NCCN updates 2021 Heme malignancies

 AML

Newly diagnosed AML

a. If CBF positive--> add GO to 7+3

b. FLT 3 mutation positive--> add midostaurin to 7+3 ( age 18-60 yr per study, not per FDA label)

c. Secondary AML or t-AML--> use CPX351( liposomal cytarabine with daunorubicin 5:1 ratio) CPX-351 had a higher median OS than 7 + 3 (9.56 vs 5.95 months

Elderly AML not fit for intensive treatment

Venetoclax with Aza or decitabine

Low dose cytarabine with venetoclax

IDH1 (ivosedinib) and IDH2 inhibitor Enasedinib can be used in this space although unclear if better than venetoclax based therapy

Bladder cancer

 These are hypothetical cases

67 yo M, former smoker with a 30 pack year history of smoking, presents with 2 weeks of gross hematuria and mild abdominal pain. No weight loss or bone pain.

His labs show mild anemia with Hb 11 gm. No elevation of alkaline phosphatase or creatinine. GFR 65. PET scan is negative for distant disease. There is one suspicious lymph node near the bladder 1.2 cm in size.

He undergoes cystoscopy which showed a T2 lesion invading the muscularis propria.

1. What is the standard of care treatment in patients with T2 bladder cancer?

Ans: Neoadjuvant cisplatin-based chemo followed by surgery.

2. What is the ideal chemo regimen?

Ans: Both DDMVAC and gem-cisplatin are recommended, but data suggest that in the NACT setting DDMVAC is superior in terms of path CR and PFS. 

PFS 66% versus 56% 3 yr. 

My comment on this trial: They used 6 cycles DDMVAC rather than 3 cycles as in NCCN.

They were compared head to head in the following trial:

https://ascopost.com/news/september-2021/dd-mvac-vs-gemcitabinecisplatin-for-muscle-invasive-bladder-cancer/

3. What if the patient has residual disease at surgery?

The current SOC is surveillance. The risk of recurrence is high. Average DFS is 11 months.

Checkmate 274 showed DFS 21 months ( all comers) and median DFS not reached ( if PDL1> 1%) instead of 11 months in those who received nivolumab. This was irrespective of PDL1, but robust if PDL1> 1%.

Data is not mature for OS.

https://ascopost.com/issues/digital-supplement-genitourinary-cancer-almanac-2020-2021/nivolumab-first-adjuvant-immunotherapy-to-show-survival-benefit-in-high-risk-muscle-invasive-urothelial-cancer/

If a patient with a T1 lesion underwent a TURBT, which of the following is NOT true:

a. Gemcitabine and mitomycin are both category 1 recommendations for post TURBT intra vesical chemo

b. Intravesical chemo should be given within 24 hr, ideally 6 hr

c. Thiotepa is just as good as the first 2 agents

d. Intravesical chemo reduces recurrence by 35% in 5 yr, NNT=7

e. Bladder perforation and allergy are contraindications to post-op intravesical chemo

f.  This is not effective in patients with > 1 recurrence per year and more than 8 tumors in the bladder

Who are the patients who can undergo bladder preservation?

Solitary tumors < 3cm, no tumor related hydronephrosis, no CIS, no nodes, good renal function.

Bleeding and Thrombosis in Hematological conditions

 Bleeding in patients with heme malignancies

1. Thrombocytopenia in heme malignancies

2. MPN

3. Tyrosine kinase inhibitors: Ibrutinib, dasatinib

4. APL

Low plt count in heme malignancies

1. PLADO Study: NEJM 2010

Adults had lower bleeding than children. Highest risk of bleeding were as follows:

unrelated donor allo> chemo for heme malignancies> auto/ related donor allo

> 25% bleeding if plt< 5K, 8% bleeding if plt count > 80K

2. Where did the 10K prophylactic threshold come from?

Wandt 2012 Lancet

The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia

3. Hypoproliferative low plt more likely to bleed than ITP.

No linear relation between 10K in ITP compared to other causes.

Myeloproliferative neoplasms

U shaped phenomenon

Rate of bleeding is lowest between 200-600K. Above 600K or lower than 200K  higher bleeding noted.

> 600K--> Why is bleeding seen? Reasons below:

• acquired VWD. 
• reduced fibrinogen binding leads to acquired plt dysfunction. 
• endothelium in MPN contribute to bleeding phenotype. JAK2 mutations+ can be seen in the endothelium

Aspirin major hemorrhage 0.4% P vera low dose ASA, any bleeding 9%

What if the patient is already on aspirin, gets diagnosed with P vera or ET, and now has a new clot?

REVEAL study

Answer: stop asa, switch to anticoagulation if new VTE while on aspirin due to 3 fold increased risk of bleeding in MPN

Tyrosine kinase inhibitors in Heme malignancies

a. Ibrutinib: affects collagen mediated plt aggregation through glycoprotein receptors. Any bleeding 38%, risk of major bleed ( 3/4) 3%. Mantle cell has a higher overall risk of bleeding, unclear if this is due to ibrutinib.

