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Disclosures of Francesco Rodeghiero

44° CONGRESSO NAZIONALE SIE Società Italiana di Ematologia

Verona, 20-23 ottobre 2013

Piastrinopenia immune

Francesco Rodeghiero

Dipartimento di Terapie Cellulari ed Ematologia Ospedale San Bortolo, Vicenza

44°Congresso Nazionale SIE Verona

20-23 Ottobre 2013

Clinical vignette A 32 yrs old woman is referred

§  Previous history

–  1 year before she had a healthy baby. During the last trimester of pregnancy plt count 105x109/L

–  No breast-feeding: start oral contraceptives. After 4 months unprovoked popliteal DVT: plt count 125x109/L; thrombophilia and APA screenings negative; LMWH started at 100 U/kg x 2/die.

–  2 months later cutaneous ecchymoses; 1 week before had taken amoxicillin for tonsillitis

§  Physical examination unremarkable, some petechiae and two small ecchymoses on the legs

§  Plt count 35x109/L. Hb and WBC normal

First things first

§  Exclusion of : –  Anti-phospholipid syndrome (APA) –  If excluded, reduce or stop LMWH

§  Then exclusion of: –  Heparin-induced thrombocytopenia –  Drug-induced thrombocytopenia –  Inherited thrombocytopenia

§  Consider primary or secondary ITP

§  In our case: APA negative and LMWH stopped

Heparin - induced thrombocytopenia

The 4 T pre-test probability of HIT §  0-3: low §  4-5: intermediate §  6-8 high

Lo GK et al, JTH 2006

Drug-induced TCP

A challenging clinical problem:

§  Underrecognized

§  Difficult to diagnose

§  Associated with severe bleeding complications (also death)

§  Unnecessary treatment

§  Diagnostic algorithms available

−  Arnold DM et al, Transfus Med Rev 2013 −  http://www.ouhsc.edu/platelets/ditp.html (J. George, Oklahoma Univ.)

Diagnosis: recommendations for the diagnosis of ITP in children and adults

(ICR - Provan et al, Blood 2010)

Basic evaluation Tests of potential utility Tests of unproven benefit

Patient/family history Glycoprotein-specific antibody TPO

Physical examination Antiphospholipid antibodies (including anticardiolipin and lupus anticoagulant) Reticulated platelets

Complete blood count and reticulocyte count Antithyroid antibodies and thyroid function PalgG

Peripheral blood film Pregnancy test in women of childbearing potential Bleeding time

Quantitative immunoglobulin level measurement* Antinuclear antibodies Platelet survival study

Bone marrow examination (in selected patients) Viral PCR for parvovirus and CMV Serum complement

Blood group (Rh) *Quantitative immunoglobulin level measurement should be considered in children with ITP and is recommended in those children with persistent or chronic ITP as part of reassessment evaluation **Recommended by the majority of the panel for adult patients regardless of geographic location

Direct antiglobulin test

H. Pylori**

HIV**

HCV**

Rh, rhesus; H. pylori, Helicobacter pylori; HIV, human immunodeficiency virus; HCV, hepatitis C virus; PCR, polymerase chain reaction; CMV, cytomegalovirus; TPO, thrombopoietin; PaIgG, platelet-associated immunoglobulin G

Diagnosis and initial treatment (3 days after first consultation)

§  Plt count 25x109/L

§  Diagnosis: newly diagnosed primary ITP

§  The patient refuses to be enrolled in the GIMEMA study standard deltacortene vs high dose dexamethasone

§  Treatment: deltacortene 1 mg/kg x 4 weeks, then tapering in another 4 weeks

§  Oral contraceptives stopped

§  No anticoagulation

10 months later: new consultation §  After initial response, the patient maintained plt count

> 100x109/L

§  For rapid development of skin and mucosal bleeding, plt count was done: 21x109/L - SMOG: S2M2O0 à persistent ITP

§  Patient anxious

§  Deltacortene restarted at standard dose, plt count increases to 100-120x109/L but falls down to ∼ 20x109/L after end of tapering

§  Diagnostic reevaluation: search for H pylori (urea breath test and stool) negative

In general, in persistent ITP one may consider also IVIg on demand, danazol, immunosuppressive tx, TPO-ra (off label)

§  S2M2O0 = > 10 petechiae in a palm-sized area and 2 small ecchymoses, and > 3 oral bullae, no organ bleeding

13 months from diagnosis Diagnosis: chronic primary ITP

IWG - Rodeghiero et al, Blood 2009

100% Initial Tx:

Corticosteroids IVIg

80% continue with initial or on demand Tx

Danazol? Immunosuppressants?

