Napoleon Register Treatment Recommendation …...2015/06/30 · Page 7 of 32 duration in either...

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GERMAN INTERGROUP RECOMMENDATIONS ON THE DIAGNOSTIC

AND THERAPEUTIC MANAGEMENT OF

ACUTE PROMYELOCYTIC LEUKEMIA (APL)

Version: Final V3.0

30.06.2015

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Steering committee:

Prof. Dr. U. Platzbecker

Dresden, for the SAL group Universitätsklinikum Carl Gustav Carus Technische Universität Dresden Medizinische Klinik und Poliklinik I Fetscherstr. 74 01307 Dresden, e‐mail: uwe.platzbecker@uniklinikum‐dresden.de

PD Dr. E. Lengfelder

Mannheim, for the AML‐CG group Universitätsklinikum Mannheim der Universität Heidelberg III. Medizinische Klinik Hämatologie und Internistische Onkologie Theodor‐Kutzer‐Ufer 1‐3 68167 Mannheim, e‐mail: [email protected]

Prof. Dr. R. F. Schlenk

Ulm, for the AML‐SG group Universitätsklinikum Ulm Klinik für Innere Medizin III Albert‐Einstein‐Allee 23 89081 Ulm, e‐mail: Richard.Schlenk@uniklinik‐ulm.de

Review committee:

Prof. Dr. M. Bornhäuser

PD Dr. Ch. Röllig

Prof. Dr. G. Ehninger

Universitätsklinikum Carl Gustav Carus Dresden

Medizinische Klinik und Poliklinik 1

Prof. Dr. H. Serve Klinikum der J.W. Goethe‐Universität, Medizinische Klinik II

Prof. Dr. H. Döhner

Prof. Dr. K. Döhner

Universitätsklinikum Ulm

Klinik für Innere Medizin III

Prof. Dr. M. Lübbert Universitätsklinikum Freiburg, Medizinische Klinik 1

Prof. Dr. U. Germing Heinrich‐Heine Universität Düsseldorf

Klinik für Hämatologie, Onkologie u. Klinische Immunologie

Prof. Dr. D. Niederwieser Universitätsklinikum Leipzig

Abteilung für Hämatologie und Internistische Onkologie

Prof. Dr. W. Hiddemann

Prof. Dr. K. Spiekermann

Klinikum der Universität München, Campus Großhadern Medizinische Klinik und Poliklinik III

Prof. Dr. A. Ganser Klinik für Hämatologie und Onkologie, Medizinische Hochschule Hannover

Prof. Dr. T. Büchner

Prof. Dr. W. Berdel

Universitätsklinikum Münster

Medizinische Klinik A

Prof. Dr. F. Lo‐Coco University of Tor Vergata Rome, Italy

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Glossary

AML acute myeloid leukemia

APL acute promyelocytic leukemia

aPTT activated partial prothrombin

time

Ara‐C cytarabine

ATO arsenic trioxide

ATRA all‐trans retinoic acid

BMP Bone marrow puncture

CD cluster of differentiation

CR complete remission

CRF Case report forms

CRm molecular complete remission

DIC disseminated intravascular

coagulation

FAB French‐American‐British

classification

FISH fluorescence in‐situ

hybridization

Gpt gigaparticles

hCR hematological complete

remission

ITD internal tandem duplication

MRD minimal residual disease

NUMA nuclear mitotic apparatus

OS overall survival

PML‐

RAR promyelocytic retinoid acid

receptor

POX peroxidase

QoL/

QLQ

quality of life/ quality of life

questionnaire

RDM molecular resistant disease

RT‐PCR reverse transcriptase

polymerase chain reaction

HSCT hematopoietic stem cell

transplantation

WBC white blood counts

WHO World Health Organization

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TABLE OF CONTENT

1 DIAGNOSTIC AND THERAPEUTIC MANAGEMENT OF PATIENTS WITH APL ................................ 5

1.1 Definition of APL ............................................................................................................... 5

1.2 Diagnostics of APL ............................................................................................................ 5

1.3 Therapeutic approaches in APL ......................................................................................... 6 1.3.1 ATRA-based induction therapy ...................................................................................................... 6 1.3.2 Consolidation therapy ................................................................................................................... 7 1.3.3 Maintenance therapy ..................................................................................................................... 7 1.3.4 Treatment of minimal residual disease (MRD) or relapse ............................................................. 7 1.3.5 ATO in APL ................................................................................................................................... 8

1.4 Intergroup guidelines for the treatment of APL ................................................................. 8 1.4.1 Treatment recommendation for high-risk APL (WBC >10 Gpt/l at initial diagnosis) according to

AIDA ............................................................................................................................................ 11 1.4.1.1 Induction therapy (high-risk APL)5 .......................................................................................................... 11 1.4.1.2 Consolidation therapy (high-risk APL) ..................................................................................................... 11 1.4.1.3 Maintenance therapy (high-risk APL) ...................................................................................................... 13 1.4.1.4 Dose modifications ................................................................................................................................... 14

1.4.2 Treatment recommendation for non-high-risk APL (WBC ≤10 Gpt/l at initial diagnosis) according to AIDA ....................................................................................................................... 14