Low plt count prior to starting ibrutinib was the greatest predictor of hemorrhage.

What about the need for aspirin or anticoagulation in patients with ibrutinib?

Aspirin is ok, 

AC does cause increased bleeding, but combination of Aspirin and AC significantly increases bleeding

b. Dasatinib: overall hemorrhage 25 %, rarely severe.

Most bleeding is GI bleeding.( lower GI 59%,22% UGI). Bleeding can happen even if plt >100K.

Like ibrutinib, dasatinib also inhibits plt aggregation mediated through collagen. But unlike ibrutinib, antiplatelet effects are reversible in 48 hr.

Acute promyelocytic leukemia

low plt, low fibrinogen, increased PT/PTT

5% intracranial hemorrhage

Increased fibrinolysis also noted. (Increased Annexin 2 on APL cancer cells overwhelms natural alpha-2 antiplasmin leading to fibrinolysis)

ATRA corrects the above mechanism by reducing Annexin 2.

Coagulopathy of APL management:

a. start ATRA empirically in the ER

b. Fibrinogen > 150 rather than 100 ( cryo or fibrinogen concentrates)

c. Plt target count > 20-30K

d. avoid invasive procedures

Hematological neoplasms and thrombosis

 Risk assessment models

ET- IPSET-T

Lymphoma Rome model

Myeloma SAVED and IMPEDE models

Khorana risk score over estimates risk of thrombosis in indolent lymphoma so does not work.

DOAC can be used based on studies such as ADAM-VTE, Caravaggio, Hokusai etc, but the percentage of heme malignancies was low.

Interestingly, heme malignancies:

- have more arterial thrombosis

- thrombosis at unusual sites

- can be due to treatment leading to thrombosis

Hypereosinophilic syndrome

If eosinophil count > 6K and duration of disease > 12 months, higher risk of thrombosis

1/2 are arterial, 1/2 venous events

40% can have thrombosis

May benefit from prophylaxis in ambulatory setting.

No increased risk of bleeding.

Chronic MPN

JAK2 and MPL higher risk of thrombosis, compared to wildtype

Arterial thrombosis 60-70%

CNS, splanchnic 15%

Platelet counts do not correlate with thrombosis, but rather WBC count > 15K correlates with thrombosis

Ruxolitinib rx reduced risk of VET ( 1.2% versus 8% best available rx)

Hct < 45 and aspirin 100 mg ( RR0.42) improves thrombosis free survival(ECLAP study)

AIRPORT MPN- ongoing study comparing apixaban versus aspirin

JAK2 mutated CHIP

25% with thrombosis, consider aspirin prophylaxis

CML

Is not prothrombotic, but imatinib ( 1% at 1 yr), nilotinib( 6%) ponatinib ( 25%).

Aspirin or plavix for prophylaxis. Consider dose reduction of ponatinib.

MDS 5 q minus

Platelets are higher, rx with lenalidomide should be prophylaxed

ALL

Risk factor: CVC, age, L asparaginase

Over 30 yr 40% risk of thrombosis with L asparaginase

CNS thrombosis in regimens with L asparaginase

Lymphoma

Risk of thrombosis < 5% HL, indolent

15% NHL

Primary mediastinal B cell with bulky masses 70% have thrombosis at presentation

Primary CNS lymphoma also with high VTE

Compression is an important factor, 95% happen in the first month

Rome score is the best for lymphoma

Three risk levels: Highest risk ( CNS involvement), intermediate ( poor PS, bulky disease), everything else is standard risk.

No guidelines for prophylaxis

MGUS:

Not associated with increased risk of  Thrombosis, except light chain MGUS 

Myeloma

use risk stratification tools liked SAVED and IMPEDE score.

DOAC can be used for prophylaxis ( high risk) ,aspirin for low risk. DOAC not approved but US phase IV trial.

Pearls:

1. Elevated PT/PTT in non APL leukemia

- there is no correlation in a nonbleeding patient

- no need to provide FFP in nonbleeding patient without liver issues

2. Coronary angioplasty in Ibrutinib? If antiplatelet or AC needed, change Rx for CLL? Consider switching to acalabrutinib or zanubrutinib.

3. ALL : LMWH versus heparin ( UFH with antithrombin)

Coagulopathy of L aspariginase therapy: Guidance statement ISTH

4. Empiric antifibrinolytic therapy is not recommended in APLA thrombosis in CNS.

5. Afib in MPN: if non valvular Afib, ok to start 

6. Stopping TKI before surgery: Dasatinib is reversible, Ibrutinib is not reversible ( covalently binds) platelets and inhibits collagen induced aggregation

7. What anticoagulation if thrombocytopenic patients with heme malignancy?

Emcizumab- new bispecific antibody for hemophilia A

 Emcizumab

The new kid on the block for hemophilia patients.