40% will require Tx

3 main options:

Rituximab (off label)

Splenectomy TPO-ra

(particular cases)

Up to 40% will stay in a therapeutic limbo

No data on their natural history

20% will not require further Tx

Main treatment options in ITP

Diagnosis

3 months

12 months

Chronic ITP or patients at high risk of bleeding not responsive to first line

treatment

§  Splenectomy?

§  Rituximab?

§  TPO-ra? (Nplate – romiplostim or Revolade – eltrombopag?)

§  Which sequence for the three approaches? –  Patients preferences

–  Patients’ risk profiles for bleeding (and thrombosis?)

–  Patients’ risk profiles for side effects

–  No clinical or laboratory marker is predictive of response

Splenectomy

§  A turning point in the management of ITP

§  Have new treatment options challenged the role of splenectomy?

Short and long term response in terms of plt count to splenectomy (Kojoury et al, Blood 2004)

Response All series

Series > 5 yrs follow up

CR + PR 88% CR 66% at 29 months

CR 64%

Relapse 15%

Median time to relapse 33 months

Mortality 0.2% - 1%

Risk of sepsis 0.7/1000 P/Y

Risk of thrombosis 1/1000 P/Y

Other morbidity 9.6% - 12.9%

Revision of 135 case series (1966-2004, 2622 adults)

Response duration after splenectomy 233 pts from 6 European Centers followed

for more than 10 years

Vianelli et al, Haematologica 2012

RFS was 67% for all responding patients, 73% for CR patients and 27% for R patients (p<0.001).

Negative consequences of splenectomy can be minimized by:

§  Vaccination against pneumococcus, meningococcus and haemophilus influenzae type b

§  Patient awareness and instruction

§  A protocol for early detection of spleno-portal vein thromboembolism

Rodeghiero et al, Br J Haematol 2012

Rituximab

Response duration to rituximab in adults whose initial response lasted at least 1 year

Patel et al, Blood 2012

Randomized, blinded, controlled trial in 7 centers in Canada – rituximab (n.32) vs placebo (n.26)

Arnold et al, Blood 2012

32 rituximab 26 placebo (saline)

Event = platelet count or bleeding or rescue tx

Eligible pts: not splenectomized, newly diagnosed or relapsed with plt count < 30x109/L, within 1 month from starting standard treatment were randomized 1:1 to receive either rituximab 375 mg/m2 x 4 wks or saline while continuing standard therapy

not significant

Randomized open label trial in 9 Danish centers rtx + dexa (62) vs dexa only (71)

Gudbrandsdottir et al, Blood 2013

Eligible pts: newly diagnosed, plt < 25x109/L or < 50x109/L if bleeding

Dexa 40 mg daily for 4 days + rtx 375 mg/m2 x 4 wks

Recruitment 2006-2011; in 2009 amendment allowing dexa to be repeated every 1 – 4 wks for up to 6 cycles in both arms

Sustained response at 6 months: 58% rtx+dexa vs 37% dexa (P=0.02)

Longer time-to-relapse and time-to-rescue treatment in rtx+dexa (P=0.03 – 0.07)

Splenectomies: 10% rtx+dexa vs 7% dexa

Increased grade 3-4 AEs in rtx+dexa

Short and long term toxicity of rituximab

§  First infusion reactions §  Serum sickness (5-10% in children) §  Rare complications

–  Fulminant hepatitis B –  Progressive multifocal leukoencephalopathy (PML) –  Failure to respond to vaccines (Nazi et al, Blood 2013)

§  Delayed neutropenia, hypogammaglobulinemia §  Severe infections (2.7%, 1.3% fatal) (Arnold et al, Ann Inter

Med 2007)

§  Diverse idiosyncratic reactions §  Pregnancy and fetal related toxicity (trans-placental)

Kuter DJ, Blood 2007

Recombinant human TPO

Fc carrier domain" Peptide-containing domain"

Romiplostim

Eltrombopag

Patient platelet response and romiplostim dose remained stable over time

Note: data points with n < 5 not plotted

Mea

n D

ose

(µg/

kg)

0

2

4

6

8

10

12

n = 291 279 272 262 254 244 230 227 206 162 136 118 111 108 103 100 97 95 89 87 83 78 68 58 51 41 28 22 22 23 21 19 16 15 91 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 2800