1.4.2.1 Induction therapy ...................................................................................................................................... 14 1.4.2.2 Consolidation therapy ............................................................................................................................... 15 1.4.2.3 Maintenance therapy ................................................................................................................................. 16 1.4.2.4 Dose modifications ................................................................................................................................... 16

1.4.3 Treatment recommendation for non-high-risk APL (WBC ≤10 Gpt/l at initial diagnosis) according to the APL0406 study .................................................................................................. 17

1.4.3.1 Induction therapy ...................................................................................................................................... 17 1.4.3.2 Consolidation therapy ............................................................................................................................... 18 1.4.3.3 Dose modifications ................................................................................................................................... 19

1.4.4 Salvage therapy ........................................................................................................................... 19 2 SUPPORTIVE MANAGEMENT OF APL ..................................................................................... 20

2.1 Treatment of leukocytosis .............................................................................................. 20

2.2 Treatment of coagulopathy............................................................................................. 20

2.3 Differentiation syndrome (formerly “ATRA syndrome”) .................................................. 21

2.4 Pseudotumor cerebri with ATRA therapy ........................................................................ 21

2.5 Hepatotoxicity with ATO/ATRA ....................................................................................... 21

2.6 QT prolongation with ATO therapy ................................................................................. 22

3 EVALUATION OF RESPONSE ................................................................................................... 23

3.1 Hematological remission criteria ..................................................................................... 23

3.2 Molecular remission criteria ........................................................................................... 23

4 DIAGNOSTIC EXAMINATION PROGRAM ................................................................................ 24

5 LITERATURE .......................................................................................................................... 27

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1 DIAGNOSTIC AND THERAPEUTIC MANAGEMENT OF PATIENTS WITH APL

1.1 Definition of APL

Acute promyelocytic leukemia (APL) is considered a rare disease with estimated 200 to 300

newly‐diagnosed cases per year in Germany. According to the FAB classification APL is

designated as"M3 leukemia" and assigned to the WHO defined type of AML with recurrent

cytogenetic abnormalities, "acute promyelocytic leukemia with t(15;17)(q22;q12),

(PML/RARα) and variants". Detection of PML‐RARα fusion is carried out by conventional

cytogenetics including fluorescence in situ hybridization (FISH) and/or RT‐PCR. Alternative

fusion partners are the zinc finger (PLZF), the nucleophosmin gene (NPM), the nuclear

mitotic apparatus (NUMA) or the STAT5b gene. These fusion partners may be of therapeutic

relevance, e.g. for the sensitivity to all‐trans‐retinoic‐acid (ATRA), which does not exist with

the involvement of the PZLF gene [t(11;17)(q23;q21)].

APL is often clinically characterized by the presence of coagulative abnormalities1, including

disseminated intravascular coagulation (DIC), hyperfibrinolysis and unspecific proteolysis.

In up to 45 % of cases mutations of the FLT3 gene with an internal tandem duplication (ITD)

of the juxtamembranous domain and point mutations in the tyrosine kinase domain II can be

detected2, although their independent prognostic impact has not been demonstrated. Both

mutations are correlated with higher leukocyte counts while a FLT3‐ITD mutation is

associated with the M3v subtype and the S‐type PML/RARαprotein.

In addition to age, the most important prognostic factor is the leucocyte count at diagnosis

which divides patients into a high risk (> 10 Gpt / l) and a non‐high‐risk group ( 10 Gpt / l). Through use of a risk‐guided therapeutic approach the outcome of patients within both

groups including risk of relapse has become almost comparable3‐5.

1.2 Diagnostics of APL

The vast majority of APL cases mostly display a characteristic abnormal hypergranulation of

blasts6‐8. The nuclei of the cells vary in shape and size, being often bilobulated and kidney‐

shaped. Cytoplasm of the cells is completely filled with densed and partially condensed

granulation. In some cells the cytoplasm is filled with dust granulation. Cells with

characteristic bundles of Auer rods are found in the bone marrow or in the peripheral blood,

the so called Faggot‐cells. The M3v, however, contains fewer cells with hypergranulations or

bundles of Auer rods. Hypergranulated promyelocytes strongly react with POX, SSB und

chloracetate esterase. The expression of CD33, CD117 and absence of HLA‐DR and CD34 on

the surface of APL blasts is characteristic of the disease.

The t(15;17) translocation and the respective PML‐RARfusion transcript are diagnostically conclusive and represent definitive hallmarks of APL diagnosis7‐9. According to the current

WHO classification cases with specific cytogenetic and molecular genetic aberrations e.g.

t(15;17)(q22;q11‐12) resulting in the fusion transcript PML/RAR‐ are classified as AML

independently of the percentage of blasts in the bone marrow and peripheral blood9.

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The molecular analysis for the detection of the promyelocytic retinoic acid receptor (PML‐

RAR ) fusiongene is carried out by a reverse transcriptase‐polymerase chain reaction (RT‐

PCR). This method provides a fast and a highly sensitive verification of the initial diagnosis

and of minimal residual disease (MRD) in the course of APL therapy. The results of several

independent studies have shown that a positive detection of PCR transcripts for PML‐RAR hybrid gene during cytomorphological remission within consolidation cycles is a predictive

factor for an early hematological recurrence, whereas an abiding negative PCR in the bone

marrow is usually associated with long‐term survival and cure after therapy (also in patients

with relapse)10;11.