Key points:

1. This is a bispecific antibody that restores the function of factor 8. It binds to factors 9 and 10, and activates the clotting.

2. Subcutaneous, can be given every 2-4 weeks.

3. Injection site pain, swelling. Risk of clotting in those with previous factor 8 inhibitors.

4. Do not combine with APCC.

Inherited bone marrow failure syndromes ASH education 2020

 Fanconi Anemia

Diamond Blackfan

Short telomere syndrome

Fanconi Anemia

1. Use radiation-free RIC conditioning regimens

2. Bone marrow T replete is the preferred source, since peripheral blood is associated with higher risk of malignancies and GVHD

3.  Fanconi anemia- confirm with DEB test. HCT in indicated before MDS, AML and transfusion dependence. Low-dose cyclophosphamide (CY) 20 to 40 mg/kg and fludarabine with or without antithymocyte globulin (ATG) is the most common regimen. OS over 90%. 

4. Androgens in the aplastic phase while awaiting HCT can lead to response in 80% of patients.

5.  What to counsel and monitor when giving androgens: does not prevent clonal evolution. Need to monitor for LFT abn, liver adenomas, lipid issues and virilization in young girls. Donor may not be available later.

6. HCT after MDS or AML leads to lower survival. Less than 50% at 5 yr

7. FA patients continue to be at risk for developing cancer after transplant, especially head and neck SCC, and the use irradiation-containing regimens and/or GVHD may increase the incidence of this complication. Lifelong aggressive surveillance for early detection of cancer is recommended because the treatment options in FA are limited

Telemore biology disorder-- Dyskeratosis congenita 

1. TINF2 mutation

2. Dyskeratosis congenita (DC) represents the prototype of TBD and is characterized by bone marrow failure and the classical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy.

3. Pulm AV malformations, GI telangiectasia common. Can develop hepatopulmonary shunts.

4. 10 yr survival after HCT only 30%.

Diamond Blackfan

1. Defective ribogenesis

2. standard of care for DBA includes corticosteroids and chronic transfusions with adequate iron chelation

3. Chelation when patient has received 200 ml/kg bwt of transfusion.

4. HCT is the only curative option for the hematologic manifestations of DBA and is recommended for patients who fail to respond to corticosteroids and/or need chronic transfusion. We and others consider treatment failure as needing corticosteroids (dose >0.3 mg/kg per day) to maintain hemoglobin >8 g/dL.

5. Screen potential donors for silent DBA trait. Test- elevated erythrocyte deaminase

Others:

Shwachman-Diamond syndrome is a recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. Malignant transformation is frequent, ranging between 5% and 25%. The indications for transplant are worsening cytopenias and transformation into MDS and AML

Locally advanced TNBC

 
Triple-negative breast cancer

- Total 12% of all breast cancer

- Worst 5 yr survival 77% ( HR-positive, HER 2 neg 5 yr survival 92%)

- Clinical pearl--> abnormal-looking LN by imaging should be percutaneously biopsied; avoid sentinel LN staging before neoadjuvant chemo if that is being planned in order to accurately assess response.

-Distant recurrent rates are similar with adjuvant versus NACT

-RCB should be noted in the post op specimen

-recent meta-analysis of 5,161 patients treated with NAC, 5-year event-free survival among those with TNBC was 91% for RCB-0 (indicating pCR), 80% for RCB-I, 66% for RCB-II, and 28% for RCB-III disease

-CREATE-X trial: capecitabine improved disease-free survival and OS, with a particular benefit among patients with TNBC (5-year disease-free survival, 69.8% in the capecitabine group v 56.1% in the control group; hazard ratio, 0.58; 95% CI, 0.39 to 0.87)

Surgery after NACT-- mastectomy versus breast conserving surgery

• risk factors for local recurrence after NAC and breast-conserving therapy:
• cN2/3 disease
•  presence of lymphovascular space invasion
• residual tumor > 2 cm
• multifocal pattern of residual disease

 If multiple risk factors are present, the local recurrence risk after breast conservation exceeds 10% despite optimal surgery and radiation therapy.

What is the rate of recurrence in breast for those undergoing BCS?

Path CR: inbreast recurrence 0 to 2.6% irrespective of subtype

No path CR: in breast recurrence varies with hormone status/ HER 2 status did not matter

• HR positive 5%
• HR negative 10-13%

Radiation after lumpectomy

hypofractionated whole-breast irradiation (40 Gy in 15 fractions plus a boost of 10-16 Gy in five to eight fractions) is typically recommended

Regional nodal radiation

cT1/2 N0 breast cancer, PMRT/RNI is not generally recommended, provided these tumors remain pathologically node-negative after NAC. Locoregional recurrence of 6% in 10 years.

RNI should be done for those with clinical node positivity who remain node positive. The recurrence is 13 to 40% without radiation.

However, ongoing clinical trial looking at RNI versus no RNI if nodal path CR in cT1-T3 N1 disease. NRG B-51.

