Acute Myeloid Leukemia Summary

Chemicals:

·         Extensive exposure to benzene containing compounds may lead to marrow damage that eventually can manifest as aplastic anemia, myelodysplasia or AML. Benzene is widely used in industry, particularly for organic synthesis and as a solvent and constitutes about 1% of unleaded gasoline.

Drug and therapy related leukemias:

	Causative agents
	Alkylating agents	Topoisomerase II inhibitors	Anthracyclines, mitoxantrone
Chromosome abnormality	Del(5q),-5	11q23	T(15;17)
	Del(7q),-7	21q22
Preleukemia phase	MDS	None	None
FAB morphology	Not classifiable	Usually M4, M5	M3
Latency	5-7 yrs	6 months to 3 yrs	2-3 yrs
Response to induction	Poor	Good	Good
Long term survival	Poor	Poor	Good

·         Among the alkylating agents; melphalan and nitrosoureas seems to be associated with increased risk

·         Patients with lymphoma who undergo autologous hematopoietic cell transplantation are at increased risk of leukemia, with a cumulative incidence as high as 10%

Biology:

·         The leukemia stem cell gives rise to progeny that fail to differentiate and continue to proliferate in an uncontrolled fashion, resulting in replacement of normal marrow by a clonal population of immature myeloid cells

·         The leukemic cell has discrete nuclear chromatin, multiple neucleoli, and azurophilic granules in the cytoplasm.

·         FAB classifications:

o   M0: Acute myeloblastic leukemia with no maturation

o   M1: Acute myeloblastic leukemia with minimal maturation

o   M2: Acute myeloblastic leukemia with maturation

o   M3: Acute promyelocytic leukemia

o   M4: Acute myelomonocytic leukemia

o   M5a: Acute monoblastic  leukemia

o   M5b: Acute monocytic leukemia

o   M6: Acute erythroid leukemia

o   M7: Acute megakaryoblastic leukemia

·         There is another more recent extensive classification called the WHO 2008 classifacation.

·         Stains for myeloperoxidase react specifically with FAB types M1, M2, M3 & M4 and fail to react with lymphoid leukemias.

·         Most AML express CD13, CD33, CD34, M5 express CD14, M6 express CD36, CD71, M7 express CD41a & CD61

·         Acquired abnormalities in chromosome number or structure is found involving all of the malignant cells, and are not found in healthy cells.

·         APL :

o   Always has a translocation involving the promyelcytic leukemia (PML) gene on chromosome 15 and retinoic acid receptor alpha gene (RAR-alpha) on chromosome 17, t (15; 17) (q22; q11-12).

o   The resultant abnormal fusion protein inhibits the transcription of genes needed for myeloid differentiation.

o   All-trans retinoic acid (ATRA) binds to the fusion protein, changing its configuration and permitting resumption of transcription.

·         Patients with M4 and abnormal eosinophilia often have an inversion in chromosome 16 (inv[16][q13q22])

·         Some patient with M2 have translocation between chromosomes 8 & 21, t(8;21)9q22;q22)

·         t(8;21) & inv(16) each account for 5-8% of AML cases, are more prominent among younger patients, and have a relatively favorable prognosis.

·         Some cases of t(8;21) & inv(16) also have mutations in the receptor tyrosine kinase gene KIT; such cases are associated with a less favorable outcome.

·         Trisomy 8 is seen in approximately 9% of AML cases and carries an intermediate prognosis

·         Risk categorization: (blood;2010;115; 453)

Favorable risk group	t(8;21), inv(16) , t (15; 17) Mutated NPM1 w/o FLT3-ITD Mutated CEBPA
Intermediate-1  risk group	Mutated NPM1 with FLT3-ITD Wild type NPM1 with FLT3-ITD Wild type NPM1 w/o FLT3-ITD
Intermediate-2 risk group	t(9;11) cytogenetic abnormality neither favorable nor adverse
Unfavorable risk group	Inv(3) t(6;9) t(v;11) Del(5q) or -5 Del(7q) or -7 Complex karyotypes Any monosomy

·         Nonrandom mutations undetectable by routine cytogenetics also have been identified and affect risk assessment and may guide therapy as (FLT3, NPM1, CEBPA)

·         FLT3 is a receptor tyrosine kinase and activating mutations in FLT3 have been found in 20-40% of cases

·         FLT3 mutations are more common in older patients and associated with higher blast count at diagnosis and less favorable response to therapy.

