High bleeding and clotting risk conditions- Difficult DOAC case study

 

Examples of patients with AF at very high risk of stroke or systemic embolism: • CHADS2 ≥4 • Valvular AF (mechanical valve and/or moderate‐severe mitral stenosis) • Transient ischemic attack or ischemic stroke within the past 3 months

Examples of patients with a history of VTE at very high risk of recurrent thrombosis: • VTE within the past 3 months • History of recurrent VTE after anticoagulation is stopped • Triple positive antiphospholipid antibody syndromea • Heparin‐induced thrombocytopenia within 3 months • Active cancer with history of cancer‐associated thrombosis

Examples of patients at very high bleeding risk: • Multiple risk factors for bleeding (e.g., extreme age, advanced kidney disease) • Thrombocytopenia (platelets less than 50) • Unresected gastrointestinal tumours • Angiodysplasia • Severe colitis • Lobar ICH secondary to cerebral amyloid angiopathy

https://www.jthjournal.org/article/S1538-7836(22)00495-0/fulltext

1. Dose reduce Apixaban to 2.5 mg BID if high risk of clotting and high risk of bleeding. If Afib consider if candidate for Watchman

Discussion for patients with VTE

VTE affects 1–2 per 1000 persons each year and has a lifetime risk of 8% after age 45. Upto 50% of VTE can be unprovoked. 

1. Risk of recurrence and impact of anticoagulation: 10% risk of recurrent VTE in year 1 and 2, 30% recurrence in 5 years if AC discontinued. 80-90% reduction in risk of recurrence with anticoagulation.

2. Other complications of VTE that are chronic besides recurrent VTE: 

•  PTS risk : 20% to 50% incidence ( ipsilateral DVT recurrence is associated with a 4–6 times increased risk of PTS)
• 0.1 to 4% risk of CTEPH after PE  

3. Long term anticoagulation options: DOAC versus aspirin. Data from 2 trials: AMPLIFY- EXT and EINSTEIN choice suggest that reduced dose can be used with equal efficacy. ASH 2020 guideline: For patients with DVT and/or PE who have completed primary treatment and will continue with a DOAC for secondary prevention, the ASH guideline panel suggests using standard dose DOAC or lower dose DOAC. European guidelines suggest reduced dose after  6-12 months after full dose.

4. Who should consider full dose rather than reduced dose for long term anticoagulation?

Patients with any of the following should continue on full dose anticoagulation:  AFib, recurence on DOAC in the past, initial thrombotic event was life threatening or with hemodynamic compromise, chronic TEPH, severe post thrombotic syndrome, active cancer and obesity.

5. HERDOO 2 risk evaluation in women with unprovoked VTE: if high, ct standard dose

Pregnancy and VTE prophylaxis

 

Reference: ASH 2018 guidelines 

1. Start prophylaxis if : she has a hx of  VTE that was unprovoked or associated with a hormonal risk factor, the ASH guideline panel recommends antepartum anticoagulant prophylaxis over no anticoagulant prophylaxis. continue that for 6 weeks post partum.

2.  Do not start prophylaxis  if the prior VTE  was associated with a nonhormonal temporary provoking risk factor and no other risk factors.

3.  Antepartum+ post partum prophylaxis in thrombophilias: 

-antithrombin deficiency + family history of VTE 

-homozygous for the factor V Leiden mutation 

-combined thrombophilias, regardless of family history of VTE

Questions to ask:

- every had a VTE? Provoked? Unprovoked? Related to hormones?

- family hx of VTE: pregnancy associated

- known thrombophilias

-any other risk factors: inflammatory diseases, smoking, obesity, pregnancy losses

Choice: standard dose LMWH in antepartum; standard or intermediate risk in post partum

Reference: Antiphospholipid Ab in pregnant women 

CMML

 Reference: CMML How I treat

Reference: Teferri American Journal of Hematology 2024

CMML is relatively homogeneous, demonstrating approximately 10-12 somatic variants per kilobase of coding region, with most pathogenic variants involving TET2 (60%), ASXL1 (40%), SRSF2 (50%) and RAS pathway (30%) genes. Broadly, CMML can be classified into dys-plastic CMML (dCMML), presenting with cytopenias and clinical signs and symptoms related to the same (fatigue, bruising and transfusion dependence) and proliferative CMML (pCMML), presenting with significant myeloproliferation, extramedullary hematopoiesis and associated constitutional symptoms :fever, weight loss, night sweats, anorexia, pruritus, bone pain and cachexia.

