How I treat acute myeloid leukemia in adults (strategies)

May 31, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments , , , , ,

More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Few diseases other than acute myeloid leukemia (AML) engender so much personal and institutional passion regarding treatment strategies. The median age of AML is 72 years of age, as reported by the Swedish Acute Leukemia Registry, a model for collection of real world data.

Although some improvement during the last 4 decades is apparent among younger patients, still only approximately 35% of such patients entered on clinical trials are cured of their disease. However, little progress occurred among older patients and indeed only those with acute promyelocytic leukemia (APL) which is a rare subgroup enjoy the excellent outcome and likelihood of cure we all desire.

Management of AML in Adults

To some extent, the management of adults with AML appears to be standardized. However, much of the so-called conventional therapy has been established with a lack of data or without rigorous review of the existing evidence; and so, considerable uncertainty remains. Such uncertainty is reflected in the significant diversity in the management of patients with AML, both in induction of older patients and postremission therapy of all patients.

Generally, the management of AML can be divided into three parts including the induction therapy, the postremission therapy, and the hematological emergent management. The induction therapy regimen now is standarized. The choice of induction and postremission thearpy is primarily and solely determined and based on the cytogenetic and molecular determinants at diagnosis. However, possibly minimal residual disease (MRD) after induction therapy, as determined by refined molecular or immunophenotypic analyses, plays a role in deciding the choice of postremission therapy.

When a patient is newly diagnosed with AML, the first thing to do is to evaluate the cytogenetics and karyotype of the patient,since that the two is important in the determining of the risk status, the prognosis, and then the treatment strategy of AML. According to the cytogenetics and karyotype the risk status of AML can be divided into three categories consisting of better-risk (favorable), intermediate-risk, and poor-risk (unfavorable).

Table 1. Risk Status of AML Based on Cytogenetics and Molecular Abnormalities

Table 2. Standardized Reporting for Correlation of Cytogenetic and Molecular Genetic Data in AML with Clinical Data

Induction Therapy

Although in the early 1990s several randomized studies of induction therapy suggested that using idarubicin, mitoxantrone, aclarubicin, or amsacrine demonstrated superior results compared with daunorubicin, there is no evidence that these studies reflected a true biologic advantage rather than a lack of dose equivalence. So the standard induction therapy regimen remains the “3+7”. It has now been established that the traditional approved dose of daunorubicin (45 mg/mfor 3 days) is no longer appropriate as induction therapy for AML. A recent randomized trial for younger patients under age 60 years reported a significantly higher complete remission (CR) rate for patients receiving 90 mg/m2 of daunorbuicin compared with 45 mg/m2. The overall survival was also improved with the higher dose of daunorubicin.

The E1900 trial, which was undertaken by the Eastern Cooperative Oncology Group (ECOG) in 657 younger patients, compared a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 in a 3+7 schedule for the first induction course. The higher dose achieved a significantly higher overall remission rate, with more patiens in CR after the first course and a better overall survival (23.7 vs 15.7 months). However, a study by Dutch-Belgian Hemato-Oncology Cooperative Group showed that with the similar approach in older patients with AML the overall remission rate was similarly improved, but overall survival was not, except in the case of patients in the 60- to 65-year subgroup.

So the induction therapy regimen is 3+7 that daunorubicin 90 mg/m2 for 3 days together with cytarabine 100 mg/m2 for 7 days.

Postremission Therapy

Once the patient get CR after induction therapy postremission therapy need consideration. The choice of postremission therapy could be allogeneic hematopoietic cell transplantation (allo-HSCT), autologous transplantation (auto-HSCT), and consolidation chemotherapy. The decision for postremission therapy should be based on cytogenetic and molecular determinants, regardless of other factors.

Allo-HCT provides the most potent antileukemic effect of any postremission strategy in AML, as demonstrated by the lowest rates of relapse in all clinical studies. The donor categories of allo-HCT consist of HLA-identical sibling donor, matched unrelated donor (MUD), genetically haploidentical donor, and umbilical cord donor. Probably the HLA-identical sibling donor is the first-line and preferred choice, because other three choices might have higher rates of mortality and morbidity associated with GVHD (graft-versus-host disease). Although there is a substantial transplantation-related mortality of 15% to 20% with allo-HCT, the reduction in the relapse rate significantly outweighs the transplantation-associated risk.