1.3 Therapeutic approaches in APL

APL disease must be classified as an emergency with immediate initiation of supportive

therapy. In the case of morphological and clinical suspicion of APL, therapy must be started

immediately before a genetic diagnosis is available because of the potential lethal

complications and the possibility of a curative therapy. Prior to therapy a bone marrow and

blood diagnostic is essential. First‐line treatment recommendations differ for patients of the

high‐risk group and the non‐high‐risk group according to the Sanz Score which are defined as

follows5:

WBC in high‐risk group WBC in non‐high‐risk group

> 10 Gpt / l 10 Gpt / l

1.3.1 ATRA‐based induction therapy

Anthracycline and Ara‐C‐based combination chemotherapy were used until the 1980s and

complete remission rates (CR) of up to 80 % were achieved. However, disease recurrences

were observed in two thirds of the patients. Furthermore, this therapy was associated with a

high rate of early death due to toxicity and bleeding12‐15.

The introduction of all‐trans retinoic acid (ATRA) significantly changed therapeutic success in

APL patients. ATRA causes differentiation of abnormal promyelocytes to mature neutrophils

in vitro and in vivo. Complete remission rates were achieved with single agent ATRA in up to

80‐90 % of newly‐diagnosed and relapsed patients with APL16‐21. Furthermore, ATRA rapidly

alleviates the disturbed coagulation cascade. However, the accelerated differentiation to

mature neutrophils often induces a rapid increase of leukocytes. In fact, in 15‐20 % of

patients an ATRA‐ or better “differentiation‐syndrome” can occur which is associated with a

high mortality rate22‐25.

The duration of remission with single agent ATRA therapy however was often not

enduring16;17. Therefore, concepts with combined and concomitant administration of ATRA

and intensive chemotherapy were explored26;27. These studies consistently showed a higher

CR rate (>95 %) compared to conventional chemotherapy as well as prolonged remission

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duration in either randomized or historical comparisons28‐37. The most widely used

combination for induction therapy irrespective of APL risk is the combination of ATRA plus

Idarubicin (AIDA).

1.3.2 Consolidation therapy

Molecular remissions can be achieved in more than 90 % of patients if at least two

anthracycline‐containing consolidation therapies are used. Therefore, this is considered the

present therapeutic standard for all patients with APL in CR after induction chemotherapy38.

There is no comparative study on the efficacy of ATRA in addition to chemotherapy during

consolidation. However, historical comparisons have demonstrated that incorporation of

ATRA contributed to improved outcome27;39.

The role of Ara‐C in APL has long been controversial. However, comparative cohort studies in

high‐risk patients (WBC > 10 Gpt / l) show a clearly positive effect with a significant higher

remission rate, better disease‐free and overall survival rate in favour of Ara‐C‐based therapy

during consolidation6;27;35.

1.3.3 Maintenance therapy

In the European APL‐93 study it was shown that a three‐fold maintenance therapy with

ATRA, 6‐mercaptopurine and methotrexate results in a lower recurrence rate, especially in

patients with high white blood cell count at diagnosis. However, this study did not differ

between patients according to the PCR‐status after consolidation31. Furthermore, no

advantage of maintenance therapy in patients who tested negative after consolidation was

observed by the Italian GIMEMA group40. Therefore, maintenance therapy is based on a

relatively low level of evidence. Despite these controversial results, maintenance therapy is

still included in the most ATRA‐plus‐chemotherapy‐based protocols.

Due to the high cure rate with ATRA and chemotherapy in APL, there is no indication for

hematopoietic stem cell transplantation (HSCT) in patients who are in first molecular

remission after completion of consolidation therapy.

1.3.4 Treatment of minimal residual disease (MRD) or relapse

Despite successful first‐line treatment approximately 10‐15 % of patients relapse. In case of

persistence of minimal residual disease (MRD) with PML/RARa detection or molecular or

hematological relapse, treatment with arsenic trioxide (ATO) +/‐ ATRA for induction and

consolidation therapy is the treatment of choice. This should be followed by further post

consolidation therapy. Autologous HSCT after high‐dose therapy probably contributes to the

stabilization of remission, provided that PML/RARα is negative by PCR in the autologous

graft and in the patient bone marrow prior to transplantation41‐46. In patients not achieving

clearance of MRD by conventional therapy including ATO an allogeneic HSCT should be

considered.

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1.3.5 ATO in APL

ATO is the most effective single agent in APL47. ATO acts via complex mechanism in APL that

is not yet fully explained. At a high concentration (0.5 to 2.0 μmol/l) ATO induces apoptosis

in vitro, while at lower concentrations (0.1 to 0.5 μmol/l) it induces partial differentiation of

leukemic promyelocytes through PML/RARα degradation and inhibits angiogenesis48‐51.

ATO is licensed for the treatment of relapsed and refractory APL in the USA and

Europe44;45;52‐58 and can achieve remission rates in up to 90 % of patients. Concerning its

toxicity profile, ATO is usually well tolerated and its use is associated with a series of

manageable adverse events (hyperleucocytosis, increase of liver enzymes, APL

differentiation syndrome, prolongation of the QT interval59). Most of the adverse events

mentioned above are usually mild and manageable44;58.

