Challenges and Advances in Managing ThrombocytopenicCancer Patients

1. Dr/ Marwa Mahmoud Khalifa , MD PHD
Damanhour Oncology Center

2. Agenda
 Magnitude of the problem
 Mechanisms of chemotherapy induced thrombocytopenia
 Challenges in managing cancer and thrombocytopenia
 Evaluating thrombocytopenic cancer patients
 Platelet Transfusion in CIT
 Role of thrombopoeitic agents

3.  Thrombocytopenia is a common problem in cancer
patients.
 A large observational study of 43,995 patients (62,072
chemotherapy regimens) showed the overall incidence
of chemotherapy-induced thrombocytopenia (CIT)
was 52% in patients with solid tumors treated with
four main regimens (platinum-based, anthracycline-
based, gemcitabine-based, and taxine-based).

4.  Cancer patients have varying incidence, depth and
duration of thrombocytopenia
 Depending on
Cancer type (hematologic al > non hematological
cancers, colorectal cancer, followed by non-small cell
lung cancer, and ovarian cancer)
Anticancer treatment (gemcitabine-based regimens,
platinum based regimens)
Bone marrow involvement
Comorbidities (fever, renal failure, liver dysfunction,
hematocrit < 25% and use of antithrombotic drugs)

5. Mechanisms of CIT

6. Challenges in managing cancer
and thrombocytopenia
 Currently, there are no standardized guidelines for the
prevention or treatment of CIT
 High rates of bleeding despite platelet transfusion
 Thrombocytopenia-driven anticancer treatment dose
reductions or delay
 Platelet-transfusion refractoriness
 Managing antithrombotic drugs when indicated.

7. Evaluating thrombocytopenic
cancer patients
 Is the underlying disease the cause of the
thrombocytopenia? Bone Mets / primary
hematologic malignancies
 Is there an associated ITP? secondary ITP
 Has there been a recent infection?

8. Evaluating thrombocytopenic
cancer patients
 Has the patient received a new medication? HIT/
antibiotics/ antiviral
 Has there been a recent transfusion? post-transfusion
purpura
 Does the patient have a coagulopathy? some tumors
(eg, gastric and pancreatic adenocarcinomas) can
produce chronic DIC

9. Platelet Transfusion in CIT
 Platelet transfusion is the fastest and most effective
treatment for severe CIT.
 However, as a rescue therapy, it is associated with
temporary effectiveness, unpredictable , adverse
reactions, and platelet refractoriness with repeated
administrations

10.  Platelet transfusions are indicated:
1- Prophylactically when platelets counts are <10 × 109/L
in hematologic malignancies and potentially higher
platelet thresholds < 20 × 109/L in some solid tumors
2- Therapeutically when bleeding occurs with platelets <
50 × 10 9/L

11. Recombinant Human Interleukin-11
(rhIL-11) (oprelvekin)
 rhIL-11 is the only platelet growth factor approved by
FDA for CIT.
 But its use is severely restricted by the narrow
therapeutic index and significant side effects including
edema and arrhythmia.

12. Recombinant Human Interleukin-11
(rhIL-11)
 So rhIL-11 must be used cautiously for cancer patients
with renal dysfunction or cardiac disease, especially
the elderly and not recommended for patients on
anthracycline-based chemotherapy.

13. Thrombopoietic agents
 Thrombopoietin (TPO) is the primary regulator of
megakaryocyte development and platelet production
 Endogenous TPO is the ligand of c-MPL receptor,
which is expressed on pluripotential stem cells,
progenitor cells, megakaryocytes, and platelets
 Thrombopoietic agents were designed to stimulate the
c-MPL receptor to promote megakaryocyte maturation
and platelet production.

14. Recombinant Human
Thrombopoietin (rhTPO)
 The rhTPO has been approved in China Food for CIT.
 Phase II/III clinical trials of rhTPO showed that
rhTPO was an effective agent for CIT (increase platelet
counts and reduce platelet transfusions) without
finding neutralizing antibodies.
 Adverse effects were primarily fatigue (0.78%), fever
(0.61%), and elevation of transaminase (0.52%).

15. Thrombopoietin receptor agonists
 Two TPO-RAs (romiplostim and eltrombopag) are
currently approved in patients with chronic ITP aged
>1-year who are refractory to at least one other
treatment and myelodysplastic syndrome.
 Eltrombopag has acquired two additional indications:
severe aplastic anemia refractory to first-line
treatment and hepatitis C patients undergoing
treatment with interferon-ribavirin
 However, they are not approved for use in preventing
or treating CIT outside of clinical trials

17.  In a case series of persistent CIT including 20 patients
with solid tumors and lymphoma, weekly romiplostim
achieved adequate platelet recovery in most patients
by two weeks, and allowed resumption of
chemotherapy without recurrence of CIT.

18.  Adverse events of romiplostim such as osteonecrosis,
thrombosis, rebound thrombocytopenia (after
stopping), and bone marrow fibrosis were reported in
some small trials

19. When CIT refractory to romiplostim treatment:
(1) bone marrow invasion
(2) prior pelvic irradiation
(3) prior temozolomide.
Additionally, the phase II romiplostim trial found
that 100% of patients with liver involvement from their
cancer responded to romiplostim.

20.  In a phase II study in patients with solid tumors who
received first-line carboplatin/ paclitaxel daily oral
eltrombopag 50 mg (N = 45), 75 mg (N = 45), and 100
mg (N = 46) for 10 days, platelet counts increased after
eltrombopag treatment compared with placebo , the
most common adverse events were nausea and
alopecia

21.  In a phase II randomized, placebo-controlled study of
patients with advanced solid tumors receiving
gemcitabine-based chemotherapy, eltrombopag
treatment shortened the time to platelet recovery and
reduced dose delays/reductions due to
thrombocytopenia.

22. To sum up,,,
 Despite the lack of US FDA approval for TPO RAs, they can
be considered in patients who cannot be supported by
platelet transfusions and for whom the maintenance of
dose intensity is crucial for remission or survival.
 In this setting, romiplostim at 2–3 µg/kg weekly, or 50–75
mg of eltrombopag daily to maintain platelet counts over
100,000/µL, in order to allow continuation of
chemotherapy.

23.  Thrombopoietin receptor agonists would be started
only when the patient’s platelet count had failed to
recover to levels > 100,000/µL before the next
scheduled chemotherapy.
 No significant adverse events have been associated
with the use of TPO-Rs to treat CIT

24. References
1- Leader A et al. J. Clin. Med. 2021, 10, 1169.
2- Zhang X et al. Cochrane Database of Systematic
Reviews 2017, Issue 11.
3- Shaw et al. Eur J Haematol. 2021;106:662–672.
4-Gerald A. J Clin Oncol 37:2892-2898.
5- Qiuhua Zhu. Front. Oncol. 2021, 11:701539.