Patients with more advanced disease, such as cT4 or N2 or N3, PMRT/RNI is always recommended regardless of pathologic response.

JCO grand rounds

Consensus guidelines on management of axilla

NeoSTOP trial : a phase II anthracycline free chemo regimen

Two cases- RCC stage 4, early upper tract urothelial

Cases

1. Renal cell ca

 68 yo M with T1b left renal mass s/p partial nephrectomy.

Pathology: Clear cell without sarcomatoid features

Fuhrman 3. Final stage pT1b Nx

11 months later with peritoneal nodules.

KPS90

IMDC intermediate risk

Started on ipi+nivo--> progression

What are the factors to consider:

a. Progression versus pseudoprogression

b. The pace of progression slow ie > 18 months, quick < 6 months, or something in between

c. How symptomatic

d. Brain mets- yes or no

Choice of agent: second line, consider cabozantinib

If slow progression, consider axitinib pembro, otherwise lenvatinib with everolimus

2. Upper urinary tract cancer

70 yo M with right renal pelvis urothelial tract tumor presented with hematuria.

Undergoes stent placement.

What is the role of adjuvant treatment?

POUT trial showed 3 yr DFS benefit with adjuvant chemo ( platinum with gem) for pT2 or higher, or node-positive upper tract high grade urothelial.

LN dissection must be performed in high-grade urothelial cancer.

Intravesical post-op and adjuvant ( i.e 3-4 weeks after) for those not candidates for nephroureterectomy. Typical agents mitomycin, gemcitabine for both post-op and adjuvant.

BCG can be done adjuvant weekly for 6 weeks, then SWOG protocol for up to 2 yr.

A note about adjuvant nivolumab for 1 yr---> benefit in bladder but not upper tract cancer if no path CR after NACT or ineligible for cisplatin  based adjuvant for high risk early tumors.

https://ascopost.com/issues/digital-supplement-genitourinary-cancer-almanac-2020-2021/nivolumab-first-adjuvant-immunotherapy-to-show-survival-benefit-in-high-risk-muscle-invasive-urothelial-cancer/

Most patients had bladder tumors (79%), with the remaining having tumors of the upper tract; 40% had PD-L1–positive disease, and 43% had previously received neoadjuvant therapy.

Minimum follow-up was 5.9 months; median follow-up of both the nivolumab and the placebo groups was around 21 months. Treatment discontinuations were reported in 53.3% of the nivolumab group and 56.3% of the placebo group, most commonly due to recurrent disease.

Subgroup analyses of the intent-to-treat group showed that the disease-free survival benefit was driven by patients with tumors of the urinary bladder, with a 38% improvement with nivolumab, and no benefit was observed for those with tumors of the renal pelvis or ureter.

Guidance on cancer associated thrombosis

1. VTE prophylaxis in hospitalized oncology patient

ASCO- acutely ill patients recommend LMWH. It does not recommend thromboprophylaxis in patients admitted for chemotherapy or stem cell transplantation. 

Prophylaxis may be offered to hospitalized medical oncology patients without risk factors

NCCN 2020- MLWH, UFH or fondaparinux if no contraindication

ISTH 2014- Recommend pharmacologic thromboprophylaxis for patients with platelets ≥50,000/μL.

Suggest individualized approach to patients with platelets 25,000–49,000/μL.

Recommend against pharmacologic thromboprophylaxis in patients with platelets <25,000/μL

International Initiative on Thrombosis in Cancer 2019

Recommend LMWH or fondaparinux (when CrCl is ≥30 mL/min) or UFH recommended in hospitalized patients with cancer and reduced mobility (grade 1B). DOACs not recommended routinely in this setting (guidance).

Patients with acute medical illness or reduced mobility should be offered

pharmacological thromboprophylaxis in the absence of bleeding or other

contraindications. (Recommendation type: evidence-based; evidence quality:

intermediate; strength of recommendation: moderate.

2.  Ambulatory oncology patients

ASCO- routine thromboprophylaxis for all patients not indicated. High risk or intermediate risk cancer patients with Khorana score 2 or higher may benefit. LMWH or DOAC.

Patients with multiple myeloma receiving thalidomide‐ or lenalidomide‐based regimens with chemotherapy and/or dexamethasone should be offered thromboprophylaxis with either aspirin or LMWH (lower‐risk patients) or LMWH (higher‐risk patients). (Recommendation type: evidence‐based; evidence quality: intermediate; strength of recommendation: strong.)

NCCN 2020- Consider apixaban or rivaroxaban for up to 6 months in high‐risk patients with cancer (KRS ≥2) starting a new chemotherapy regimen (grade 2A).

Recommend LMWH or VKA (INR 2–3) for high‐risk patients with myeloma (IMPEDE‐VTE score >3 points or SAVED score ≥2 points) (grade 2A).

Recommend aspirin (81–325 mg daily) or no prophylaxis for low‐risk patients with myeloma (IMPEDE‐VTE score ≤3 points or SAVED <2 points) (grade 2A).

