THSNA 2022 key points

1.  Anemia and Von Willebrand factor levels

Anemia can falsely elevate levels of VWF and factor 8, which can affect diagnosis. This applies only to type 1 disease. So correct anemia and recheck levels in suspected VWD.

2. Prophylaxis with recombinant VWF in severe VWD ( 3 or more spontaneous bleeds in prior 12 months) Vonicog alpha, phase 3 trial

VWF: Ristocetin level < 20, so patients with severe disease were included.

Vonicog alpha was better than on-demand prophylaxis ( previously using plasma product) and reduced the annualized bleeding rate. It was as good as plasma product in those who were on plasma-based routine prophylaxis with no new adverse events.

3.  New guidelines for diagnosis and management of VWD

• In patients with intermediate ( abnl coag studies e.g) and high ( first degree relative with VWD) probability of VWD, do not use a validated BAT. Use BAT if there is a low probability ( ie PCP's office).
• ISTH BAT 4 or higher in men, 6 or higher in women in predictive of bleeding disorder.
• Use VWF binding to GP1B instead of Ristocetin cofactor assay as the preferred functional assay when possible.
• VWF levels pre op:
• minor surgeries: > 0.5, major surgeries and neurosurgery > 1.0
• DDAVP challenge: positive result if the level rises at least 2 fold and is sustained at 1 hr and 4 hr
• Type 1 C VWD increased clearance of VWF --> good level at 1 hr, but drops levels in 4 hr. The VD pro peptide is still elevated at 4 hr.
• Type 1 VWD levels < 30% with or without bleeding
• Type 1 VWD if levels between 30-50% then some abnl bleeding is needed to make the diagnosis.
• Make diagnosis at a steady healthy state esp after correcting anemia.

4. VWD in women

Type 1 VWD: levels increase, factor 8 also, but both fall 2 weeks after delivery, with VWF levels falling more than factor 8 post partum

Type 2: no improvement in activity. 2B worsening thrombocytopenia, 2 No increase in factor 8

type  3 VWD: no increase

vWF must be tested in the 3rd trimester: Ag and or activity

5. Acquired von Willebrand's syndrome:

Causes fall into 4 groups: cardiac, hypothyroidism, malignancy, and autoimmune diseases.

Cardiac: aortic stenosis, VAD, congenital heart disease (  high shear rate with increased clearance)

cancer: MGUS, Waldenstrom's, myeloma, ET and Pvera

Wilm's lung bladder  ( clearance by AB or cell adsorption)

Hypothyroidism: decreased production

MGUS associated VWD may need IVIG and or myeloma rx if bleeding refractory despite factor replacement

Vignettes Blood Journal

 AML over 60 yr

1. Secondary AML increasingly resistant to frontline chemo , worse RFS but not increased TRM

2. TP 53 mutated AML and MDS EB similar in outcomes

Asciminib in CML

 Mechanism: Binds to the non-kinase domain of BCR-ABL where ATP binds.

This is the only CML TKI that works in this way.

Asciminib is preferred to ponatinib in those with intolerance or lack of response to first and second-line TKI.

However, ponatinib may be preferred if BCR ABL> 10% at 6 months.

Both ponatinib and asciminib may be acceptable in T315 mutation or non-T315I kinase domain mutations.

Omacetaxine is another drug approved for T315 I mutations.

2024 update

https://www.nejm.org/doi/full/10.1056/NEJMoa2400858

How to counsel pt: Imatinib was the first generation TKI. It is still the standard of care. The second gen TKI can induce deeper molecular remission and greater chance of going into TFR, but the OS is not different. The MR3 at 48 weeks is 40% imatinib, 45% second gen and 68% asciminib. 

The drug that induced the highest MR3 was ponatinib but the front line trial EPIC was aborted due to concern for vascular events.

Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).

In conclusion, asciminib is much better tolerated and induces deeper responses that imatinib. The MR3 for asciminib was not statistically superior to second gen TKI.

Adverse events ( G3 or higher):

Asciminib 38%, Imatinib 44%, Second gen TKI 55%

Discontinuation:

Asciminb 4.5%, Imatinib 11%, Second Gen TKI 10%

Complement inhibition in hematologic disease

 

PNH

Loss of CD55 and CD59 due to loss of PIGA coded proteins which bind these proteins using GPI anchors--> alternative pathway for complement activation --> RBC hemolysis.

-C5 inhibitor Ravulizumab

-C3 inhibitor Pegcetacoplan: FDA approved, given subcut twice a week. Main AE infection with encapsulated bacteria. black box warning meningococcal d/s

Cold Agglutinin disease

Ig M binds to RBC and brings along C3b as a companion in lower temp.

 In warmer temp, Ig M dissociates from the RBC, leaving C3b on the RBCs --> hemolysis.

Current rx: avoid cold, rituxan front line, relapsed disease fludarabine rituxan, velcade, BR therapy

-FDA approved sutimlimab--> inhibits classical complement C1

Caution: vaccinate against encapsulated bacteria before starting the treatment.

Initially weekly for 2 doses then every other week.

Transplantation-associated microangiopathy: 

thrombocytopenia, microangiopathic hemolytic anemia, organ damage

Current rx: stop the calcineurin inhibitor, PLEX, rituxan, steroids eculizumab

Lectin pathway and complement inhibition are being investigated in those resistant to eculizumab ( narsoplimab and conversion)

ITP: Sutimlimab being investigated for ITP resistant to prior therapies

Ref: Blood June 2022

Relapsed refractory Hodgkin lymphoma treatment: Nivo with ICE

 

Standard of care for RR HL--> salvage chemo followed by ASCT

Standard chemo yields 54 to 73% PET neg CR which is the most imp predictor of outcomes.

BV with nivo ( no chemo) salvage--> 67%

However, BV is now being used frontline.

Nivo monotherapy --> 27 to 43% CR without chemo.

PET adapted sequential nivo followed by nivo with ICE

Nivo q 2 weeks up to 6 doses. If CR-->ASCT

If not CR after 6 cycles or PD at any point, then 2 cycles ICE+ nivo--> ORR over 90%

2 yr PFS all comer 72% 2 yr OS 95%