Rare Bleeding Disorders

 ASH review series

1. Factor XI def: typically isolated PTT prolongation, manifests as bleeding after surgery, common in certain Jewish population

- also called hemophilia C

-AR or AD inheritance

- weak connection between severity of bleeding and factor 11 levels

Mainstay of factor 11 def treatment: antifibrinolytics, OK to use periop FFP( prior bleeding hx or level < 10%)also can use rFactor 7.

2. Factor VII def: 

-AR inheritance

- correlation between level and bleeding intensity not clear but better than factor 11.

-PT elevation isolated, rest PTT, thrombin time , reptilase time WNL

-Severe bleeding if less than 10%

-4% can present with VTE ( Pearl for boards--> the factor def that can present with thrombosis)

RX- Antifibrinolytics, factor VII a replacement

3. Factor X def: can be acquired or inherited

Both mucocutaneous and visceral bleeding ( including intracranial)

-both PT and PTT prolonged, TT normal

- associated with AL amyloid and myeloma

- Factor X concentrates, FFP

-Level correlation good

4. Factor V def is very rare

- inherited, can be combined with factor 8 def in LMAN or MCFD mutations

-acquired ( bovine thrombin, Quebec plt disorder, autoantibodies to factor V)

-prolonged PT and PTT, level correlation poor

-can treat with platelet transfusion in addition to FFP

5. Factor 13 def: rare

PT and PTT normal

Can present in infancy with umbilical stump bleeding or intracranial bleeding, pregnancy loss, poor wound healing

-Clot lysis test for diagnosis

Imp: 95% time, the def is in factor 13 A subunit. If so, can treat with recombinant factor 13. If in the B subunit ( 5% of cases), use FFP or cryoppt which has both A and B units.

To differentiate between the 2 types, a genetic test is needed.

Level correlation good.

If factor 13 level less than 10%, use monthly prophylactic infusions of recombinant factor 13 ( pearl)

6. Factor 2 def:

Prothrombin def. Can be acquired in APLA.

Typically reptilase time is normal but if APLA is associated with antibodies against factor 2, PT gets prolonged and patient may bleed.

Rx: PCC

Prophylaxis: Weekly prophylaxis if < 10% levels

Poor correlation of clinical manifestations with level

7. Fibrinogen def or factor I: 

quantitative or qualitative

Afibrinogenemia--> neonatal umbilical stump bleeding

Dysfibrinogenemia: can have thrombosis risk

PT, PTT, TT and reptilase time all prolonged

( TT can be prolonged by heparin but reptilase time is prolonged only by problems with fibrinogen)

Rx: Fibrinogen concentrate, FFP, cryo

8. Vit K dependent coagulation factor def--mutation of vit K epoxide reductase or gamma glutamyl carboxylase. Normal vit K level. Treat with vitamin K

9. Alpha 2 antiplasmin def and PAI-1 def: treat with antifibrinolytics

10. Acquired hemophilia: autoimmune or cancer

Mucocutaneous bleeding, RP bleeding, or abd bleeding

Rx: FEIBA, rVIIA, rfactor 8 porcine

Emicizumab not approved, but can be used

Cytoxan + steroid+ rituxan to eradicate antibodies

No role for immune tolerance

11. HHT: AD inheritance

Mutations in TGF b--> excess  angiogenesis

Curacao criteria, Genetic tests for diagnosis

Can be a picture question with Xray of lung with AVM, etc

IV iron, PRBC, antifibrinolytics, Oral thalidomide or IV avastin, local nose procedures, laser etc or other ablative therapies

12. Heyde's ( pronounce Heidi) syndrome:

Aortic stenosis, AVM in bowels, acquired VWD 2 A

Check for VW multimers, acquired type 2 A VWD

Rx: AV replacement, fibrinolytics, octreotide

Metastatic prostate cancer

 

Prostate cancer

With onset of mets, 5 yr OS is 30%. Therefore delaying metastatic disease is a good surrogate goal.