The antileukemic efficiency of ATO is increased when combined with ATRA. ATO as single

agent is able to induce durable molecular remission after two cycles in the majority of

patients treated for disease recurrence57. Results of various studies conducted with ATO as

single agent or combined with ATRA for newly diagnosed APL patients reported CR rates of

86‐95 %, molecular remission rates after two cycles of 76‐100 % and survival rates of 86‐

88 %, with significantly better responses being obtained in patients with non‐high risk

disease as compared to high‐risk patients60‐64. Recent data of the APL0406 – Intergroup

Study (GIMEMA – AML‐SG/SAL) showed that ATO plus ATRA is at least as effective as AIDA‐

based therapy as first‐line treatment in non‐high risk APL patients65. In particular, early

mortality was almost absent in the experimental treatment arm combining ATO and ATRA. In

addition, the results of a recent published randomized trial evaluating ATO in first‐line

therapy during consolidation demonstrated that ATO further reduced the risk of recurrence

and improved survival66.

1.4 Intergroup guidelines for the treatment of APL

APL is a highly curable malignancy. Once regarded as the most aggressive and rapidly fatal

human leukemia, APL has become over the past 2 decades a curable disease, with more than

80% of patients now being long‐term survivors. However, treatment of APL is still

challenging, in particular during induction therapy, and high rates of cure can only be

achieved in centers with well trained staff. Therefore, treatment in highly specialized and

experienced centers is mandatory including standardized procedures. The recommendations

on APL diagnostics and therapy of newly diagnosed and relapsed APL are based on national

(http://www.dgho‐onkopedia.de/de/onkopedia/leitlinien/akute‐promyelozytaere‐

leukaemie) and European (ELN) guidelines38 (http://www.leukemia‐

net.org/content/leukemias/aml/apl/apl_recommendations/index_eng.html).

The detailed German intergroup treatment guidelines are provided below (Figure 1) and

depend on the leukocyte counts at initial diagnosis (see 1.3).

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FIGURE 1: OVERVIEW OF TREATMENT RECOMMENDATIONS FOR NEWLY DIAGNOSED APL

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FIGURE 2: OVERVIEW OF RECOMMENDATIONS FOR MOLECULAR RESISTANT OR RELAPSED PATIENTS

* for details of consolidation and postconsolidation therapy and list of options see ELN website:

http://www.leukemia‐net.org/content/leukemias/aml/apl/apl_recommendations/index_eng.html

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1.4.1 Treatment recommendation for high‐risk APL (WBC >10 Gpt/l at initial diagnosis)

according to AIDA

1.4.1.1 INDUCTION THERAPY (HIGH‐RISK APL)5

Standard induction therapy ‐ high‐risk APL

Drug Dose Route Administration Comments

ATRA 45 mg/m2 p.o. in two

single

doses

daily until CR, max. 60 days;

doses will be rounded‐up to next

10 mg increment

Idarubicin 12 mg/m2 i.v. day 1, 3, 5, 7 only 3 days in elderly and comorbid

patients

prophylaxis of APL differentiation syndrome with prednisone 0.5 mg / kg / day p.o. from

day 1 of ATO application to the end of induction therapy and possibly hydroxyurea (see

2.1) when leucocytes further raise up to > 10 Gpt / l

bone marrow puncture on day 28

induction therapy should be terminated on the basis of morphological criteria (if CR or

CRi is reached on day 28)

in case of not achieving CR or CRi on day 28, ATRA therapy should be continued up to

max. day 60 until terminal differentiation is reached; this should be accompanied by

serial bone marrow assessments to definitively demonstrate CR

cytogenetic and molecular assessment at the end of induction therapy has no value in

case of CR. Molecular responses should be assessed after consolidation only

1.4.1.2 CONSOLIDATION THERAPY (HIGH‐RISK APL)

After achieving a hematological CR after induction therapy, 3 courses of ATRA plus

chemotherapy are intended. Start of consolidation cycles is considered after hematological

recovery with neutrophils ≥ 1.0 Gpt / l and platelets ≥ 100 Gpt / l. In case of morphological

CR and regenerated blood counts, consolidation therapy should be started within 4 weeks

after documented CR. Each course of therapy should be initiated at hematological recovery

from the previous course. The PCR status after the end of consolidation is an important

stratification parameter for the subsequent therapy.

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1. Consolidation therapy ‐ high‐risk APL



single doses

days 1 ‐ 15 doses will be rounded‐up

to next 10 mg increment

Idarubicin 5 mg/m2 i.v. day 1, 2, 3, 4 prior to Ara‐C

administration

Ara‐C 1000 mg/m² i.v. over 3h day 1, 2, 3, 4 after the end of

Idarubicin




single doses



Mitoxantrone 10 mg/m2 i.v. day 1, 2, 3, 4, 5




single doses



Idarubicin 12 mg/m2 i.v. day 1 prior to Ara‐C

administration

Ara‐C 150 mg/m2/8h i.v. day 1, 2, 3, 4, 5

During all consolidation cycles (1‐3) the following diagnostics are recommended:

bone marrow samples should be collected with regenerated blood counts before the

start of second and third consolidation cycle as well as after the last consolidation cycle

and should be tested for morphology and by RT‐PCR for assessment of molecular

remission

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patients without molecular remission at the end of the entire consolidation program will

be considered as molecularly resistant (see 1.4.4)

Intracranial prophylaxis before each consolidation cycle is not recommended in general, but

may be considered in high risk patients, according to local guidelines.