·         Mutations in the nucleophosmin gene (NPM1) have been indentified in 20-30% of AML cases (usually those with normal karyotype) and seem to be associated with a favorable clinical outcome.

·         CEBPA is a gene coding a leucine zipper transcription factor and is mutated in 4-15% of cases and is associated with a favorable prognosis.

Clinical features:

·         Most patients present with anemia and thrombocytopenia. The WBC may be elevated, normal or low but most patients will have granulocytopenia, and 1/3 will present with signs of substantial or life threatening infection

·         AML cells sometimes infiltrate the skin, causing a non-pruritic raised rash (leukemic cutis), or may collect in extramedullary masses (sometimes termed myeloid sarcomas or chloromas).

·         In 2-3% of cases, AML will involve the CNS at the time of diagnosis.

Treatment:

·         If untreated, AML results in death within several months.

·         Age and cytogenetics are the major prognostic factors in AML.

·         High WBC count at diagnosis is a poor prognostic factor.

Initial chemotherapy approach for young patients (<60yrs):

·         For 3 decades, the standard remission induction therapy is a combination of 3 days of an anthracycline (usually daunorubicin) and cytarabine (100-200 mg/m2 by continuous infusion) for 7 days.

·         With this regimen, complete remission (CR) can be expected in 60-80% of patients up to age 60.

·          1 randomized trial compared 3 days of daunorubicin at 45 mg/m2/day with 90 mg/m2/day, both combined with standard dose cytarabine (100 mg/m2), in pts < 6o yrs and found higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P = 0.003). The rates of serious adverse events were similar in the two groups. (NEJM 2009;361;1249)

·         Another randomized study compared daunorubicin at 50 mg/m2 for 5 days with idarubicin at 12 mg/m2 for 3 days, both combined with 7 days of standard dose cytarabine, in pts < 65 yrs and found equivalent outcomes. (blood 2011;117;2358)

·         Another study compared a standard dose of idarubicin combined with cytarabine at either 200 mg/m2/day by continuous infusion for 7 days or high dose cytarabine at 1000 mg/m2 over 3hr twice a day on days 1though 5. No difference in outcome was seen however more toxicities were seen in the high dose arm. (NEJM 2011;364;1027)

·         These studies taken together suggests relative equivalence of Idarubicin 12 mg/m2 for 3 days, Daunorubicin 90 mg/m2 for 3 days, Daunorubicin 50 mg/m2 for 5 days, and no obvious advantage for high dose cytarabine for AML induction.

·         Addition of Gemtuzumab to induction therapy showed survival benefit for young patients with favorable cytogenetics, no benefit for patients with poor-risk disease, and a trend for benefit in intermediate-risk patients. MRC AML15 Trial (JCO;2011;29;369)

·         There is no consistent evidence that adding any other drug, such as etoposide or thioguanine, improves outcomes.

·         Use of growth factor support can diminish the period of pancytopenia after induction chemotherapy, causing less hospitalization and anitmicrobial medications use but there is little evidence that growth factor support alters the remission rate or overall survival (results the same in young and elderly pts). (blood;1997;90;4710) (blood;1998;91;3607)

·         With standard induction regimen almost 50% of pts will have > 5% blasts in their marrow 1 week after last dose of chemotherapy (day 16 BMB). Most experts would recommend beginning a 2^nd cycle of induction. The presence of >5% blasts 1 week after last dose of chemotherapy is associated with reduced complete response rates and poorer overall survival.  The German AL cooperative group AMLCG 1992 trial. (blood;2003;101;64)

Chemotherapy after remission:

·         Large randomized trials have demonstrated that chemotherapy after remission improves DFS & OS. (blood;2010;115;453)