Metastatic castration sensitive disease

• Corner stone of rx is ADT ( surgical or pharmacological)
• AE of ADT: sexual dysfunction, cardiovascular disease, diabetes, cognitive dysfunction, and decreased mineral bone density.

CHAARTED and STAMPEDE trials: use of docetaxel with ADT as front line Rx

The use of upfront docetaxel was shown to improve overall survival (OS) in patients with mCSPC, especially for men with high-volume disease (presence of visceral metastases and/or ≥ 4 bone metastases with ≥ 1 metastasis not involving the axial skeleton or pelvis). In an updated analysis of the CHAARTED trial, the median OS, the primary end point, was significantly improved in the 513 patients with high-volume disease (hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79) but not in the 277 patients with low-volume disease.

Metaanalysis of the above 2 trials and GETUG-15-->  addition of docetaxel to ADT reduced all-cause death as compared to ADT alone in the overall population (HR, 0.77) So the docetaxel group has a 77% risk of all cause death compared to ADT alone group.

Main AE: docetaxel group--> higher rate of neuropathy and neutropenia

LALITUDE: Abiraterone

Addition of abiraterone to ADT in patients with newly diagnosed high-risk mCSPC (defined as the presence of ≥ 2 of the following: Gleason score ≥ 8, ≥ 3 bone lesions, or presence of measurable visceral metastasis) was shown to improve OS (HR, 0.66; 95% CI, 0.56 to 0.78) as well as quality of life (QoL) in the LATITUDE trial.

A post hoc analysis of the STAMPEDE trial provided the rationale for using abiraterone in men with mCSPC regardless of risk stratification (OS: HR, 0.54; 95% CI, 0.41 to 0.70; 3-year failure-free survival: HR, 0.31; 95% CI, 0.25 to 0.39).

TITAN: Apalutamide

TITAN enrolled patients with confirmed adenocarcinoma of the prostate and documented distant metastatic disease (i.e. ≥ 1 lesion on bone scanning, with or without visceral or lymph node involvement) who were castration sensitive (i.e. were not receiving ADT at the time of disease progression)

The 2-year OS was 82.4% in the apalutamide group compared with 73.5% in the ADT only group.

48% reduction in the risk of death with apalutamide (HR, 0.52).

ENZAMET and ARCHES: Enzalutamide

 In ENZAMET, 5-year overall survival of 57% (0·53–0·61) in the control group and 67% (0·63–0·70) in the enzalutamide group.

43% received triplet therapy but only 30% completed all 6 cycles of docetaxel in addition to enza. The benefit did not reach statistical significance but the trial was underpowered to detect a benefit. So for now, not recommended. AE was signficantly higher.

ARCHES: Overall survival at 24, 36, and 48 months was 86% vs 82%, 78% vs 69%, and 71% vs 57%

enzalutamide plus ADT significantly reduced the risk of death in patients with metastatic hormone-sensitive prostate cancer by 34% vs placebo plus ADT.

TRIPLET Therapy

ADT+ Docetaxel with abiraterone or darolutamide: PEACE 1 ( Abi), ARASENS( daro). Use in high vol disease per NCCN in those fit for chemo.

PEACE 1- 10% more SE with triplet. Better OS and rPFS in Abiraterone arm. oS HR 0.82

ARANSENS- 12% 4 yr OS benefit ( 62% versus 50% favoring daro at 4 yr) HR 0.68 ( risk of death lower by 32%)

