TEACHING

1. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
َ‫م‬ْ‫ل‬ِ‫ع‬َ‫ال‬ َ‫ك‬َ‫ان‬َ‫ح‬ْ‫ب‬ُ‫س‬ْ‫ا‬‫و‬ُ‫ل‬‫ا‬َ‫ق‬َّ‫ل‬َ‫ع‬ ‫ا‬َ‫م‬َّ‫ال‬ِ‫إ‬‫ا‬َ‫ن‬َ‫ل‬َ‫ك‬َّ‫ن‬ِ‫إ‬‫ا‬َ‫ن‬َ‫ت‬ْ‫م‬
ُ‫يم‬ِ‫ك‬َ‫ح‬ْ‫ل‬‫ا‬ُ‫يم‬ِ‫ل‬َ‫ع‬ْ‫ل‬‫ا‬ َ‫نت‬َ‫أ‬
‫البقرة‬ ‫سورة‬(32)

2. Cytopenias &
TKIs
Dr Manal M Albessa
MD Hematology
Alexandria University, Egypt

3. Outlines
Introduction
Incidence of cytopenia
Pathogenesis of cytopenia in TKIs
Kinetics of cytopenias
Significance of cytopenias
Approach of management

4. CML and TKIs
Treatment and prognosis of CML has been radically changed with the
introduction of TKIs, the first example of highly effective target therapy in
hemato-oncology.
TKIs have significantly increased life-expectancy in CML patients, and
patients treated with imatinib, with longest follow-up, have a survival
close, if not equal, to that of general population.
Keskin D, et al. Eur Oncol Haematol. 2015;11(1):30–31.

5. CML and Quality of life
Since the life expectancy of CML patients has increased in the era
of the TKIs, physicians caring for CML patients started to face
another important issue – quality of life (QoL).
In order to improve QoL, monitoring for and managing adverse
events (AEs) promptly help in maintaining patients’ adherence to
TKI treatment and optimize patient outcomes
Kirkizlar O et al. Expert Review of Quality of Life in Cancer Care, 20171:5, 353-359

6. Most reports of TKIs in CML focus on efficacy, particularly on molecular
response and outcome. In contrast, infrequent publications about adverse
events (AEs).
Although, The attention to AEs has grown over recent years, our
understanding remains poor. We have no knowledge of why some (and not
all) patients develop particular AEs.
Giannoudis A, et al. Blood 2013; 121: 628–637
CML and TKIs adverse events

7. Cytopenias &TKIs
Cytopenias is a frequent AEs and likely to alter treatment course and
intensity for all TKIs.
While categorized as toxicity, cytopenias have been generally viewed as
a mixture of ‘response effect’ and undesired effect.

8. Cytopenia
Grading of toxicity
ADVERSE EVENT
GRADE
1
Of
2
Toxicity
3 4
Anemia LLN-10 gm/dL <10.0 -8.0g/dL 8.0-6.5 gm/dL <6.5 gm/dL
Neutropenia ≥1.5 - <2x109 /L ≥1.0 - <1.5 x109 /L ≥0.5 - < 1x109 /L <0.5 x109 /L
Thrombocytopenia LLN- 75x 109 /L ≥ 50.0 - < 75.0x109 /L ≥10.0 - < 50.0x109 /L < 10 x109 /L
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Publish Date: August 9, 2006

9. Incidence of cytopenias in TKIs
Data about Hematological toxicity of TKIs from different studies have been
reported , (in different disease phases (chronic phase CP or advanced disease), in
different lines of therapy and at doses) .
These data have been pooled together in order to offer a comprehensive
overview of hematologic toxicities.
Delphine R, Ann Hematol (2015) 94(Suppl 2):S149–S158

10. In1st line TKIs

11. 2nd line TKIs

12. 3rd line TKIs

13. Neutropenia is most frequent, followed by thrombocytopenia and
anemia.
Cytopenias occur in patients in whom TKI treatment is changed (resistance
or intolerance) tend to be more severe than in the first line setting.
Cytopenias is tightly correlated with disease phase, being more common
and more severe in advanced disease.
Cortes JE, et al. Blood , 2011, 118:4567–4576

14. Cytopenia & TKIs,
pathogenesis
After TKI-induced reduction of leukemic hematopoiesis, normal stem and
progenitor cells need time to recover from pre-existing suppression by the
malignant clone and to re-populate the bone marrow
Sneed TB, et al. Cancer 2004; 100: 116–121.

15. Thus, what makes cytopenias is an expression of efficacy rather than a true
toxicity :
1. Cytopenias is predominant at the initiation of treatment and decreases substantially
with longer exposures to any TKI.
2. It is rare once a remission has been achieved
3. Cytopenias as AE of TKIs are (mostly) dose dependent, reversible on treatment
cessation or dose reduction, and affect all three lineages to a variable degree.
Sneed TB, et al. Cancer 2004; 100: 116–121.

16. Off –target effect of TKIs
In addition, it is conceivable that ‘off-
target’ effects, such as the inhibition of
KIT, may inhibit the expansion of normal
hematopoiesis in the presence of drug.
Cytopenia & TKIs,
pathogenesis
M.J. Mauro et al. Best Practice & Research Clinical Haematology 22 (2009) 409–429

17. Kinetics of cytopenias
Hematological toxicity is almost always limited to the first weeks or
months of treatment but late cytopenias have also been observed
In CP CML patients, the peak incidence of cytopenias is within the first 4–
6 weeks after starting TKI treatment: the decline of platelets generally
occurs 1–2 weeks later than the decline in neutrophil count and
decreases substantially with longer exposures to any TKIs.
Baccarani M, et al. Blood 2013; 122: 872–884.