·         In a randomized trial, the median duration of remission was 4 months for patients who received no therapy after remission, and disease relapsed in all patients. (JCO;1988;6;583)

·         High-dose cytarabine:  A landmark study performed by Cancer and Leukemia Group B (CALGB) showed that 4 cycles of HiDAC (3 g/m2 per q12h on days 1, 3, and 5) are superior to 4 courses of intermediate- (400 mg/m2 continuous IV on days 1-5) or standard dose (100 mg/m2 continuous IV on days 1-5). The survival benefit was largely restricted patients with favorable-risk cytogenetics.

·         Other studies suggested relative equivalence of intermediate dose cytarabine (1 gm/m2 every 12 hrs for 6 days) and high dose cytarabine (3 gm/m2 every 12 hrs for 6 days).  (JCO;2011;29;2696)

·         Standard of care for younger patients who are not candidate for transplantation is treatment with multiple cycles of some form of intermediate or high dose Cytarabine.

·         Leukemia recurrence occurs in CNS in less than 10% of adults. The results of randomized trials have not found evidence that CNS prophylaxis improves either DFS or OS.

Initial chemotherapy approaches for older patients (>60yrs):

·         A trial comparing conventional dose daunorubicin (45 mg/m2/day for 3 days) with high dose daunorubicin (90 mg/m2/day for 3 days), both combined with conventional dose cytarabine as induction therapy in older patients, found that the high dose resulted in higher CR rate and improved survival. This advantage was largely limited to those patients age 60-65 and was not seen in pts > 65 yrs. (NEJM; 2009;361;1235)

·         Pts in both arms of the above mentioned trial, received one cycle of consolidation therapy using Cytarabine at a dose of 1000 mg/m2 every 12 hrs for 6 days. The higher doses of cytarabine that are used in younger pts frequently lead to neurotoxicity in older pts and should be avoided.

·         With high dose induction and cytarabine consolidation, event free survival for pts with AML >60 yrs is slightly <20% at 3 yrs from disease.

·         Patients > 75 yrs and those with poor performance have an increased likelihood of dying directly as a result of the toxicities of initial induction therapy.

·         A randomized trial demonestrated that low dose cytarabine (20 mg by SC injection twice daily for 10 consecutive days) was superior to hydroxyurea both in terms of complete response rates (18% vs 1%), duration of CR (80 wks vs 10 wks) and overall survival (OR 0.6%). (cancer; 2007;109;1114)

·         A recent phase II trial (SWOG s0703) tested a regimen consisting of hydroxyurea followed by azacitidine 75 mg/m2 for 7 days, and gemtuzumab ozogamicin, 3 mg/m2 on day 8, in older patients. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. Patients who are 70 yrs or older and have a performance status of 2-3 have a CR rate of 35%, 30 day mortality of 14%, median OS of 11 months. (Same group of pts in previous trials with 7+3 have a CR rate of 29%, 30 day mortality of 48%, median OS 4-9 months). For pts age 60-69 yrs or > 60yrs with performance status of 0-1 they have CR rates of 44%, 30 day mortality of 8% and median OS of 11 months. (Same group of pts in previous trials with 7+3 have a CR rates of 45% and a 30 day mortality rate of 17%). The toxicity with this regimen is much less that with conventional chemotherapy regimens. This can be the new standard of care for elderly pts with poor performance. (blood; 2013; 122:3432)

Treatment for resistant and recurrent disease:

·         Allogenic HCT is generally recommended for patients who don’t experience CR (primary induction failure) with initial induction chemotherapy. Although the post-transplantation relapse rate is high, the 20%-30% OS rate with allogenic HCT is better that what would be expected with further chemotherapy.