50

100

150

200

250

300

350

n = 291 227 194 81 74 41242 210 95 80 57 26257 228 100 82 67 31233 210 92 75 45 22156 129 110 86 83 1723 141319 11

Study Week

Med

ian

(Q1,

Q3)

Pla

tele

t Cou

nt x

109 /L

Kuter et al, Blood (ASH Annual Meeting Abstracts) 2010; 116:68 and Br J Haematol 2013

Mean romiplostim dose 5-8 µg/kg

211 uninterrupted self-injection

95% responded at least once

Plt response maintained on a median of 92% of study visits

Incidence and severity of bleeding events over time (romiplostim)

n = number of patients who started that period Bleeding grading scale: 1=mild, 2=moderate, 3=severe, 4=life-threatening, and 5=fatal.

<24

24-<

48

48-<

72

72-<

96

96-<

120

120-

<144

144-

<168

168-

<192

192-

<216

216-

<240

240-

<264

264-

<288

0

10

20

30

40

Grade ≥2Grade ≥3

n = 291 243 119 94 54 23272 180 104 81 28 18

Any

Grade ≥4Grade ≥5

0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0

24-Week Time Periods

Patie

nts

(%)

Kuter et al. Blood (ASH Annual Meeting Abstracts) 2010; 116:68 (Oral presentation)

Median platelets during EXTEND (eltrombopag). Shaded area indicates assessments of ≤ 15 pts

Saleh et al, Blood 2013

Bleeding during EXTEND (eltrombopag). Shaded area indicates assessments of ≤ 15 pts

Saleh et al, Blood 2013

TPO-ra Class Effect Adverse events of special interest identified in pivotal

studies

Cataract incidence possibly increased by eltrombopag

§  Hepatobiliary Laboratory Abnormalities (HBLA)

§  Withdrawal thrombocytopenia

§  Deposition of reticulin fibers in the bone marrow (BM)

§  Thromboembolic events

§  Hematologic malignancies

Incidence rate of VTE x 100 patient-yrs RR 1.42

(1.01 – 2.48)

RR 2.65 (1.27 – 5.50)

Annual incidence of major VTE in general population from literature : 0.1 – 0.2/100 patient-years (Goldhaber, Best Pract Res Clin Haematol ,2012;25:235-242)

RR = relative risk *Unadjusted overall prevalence

2.9%* 1.9%* 1.5%*

Incidence rate of arterial thrombosis x 100 patient-yrs

RR 1.372 (0.94 – 2.00)

RR 1.32 (0.88 – 1.98)

Annual incidence of major arterial thrombosis from literature (major coronary events + ischemic stroke): 0.7-0.8/100 patient-years at average age 50-60 yrs (Baigent et al, AntithromboticTrialists Collaboration, Lancet 2009; Kearney et al, BMJ 2006)

4.1%* 3%* 2.8%*

RR = relative risk *Unadjusted overall prevalence

Incidence of AbVTE and VTE by splenectomy status (Boyle et al, Blood 2013)

Splenectomy vs no splenectomy Hazard ratio (CI 95%)

AbVTE < 90 days from splenectomy

5.4 (2.3 – 12.5)

AbVTE > 90 days from splenectomy

1.5 (0.9 – 2.6)

VTE < 90 days from splenectomy

5.2 (3.2 – 8.5)

VTE > 90 days from splenectomy

2.7 (1.9 – 3.8)

Abdominal VTE

VTE (DVT+PE)

Probability of thrombotic events in splenectomized (Ruggeri et al, GIMEMA study)

•  Annualized thrombotic risk 2.9% (CI 1.6 – 5.4) - 1.1% venous, 1.9% arterial constant over time

•  After 5 yrs FU, not adjusted incidence: venous 6.6%, arterial 10.2% •  Risk ratio in keeping with Boyle et al, 2013 and Thomsen et al, 2010 (RR ∼3)

0.00

0.05

0.10

0.15

0.20

0.30

0.40

0.50

Thro

mbo

sis-

free

surv

ival

, %

0 30 60 90 120Months from splenectomy or diagnosis

Splenectomy:NoYes

All events (unadjusted KM)Age and sex adjusted

Do TPO-ra further increase the risk? Thrombosis per 100 pts/year

Venous Arterial Overall Control western population

0.1 – 0.2 0.70 0.71 – 0.72

Non-ITP population* 0.42 0.67 1.09

ITP population* 0.66 0.96 1.62

Eltrompopag Extension 3.17

Romiplostim Extension 3.6

PV 0.4 – 2.5 0.7 – 3.5 1.1 – 6.0

ET 0.2 – 2.0 1.1 – 4.6 1.3 – 6.6

* Sarpatwari et al, Haematologica 2010 (UK General Practice Research Database)

