Ding Wen Wu, Rachel Friedmann, Joan Uehlinger, Sadiqa Karim, Etan Marks, Angie Bonzon-Adelson, Kala Mohandas, Evan Himchak, Ronald Walsh

May 5, 2017

Abbreviations

T/R

Simple transfusion and/ or red cell exchange

Post-HCT

Hematocrit immediately after the T/R

Post- HbS

Hemoglobin S level immediately after the T/R

Pre – HbS

Hemoglobin S level immediately before the T/R

F/u- HbS

= Pre-HbS of next T/R

Highest HbS level between 2 consecutive T/Rs

FCR

Fraction of cell remaining

calculated based on the desired Post-HbS

FCR = post-HbS/ pre-HbS

Background RCE Targets for SCA Patients

Clinical improvement

Post-HCT

≤ 30% traditionally

FCR

FCR = post-HbS/ pre-HbS

Post-HbS ≤ 30% traditionally

Background SCA mgt guidelines 2014

In children with SCA who receive transfusions long-term, the goal of transfusion should be to maintain a HbS level of <30% immediately prior to the next transfusion

Strength of recommendation: Moderate

Quality of evidence: Moderate

Reference:

Yawn BP1, Buchanan GR2, Afenyi-Annan AN3, Ballas SK4, Hassell KL5, James AH6, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. doi: 10.1001/jama.2014.10517.

New Challenge

How to maintain next pre-HbS ≤30% ?

Expert recommendation – none

Literature/ evidence – none

Thoughts: Monthly T/R with F/u-HbS ≤30%

- But how???

How to maintain HbS <30%?

Current T/ R approaches for pediatric SCA pts:

Empirical

↓ post – HbS (i.e. post-T/R-HbS)

How low? 10-15%, or 15-20%

Or ↑ post-HCT

How much? Up to 36%

Why? Suppress erythropoiesis

For pts of how old?

Some recommend for all the ped SCA pts, up to 20 y/o

Evidence-based

None

Our Study - Aims

↓ post – HbS How to predict F/u-HbS from post-HbS?

Can we predict it by calculation?

To identify a threshold

which keeps F/u HbS < 30%

↑ post-HCT

To determine if raising post-HCT to 30-36% can suppress F/u- HbS to < 30%

If yes, how to predict F/u HbS < 30% from post-HCT?

Data Inclusion Criteria

Patients of genotype HbSS

Chronic monthly T/R

i.e. ~ 1 month (20-45 days) between 2 consecutive T/R events

Or a non-monthly T/R AND a F/u-HbS ~1 month later

AND no T/R event in between the post-HbS and the F/u HbS

June 2014 – Dec. 2015

Each event has at least a set of 3 documented parameters: post- HCT, and post-HbS, and F/u-HbS

To maximize the sample size for proof of concept, this study includes both pediatric and adult patients

Data Exclusion Criteria

Patients with other hemoglobinopathies rather than genotype HbSS

Events with incomplete data points

Post-HbS > 30%

Post-HCT > 36%

SCA patients after allo-Stem Cell TxP

Results

47 SCA patients

26 children, 21 adults

17 females, 30 males

247 T/R events

74 Pediatric events 173 adult events

190 events with HCT <30% 57 events with HCT 30-36%

Results T

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Results

- A moderate correlation - Lowering post-HbS lowers F/u-HbS. - However, the value of post-HbS does not predict F/u-HbS with accuracy.

Figure 1. Linear Regression Analysis

y = 1.03 x + 18.41 R² = 0.444

-5

5

15

25

35

45

55

65

0 10 20 30

F/u

-Hb

S (

%)

Post-HbS (%)

Post-HbS vs. F/u-HbS

Figure 2. Linear Regression Analysis

_ Nearly no correlation between Post-HCT and F/u-HbS. _ Raising post-HCT does not lower F/u-HbS.

Results

Results (Table 2, comparing F/u-HbS levels)

Post-HbS ≤10% effectively keeps F/u-HbS <30%;

Raising post-HCT to 30-36% does not lower F/u-HbS to <30%

Results Table 3. Comparing frequency of 2 F/u-HbS levels in different post-HbS categories and post-HCT groups

Results

Table 4. Frequency comparison of selected F/u-HbS levels in various post-HbS categories

Results Table 5. Frequency comparison of selected F/u-HbS levels in SCA patients

Pediatric patients Adult patients

A similar trend in both Pediatric and adult SCA patients. (1) Post-HbS ≤10% keeps most of F/u-HbS <30% (2) Empirical Post-HbS 10-15% keeps only half of F/u-HbS <30% (3) Empirical Post-HbS 15-20% or above only keeps less than 10% of F/u-HbS <30% (4) Traditional Post-HbS 20-30% only keeps ≤ 85% of F/u-HbS <50%.

Conclusions Identified a threshold

Post-HbS ≤10%

to keep most of F/u-HbS <30%

for pediatric SCA pts

Demonstrated that empirically raising post-HCT to 30-36% fails to lower F/u-HbS.

Identified an additional threshold

Post-HbS ≤20%

to keep nearly 100% of F/u-HbS <50%

for “refractory” adult SCA patients

who sometimes still have SCD crisis

when on monthly T/R

To our knowledge, this is the first evidence-based study demonstrating these results.

Our Recommendations

Lower post-HbS to 5-10% for monthly T/R

for pediatric HgSS SCA patients

to maintain F/u-HbS < 30%

DO NOT raise post-Hct to >30-36%

It fails to suppress HbS production !!

It increases the risks of hyperviscosity and iron overload

Lower post-HbS to ≤ 20%

for refractory adult HgSS patients

to ensure F/u- HbS < 50%

A prospective randomized study

Acknowledgement

Deepa Manwani, MD

Pediatric Hematology

Yungtai Lo, PhD, Statistician

Gurbakhash Kaur, MD

Hematology/ Oncology