1.4.1.3 MAINTENANCE THERAPY (HIGH‐RISK APL)

The clinical benefit of maintenance therapy is of lower evidence according to recent

studies28;33;40 and should be initiated only in patients who are in a molecular remission (PML‐

RARα‐negative in the bone marrow).

The start of maintenance therapy is one month (up to a maximum of 3 months) after

consolidation therapy if neutrophils are ≥ 1.0 Gpt / l and platelets are 100 Gpt / l. The duration of maintenance therapy is a total period of 2 years. During this time, patients

receive 7 courses with 6‐mercaptopurine and methotrexate (each lasting 3 month) and 6

courses of ATRA for 15 days.

The last cycle ends with the administration of 6‐mercaptopurine and methotrexate.

Maintenance therapy – high‐risk APL


6‐Mercaptopurine 50 mg/m2 p.o. daily (day 1‐91)

followed by 15

days of rest

for 7 cycles; rounded

down to the nearest

10 mg increment

Methotrexate 15 mg/m2 i.m./p.o. once weekly for

91 days followed

by 15 days of rest

for 7 cycles


single doses

daily for 15 days

(prior to day 1 or

after day 91)

every 3 month for a

total of 6 cycles;

during ATRA therapy

treatment break of

6‐MP und MTX

Consider cotrimoxazol as pneumocystis prophylaxis

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bone marrow samples should be collected with regenerated blood counts at the

beginning of each maintenance cycle as well as after the last maintenance cycle and

should be tested for morphology and by RT‐PCR for assessment of molecular remission

1.4.1.4 DOSE MODIFICATIONS

Dose modifications of ATRA and conventional chemotherapeutic agents (mitoxantrone, ida‐

rubicine, methothrexate and 6‐mercaptopurine) should be performed according to the

SMPC.

In case of ATRA‐induced non‐hematological toxicities (grade 3/4 according to CTCAE Version

4.0) the following dose modifications are recommended:

Dose level 0 (Start level) ‐1 ‐2 ‐3

ATRA [mg/m2] 45 37.5 25 20

In general, as soon as the symptoms and the patients’ clinical conditions improve, the treat‐

ment with conventional chemotherapeutic agents should be resumed at 50 % of the previ‐

ous dose. Thereafter, in the absence of worsening of the previous toxicity, conventional

chemotherapeutic agents should be resumed at full dosage. In the case of the reappearance

of symptoms, conventional chemotherapeutic agents should be reduced to the previous

dosage.

1.4.2 Treatment recommendation for non‐high‐risk APL (WBC ≤10 Gpt/l at initial

diagnosis) according to AIDA

1.4.2.1 INDUCTION THERAPY

The induction therapy will be conducted according to the treatment recommendations for

patients of the high‐risk group.

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Induction therapy ‐ non‐high‐risk APL



single doses

daily until CR, max. 60 days;


10 mg increment

Idarubicin 12 mg/m2 i.v. day 2,4,6, 8 only 3 days in elderly and

comorbid patients



2.1) when leucocytes raise up to > 10 Gpt / l




in case of not achieving CR or CRi on day 28, ATRA therapy should be continued up to





1.4.2.2 CONSOLIDATION THERAPY

After achieving a hematological CR after induction therapy, 3 courses of ATRA plus

chemotherapy are intended. Start of consolidation cycles is considered after hematological

recovery with neutrophils ≥ 1.0 Gpt / land platelets ≥ 100 Gpt / l. In case of morphological CR

and regenerated blood counts, consolidation therapy should be started within 4 weeks after

documented CR. Each course of therapy should be initiated at hematological recovery from

the previous course. The PCR status after the end of consolidation is an important


of 32

1. Consolidation therapy – non‐high‐risk APL



single doses

days 1 ‐ 15 doses will be rounded‐up to

next 10 mg increment

Idarubicin 5 mg/m2 i.v. day 1, 2, 3, 4




single doses



Mitoxantrone 10 mg/m2 i.v. day 1, 2, 3, 4, 5




single doses



Idarubicin 12 mg/m2 i.v. day 1



start of second and third consolidation cycle as well as after the last consolidation cycle

and should be tested for morphology and by RT‐PCR for assessment of molecular

remission


be considered as molecular resistant (see 1.4.4)

An intracranial prophylaxis before each consolidation cycle is not recommended in general.

1.4.2.3 MAINTENANCE THERAPY

Maintenance therapy is provided in section 1.4.1.3


Dose modifications are provided in section 1.4.1.4.

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1.4.3 Treatment recommendation for non‐high‐risk APL (WBC ≤10 Gpt/l at initial

diagnosis) according to the APL0406 study

Recently, the APL0406 study provided evidence that the combination of ATO and ATRA is at

least as effective as the AIDA regimen65, while sparing mainly hematological toxicity. In fact,

there was even an improvement in survival with the ATO/ATRA arm. Therefore, this regimen

was included here since physicians might consider it for their patients although ATO has only

marketing authorization in the EU for relapsed APL.

