Diagnosis and Management of Acute Myeloid Leukemia in France

Diagnosis and Management of Acute Myeloid Leukemia in France

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Acute myeloid leukemia (AML) represents a group of clonal hematopoietic stem cell disorders that is characterized by both failures to differentiate and over proliferation of the stem cell compartment by nonfunctional cells called myeloblasts at the expense of the normal cells that constitute the hematopoietic compartment. AML is a heterogeneous disorder, the current World Health Organization (WHO) classification attempts classify this disorder based on the molecular pathology, where this is known. It is important to recognize at the very onset that the treatment outcome of young adults has steadily improved over the last three decades while the clinical outcome in the elderly remains dismal with no significant improvement over the last three decades in spite of these advances. Accurate diagnosis and optimal use of prognostic markers along with expertise in management of prolonged neutropenia which results from chemotherapy are the key elements for success. A number of these elements are unfortunately available only in tertiary centers and hence it is preferable to refer such cases as soon as possible to such a center. Without adequate infrastructure, it is difficult to diagnose and treat these patients. However, even at a primary physician level it is important to understand and recognize the nature of this condition so that appropriate counseling and decision on referral are made in a timely manner.

Clinical Presentation and Diagnosis

Clinical presentation of acute leukemia is almost always of a very short duration of symptoms and signs related to cytopenia and susceptibility to infections. Bleeding manifestations and a florid disseminated intravascular coagulation are common in acute promyelocytic leukemia (APL). AML subtypes M4 and M5 have a higher incidence of central nervous system (CNS) involvement than other subtypes. Patients can occasionally present with very high white cell counts resulting in features of leukostasis. Diagnosis is usually obvious by the presence of myeloblasts in the peripheral smear though occasionally cases can present with pancytopenia and the diagnosis is only made on evaluation of a bone marrow aspirate. Immaterial of the presence of myeloblasts in the peripheral smear a bone aspirate is mandatory to establish the diagnosis and samples obtained from an aspirate should be sent prior to starting therapy for:

Aspirate smear for morphology and cytochemistry

The sample for immunophenotyping (IPT)

The sample for cytogenetic evaluation

The sample for molecular markers.

Morphology and Cytochemistry

To make a diagnosis of AML at least 20% blasts must be documented on a bone marrow aspirate smear. Common morphological features of AML include large blasts with abundant basophilic cytoplasm often containing azurophilic granules and perinuclear clearing. Auer rods are frequently found; they appear as long and sharp rods in the cytoplasm and are diagnostic of AML. Cytochemistry reveals that greater than 3% of the blasts are
myeloperoxidase or Sudan black positive; in case of M4 and M5 variants these can be negative but are classically nonspecific esterase positive. Morphological variations such as the increase in monocytoid forms, abnormal erythroblasts or abnormal megakaryocytes are seen in different subsets of AML that can be diagnostic or may require additional cytochemistry or immune-phenotypic information for accurate subtyping.

Immunophenotyping (IPT)

Classically myeloblasts are CD13, CD33 positive and myeloperoxidase positive. A significant proportion of blasts are also likely to express immature markers such as CD34 and human leukocyte antigen. Lymphoid markers especially CD7 are also frequently detected. IPT is especially important in the diagnosis of AML with minimal differentiation that is usually morphologically and to-chemically impossible to differentiate from acute lymphoblastic leukemia with L2 morphology.

Cytogenetics

Cytogenetic evaluation at diagnosis is critical in accurate prognostication and in decision making on optimal consolidation. It continues to remain one of the most robust prognostic markers in the management of AML. However, in approximately 50–60% of cases the cytogenetic evaluation does not reveal any abnormality.

Molecular Markers

There has been an explosion in the recognition of molecular markers that can convey both good- and poor-risk status. These are specifically relevant to the large proportion of cases that have a normal karyotype. The relevance of these markers is evolving though some of them such as nucleophosmin and FMS-like tyrosine kinase 3 mutation statuses are well established and are important in risk stratification and deciding on optimal consolidation therapy.

Treatment of newly diagnosed acute myeloid leukemia

Therapy for newly diagnosed patients can be considered under the following headings and the discussion is limited to patients less than 60 years of age. Therapy for older patients should preferably be on clinical trials since the alternative is essentially palliation.
Induction chemotherapy
Consolidation: Options include:

 High-dose chemotherapy (non-myeloablative chemotherapy)
Autologous stem cell transplantation (SCT)
Allogeneic SCT.

Induction Chemotherapy

Based on earlier studies the standard induction regimen has consisted of cytosine (Ara-C) administered as a continuous infusion for 7 days and daunorubicin (DNR) administered at for 3 days. Use of alternative anthracyclines especially idarubicin (IDR) with its potentially superior pharmacokinetic profile has been compared with DNR. In four large trials, there was a significant improvement in complete remission rates in the group that received IDR; however, in only one of these trials did this translate into an improved DFS. In another large trial conducted by the French Groupe Ouest Est Leucémies Aiguës Myéloblastiques group, there was no beneft on either remission induction or on long-term survival. Successive Eastern Cooperative

Oncology Group studies have demonstrated that DNR and IDR showed equivalent response rates. More recently data suggests that increasing the DNR dose may be optimal though this is associated with a marginal increase in toxicity. This should be considered with some caution in our setting where the major problem following administration of induction therapy is infection related deaths due to the duration of neutropenia which is likely to further increase with increasing dose of anthracycline.