3. Cancer patients- perioperative prophylaxis

ASCO 2020- All patients undergoing major surgery should be offered pharmacological prophylaxis with UFH or LMWH unless contraindicated. (Recommendation type: evidence‐based; evidence quality: high; strength of recommendation: strong.)

Prophylaxis should be commenced preoperatively,ct up to 4 weeks in high risk abdominal or pelvic surgery.

What is high risk: obesity, immobility, prior VTE.

ITAC: high risk--anesthesia time >2 hours, gastrointestinal (GI) malignancies, previous VTE, advanced‐stage disease, bed rest of ≥4 days, or age >60 years in addition to ASCO high risk

International Initiative on Thrombosis and Cancer 2019

LMWH (if CrCl ≥30 mL/min) once daily or low‐dose UFH three times a day is recommended. Pharmacologic prophylaxis should be started 2–12 hours preoperatively and continued for at least 7–10 days. No data to suggest one LMWH superior to another (grade 1A). Values and preferences: Once‐daily LMWH more convenient.

4. Cancer associated thrombosis

ASCO: For patients with primary or metastatic CNS malignancies and VTE, anticoagulation should be offered, although uncertainty remains as to choice of agent and the type of patients most likely to benefit.

No role for IVC filter except absolute CI to anticoagulation; progressive thrombosis despite maximal anticoagulation 

Rx LMWH, DOAC, fondaparinux. 

Duration of rx for CAT--> ASCO 6 months or beyond for those with metastatic disease. NCCN recommends 3 months at least or for as long as cancer is active or undergoing treatment, whichever is longer 

DOACs are associated with increased major bleeding in GI and potentially GU malignancies. Caution with DOACs is warranted in other settings with high risk for mucosal bleeding. Drug‐drug interactions should be checked before use of DOACs

ISTH-Suggest edoxaban and rivaroxaban for patients with cancer with acute VTE, a low risk of bleeding, and no drug‐drug interactions. LMWHs are an acceptable alternative. Suggest LMWH for patients with acute VTE at high risk for bleeding, including those with luminal GI malignancy with intact primaries, GU malignancies, nephrostomy tubes, or GI mucosal abnormalities. Edoxaban and rivaroxaban are acceptable alternatives if no drug‐drug interactions.

IVC filters may be considered for initial treatment when anticoagulation is contraindicated or when PE occurs despite optimal anticoagulation.

In the event of recurrent VTE, three options can be considered: (a) increase LMWH by 20%–25% or switch to DOAC; (b) for DOACs, switch to LMWH; and (c) for VKAs, switch to LMWH or DOAC.

NCCN 2020- Apixaban (category 1), edoxaban after at least 5 days of parenteral anticoagulation (category 1), or rivaroxaban (category 2A) preferred over LMWH for patients without GI malignancies.

Dabigatran after at least 5 days of parenteral anticoagulation (alternative to apixaban, edoxaban, rivaroxaban, or LMWH if not appropriate or unavailable) (category 2A).

LMWH (dalteparin category 1) preferred over DOACs in patients with GI malignancies.

Apixaban and edoxaban are contraindicated in patients with clinically significant liver disease (total bilirubin >1.5 × ULN or transaminases >2 × ULN). Dabigatran and rivaroxaban are contraindicated if transaminases >3 × ULN.

Dabigatran, edoxaban and rivaroxaban are contraindicated with CrCl <30 mL/min. Apixaban is contraindicated if CrCl <25 mL/min.

Apixaban and rivaroxaban should not be used in conjunction with strong inducers/inhibitors of CYP3A4 and P‐glycoprotein.

Dabigatran and edoxaban should not be used in conjunction with strong inducers/inhibitors of P‐glycoprotein.

Recurrent VTE -treatment

For recurrent VTE on UFH, recommend considering HIT, antiphospholipid syndrome (check UFH anti‐Xa level), increase dose of UFH, or switch to LMWH or DOAC (category 2B).

For recurrent VTE on LMWH, recommend considering HIT, switch to twice‐daily injections or increase dose or switch to fondaparinux or DOAC (category 2B).

For recurrent VTE on fondaparinux, recommend considering HIT or switching to UFH, LMWH, or DOAC (category 2B).

For recurrent VTE on warfarin, recommend switching to LMWH, UFH, fondaparinux, or DOAC (category 2B).