1.4.3.1 INDUCTION THERAPY

Induction therapy ‐ non‐high‐risk APL


ATO 0.15 mg/kg i.v. over 2 h daily starting on day 1; until CR, max. 60

days


single doses

daily starting on day 1; until CR, max. 60

days;


10 mg increment



2.1) when leucocytes raise up to > 10 Gpt / l




in case CR or CRi is not achieved by day 28, ATO/ATRA therapy should be continued up to





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1.4.3.2 CONSOLIDATION THERAPY

ATO/ATRA‐based induction therapy is followed by 4 courses of ATO/ATRA‐based

consolidation. Start of consolidation cycles is considered after hematological recovery with

neutrophils ≥ 1.0 Gpt / land platelets ≥ 100 Gpt / l. In case of morphological CR and

regenerated blood counts, consolidation therapy should be started within 4 weeks after

documented CR. Each course of therapy should be initiated at hematological recovery from

the previous course. The PCR status after the end of consolidation is an important


Consolidation therapy ‐ non‐high‐risk APL


ATO 0.15 mg/kg i.v. over 2 h daily for 5 days a

week; treatment

break on day 6

and 7

4 weeks on 4 weeks off for a total

of 4 courses;

last cycles will be administered on

week 25‐28


single doses

daily 14 days on, 14 days off for a total

of 7 courses;


10 mg increment

Dose‐modifications in case of toxicities (e.g. liver, QTc time) should be made according to

SmPC (attached in section 1.4.3.3).



start of second, third and fourth consolidation cycle as well as after the last consolidation

cycle and should be tested for morphology and by RT‐PCR for assessment of molecular

remission


be considered molecularly resistant and should be offered conventional chemotherapy

(e.g. AIDA) followed by an autologous or allogeneic HSCT (see figure 2).

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In case of non‐hematological toxicities (grade 3/4 toxicities according to CTCAE Version 4.0)

of ATO and ATRA (e.g. QT prolongation, differentiation syndrome, hepatotoxicity,

pseudotumor cerebri) the following dose modifications are recommended:

Dose level 0 (Start level) ‐1 ‐2 ‐3

ATO [mg/kg] 0.15 0.11 0.10 0.075

ATRA [mg/m2] 45 37.5 25 20

As soon as the symptoms and the patients’ clinical conditions improve, the treatment with

ATRA and/or ATO should be resumed at 50 % of the previous dose during the first 7 days

after the disappearance of the symptoms. Thereafter, in the absence of worsening of the

previous toxicity, ATRA and/or ATO should be resumed at full dosage. In the case of the re‐

appearance of symptoms, ATRA and ATO needs to be reduced to the previous dosage.

1.4.4 Salvage therapy

Patients with molecular resistance or relapse (hematological or molecular) should be treated

according to the European recommendation for salvage therapy of relapsed APL (Figure 2),

which is available via the website of the European LeukemiaNet (http://www.leukemia‐

net.org/content/leukemias/aml/apl/apl_recommendations/index_eng.html).

In fact, due to its high anti‐leukemic efficiency and low toxicity profile ATO is currently

considered to be the treatment of choice in molecular or hematological relapse of APL or

primary refractory patients. Concerning molecular or hematological relapse or persistence or

reappearance of PCR positive after frontline therapy with ATRA‐plus‐chemotherapy, an early

intensified ATO/ATRA‐based salvage is the treatment of choice. Usually induction therapy

should be performed by a course of ATO, followed by one to 4 cycles of consolidation and

should be combined with ATRA.

Whether this applies as well to patients with previous ATO exposure (e.g. within the

APL0406 study) is unknown. Limited data suggest a loss of efficacy of ATO salvage after ATO

frontline67. Therefore an ATRA‐plus‐chemotherapy‐based salvage (see 1.4.1.1) might be

considered. Patients with subsequent molecular remission in the bone marrow and the stem

cell graft probably benefit from an autologous transplantation while an allogeneic

transplantation should be performed in case of persistence of PML‐RARα MRD. However,

long term remissions are observed with prolonged ATO treatment as well.

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2 SUPPORTIVE MANAGEMENT OF APL

APL is an acute vital threat to the patient often caused by a severe plasma coagulation

disorder that can be increased by the introduction of conventional therapy68.

2.1 Treatment of leukocytosis

Guidelines for administering hydroxyurea in patients who develop sustained leukocytosis

(>10 x 109/l) after initiation of therapy are detailed below:

Hydroxyurea should be continued at a given dose to keep the WBC count <10 x 109/l and

subsequently tapered.

Recommendation for initiation of hydroxyurea:

WBC 10 – 50 x 109/l 500 mg four times a day

WBC > 50 x 109/l 1000 mg four times a day

2.2 Treatment of coagulopathy

The pathogenesis of hemorrhagic complications of APL is complex and in particular includes

factors of blood coagulation and fibrinolysis. The coagulopathy is biochemically conspicuous

manifesting as a severe hypofibrinogenemia, increased levels of fibrin degradation products,

a prolonged prothrombin time, a prolonged partial thromboplastin and thrombin time and

thrombocytopenia.

It must be noted that the combination with ATRA can result in a reversion of the clotting

disorder into a thrombophilic constellation with thromboembolic complications.

Administration of fibrinogen (2 g i.v.) is recommended if fibrinogen levels are below 1 g / l. In

case of unavailability of pure fibrinogen preparation, a substitution with fresh frozen plasma

(FFP) is indicated. We recommend to keep platelet counts around 30‐50 Gpt / l in the initial

phase of therapy and Hb‐values should be maintained at > 8 g/dl.