In AML patients, it is clear that fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. So to obtain CR before transplantation in AML is a rule (see post “The Management of Myelodysplastic Syndromes”). However, in relapsed AML, patients with CR1 less than 6 months have less than 20% of likelihood to achieve CR2, where we would elect to proceed to an transplantation in an untreated first relapse. But there is a expection, it is older individuals with relapsed AML, more than or equal to 60 to 65 years. In these patients a RIC often is the preferred conditioning regimen before transplantation, but the likelihood of a cure when transplantation a patient with elevated blasts with RIC is low, where our own preference in this case would be to administer one cycle of induction therapy in an attempt to obtain a better control of the disease before transplantaion.

However, not all patients with AML should undergo hematopoietic cell transplantation. Patients whose leukemia cells expressing more favorable mutations with normal karyotype at diagnosis such as mutation of NPM1 or CEBPA have a more favorable outcome and may not benefit from an allo-HCT. These patients should not undergo allo-HCT.

Table 3. Suggested indications for allo-HSCT

If there is no HLA-identical sibling donor, MUD donor, genetically haploidentical donor, or umbilical cord donor could be the alternative approach. But, a recent study showed that there was an increased replase rate in MUD transplantation for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation.

There was an increased relapse rate in MUD transplantations for AML patients in CR1 and the leukemia-free survival was also significantly improved for patients receiving a sibling transplantation. Although the presence of GVHD is associated with reduced relapse of AML, it dose not appear that such an effect is dependent on the degree of genetic disparity and the best donor remains the most closely matched donor.

If allo-HCT is chosen, a fully myeloablative conditioning regimen is appropriate and the reduced-intensity conditioning (RIC) regimen should be reserved for older patients or those with significant comorbidities. The transplantion should be underwent immediately after the CR1 without any consolidation chemotherapy. 2 retrospective analyses from large international registries suggest that there is no benefit to adding any consolidation therapy before an allo-HCT. Also the allo-HCT transplantation should not be delayed or reserved until the patient has a event of relapse. Delaying transplantation until after relapse is a misleading strategy.

In the majority of major prospective studies published over the past decade, a lower relapse rate was reported for patients undergoing an autologous transplantation compared with chemotherapy. If autologous transplantation is chosen, the patient should receive 2 cycles of consolidation therapy with high-dose cytarabine (3g/m2 given every 12 hours on days 1, 3, and 5) followed by the transplantation. The rationale for using an autologous transplantation is based on the fundamental concept that the optimal approach to postremission therapy is based on the regimens with the most potent antileukemic activity, provided this effect is not abrogated by unacceptably high mortality. Currently, the mortality rate associated with an autologous transplantation is less than 2%, which results from the technology that collecting hematopoietic cells from the peripheral blood. Of note, if the patient is in the poor-risk group, autologous transplantation should be avoided. I think the reason is associated the unfavorable cytogenetic mutations or karyotype.

One point must be emphasized that if the patient dosen’t achieve CR after the first induction course (i.e., the patient dosen’t clear his/her blasts in bone marrow by day 14 after the first induction therapy) but subsequently achieve CR after the second induction therapy, the prognosis is similar to those achieving CR with one cycle of induction. Thus, the postremission strategy should not be altered if the patient eventually responds successfully to the induction therapy.

Table 4. Response Criteria in AML

Blood 2009; 115: 453-574

Hematological Emergencies

Patients with initial AML may experience hyperleukocytosis which could result in leukostasis (when the WBC > 200 × 109/L) and therefore potentially lethal central nervous system and pulmonary complications. The optimal emergent management is uncertain, and one approach is to initiate immediate induction thearpy. An alternative strategy consists of daily leukapheresis with the concurrent administration of hydroxyurea at doses of 2 to 6 g/day. Generally, some experts suggest this alternative approach and wait for the initiation of induction therapy until the WBC has fallen below 40 × 109/L to 50 × 109/L, they think that this approach would increase the likelihood of achieving CR with a single cycle of chemotherapy.

The issue of prophylaxis for the central nervous system is controversial in any patients with AML and is often considered in a patient who presents initially with a high WBC. The experts don’t recommend the prophylaxis routinely if in the absence of any symptoms related to the central nervous system.

Table 5. Outcome Measures in AML

Outcome Measures in AML

Quizartinib: Surprising, Unprecedented Activity in Relapsed AML

January 29, 2013 Chemotherapy, Drug Informatics, Hematology, Pharmacotherapy, Therapeutics No comments , , , ,

ATLANTA, Georgia — The investigational agent quizartinib (Astellas/Ambit) has shown unprecedented activity in patients with relapsed and refractory acute myeloid leukemia (AML) in a phase 2 clinical trial.