For recurrent VTE on DOAC, recommend switching to LMWH or fondaparinux (category 2B).

https://theoncologist.onlinelibrary.wiley.com/doi/epdf/10.1002/onco.13596

Antibody drug conjugates in solid tumors

 Solid tumor

1. Enfortumab

2. Sacituzumab

3. TDM-1

Heme malignancies

1. Gemtuzumab

2. Brentuximab

3. Inotuzumab

Enfortumab

ADC targets Nectin-4

Approval 2019

Indication: locally advanced or stage 4 bladder ca, who have progressed on both platinum( or ineligible) and PDl-1 agent

Dose 1.25 mg/kg , max 125 mg, weekly 3 weeks on 1 week off, 28 day cycle

Side effects and issues to watch for:

a. DM: Do not start if CBG > 250.  Closely monitor CBG weekly. Can be seen even in those without DM.

b. Eye issues:  Baseline eye exam, prophylactic eye drops for dry eyes, consider steroid eye drops. Regular eye exam.

c. Peripheral neuropathy- hold, dose reduce

d.  Skin reaction: consider antihistamine prophylactic

 Dose Modifications 

 Hyperglycemia :Blood glucose >250 mg/dL Withhold until elevated blood glucose has improved to ≤ 250 mg/dL, then resume treatment at the same dose level.

 Peripheral Neuropathy  Grade 2 Withhold until Grade ≤1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤1 then, resume treatment reduced by one dose level. Grade ≥3 Permanently discontinue. 

Skin Reactions: Grade 3 (severe) Withhold until Grade ≤1, then resume treatment at the same dose level or consider dose reduction by one dose level. Grade 4 or recurrent Grade 3 Permanently discontinue.

 Other nonhematologic toxicity Grade 3 Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level Grade 4 Permanently discontinue. 

 Hematologic toxicity Grade 3, or Grade 2 thrombocytopenia Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level. Grade 4 Withhold until Grade ≤ 1, then reduce dose by one dose level or discontinue treatment. 

Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. 

 Recommended Dose Reduction Schedule

 Dose Level Starting dose 1.25 mg/kg up to 125 mg 

First dose reduction 1.0 mg/kg up to 100 mg 

Second dose reduction 0.75 mg/kg up to 75 mg 

Third dose reduction 0.5 mg/kg up to 50 mg

Sacituzumab

Target: Trop 2 Ab with a topoisomerase inhibitor SN-38 ( similar to irinotecan, therefore caution with UGT1-A inhibitors)

Approval: 2020 breast cancer, 2021 bladder cancer

2 indications: 

-Metastatic TN breast cancer after 2 lines of treatment for MBC

- metastatic bladder cancer

Dose: 10 mg/kg body weight, IV day 1, day 8, q 21 days

ORR in bladder cancer in single-arm trial 27%

Bladder cancer: TROPHY trial, a single-arm, multicenter trial that enrolled 112 patients with locally advanced or mUC who received prior treatment with platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. 

AE: neutropenia, nausea, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain

TNBC, stage 4: pFS 5.6 months, OS 12 months. ORR 35%NEJM Sacituzumab

DLT- diarrhea, neutropenia ( black box warning for both)

Hold for grade 3 diarrhea and ANC< 1500

Neratinib induced diarrhea

 Prophylaxis:

Current diarrhea prophylaxis recommendations are 4 mg with the first dose of neratinib, then 4 mg 3 times on day 1 (for a total of 16 mg on day 1), 4 mg 3-times daily (for a total of 12 mg/day) on days 2 and 3, reducing to 2 mg 3- or 4-times daily (for a total of 6-8 mg/day) for the remainder of the first cycle. Nonpharmacologic interventions, including dietetic changes and increased fluid intake, are recommended for new-onset uncomplicated diarrhea.

1. Activated charcoal62 and oral alkalinization63 may be beneficial for irinotecan-associated diarrhea

2. Probiotics may have a role in preventing 5-fluorouracil (5-FU)-related diarrhea. However, studies of prophylactic octreotide and an intestinal adsorbent did not show benefit.

Reference:

Neratinib diarrhea

BCCA guideline diarrhea general

ESMO guidelines

Burkitt's lymphoma- review

 Reference:

Blood Journal Feb 2021

Burkitt's is a highly aggressive B cell lymphoma.

Key points:

1. Sporadic, endemic, immunodeficiency associated.

2. Molecular feature is translocation and dysregulation of proto-oncogene- c-myc. t(2:8) or t(8:22) with heavy chain on chr 2 or light chain on chr 22 with c-myc gene on chromosome 8.

3. Endemic Burkitt's--> equatorial Africa, chronic B cell stimulation due to EBV. bm not involved but extranodal involvement of GI tract, adrenals, kidneys, and gonads, is common

4. Sporadic is more common in the western world. CNS and bm involvement common. Leptomeningeal rather than parenchymal is common.

5. HIV-associated Burkitt's is seen in patients with preserved CD4 counts, so ART has not changed the incidence. Nodal involvement is typical, but can also have CNS, GI, and bm involvement.

