DOACS in APS

 Meta analysis of DOAC versus VKA

- higher risk of stroke on DOAC

- no increase in VTE or bleeding on DOAC

Rapid Resource:

Myelofibrosis ASH education 2022

 

Difference between proliferative MF and cytopenic MF

Proliferative MF: higher WBC, Hb and plt. Typically less blasts, less fibrosis, and lower risk score.

More likely to be associated with post PV or ET. 

Bigger spleen+, higher JAK2 VAF

More treatment options, better outcomes

1.  Ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF.

2. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 10⁹/L

Steps in the initial assessment of patient with MF:

a. Risk stratification: MIPSS 70 and or GIPSS, DIPSS plus etc

b. Assess symptom burden with MPN-10

c. Clinical exam: constitutional symptoms, splenomegaly

d. Decide if cytopenic type or proliferative type

Lower risk MF ( DIPSS < 2, DIPSS plus 0 or 1, MIPSS 70 3 or less)

1. Asymptomatic: observe

2.  Symptomatic: anemia--> measure epo level. If epo < 500, use ESA +/- danazol, luspatercept

3. Symptomatic: constitutional and splenomegaly: Ruxulotinib, fedratinib, pacritinib. Low dose Jakafi if plt count 50-100 k, if plt < 50K use pacritinib ( approval based on spleen size)

Higher risk: (DIPSS 2 or higher) if transplant candidate--> allow HCT if bridging Jakafi

If not a transplant candidate, treat as for symptomatic low risk.

Degree of anemia and tpenia correlate with worse OS and risk of AML transformation ( if plt < 50K).

Plt < 50K--> more fibrosis and higher blast count.

Cytopenic is more common in primary MF.

Jakafi:

Starting dose based on platelet count and escalate as able.
Early anemia is common, with gradual improvement (so dose adjustments not indicated for early anemia

Fedratinib: can use after Jakafi failure and still gets spleen vol reduction. GI se common. Wernicke's. 400 mg daily. Black  box --> thiamine monitoring.

No starting dose reductions needed for moderate thrombocytopenia, but dose reduce for worsening platelets.
Early nausea or diarrhea are common.
Monitor thiamine and for signs of encephalopathy.
Monitor renal function and liver function.

Pacritinib: 200 mg BID. cardiac toxicity in earlier trials. Monitor Qtc and EF.

Less myelosuppression.
Early nausea/diarrhea are common and generally improve with supportive care.
Caution in those with CV disease or recent hemorrhage.
Monitor QTc.
Monitor for bleeding

Momelotinib

Rare risk of neuropathy

Myelodysplastic syndrome

 Myelodysplastic syndrome

Patient evaluation template:

ECOG:

IPSS-R:IPSS-R

IPSS-M: Molecular IPSS

Prognosis based on IPSS category

Transfusion requirement: e.g 2 units PRBC every 3 weeks etc

Transplant candidate: Yes or no

Goals of treatment: Curative versus palliative

Supportive care plan: GCSF, transfusion, antimicrobials.

Treatment options:

1. Standard of care: Azacitidine is the only hypomethylating agent shown to improve survival.

AZA-001 study: Azacitidine demonstrated increased OS compared with conventional care regimen, 24.4 months vs 15 months, respectively (P = .0001). In addition, there was a 74% OS improvement with azacitidine (hazard ratio [HR], 0.58.

However with repeat studies the OS has been in the 15-17 month range and the OS of the AZA-001 study has not been duplicated.

2. Side effects: Initial worsening of cytopenias in the first 1–4 months of treatment, lack of adequate predictors of response, and prolonged therapy

3. Other agents, including oral combinations: IV decitabine ( no OS benefit), oral decitabine with cedazuridine, similar CR to azacitidine but no OS benefit so far. However, QOL factors are better. Increases compliance and reduces vascular access.

Other options not yet SOC:

1. Venetoclax 400 mg 14 days out of a 28 day cycle + azacitidine 75mg/m2 day 1-5. High CR but 1% mortality

2. IDH 1 and IDH2 mutated MDS relapsed setting with IDH inhibitors with high CR rates > 40%.

3. Sabatilomab targets TIM-3, Magrolimab anti CD 47

AZA: dose adjustment from cancer care ontario

Chemotherapy induced thrombocytopenia

CIT Key points

1.  Rule out other causes of low plt, even if the cause is most likely CIT

2.  Two types: persistent CIT, and nadir CIT

3. Persistent CIT: typically plt count < 50K, requiring dose reduction or dose delays.

4. N-plate has most data compared to oral thrombopoietin agonists.

Starting dose 2-4microgram per week gives best results, compared to intracycle dosing. Can titrate dose up or down by 1 microgram per week depending on plt level. If plt level > 200K, dose down.