·         For patients who experience disease relapse after achieving CR, the likelihood of achieving a 2^nd CR is higher in pts with a long first remission, in those who are younger, and in those with favorable-risk cytogenetics.  (ICO 2005;23;1969)

·         Standard chemotherapy for recurrent disease has been retreatment with daunorubicin and cytarabine. This approach yields a 2^nd CR for 30%-50% of pts, with an average remission of 6 months. If the initial remission was longer than 18 months, the CR is higher (64% in one study) and the average duration of 2^nd remission is longer (8 months). If the 1^st CR is < 18 months, the chance of successful repeat induction is lower (averaging 25%), and the average duration of 2^nd remission is only 3 months. (Leukemia; 2000; 14;476)

·         Pts with a long initial remission should be retreated with intensive induction with either an anthracycline & cytarabine or cytarabine in high doses.

·         Pts with a short 1^st remission are candidates for alternative regimens, such as clofarabine, which is a purine nucleoside analog.  (blood;2003;102;2379)

·         Allogenic HCT should be strongly considered for pts who achieve a 2^nd CR by whatever means because it provides the best likelihood of long term remission.

Hematopoietic cell transplantation:

·         The following discussion of timing concerns HCT for patients younger than age 60.

·         If CR is not achieved with initial induction and the patient has an HLA-identical sibling, HCT should be considered as 20% of these patients become long term survivors, whereas 2^nd line chemotherapy offers almost no chance of cure.

·         Patients in whom 1^st remission is achieved, the choice of continuing with chemotherapy or having HCT is more difficult.

·         Systematic review and meta-analysis of prospective clinical trials of allogeneic HCT for AML in 1^st remission showed improved RFS & OS for patients with intermediate & poor risk and not for those with good risk. (JAMA; 2009;301;2349)

·         Prospective studies demonstrated a survival advantage with allogeneic HCT in 1^st remission for patients with FLT3 mutations with or without NPM1 mutation but not for those with normal karyotypes that are NPM1 mutated and FLT3 wild type. (NEJM; 2008;358;1909)

·         Allogeneic HCT from a matched sibling can be expected to result in a cure in 50% to 60% of patients undergoing transplantation in 1^st CR, while in untreated 1^st relapse and 2^nd remission result in cure of approximately 35%-40% of patients.

·         Because a 2^nd remission is achieved in approximately 50% of pts with AML who receive chemotherapy, and complications precluding subsequent transplantation occur in some of those pts, there seems to be a little advantage to administering additional chemotherapy or attempting to achieve a 2^nd remission before marrow transplantation if relapse is detected early and a transplant can be performed promptly.

·         The use of mobilized stem cells from peripheral blood has largely replaced marrow as the source of stem cells for autologous transplantation because of the ease of collection and quicker engraftment.

·         The use of peripheral blood stem cells for allogeneic transplantation from matched sibling, when compared with the use of marrow, is associated with more rapid engraftment, increase in chronic GVHD, decrease in relapse rates and a trend toward improved OS. (JCO:2005:23;5074)

·         Studies comparing peripheral blood with bone marrow for unrelated donor transplantation suggest equivalent survival but more chronic GVHD with peripheral blood stem cells.

·         HLA-identical sibling can be found in approximately 30% of cases.

·         The outcomes for transplantation using a fully matched (8 out of 8) unrelated donor and a matched sibling are similar. (Leukemia;2010;24;1276)

·         Results using a one antigen-mismatched unrelated donor are somewhat worse than with an 8 out of 8 match

·         The clearest indication for autologous transplantation for AML is disease in 2^nd remission. The results of several studies have demonstrated that 30% to 35% of patients will become long-term disease free survivors.

·         No prospective study has definitively shown an advantage of autologous transplantation in 2^nd remission compared with continued chemotherapy.

·         No prospective trials comparing autologous transplantation in 2^nd remission with allogeneic transplantation have been reported.

·         A meta-analysis of contemporary randomized trials of autologous transplantation in 1^st remission shows improved DFS but no OS advantage compared with chemotherapy. (leuk Res. 2004;28;605)

·         The preparative regimen should eradicate all disease; suppress the immune system adequately to permit sustained engraftment (in allogeneic setting).