6. TLS is a medical emergency and can be seen even before treatment starts ie. spontaneous TLS.

evidence of spontaneous TLS or those at high risk, defined as stage III/IV disease and/or LDH ≥2 times the upper limit of normal, consensus guidelines recommend the use of rasburicase

Copyright ASH 2021

Treatment:

1. Low risk- single lesion < 10 cm, or resected abdominal disease and normal LDH-CODOX-M 3 cycles

The CODOX-M regimen is as follows:

• Cyclophosphamide 800mg/m² IV on day 1, followed by 200 mg/m² IV on days 2-5

• Doxorubicin 40 mg/m² IV on day 1

• Vincristine 1.5 mg/m² IV (no capping of dose) on days 1 and 8 (cycle 1), as well as on days 1, 8, and 15 (cycle 3)

• Methotrexate 1200 mg/m² IV over 1 hour on day 10; then 240 mg/m²/h for the next 23 hours; leucovorin rescue begins 36 hours from the start of the methotrexate infusion

• Intrathecal cytarabine 70 mg (patient older than age 3 y) on days 1 and 3

• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 15

2. All other patients i.e. high risk-CODOX-M alternating with IVAC for 2 cycles. Add Rituxan to this regimen if using.

The IVAC regimen is as follows:

• Ifosfamide 1500 mg/m² IV on days 1-5, with mesna protection

• Etoposide 60 mg/m² IV on days 1-5

• Cytarabine 2 g/m² IV every 12 hours on days 1-2

• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 5

Administration of colony-stimulating factors is usually started 24 hours after completion of chemotherapy and continues until the ANC >1000/μL.

Preferred regimen- DA-R-EPOCH

Patients were treated with 2 cycles beyond complete remission (6 to 8 total) with the exception of HIV patients who received 1 cycle beyond complete response (3 to 6 total) with 2 doses of rituximab administered with each cycle. CNS-directed therapy consisted of 8 doses of prophylactic intrathecal methotrexate with additional doses for patients with leptomeningeal disease. With long-term follow-up of >6 years, freedom from progression and OS were 95% and 100%, respectively.

Anthracycline free regimen in early TNBC?

 56 yo postmenopausal F with no family hx, positive for BRCA 1, presents with R breast self palpated lump 2.3 cm, 1 LN in R axilla biopsy-proven.

You discuss neoadjuvant treatment with her.

a. What is the current standard of care?

b. What do you tell her about prognosis?

c. What new data has come out in the last few years that may indicate a future direction?

Answers:

a. Current SOC is an anthracycline-based NACT. The goal is to achieve path CR. For those who do not achieve path CR, adjuvant capecitabine based on CREATE-X is recommended.

Using data from KEYNOTE 522 data NEJM which I will discuss later, the path CR in the SOC arm which included anthracyclines was 51.2%. Very high grade 3 toxicity in both arms, approximately 73%.

Path CR in the pembro arm was 65% with grade 3 or higher of 78%. Remember this arm also got anthracycline.

The question now is can we avoid anthracycline altogether?

2 papers:

NEOSTOP trial showed path CR rates of 54% in anthracycline arm+ platinum and taxol ( standard 12 weeks platinum taxol then 4 cycles DDAC) and platinum taxotere alone for 6 cycles.

At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in anthracycline arm compared with anthracycline free, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. 

Below are the results of a meta-analysis that further supports this notion of anthracycline free chemotherapy regimens.

Meta-analysis JCO

"For TNBC, adding Pl or B into the neoadjuvant therapy regimen brings about a higher pCR rate, though they are associated with an increase in hematologic or gastrointestinal complications. The benefit of adding anthracyclines to the neoadjuvant chemotherapy regimen for TNBC is not apparent"

Based on this, my suspicion is that we will be moving to 12-16 weeks of carboplatin-taxane and keytruda followed by Keytruda maintenance if this can be proven in a phase III RCT.

Prognosis of patients who get NACT with or without path CR- refer to CREATE X trial results

What about low dose Xeloda maintenance?

Ans: applies to those who got adjuvant rather than NACT

PARP and prostate cancer

PROFOUND study

Reference NEJM: Olaparib mCRPC

Germline and somatic BRCA mutation, progressed on hormonal agent like abi or enza

Longer PFS by 3 months in PARP group( 7.4 versus 3.6 months)

Anemia is the most common AE. No AML or MDS reported.

Nausea also common

Key points

1. ATM mutations do not respond to PARP inhibitors
2. Can use PARP inhibitor even with monoallelic BRCA mutation
3. DO not sequence another PARP after failure of one PARP
4. Do germline testing in all metastatic prostate cancer patients. Somatic testing is also recommended.

TTP-aHUS

 Causes of thrombotic microangiopathies beyond TTP and HUS

1. Sepsis
2. DIC
3. Malignant hypertension
4. Pregnancy
5. Drug induced
6. Cancer associated
7. Hematopoietic Stem cell transplant TMA
8. Cobalamin C defect
9. DGKE deficiency

Reference: ASH education TTP HUS and beyond

Approach- pearls

1. In a patient who responds poorly to PEX with no other clear explanation for the TMA findings, a diagnosis of aHUS might then become more plausible on the differential diagnosis as an explanation for the TMA.