CMML inherent risk to transform to acute myeloid leukemia (AML; 15%–20% over 3–5 years

Pearls:

1. Unlike in MDS, MPN or AML, TP53 mutations are extremely infrequent in CMML (<1%), and are only really encountered at the time of CMML to AML transformation, or in the context of therapy-related CMML

2. In the absence of dysplasia, a diagnosis of CMML can be made if the monocytosis has persisted for ≥3 months, reactive causes have been excluded, or somatic cytogenetic or molecular markers frequent in CMML (e.g., ASXL1, TET2, SRSF2 and SETBP1) can be documented.

3. 2022: Threshold for monocytosis now >0.5 not 1.0- the ICC and WHO criteria are different. Peripheral monocytosis > 10%.  ICC needs cytopenia, WHO 2022 needs bone marrow dysplasia in one or more myeloid lineages > 10%.

4. Chromosomal translocations/rearrangements involving PDGFRA and PDGFRB can give rise to myeloid neoplasms, often characterized by prominent eosinophilia and responsiveness to imatinib. Among these, PDGFRB-rearranged myeloid neoplasms can be associated with absolute monocytosis (<1% of all cases morphologically diagnosed as CMML), usually with concomitant eosinophilia, and given their unique responsiveness to imatinib are best classified as molecularly defined neoplasms and not as CMML.

5. Causes of monoctyosis: Reactive monocytosis is very common in practice and while viral infections and recovering bone marrow (from injury, drugs or chemotherapy) are frequent causes, sustained reactive monocytosis is more common in chronic infections such as subacute bacterial endocarditis, tuberculosis, brucellosis, leishmaniasis and leprosy and in autoimmune/inflammatory disorders such as systemic lupus erythematosus, sarcoidosis and mixed connective tissue disorder. Reactive monocytosis can also be seen in the context of metastatic visceral neoplasms, either due to enhanced mobilization of monocytes from the bone marrow, or due to increased monopoiesis.

6. CMML is the most frequent hematologic neoplasm associated with SM. Always assess CMML for coexistent mastocytosis with tryptase level and aberrant expression of CD2 and CD25 on mast cells.

7. Oligoclonal CMML usually evolves ( greater than 0.5 ). Now this is considered CMML.

8. monocyte repartitioning by flow: useful tool to differentiate between JAK 2 associated CMML versus MPN with monocytosis.

9. Prognosis: MD Anderson CMML model and Mayo CMML prognostic models

Treatment

ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease. Drug therapy is currently not disease-modifying and includes hydroxyurea and hypomethylating agents; a recent phase-3 study (DACOTA) comparing hydroxyurea and decitabine, in high-risk MP-CMML, showed similar overall survival at 23.1 versus 18.4 months, respectively, despite response rates being higher for decitabine (56% vs. 31%).

In other words, in proliferative CMML HMA are only as good as hydroxyurea.

 Lower risk CMML patients that present with MPN-like features are effectively managed with hydroxyurea. Hypomethylating agents are associated with overall response rates of ~40%–50%, with complete remission rates of <20%. These responses are generally not sustained and do not alter mutational allele burdens, and survival after loss of response is often dismal (<6 months). Allogeneic HSCT remains the treatment of choice for younger patients with higher risk disease.

Unique Disease Associations

These include systemic inflammatory autoimmune diseases, leukemia cutis and lysozyme-induced nephropathy; the latter requires close monitoring of renal function during leukocytosis and is a potential indication for cytoreductive therapy.