On the basis of these results, larger phase 3 clinical trials with the drug are being planned, according to Astellas/Ambit.

Patients with AML can develop many different genetic mutations, but one of the most threatening is FLT3 internal tandem duplications (ITD), which makes the leukemia even more aggressive and typically leads to resistance to standard chemotherapy. This mutation develops in 34% of AML patients and is associated with more rapid relapse and reduced overall survival, explained lead author Mark Levis, MD, PhD, associate professor of oncology, pharmacology, and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland.

“Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy,” he said. “It caught us by surprise how well it worked.”

Dr. Levis presented results from a large phase 2 study of patients with relapsed or refractory AML here at the American Society of Hematology (ASH) 54th Annual Meeting. Many patients achieved a complete response to quizartinib, and one third were stabilized with quizartinib for long enough to undergo potentially life-saving hematopoietic stem cell transplantation (HSCT).

“The number of patients bridged to a transplant was very significant,” Dr. Levis said in a statement. “We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible for patients who previously had no hope for a cure,” he added.

“I am desperate to get this drug in the clinic…. I treat mainly a refractory patient population, and this is the drug that I want to use in them,” he explained.

Patients with a FLT3 mutation present a “major management problem,” said ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada. “You can put them in remission, but then they relapse…and the disease progresses so quickly that they don’t get a chance for transplant and for cure,” he said.

“This study is important because it shows that quizartinib can stabilize these patients for long enough to do a transplant. It shows that this is possible in about a third of patients,” Dr. Keating reported. It is another example of a new drug offering fresh hope for a hard-to-heal patient population, he said at a premeeting press briefing.

Mutation Is Like a Power Switch

“The FTL3 mutation is essentially a power switch that leukemia cells use to spread more aggressively and helps them to grow back immediately after chemotherapy,” Dr. Levis explained. “The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long.”

Quizartinib appears to do just that. It was designed to “turn off” the mutated FLT3 enzyme, which forces the immature cancer cells to die immediately or to undergo maturation and then die. This eliminates enough cancer cells to stabilize the patient for long enough to offer them another treatment, including transplantation.

The phase 2 study of quizartinib was conducted in AML patients who had relapsed, did not respond to second-line therapy, or had relapsed after HSCT. The patients were divided into 2 groups: 133 were older than 60 years, and 137 were 18 to 60 years.

Dr. Levis presented data from the younger cohort. Of the 137 patients, 99 had the FLT3 mutation and 38 did not.

Oral quizartinib was used alone at a starting dose of 135 mg/day for men and 90 mg/day for women, and was given continuously in 28-day cycles. The difference in the dose between the sexes relates to an adverse cardiac effect of the drug; quizartinib can cause a prolongation of the QT interval on electrocardiogram, and women are more sensitive to this effect than men, Dr. Levis explained.

The drug elicited responses in patients with and without the mutation, but the responses were better in those with the mutation. The primary end point was a composite complete remission rate (CR), which included complete remission with no active disease, complete remission with incomplete platelet recovery (so no active disease but an incomplete platelet count), and complete remission with incomplete hematologic recovery (no active disease but abnormal red and white blood cells counts).

For the 99 patients who had the FLT3 mutation, the composite CR was 44% (4% with CR, 0% with incomplete platelet recovery, and 40% with incomplete hematologic recovery). The median duration of response was 11.3 weeks and median overall survival was 23.1 weeks.

For the 38 patients without the mutation, the composite CR was 34% (3% with CR, 3% with incomplete platelet recovery, and 29% with incomplete hematologic recovery). The median duration of response was 5.0 weeks and median overall survival 25.6 weeks.

Of the 137 patients 18 to 60 years of age, 47 (34%) underwent HSCT after responding to quizartinib. Some of these patients have survived more than 2 years without any disease recurrence, Dr. Levis said.

Adverse events included nausea (reported by 38% of patients), anemia (29%), QT prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). Adverse events led to discontinuation of treatment in 10% of patients.

Quizartinib was “extremely well tolerated,” Dr. Levis noted. The main adverse events are the QT prolongation and myelosuppression, but these are “manageable,” he said.
“We are still playing around with the dose,” he explained. A future trial will look at using lower doses of the drug, and a randomized trial of 30 mg vs 60 mg is planned.

The findings from this phase 2 trial of quizartinib in patients with relapsed and refractory AML are “especially encouraging,” said Jorge Cortes, MD, deputy chair in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, in a statement. “In the patients with the FLT3-ITD mutation, quizartinib represents the most active single agent we have observed with any class of investigational drugs in this challenging patient population,” he added.

