% CI, 4%-39%), respectively (P < .001). Increasing score was predictive of nonrelapse mortality (P < .001) and remained applicable to primary (0.718) and post-essential thrombocythemia (ET)/polycythemia vera (PV) myelofibrosis (0.701) improving prognostic ability in comparison with all currently available disease-specific systems. In conclusion, this MTSS predicts outcome of patients with primary and post-ET/PV myelofibrosis undergoing allogeneic stem cell transplantation.
•The MTSS includes clinical-molecular and transplant-specific factors predicting posttransplant outcome.•The MTSS is applicable to primary and post-ET/PV myelofibrosis reflecting posttransplant outcome better than disease-specific systems.
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