Metastatic castration resistant prostate cancer

1. Abiraterone: docetaxel pretreated patients median OS- 14.8, docetaxel naive median OS 34 m, COU-AA-1 and COU-AA-2 trials
2. Enzalutamide: AFFIRM and PREVAIL for pretreated and naive respectively, median OS 18 months and 32 with enza
3. Cabazitaxel : approx 25 months OS with C20 and C25mg/m2 q 3 weeks FIRSTANA trial, but not superior to docetaxel
4. Docetaxel : TAX 372 median OS 19 months ( versus mitoxantrone)
5. Radium 223: ALSYMPCA mCRPC with symptomatic bone metastases, without evidence of visceral disease and the maximum lymph node diameter of ≤ 3 cm. HR for median OS 0.70.
6. Sip-T: dendritic cell vaccine. Sipuleucel-T is a dendritic cell vaccine prepared from patients' peripheral blood mononuclear cells obtained through leukapheresis. It is approved for the treatment of asymptomatic or minimally symptomatic patients with mCRPC without evidence of visceral disease.
7. Pembrolizumab: high TMB or MSI high ( less than 3% of men with mCRPC) in the third line setting only ( ie similar to Lu-PSMA space but not category 1)
8. 177Lu-PSMA-617 : VISION tria. Approved for progression after taxane and novel AR therapy. Improves median OS. 15 months.patients with more than1 PSMA-positive lesion and/ or metastatic disease that is predominately PSMA-positive and with no dominant PSMA-negative metastatic lesions. 22% of patients in this trial had visceral mets, so this can be used for patients in the third line setting with visceral mets and PSMA positive lesions.
9. Single agent PARP inhibitors: Olaparib: olaparib was approved in May 2020 for patients with mCRPC who previously progressed on enzalutamide or abiraterone and who carry alterations (germline and/or somatic) in any of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L. 
10. PARP inhibitors with Abiraterone: Olaparib with abiraterone: not yet approved frontline although ProPEL trial showed a rPFS benefit irrespective of HRR status. Niraparib showed a benefit only in HRR patients when given with Abiraterone front line in CRPC.

Malignant mesothelioma treatment summary

 Malignant mesothelioma- epithelioid, sarcomatoid, mixed( biphasic)

BAP1 IHC loss is a molecular marker that is useful for diagnosing mesothelioma.

Histology: Aberrant BAP1 protein expression, which is defined as absence of nuclear BAP1 IHC staining, occurs in about 50% to 70% of patients with epithelioid mesothelioma but in less than 20% of those with sarcomatoid mesothelioma.

• Cisplatin with pemetrexed 12.1 months OS ( vrsus 9 for Cis alone). No maintenance. Carbo if cis ineligible.
• Cisplatin pem bev--> bev maintenance  18 months median OS ( MAPS  trial). Not FDA approved but listed on NCCN.
• Checkmate 743- practice changing esp for sarcomatoid. 18 months OS when compared with pem cis. In the control arm, bev was not included. So the benefit in epithelioid patients not clear.

So for epithelioid histology and patients over 75 use platinum doublet with bev front line, although NCCN 2022 update lists nivo 3mg/kg q 2 weeks + ipi 1 mg/kg q 6 weeks also as an option for 2 yr.

• In the second line setting after chemo, doublet IO recommended. Single agent IO nivo better than best supportive care but not necessarily any better than 2nd line chemo.
• No OS benefit with IO+ chemo front line. 

• No data to support any particular chemo after 1st line doublet IO, but vinorelbine median OS 11.6 months
• no role for maintenance pemetrexed after 1st line platinum doublet but bev maintenance ok for epithelioid. Another option is gemcitabine maintenance after 4-6 cycles platinum doublet.
• Gem+ ramucriumab is a 2nd line option
• If sarcomatoid but cannot get IO, add pegargiminase to platinum doublet

March 2025 ASCO updated guideline

• If candidate for rx, get either a thoracoscopic pleural biopsy or open pleural biopsy if the initial fluid cytology suggests mesothelioma
• Get PET if candidate for surgery. Otherwise CT A/P.
• Contralateral thoracoscopy and laparoscopy if suspected contralateral or abd disease respectively
• If candidate for maximal surgical cytoreduction, evaluate the mediastinum with mediastinoscopy or endobronchial ultrasound
• Surgery should be offered to pt with T1-T3N0 epithelioid disease
• Sarcomatoid should not be offered surgery.
• All patients with mesothelioma should be offered germline testing
• Tumor treatment fields not recommended