The study was funded by Astellas/Ambit, the developers of quizartinib. Dr. Levis reports consultancy for Ambit Biosciences. Several of his coauthors are company employees. Dr. Keating reports serving on the data safety monitoring board for Clavis, Novartis, and Pfizer.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 673. Presented December 10, 2012.

Novel Approaches to the Treatment of Acute Myeloid Leukemia

August 14, 2012 Chemotherapy, Cytogenetics, Hematology, Therapeutics No comments , , , , , ,

Morphology of AML.

Yesterday and today I read an literature by Gail J. Roboz in the Education Program Book by American Society of Hematology (ASH), which is named “Hematology” and published annually by the ASH in one volume per year. The name is “Novel Approaches to the Treatment of Acute Myeloid Leukemia”. In this article the author discussed several aspects of Acute Myeloid Leukemia (AML) including: the general, the chemotherapy regimen, the stem cell transplantation, and the prognostic of AML. Now let’s get into this article.

In the introduction section. Approximately 12,000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, with a median age of 67 years. Despite advances in therapeutics and supportive care, the majority of patients with AML die from their disease. But among the subtypes acute promyelocytic leukemia (APL) is an important exception to the general statement of AML. In this subtype >75% of patients are cured with a combination of anthracycline-based chemotherapy, all-trans retinoic acid, and arsenic trioxide. For some APL patients, it is possible to eliminate cytotoxic chemotherapy altogether and to achieve cure with arsenic and all-trans retinoic acid alone. In this article we don’t discuss this subtype of AML in detail.

For all other subtypes of AML, the mainstay of initial treatment was developed nearly 40 years ago as a combination of cytosine arabinoside (ara-C) with an anthracycline, and this regimen remains the worldwide standard of care. Without stem cell transplantation, the age of patients is an in dependent major determinant indicator of the prognostic. For patients <60 years of age approximately 70%-80% of those will achieve complete remission, but most ultimately relapse and overall survival is only 40%-45% at 5 years. Among patients >60 years of age, 40%-50% of those with a good performance status can achieve complete remission, but cure rates are <10% and median survival is <1 year. Later in another section we will discuss the older AML patients in detail.

Advances in genomics technologies have identified AML as a genetically highly heterogeneous disease. As the technologies is well developed today, we are able to assign AML patients to many subgroups based on their molecular genetic defects. First we can assign AML patients to two subgroups which are cytogenetically normal and cytogenetically abnormal.

Cytogenetically normal patients comprise the largest subgroup of AML. This subgroup can now be further divided into a myriad of molecular subgroups too. Some subtypes of molecular genetic defects are know to have significant prognostic implications. For example, mutations in FLT3-ITD have been associated with an aggressive disease phenotype and poor outcomes. In contrast, patients with biallelic mutations in CEBPA and NPM1 without concomitant mutations in FLT3-ITD have significantly more favorable outcomes.

Also there is subgroup with abnormal cytogenetics. For example, mutations in KIT may negate the “favorable” classification previously associated with t(8;21).

Treatment of Acute Myeloid Leukemia

The treatment paradigm for AML generally includes remission induction, followed by consolidation with either 1-4 cycles of chemotherapy or stem cell transplantation.

The drugs for remission and consolidation have been variations on a theme of ara-C combined with an anthracycline or anthracenedione. In 1973 Yates et al first reported the result of a pilot trial of infusional cytarabine combined with daunorubicin in AML. The treatment was called “7&3 DNR 45” to indicate the dose of daunorubicin, 45 mg/m2. And there are many former studies to show the effects of the anthracyclines. There are five recommands for the treatment of AML.

  • Cumulative anthracycline dose for induction should be at least 180 mg/mof daunorubicin or 36 mg/m2 of idarubicin and consider daunorubicin 270 mg/m(It’s called intensive therapy, we will discuss about it later) for patients up to 65 years of age with a good performance status and adequate cardiac function.
  • Consider carefully if offering intensive consolidation to patients >60 years of age because this has not been shown to prolong survival and is associated with significant toxicity.
  • Refer potential transplantation candidates immediately at time of diagnosis to allow adequate time for donor identification and transplantation planning.
  • Age is not a major determinant of outcome after reduced intensity allogeneic transplantation; do not exclude patients on the basis of chronological age alone and refer older patients with good performance status early.
  • Almost every patient with AML should be considered for a clinical trial, including those who are already in remission. (more…)