The role of high-dose cytosine in induction has been considered in a few publications. In the initial Australian Leukemia Study Group study, the treatment-related mortality was significantly higher in the high-dose arm compared to the standard induction, though there was a significant improvement in DFS and overall survival (OS). Similar findings were noted in the Southwest Oncology Group trial except that there was no significant difference on the OS.

Following achievement of CR after induction chemotherapy failure to give consolidation therapy will lead to 100% of the patients relapsing. Prior to starting induction chemotherapy, it is very important to assess if the patient and family has adequate resources and support to proceed with consolidation therapy. If this is not possible it is better not to proceed with standard induction therapy that is expensive and will only function as a very expensive form of palliation. For patients who achieve remission following induction chemotherapy, the options of consolidation therapy include:
Intensive nonmyeloablative consolidative chemotherapy
Autologous SCT
Allogeneic SCT.

Intensive consolidation chemotherapy is associated with the lowest TRM, but it has the highest risk of disease relapse in contrast to an allogeneic SCT, which is associated with the lowest risk of disease recurrence, but it has the highest risk of TRM. An autologous SCT has an intermediate risk of TRM, with most prospective trials demonstrating a reduced relapse risk in comparison with chemotherapy alone. There has also been a steady improvement in the management of patients undergoing SCT, this has resulted in lower TRM and improved OS. This improvement makes it difficult to apply the data from the large prospective clinical trials, most of which were initiated a decade ago, to current algorithms.

The options of consolidation therapy are strongly influenced by the cytogenetic risk group. The good-, intermediate- and unfavorable risk groups have greater than 70% probability of relapse and a 4-year probability of survival of greater than 60%, 40– 50% and less than 20%, respectively. Additional parameters, such as age, white blood cell count at diagnosis, response to induction chemotherapy, and type of consolidation therapy, influence and potentially alter these predicted outcomes. In the good-risk group generally an allogeneic SCT is not considered in view of the TRM of 15–30% associated with this procedure when repetitive cycles of high-dose non-myeloablative consolidation chemotherapy can achieve long-term DFS greater than 60% with a less than 5% TRM. In the unfavorable-risk group, the choice would be to proceed if possible with an allogeneic SCT in CR1, not as much as because of the data supporting this but rather due to the well recognized dismal outcome with chemotherapy or autologous SCT. In the intermediate-risk group, which constitutes close to 40–50% of all patients with AML, the options in CR1 are less clearly defined. This group is heterogeneous in their response to therapy and most of them have a normal karyotype. New markers could help identify subsets at a high-risk of relapse and candidates for an SCT.

Consolidation Chemotherapy

Using repetitive courses of high-dose Ara-C (HiDAC) alone or in combination with other drugs has been found to be effective in the treatment of AML. Repetitive cycles of HiDAC as a single agent has been found to be effective in the management of good-risk AML. A more recent Cancer and Leukemia Group B publication addressed the issue of single agent HiDAC versus combination chemotherapy in patients less than 60 years of age and found no significant difference in the DFS between the two groups.

Based on the available data good-risk patients would benefit from repeated courses of HiDAC. Te number of courses should be more than one and preferably three to four cycles. Since patients who do relapse are easily salvaged in this subgroup, it would be reasonable to limit this to three cycles. In the intermediate-risk group, the optimal therapy is evolving and the exact role of chemotherapy alone is unclear. There is probably no role for young patients with AML in the high-risk group to receive chemotherapy alone as consolidation therapy. At our center for patients in the good-risk group, we would administer three cycles of HiDAC alone postinduction.

Retrospective analysis of the International Bone

Marrow Transplant Registry (IBMTR) and European Group for Blood and Marrow Transplantation (EBMT) data suggest that consolidation chemotherapy before an allogeneic SCT does not benefit patients with AML in CR1. Another retrospective analysis from a single center showed similar findings and suggested that multiple chemotherapy courses before an allogeneic SCT had a deleterious effect.

Bone marrow versus peripheral blood stem cells (PBSCs): Retrospective analysis of the EBMT and IBMTR database showed a benefit for use of PBSC in patients with advanced AML, but no benefit was shown in patients with AML in CR1, whereas another retrospective study showed a benefit for patients with AML in CR1 who underwent a peripheral blood stem cell transplantation. A more recent retrospective analysis of the Acute Leukemia Working Party/EBMT registry suggests that there is improved outcome with the use of bone marrow versus PBSCT when the dose of bone marrow CD34+ cells exceeded 2.7 × 106. The only prospective study addressing this issue demonstrated earlier engraftment, reduced TRM and improved DFS with PBSCT, but there was no difference in OS.

Significant strides have been made in the management of patients with AML. In addition to the increased understanding of the biology of the disease, ongoing developments in the field of chemotherapy and stem cell transplant continues to contribute to the steady improvement in the outcome of these patients. For the good-risk group, an autologous or allogeneic SCT should be reserved for patients who relapse after consolidation with intensive chemotherapy. In the unfavorable-risk group, it would be reasonable to proceed with an allogeneic SCT in CR1 preferably from an HLA-matched sibling donor. Based on the available data it would be considered reasonable to offer a MUD-SCT to young patients in the unfavorable-risk group with AML in CR1 if they do not have an HLA-matched sibling. Te optimal therapy for patients with AML in CR1 in the intermediate-risk group is evolving and several questions remain to be answered. With the available data, some guidelines can be drawn for this group, although no form conclusions can be made. Te use of new markers to identify subgroups at a high risk for relapse would help identify patients who would benefit from a stem cell transplant.

June 2018
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