·         Commonly used regimens include:

o    Cyclophosphamide 60 mg/kg for 2 days followed by total body irradiation (TBI) at dose of 10 Gy to 14 Gy over 3-6 days.

o   Cyclophosphamide 120 mg/kg with oral Busulfan 16 mg/kg.

·         GVHD affects the outcome of allogeneic HCT, resulting in both fewer relapses and increased non-leukemic deaths.

·         If the risk of recurrent leukemia is low, GVHD is likely to have a deleterious effect, but if the risk is high, mild disease may even be of some benefit.

·         The predictive factor for the development of GVHD is the degree of patient and donor matching.

·         The most widely used regimens for prevention of GVHD combine Methotrexate with either Cyclosporine or Tacrolimus.

·         The deletion of T cells in allogeneic bone marrow also is successful for decreasing the incidence of acute GVHD

·          Allogeneic transplantation using reduced intensity conditioning for older patients:

o   Trials demonstrate that with preparative regimens such as fludarabine plus low dose TBI, or fludarabine plus reduced dose Busulfan (with or without additional antithymocyte globulin), allogeneic engraftment can be consistently obtained.

o   Prelimenary results with reduced intensity transplantation from matched siblings or from matched unrelated donors for patients’ age 55 to 75 with AML in 1^st or 2^nd remission seem quite encouraging with DFS of 45% to 50% at 2 yrs and beyond. (JCO; 2010;28;2859)

o   If patients have active relapsed leukemia at the time of transplant, the results using reduced intensity conditioning are much less encouraging, with high post transplant relapse rates.

Acute promyelocytic leukemia:

·         Accounts for about 10% of all AML cases

·         Tend to be in younger patients (median age 30 to 40)

·         Overrepresented among Hispanic patients

·         Almost always presents with some of the following elements of a hemorrhagic syndrome, including hypofibrinogenemia, decreased normal coagulation factors, elevated fibrin degradation products, and increased platelet consumption. These finding are the results of both DIC as well as primary fibrinolysis

·         The leukemic blasts have the characteristic translocation t(15:17)(q22;q11.12)

·         ATRA as a single agent results in complete response rates of 80% or more for patients with recurrent disease.

·         Arsenic trioxide when used as a single agent, results in CR for 85% of patients with recurrent disease.

·         Randomized trials have demonstrated that the addition of ATRA to conventional chemotherapy improves complete response rates to approximately 90% and decreases the incidence of substantial bleeding complications.

·         A landmark phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (WBC, ≤10×109 per liter), showed ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy. (NEJM; 2013; 369;111) 

o   CR rate 100% vs 95%,

o   2yrs event free survival 97% vs 86%

o   2 yrs OS probability 99% vs 91%.

·         Another recent landmark phase 3, multicenter randomized trial comparing oral form of Arsenic (tetra-arsenic tetra-sulfide (As4S4) –containing formula named the Realgar-Indigo naturalis formula (RIF)) with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed APL. (JCO; 2013;31;33;4215)

o   DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group.

o   No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P=62)

o   overall survival at 3 years (99.1% v 96.6%; P=18

o   The rates of adverse events were similar in the two groups

·         With current therapies, survival at 3 yrs from diagnosis can be expected for > 85% of patients presenting with a white count of < 10K/mm3 & for 75% of those presenting with a white count of > 10K/mm3.

·         A small faction of patients with APL will have a different translocation, such as t(11;17) and a poor response to ATRA & Arsenic.

·         Differentiation syndrome: During induction therapy with ATRA or Arsenic trioxide, some patients will experience fever, weight gain, respiratory distress, pulmonary infiltrates, episodic hypotension, and renal failure. This condition is thought to be related to the sudden maturation of promyeloblasts and usually responds to Dexamethasone. (blood; 2000;95;90)

·         Treatment with Arsenic trioxide has been complicated by a prolongation of the QT interval and rarely by sudden death. Any electrolyte imbalances should be corrected, especially hypomagnesemia and hypocalcemia and drugs that can prolong the QT interval should be discontinued.

·         The suspicion of APL in a newly diagnosed patient with AML should trigger the immediate administration of ATRA to prevent early death.