Treatment with tranexamic acid (antifibrinolytic agent such as cyklopkapron® 3 x 1000 mg

i.v. / d), fibrin‐stabilizing factor (Factor XIII, e.g. Fibrogammin® 1250 E) and AT III (e.g.

Cybernin® HS) at values below 50 % of normal range can be considered individually although

not supported by randomized trials69. The prophylactic administration of heparin has no

proven benefit.

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2.3 Differentiation syndrome (formerly “ATRA syndrome”)

During treatment with all‐trans retinoic acid (ATRA) and ATO a differentiation syndrome can

develop rapidly. It´s diagnosis should be clinically established by the presence of at least

three of the following signs, but it is suspected already at presence of only one symptom:

weight gain

respiratory distress

unexplained fever

interstitial pulmonary infiltrates

pleural or pericardial effusions with or without leukocytosis

No single sign or symptom may be considered per se as diagnostic for the syndrome. The

release of cytokines leads to this syndrome, which can become fatal if untreated. Prophylaxis

with prednisone is recommended.

In case of diagnosis of an APL differentiation syndrome the administration of APL therapy

should be stopped in time. Early transfer of patients to an ICU for improved monitoring of

vital signs should be considered. Immediate administration of dexamethasone (10 mg) i.v.

every 12 hours for at least 3 days should be started at the first suspicion and a concomitant

diuretic therapy are recommended until the disappearance of symptoms and signs. As soon

as the patients’ clinical condition improve and the symptoms have disappeared and the WBC

count is sustainably lowered to <10 x 109/l, the APL treatment with ATRA and/or ATO can be

resumed at 50 % of the previous dose during the first 7 days. Thereafter in the absence of

worsening of the previous toxicity, ATRA and/or ATO might be resumed at full dosage. In the

case of the reappearance of symptoms, ATRA and ATO will be reduced at the previous

dosage.

2.4 Pseudotumor cerebri with ATRA therapy

Particularly in younger patients a "pseudotumor cerebri" may occur during ATRA therapy,

manifesting by headaches, nausea, vomiting and blurred vision. It is recommended to

discontinue ATRA treatment temporarily and to administer opiates. As soon as the

symptoms and the patients’ clinical conditions improve, the treatment with ATRA will be

resumed at 50 % of the previous dose during the first 7 days after the amelioration of

pseudotumor cerebri. Thereafter, in the absence of worsening of the previous toxicity, ATRA

should be resumed at full dosage.

2.5 Hepatotoxicity with ATO/ATRA

Hepatotoxicity requires temporary suspension of ATRA and/or ATO. As soon as serum

bilirubin and/or SGOT and/or alkaline phosphatase have been reduced to < 4 times the

normal upper level, the treatment with ATRA and/or ATO will be resumed at 50 % of the

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previous dose during the first 7 days. Thereafter, in the absence of worsening of the

previous toxicity, ATRA and/or ATO should be resumed at full dosage.

2.6 QT prolongation with ATO therapy

Prolongation of the QT interval in the ECG has been observed during treatment with ATO.

This can lead to ventricular tachycardia (torsade de pointes) with a fatal outcome. In this

context, possible interaction with other drugs that prolong the QT interval must also be

taken into account. For this reason, close monitoring of the ECG and of the electrolytes is

necessary during treatment with ATO. In particular, the Mg++ and K+ levels should always be

kept in the high‐normal range, taking in consideration possible concomitant treatments that

deplete electrolyte levels (e.g. amphotericin B, furosemide etc.). In ECG the QT interval is

represented by the QRS complex, the ST segment and the T wave. Its measurement starts

from the deepest point of Q wave to the end of T wave. This interval greatly depends on the

heart rate and several formulas have been proposed to adjust the QT interval for heart rate

in order to obtain the corrected QT interval (QTc); however, no one of these proposed

formulas is satisfactory. Despite that, data from medical literature indicate that one of the

most simple method for adjusting the QT interval for heart rate is the Fridericia formula:

QTc = QT/cube root of RR

For increased accuracy, the QT interval should be measured on serial ECGs and several

successive beats and averaged for each ECG. The averaged QT value obtained should be

used in the above formula in which all measurement must be expressed in msec (i.e.: 0,470

sec=470msec). Applying this formula, a QTc interval > 500 msec must be considered

prolonged (both genders).

ATO should be discontinued together with any medication known to prolong the QTc

interval and electrolytes should be repleted. The time between discontinuing ATO and

normalization of the QTc interval may be several days. Once QTc is normalized, resume ATO

at 0.075 mg/Kg (50%) for the first 7 days, and then if no further prolongation occurs, resume

at 0.11 mg/Kg for a second week. Thereafter, if no prolongation occurs, resume ATO at full

dose.

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3 EVALUATION OF RESPONSE

For the evaluation of treatment response the following hematological and molecular

remission criteria are used as basis for the documentation sheet (CRF).