18. Consequences of cytopenias.
Hematologic toxicity may cause infection and bleeding, which can be fatal.
The reported incidence of febrile neutropenia in CP CML with different TKIs is
uncommon < 1%, whereas, deaths due to infection after dasatinib or imatinib
were 1.9% and 0.4%,
Although in the phase II trial reported neutropenic fever or severe sepsis in 6–
17% of BP CML patients.
Palandri F, et al. Haematologica, 2008 93:1792–1796

19. In the IRIS study, the incidence of bleeding at any grade was 20% in imatinib arm and the
incidence of severe bleeding was almost nil.
In second line therapy, the incidence of clinically relevant dasatinib-related bleeding was
25% and severe in 3%.
In second- and third-line treatment, deaths due to bleeding after dasatinib and nilotinib
were reported in 0.9% and 0.8% of patients, respectively,
O'Brien SG, et al. N Engl J Med 2003; 348: 994–1004. Saglio G, et al. N Engl J
Med 2010; 362: 2251–2259. Larson RA, et al. Leukemia 2012; 26: 2197–2203.

20. Consequences of cytopenias.
Persistent cytopenias might lead to dose modifications, treatment delays, and
therapeutic substitutions with next generation TKIs.
In reported trials, Severe and recurrent cytopenias is an adverse prognostic factor
for achieving a major cytogenetic response,
In particular, the combination of severe cytopenias and inadequate response to
treatment in CP has been associated with a high risk of transformation to
accelerated or blastic phase.
Marin D, et al. Leukemia 2003; 17: 1448–1453.

21. Thomas B et al; Cancer, 2004 100:116–121

22. Monitoring of cytopenias:
In CP CML, during the first 4–6 weeks, blood counts should be monitored weekly.
Later with stable count, the frequency can be reduced to every 2 weeks or monthly
until month 3. After month 3, monitoring every 3 months is advised.
More frequent monitoring is advised for patients with advanced disease.

23. General principles to the management of Cytopenias
First of all, Early recognition is crucial for optimal management,
without compromising treatment continuity.
Patient education on potential AEs and their time course is vital.
Grade 1 or 2 cytopenias does not require modification of therapy;
SteegmannJL m et al Leukemia (2016) 1648 – 1671

24. General principles for the management of cytopenias
In patients with high Sokal-risk CP, advanced disease or a failure to
respond to prior therapy, the leading consideration is to deliver dose
intensity, avoiding treatment interruptions and dose reductions to the
possible extent, with aggressive blood product and growth factor
support.
On the other side, a more conservative approach is indicated in
patients with good-risk disease.
SteegmannJL m et al. Leukemia (2016) 1648 – 1671

25. General principles for the management of cytopenias
For grade 3-4 anemia, iron profile, folate and vit B12,
correct nutritional deficiency and transfusion support for
symptomatic Patients.

26. For all TKIs in CP CML patients, in the case of grade 3 or 4 cytopenias, the drug
must be stopped at the first episode.
In the case of recurrence and depending on the duration of the first episode of
cytopenia, the drug must be restarted at a lower dose
Once a stable response has been achieved, re-escalation to the target dose
should be considered.
With recurrent grade 3–4 cytopenias, especially in first-line CP , switching to an
alternative TKI
In chronic phase CML

27. Follows the general concept of keeping a higher dose intensity TKI than for
CP.
BMA to DD persistence of leukemia from hypocellularity and to rule out BM
related causes
It is unclear whether continuing TKI treatment, despite myelosuppression,
improves the response rate or simply results in greater morbidity (infectious
and/or bleeding complications).
Advanced phase CML poses highly variable hematological and clinical
situations, and therefore the TKI dose management should be optimized
based on the individual characteristics of each case.
In Advanced Phase CML

30. Febrile neutropenia
If CP CML PT receiving TKI as first line with of grade 3 neutropenia, withhold
therapy, treat infection appropriately, and resume at a lower dose when the
grade resolves to ˂3.
The same strategy is recommended for grade 4, except that G-CSF should be
considered together with a switch to another TKI when the grade resolves to
˂3.
If the patient is in second line or in advanced phase, and switching options to
another TKI are limited, then a stepwise lowering of the dose is warranted.
SteegmannJL m et al Leukemia (2016) 1648 – 1671

31. Role of growth factors
G-CSF and erythropoietic stimulating agents ESAs can be used
transiently to facilitate neutrophil or hemoglobin recovery. The
concomitant use of G-CSF or erythropoietic agents with TKIs is
effective and does not associated with TKI failure or lower
response.
Jorgensen HG, t al. Cancer 2005; 103: 210–211.

32. Cross-intolerance:
Cross intolerance for cytopenias between TKIs has been observed,
Recurrence of grade 3–4 cytopenias after switching to second line
TKI seem to be more common with dasatinib (86%) than with
nilotinib (55%), but discontinuation due to recurrence of
hematological toxicity is similar (16% vs 23%).
Khoury HJ, et al. ASCO Meeting Abstracts 2008; 26(15_suppl): 7015

33. Home message
Cytopenias are a common AEs of TKIs in CML
Serious Infection and bleeding are infrequent but unaccepted,
Long-lasting and recurrent cytopenias resulting in prolonged or repeated
TKI interruptions and dose reductions may compromise TKI efficacy

34. Home message
Optimal management of patients on TKIs requires intimate
knowledge not only of response criteria but also of potential
toxicities, their basis, best approaches to avoid them, strategies to
manage them and how they may affect response to therapy.