CHIP ICUS CCUS- pre MDS states

 When cytopenias do not meet criteria for MDS and have only mild dysplasia to none, or < 5 % blasts:

1. If cytopenias: differentiate between CCUS ( MDS mutation) and ICUS ( no dysplasia or mild, no MDS mutation)

2. No cytopenia but with either MDS mutation (CHIP) or dysplasia (IDUS)

• Cytopenia+ MDS mutation--> CCUS
• No cytopenia +MDS mutation-->CHIP

Reference

Pre-MDS	Major diagnostic features and criteria
ICUS	Peripheral cytopenia(s) a , MDS criteria not fulfilled, no MDS-related mutation b found, no or only mild (<10%) dysplasia, blast cells <5% c
CCUS	Peripheral cytopenia(s) a , MDS criteria not fulfilled, one or more MDS-related mutations b found, no or only mild (<10%) dysplasia, blast cells <5% c
IDUS	No peripheral cytopenia a , MDS criteria not fulfilled, no MDS-related mutation b found, dysplasia in ≥10% of neutrophilic, erythroid, and/or megakaryocytes found, blast cells <5% c
CHIP	No peripheral cytopenia a , MDS criteria not fulfilled, one or more MDS-related mutations b found, no or only mild (<10%) dysplasia, blast cells <5% c

Neuroendocrine tumor of the midgut

 

1. Ki 67% : low-grade if they had a Ki67 index of 0 to 2%, intermediate-grade if they had a Ki67 index of 3 to 20%, or high-grade if they had a Ki67 index of greater than 20%

Differentiate between grade 3 well differentiated NET and poorly differentiated NEC: both have mitotic rate > 20, Ki 67% > 20%, but high grade NEC large and small cell can have Ki 67> 50%

If Ki 67% greater than 55% treat neuroendocrine carcinomas( NEC)  similar to small cell. Unless primary is from the lung, no data to support use of IO. Use carbo etoposide alone.

2. Location of primary:

• Midgut: jejunum, ileum, proximal colon ( before splenic flexure)
• Pancreatic NET is different from extra pancreatic NET different diseases
• Lung neuroendocrine

NETTER 2 link: all GI neuroendocrine whereas NETTER 1 was for small bowel NET

How is Lu 177 given?

• Start arginine lysine infusion 30 min before start of Lu 117 infusion. Total 4 hr infusion.
• Lu 177 runs for 30 mins.
• At the end of arginine lysine infusion for 4 hr, give IM octreotide 30 mg .
• Lu 117 q 8 weeks times 4 doses+ octreotide LAR 30 mg q 4 weeks.

Reference: NEJM 2017 NETTER 1

CABINET Study: Cabozantinib

Hemolytic anemia- Warm and Cold

Hemolytic anemia 

Initial work up for hemolytic anemia:

1. CBC, retic count, haptoglobin, peripheral smear ( spherocytes/ RBC agglutination, nucleated RBC), urinanalysis, LDH. Ig M causes direct agglutination, spherocytes in warm AIHA

2. DAT Coomb's, Cold agglutinin titer

3. CT CAP

4. Bone marrow biopsy, SPEP IFE, Total immunoglobulins, flow cytometry

5. ANA, hx of rheum disorders

6. HIV, Hep B, C, mycoplasma Ab, EBV

7.C3, C4

8. Drug history, UDS when indicated

9. Consider work up and coverage for infections if fever

Symptoms:

- dizziness, fatigue, abd pain, fever, jaundice

Exam: 

-pallor, icterus, adenopathy, hepatosplenomegaly ( depending on underlying cause)

Reaction pattern of DAT

Ig G alone or Ig G +C3--> drug induced, warm AIHA

Complement alone: 4 possiblities-->

1. CAD ( anti I antigen with MGUS)
2. Warm AIHA with low titer Ig G or IG A bound to RBC--> get Super Coomb's
3. Paroxysmal cold hemoglobinuria( Donath Landsteiner Ab which is Ig G against P antigen, but fixes complement)
4. Drug induced--> immune complex/ternary