5. N plate is not useful for nadir thrombocytopenia if plt count recovers before the next cycle spontaneously.

6. The issue with nadir thrombocytopenia is need to hold anticoagulants that the patient is on for VTE or Afib.

7. Persistent CIT found 3 main predictors of nonresponse to romiplostim treatment: known bone marrow involvement by tumor, prior pelvic irradiation, and prior receipt of temozolomide therapy

8. There is a risk of VTE because of romiplostim, but ok to ct it if patient is on therapeutic anticoagulation.

9. No role for use of romiplostim to manage CIT in myeloid malignancies

 Reference: ASH education book 2022

Early stage non small cell lung cancer

 

SBRT versus systemic therapy for early-stage inoperable nonsmall cell

1. SABR is well tolerated. Slightly more toxic for tumors within 2 cm of the central airways. Hemoptysis can be the result.

2. A 5-year pattern of failure:  5-year in-field, locoregional, and distant failure rates of 7.3%, 25.5%, and 23.6%, respectively, and 5-year DFS of 25.5%. However one trial showed path CR of only 60% when the tumor was resected after SBRT.

Reference: JCO Jan 2022

5-year OS rates of 68% in stage IB, 53%-60% in stage II, and 36% in stage IIIA 

Early stage lung cancer Adjuvant chemo

benefit of chemo --> improved OS by 4% at 5 yr in tumors that are node positive or > 4 cm.

1. International Adjuvant Lung Cancer Trial :resected stage I-III NSCLC to three to four cycles of cisplatin-based adjuvant chemotherapy versus observation. At 5 years, chemotherapy improved OS from 40.4% to 44.5%

2. JBR.10 trial, which enrolled stage IB-II resected NSCLC and demonstrated an improvement in 5-year OS from 54% to 69% with four cycles vinorelbine/cisplatin as compared to observation

3. ANITA: cisplatin/vinorelbine improved 5-year OS by 8.6% in resected stage IB or IIIA NSCLC

Current National Comprehensive Cancer Network (NCCN) guidelines for NSCLC include a recommendation to consider chemotherapy for high-risk node-negative patients, for features including size > 4 cm, visceral pleural involvement, poorly differentiated tumors, vascular invasion, although resected via wedge resection, and unknown nodal involvement

Early stage lung ca: Adjuvant TKI

1. EGFR mutated stage I to III:

ADAURA randomly assigned patients with resected stage IB-IIIA NSCLC with an EGFR exon 19 deletion or L858R mutation to adjuvant osimertinib or placebo for up to 3 years. Adjuvant chemotherapy before osimertinib was allowed but not mandated. DFS improvement found with osimertinib, with 2-year DFS of 90% with osimertinib and 44% with placebo HR, 0.17.

ADAURA findings could potentially be extrapolated to the medically inoperable population of patients with EGFR mutations 

2. ALCHEMIST trial is testing adjuvant ALK mutated lung ca adjuvant rx.

Early stage lung ca: Adjuvant immunotherapy

1. Atezolizumab

IMPower 010: ICI following 4 cycles adjuvant chemo in stage II-IIIA post resection: IM power 010--> greatest DFS benefit HR 0.4 in those with PDL1 50 or higher. Give atezo for 1 yr. Approved for PDL1> 1% but DFS benefit not so impressive. 

2. Pembrolizumab: Keynote 091- showed DFS benefit irrespective of PDL1. 18 cycles q 3 weeks. OS data, not mature

ADAURA, Keynote091, and IMpower 010 all showed a DFS rather than OS benefit.

Consolidation ICI after 2 cycles CRT for stage III non small cell

1. PACIFIC trial- PD-L1 inhibitor durvalumab

phase III, placebo-controlled PACIFIC trial of patients with unresectable, stage III non–small-cell lung cancer (NSCLC) whose disease had not progressed after platinum-based concurrent chemoradiotherapy (CRT), administration of durvalumab (a programmed cell death-ligand 1 [PD-L1] inhibitor) for up to 12 months improved overall survival (OS; stratified hazard ratio [HR], 0.68. OS and PFS : 42.9% remain alive at 5 years and 33.1% remain alive and progression-free

Median OS was 47.5 months with durvalumab versus 29.1 months with placebo. The estimated 5-year OS rate was 42.9% with durvalumab versus 33.4% with placebo.

No OS benefit if PDL1 =0 , however there was a PFS  benefit in this group also.

PACIFIC trial in stage III NSCLC found that patients who were randomly assigned within 14 days of completing radiotherapy experienced greater benefit from durvalumab (HR 0.39 for PFS) than those with ≥ 14 days between radiation and ICI

Reference: JCO : https://ascopubs-org.offcampus.lib.washington.edu/doi/full/10.1200/JCO.22.00873