Data from prospective and retrospective studies: Patrono et al, Blood 2013; AntithromboticTrialists Collaboration; Goldhaber et al, Pract Res Clin Haematol 2012

Strengths of TPO-ra §  Strong evidence of positive efficacy/safety derived

from well designed placebo-controlled studies §  Confirmation in many long term/supportive studies

–  Excellent response rate in terms of platelet count –  Effective in reducing bleeding and in allowing safe

hemostatic challenges –  Effective in patients failing more treatment lines, including

splenectomy –  Good safety profile at up to 4-5 yrs –  Reduction or avoidance of concomitant steroids or IVIg –  Improved QoL –  Preliminary evidence of normalization of Treg, some patients

continue to respond after stopping treatment

Pros and Cons of new treatments, compared to splenectomy, in patients failing first-line therapy and/or (some) medical second-line therapies

Splenectomy Rituximab TPO-ra* Type of tx Surgical (one-shot) Medical (one-shot) Medical (continuous)

ITP-specific No, time-honored No, off-label use Yes, FDA and EMA approval

Response rate > 80% - long-term 60% Long-term 15-20% of initially treated > 65 - 80% while on tx

Response prediction

No reliable assay No reliable assay No reliable assay

Curative potential

Yes, up to 60% of patients

Uncertain. Possible in rare cases Not expected, but possible in rare cases

Short term toxicity

Perioperative morbidity Allergic reactions Fluid overload

No or minimal

Medium and long term toxicity

Small life-long risk of overwhelming sepsis Slight increase of thrombosis risk

Cases of persistent leukemia or hypogamma globulinemia, reactivation of hepatitis B Lack of efficacy of vaccination. Severe infections Rare cases of PML reported

No or minimal but to be fully evaluated, particularly for thrombotic risk

Follow up after response

On clinical ground On clinical ground Strict

Cost Affordable (also in developing countries)

High High

*In Europe, approved only for pts splenectomized or with contraindication to splenectomy

Proposed algorithm in the treatment of ITP

Initial treatment

Manage conservatively Splenectomy TPO-ra

Continue for 1–2 yrs,

try to taper

TPO-RA if splenectomy

contraindicated

Rituximab Anticipate splenectomy if required by tx toxicity

or unresponsiveness (TPO-RA as a bridge to

splenectomy may be considered)

Dia

gnos

is 3 months 12 months No response to

splenectomy Response

No response or relapse

•  Splenectomy treatment of choice as 2nd line •  Increasing use of TPO-ra as a bridge to splenectomy •  TPO-ra preferred choice in refractory to splenectomy or with contraindication

ASH guidelines endorsed this sequence (Neunert et al, Blood 2011)

Clinical vignette: consultation with patient and her husband

§  Splenectomy is proposed as first choice in her case

§  Patient refuses: fear to remove an healthy organ; need to find an assistant for the young baby

§  She asks to start with TPO-ra, despite the awareness of a slightly increased risk of thrombosis and requires to restart oral contraceptives

§  She responds to TPO-ra and reaches a plt count ranging from 50x109/L to 300x109/L during a 2-yr treatment

Two years later: outcome (I)

§  The patient wants to have another pregnancy and asks for a safe approach

§  She will accept splenectomy if «not in remission» after TPO-ra

§  TPO-ra stopped: plt count down to 20x109/L. No symptoms

§  TPO-ra restarted at the last effective dose: plt count increases again

§  Patients is vaccinated against pneumococcus, meningococcus and hemophilus influentiae type b with coniugate vaccines

§  After a few weeks, splenectomy is performed with LMWH prophylaxis (enoxaparin 4000 U two hours before and then daily for 10 days). Abdominal ultrasound examination carried out before stopping heparin

Two years later: outcome (II)

§  TPO-ra had been stopped a few days before splenectomy

§  Plt count increases to 400x109/L 1 week after splenectomy

§  Oral contraceptives stopped

§  6 months later the patient is pregnant and well

§  She will be monitored at monthly intervals

Comments

§  Be conservative: ITP is a benign disorder

§  Evidence-based treatments scarcely available

§  Clinical expertise becomes of critical importance in difficult cases

§  Patient’s tailored approach is required

§  The physician should propose a treatment after a discussion of the pros and cons of the different approaches maintaining a good compliance with the patient