Drug induced HA DAT patterns

1. Hapten ( drug dependent, ex PCN): Ig G
2. Ternary complex ( also drug dependent, ex 3rd gen cephalosporin): C3
3. True autoantibody ( not drug dependent, ex methyldopa): Ig G+ C3

Reticulocytopenia in AIHA

- folate def

-bone marrow infiltration from malignancy

-intercurrent infection

What does not work in cold AIHA: steroids, splenectomy, IVIG

Life threatening cold AIHA--> plasmapheresis to remove the IG M antibody

Discussion:

1. Warm AIHA :For patients with mild to moderate hemolysis, the recommended dose is prednisone 1 to 2 mg/kg per day for three days. Patients with severe hemolysis typically receive a high dose of steroids, such as methylprednisolone 250 to 1,000 mg per day for three days. Up to 80% of patients respond to steroids, typically within four to seven days of therapy initiation.

2. If a patient’s disease has not responded within three weeks of therapy, pt has refractory disease. 

3. For patients whose disease does not respond to steroids within two to three weeks, the next option is a course of rituximab, typically 375 mg/m2 for four weeks, which usually induces responses in 80% of patients and long-term remissions in about 60% to 70%. Rituximab is rarely used up front because it takes about a month to work while steroids begin to work within days. Patients who relapse can subsequently be treated successfully with additional courses of rituximab.

4. If severe hemolysis can use high-dose intravenous Ig. 

5. PRBC transfusion if brisk hemolysis. Patients with severe disease, particularly in cases of brisk hemolysis and precipitous anemia, may require RBC transfusions, which can be lifesaving.t RBC transfusions are discouraged for the average patient with wAIHA, but are important in some cases and not contraindicated.

6. Refractory to steroids and rituxan: approximately 25% of patients whose disease does not respond to rituximab, splenectomy is a possible treatment option for patients who are eligible. If a splenectomy does not produce the desired response, or if a patient is too medically sick to undergo surgery, additional therapy options include immunosuppressive drugs such as azathioprine, cyclosporine, bortezomib, and daratumumab.

7. Steroid dependent: use low dose prednisone maintenance

Treatment:

• Blood transfusion for severe anemia (usually with inappropriate reticulocyte response)

• For drug-induced warm antibody hemolytic anemia, drug withdrawal and sometimes IV immune globulin

• For idiopathic warm antibody hemolytic anemia, corticosteroids and, in refractory cases, rituximab, IV immune globulin, immunosuppression (eg, with azathioprine, mycophenolate mofetil, or cyclophosphamide), or splenectomy

• For cold agglutinin disease, avoidance of cold and treatment of underlying disorder. Splenectomy is usually of no value, and immunosuppressants have only modest effectiveness.

• For PCH, avoidance of cold, immunosuppressants, and treatment of syphilis if present. In children, this disease is often self-resolving. Splenectomy is of no value. Treatment of concomitant syphilis may cure PCH.

Blood transfusion is the most important treatment for patients who have symptoms and who rapidly develop severe, life-threatening anemia. In this situation, transfusion should never be withheld due to lack of "compatible" units. In general, patients who have not had a previous blood transfusion or been pregnant are at low risk for hemolysis of ABO-compatible blood. Even if transfused cells are hemolyzed, blood transfusion can be life-saving until more definitive therapy can be done. Erythropoietin may be given if the reticulocyte response is inadequate.

Reference: Merck Manual

What is transient abnormal myeloiesis in Down's?

 Transient abnormal myelopoiesis (previously transient myeloproliferative disorder) is a clonal hematopoietic disorder unique to patients with trisomy 21.

GATA 1 mutation is the key feature. PB blasts usually between 10-30%.

TAM resolves in 80% spontaneously.

When the cells acquire additional mutations-->Down's associated leukemia--> megakaryoblastic leukemia that is distinct from the one occurring in non-DS patients

What is JMML? Pathway affected?

Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder characterized by excessive proliferation of granulocytic and monocytic lineage cells.

RAS pathway is key.