3.1 Hematological remission criteria

Hematological complete remission (CR)70

5 % blasts without atypical promyelocytes in the bone marrow

Neutrophils 1,0 Gpt/l

platelets 100 Gpt/l

Hematological incomplete remission (CRi)

5 % blasts without atypical promyelocytes in the bone marrow

Neutrophils < 1,0 Gpt/l

platelets < 100 Gpt/l

Non‐Response

≥ 5 % blasts and atypical promyelocytes up to 60 days after beginning of induction

therapy

Hematological Relapse

After a pre‐existing documented morphological CR there is a relapse if:

0,1 Gpt/l of blasts in the peripheral blood

percentage of blasts / atypical promyelocytes > 10 % in the bone marrow at any time

during follow‐up

meningeosis leucemica

bioptic verifiable extramedullary relapse

3.2 Molecular remission criteria

Molecular Complete Remission (CRm)

absence of the PML‐RAR hybrid transcript by RT‐PCR in bone marrow samples

Molecular Resistant Disease (RDm)

persistence of PML‐RAR hybrid transcript in the bone marrow cells at the end of the

last consolidation cycle

it should be always confirmed in two consecutive bone marrow samples taken 2

weeks apart

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Molecular relapse

conversion from RT‐PCR negative to positive PML‐RAR hybrid transcript in the bone marrow samples collected at any time after the 3rd consolidation cycle or

recurrent PML‐RARPCR‐positivity of two successive bone marrow samples in

distance of 2‐4 weeks after the last consolidation therapy

conversion/ relapse should be always confirmed in two consecutive bone marrow

samples taken 2 weeks apart

4 DIAGNOSTIC EXAMINATION PROGRAM

The general diagnosis of APL is based on the local standards. Close monitoring of the

following lab parameters should be carried out especially during induction therapy: Quick,

PTT, fibrinogen, hemoglobin, leukocytes, neutrophils, platelets, ATIII, factor XIII and D‐

dimers (depending on the severity of the bleeding disorders up to three times daily).

An ECG, echocardiographic examination (ejection fraction and valve abnormalities) is

recommended before each induction therapy and after completion of treatment.

Diagnostic examination schedule

Molecular analyses (PCR) and morphological analyses of the bone marrow and peripheral

blood are recommended

at initial diagnosis

after induction

prior to the second and following consolidation therapy

after the last consolidation therapy

quarterly during maintenance therapy

after therapy quarterly during a 5 year follow‐up from the start of therapy

suspicion of relapse

Cytogenetic and immunophenotype analyses should be performed at the initial diagnosis

and in suspicion of relapse.

For patients with a relapsed APL an equal sample collection is also recommended.

A detailed diagnostic examination schedule is below‐mentioned.

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Diagnosis/

or suspicion of relapse

during induction

day 28/ prior cons. 1

prior cons. 2 prior cons. 3prior cons. 4(if appropr.)

after last cons.

maintenance(if appropr.)

Follow‐up (1st ‐ 5th year)

Physical examination * (incl. comorbidities)

daily, including body weight * * * * * monthly

every 3 months

Blood Counts (1) *

daily during 1st

week, afterwards 3 x/week

* * * * * monthly every 3 months

BM for morphology * *(6) * * * * every 3 monthsevery 3 months

BM for molecular biology (2)

* * * * * * every 3 monthsevery 3 months

BM for cytogenetics *

BM for immunophenotyping (3)

*

Coagulation tests (4) *

daily until normalization, 2 x a week thereafter


Serum biochemistry (5) *

2‐3 x/ week during the first 3 weeks, then weekly until CR


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Diagnosis/

or suspicion of relapse

during induction

day 28/ prior cons. 1

prior cons. 2 prior cons. 3prior cons. 4(if appropr.)

after last cons.

maintenance(if appropr.)

Follow‐up (1st ‐ 5th year)

Electrocardiogram * * * * * * once ayear once ayear

Echocardiography (7) * * * * * * once a year once ayear

Urine analysis *

Hepatitis‐ and HIV‐serology *

ChestX‐ray *

Pregnancy test (if appropriate)

*

(1) haemoglobin, leukocytes, platelets, neutrophils, blasts

(2) PML‐RARA incl. isoforms, FLT3‐ITD, FLT3‐TKD

(3) HLA‐DR, CD2, CD7, CD9, CD11b, CD13, CD14, CD15, CD19, CD33, CD34, CD56, CD117

(4) Quick, aPTT, fibrinogen, factor XIII, AT III, and D‐dimers

(5) glucose, creatinine, uric acid, bilirubin, transaminases, alkaline phosphatase, LDH, sodium, potassium, calcium, phosphorus, magnesium, total proteins, albumin, cholesterol and triglycerides

(6) if not evaluable, repeat bone marrow on a serial basis until achievement of CR or failure

(7) incl. L‐VEF

FIGURE 3: DIAGNOSTIC EXAMINATION RECOMMMENDATION

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Further Literature

Link, H. Akute Promyelozytenleukämie: APL; M3‐Leukämie. ONKODIN 2008

http://www.onkodin.de/zms/content/e2/e51675/e53188/e54107/index_ger.html

Lengfelder, E.; Platzbecker, U.; Niederwieser, D.; Schlenk, R. F.; Wörmann, B.

Leitlinie Akute Promyelozyten Leukämie, Dokumentenstand Februar 2012

http://www.dgho‐onkopedia.de/de/onkopedia/leitlinien/akute‐promyelozytaere‐leukaemie

European PROMYSE registry for relapsed APL http://www.leukemia‐net.org/content/leukemias/aml/apl/apl_recommendations/index_eng.html

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