ASH ed book 2023

Sarcoma RTP

1. Synovial sarcoma advanced- MAGE A4 T cell re-engineered therapy FDA approval 

2. types of sarcoma in which IO can be useful:

Angiosarcoma

undifferentiated pleomorphic sarcoma

3. Types of chemo sensitive sarcoma

- Ewing's, osteosarcoma, rhabdomyosarcoma, myxoid or round cell liposarcoma( very sensitive to chemo)

4.  Liposarcoma 15-20%, another 15-20% leiomyosarcoma

5. 5 different types of liposarcoma:

- well differentiated--> indolent, surgery is the main Rx

-dedifferentiated--> aggressive, not sensitive to radiation, doxorubicin can be used +/- ifosfamide. Low ORR 20%, not much to be gained with 2 agents, pFS 2-4 m, 2nd line eribulin or trabectedin per FDA, although gem taxotere can be used 1L or 2L.

-myxoid or round cell--> chemo sensitive, T cell therapy is effective, very sensitive to radiation as well

6. What's with MDM2: Even in cells that have wild type P53, MDM2 amplification can inactivate the protective effects of p53.

90% of liposarcoma, it’s a universally MDM2 amplified in all these liposarcomas, and p53 is rarely mutated.

 In lung cancer nearly 10% of lung cancer has MDM2 amplification, they have p53 wild-type. Head and neck cancers, bladder, everything is 10% or so, have high levels of MDM2 amplification and wild-type p53.

prostate 7%, breast 5%, GBM a whopping 25% have MDM2 amplifications. 

7. Brigimadlin now of interest in gall bladder ( MDM2 inhibitor) cancers https://ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.487

Immunotherapy Side effect management CCO tool

Clinical options Interactive tool

General steps:

1. Establishing the diagnosis and grading the severity

2. Differential diagnosis and baseline work up

3. Empiric rx

4. Re-evaluate at 72 hr

Grade 3- self care ADL affected:  "can't go to the bathroom" or grade 4- can't breathe at rest or sleep--> ER urgent evaluation. Dyspnea + fever in a pt on chemoimmunotherapy--> ER

Grade 2- " sleeping most of the day", need help with groceries i.e instrumental ADL

ASCO guideline: grade 3 ICI pneumonitis: high dose CS, stop ICI

Rx: high dose CS, if no response in 72 hr, infliximab, consider IVIG ( case reports, immunomodulatory effects, 1mg/kg bwt for 3 days)

ASCO guideline

Algorithm

Hemolytic anemia

 

Pearls

1. Hemolysis due to Ig M cold antibodies which cause agglutination and complement mediated destruction of RBC when temp is less than body temp.

2. Cold agglutinin titer at > 1/64 at 4 degree celsius, C3d+ on DAT

3. Fatigue out of proportion to anemia, peripheral vascular symptoms due to clumping RBC

4.  Treatment options:

- steroids generally ineffective

-Rituxan 50% effective. Can be combined with benda or fludarabine.

- eculizumab not effective in raising Hb

- dara helpful 8 weekly doses; may do maintenance

-sutimlimab C1 inhibitor--> 80% improvement in HB but no effect on peripheral symptoms.

5. Supportive care: avoidance of cold, warm blood product, avoid warming blankets ( can lead to gangrene).

Pearls ASH 2024 Hematology series

 1. CLL patients often have warm AIHA. If neg DAT, could be due to high activity low titer antibody

2. Amlodipine and Keflex can cause drug associated hemolytic anemia

3. Upto 10% of warm AIHA can be DAT neg. If less than 100-500 molecules per RBC can be low titer but high activity.

4. Spherocytes are seen Warm hemolytic anemia, cold hemolytic anemia have agglutination. Raynaud's are seen in Cold AIHA.

5. Spherocytes are seen in : hereditary spherocytosis but not in thalassemia. Spherocytes are also seen in spider and scorpion bites, thermal injury.

Reference: https://www.tandfonline.com/doi/pdf/10.1080/17474086.2024.2366540