2. In many of these disorders, the ADAMTS13 activity will be below “normal” or even very low (10%-20%) but not severely deficient (<10%), which typically characterizes acquired TTP

Let us look at the uncommon ones first:

a. DGKE deficiency presents in the first year of life and PEX does not work.

b. Cobalamin C defect: Extremely rare but important to identify.

Patients present with pulmonary artery hypertension, kidney failure, hyperhomocysteinemia, decreased methionine, and normal vitamin B₁₂ levels. Recovery is typically complete after starting treatment, which includes high-dose hydroxycobalamin, betaine, and folinic acid.

c. Hematopoietic stem cell transplant-associated TMA--> TA-TMA

TA-TMA commonly affects the kidneys and results in transfusion-dependent anemia and thrombocytopenia; however, it can also present with multisystem organ injury that includes: pulmonary hypertension, intestinal TMA, posterior reversible encephalopathy syndrome (secondary to uncontrolled hypertension), and polyserositis. Proteinuria and elevated LDH.

Trigger for complement activation ( could be a board question)-copy number variants in genes CFHR3-CFHR1 and acquired complement dysregulation through the formation of neutralizing autoantibodies to Factor H.

Treatment: Eculizumab, supportive care, discontinue calcineurin inhibitors

PEX not very effective <50%

d. Atypical HUS: Complement mediated disorder due to  either

-loss of function mutations in factor H ( board question)

-gain-of-function mutations in factor B or C3 that are potentially pathologic in aHUS

e. TMA in cancer: chemo induced, or bm involvement. Gastric, breast and mucinous adenoca at highest risk.

Compared with patients with acquired TTP, patients with cancer-associated TMA may have new or exacerbated hypertension, greater pulmonary involvement (dyspnea, cough, abnormal chest radiograph), or a leukoerythroblastic reaction on peripheral smear

Rx: treat cancer, no role for PEX, stop any offending drugs.

Common drugs in cancer associated with TMA: different immunotoxins, immunotherapy, anti-VEGF therapy (appears to be a class effect), and imatinib

f. Drug induced TMA- commonest drug is quinine. Ask for OTC anticramp tonics.

2 mechanisms- immune mediated and direct endothelial injury.

Quinine induces TMA by immune mechanism.

Direct toxicity- sirolimus and tacrolimus reduce VEGF on endothelial cells

Rare case report of bortezomib and carfilzomib induced TMA. 

Diagnosis: can be made by drug dependent antibodies

 The most common drugs associated with immune-mediated DI-TMA are quinine, oxaliplatin, and quetiapine, 

Direct toxic mechanism are cyclosporine, tacrolimus, sirolumus, bevacizumab, interferons α and β, and mitomycin. 

Gemcitabine is the only medication that has been associated with both immune-mediated³⁷  and toxic mechanisms.  Illicit drugs, specifically cocaine and IV use of oxymorphone (OPANA ER), have also been reported to cause a DI-TMA

Treatment:

1. Avoid the drug, renal recovery is the slowest, CBC improves faster

2. With immune toxicity, never rechallenge, with direct toxicity ok to rechallenge

3. PEX no use

4. Can consider eculizumab for gemcitabine TMA

HELLP syndrome- treatment --> delivery of baby, control BP

Atypical HUS is common post partum; 1/3 of HELLP can be post partum, otherwise mostly in weeks 28-36.

ddx fatty liver of pregnancy-- often indistinguishable from  HELLP. the only diagnosis to rule out is infectious hepatitis and if this is negative, plan to deliver the baby and maximize supportive care.

Clinical pearl--> in acute fatty liver of pregnancy-DO NOT do a liver bx

Liver biopsy should not be performed to confirm a diagnosis of AFLP or to distinguish AFLP from severe pre-eclampsia, because management of both conditions are the same. 

ASH education 2020 Transfusion in MDS

 RBC transfusion in MDS

1. The ideal threshold for Hb transfusion is not known. In patients, typically younger patients undergoing hematopoietic stem cell transplantation, a restrictive threshold of 7gm was considered safe.

2. Reactions- minor febrile reactions, TACO. Whether transfusing fewer units at a time, or more slowly, or accompanied by prophylactic diuretics reduces TACO risk for patients with MDS is not known.

3. Alloimmunization can be a problem upwards of 25%. antibodies to K and the Rh system antigens (especially anti-E) are the most common; therefore, providing RBCs negative for these antigens may be sufficient to minimize alloimmunization for most patients.

4. Iron overload is another problem both due to ineffective.

5. Iron chelation- can reduce transfusion requirements and should be considered early for patients who become transfusion dependent. However, determining who is a candidate for chelation can be difficult; higher-risk patients needing greater transfusion intensity will become iron loaded more quickly but may not benefit from chelation because of their shorter survival. 

Mutations in CNS tumors

 

Key points:

1. MGMT promoter methylation predicts response to alkylator treatment in IDH WT GBM, not in IDH mutant.

2. EGFR mutations in CNS disease have not been amenable to anti-EGFR treatment

3. ATRX loss to be a highly specific biomarker of astrocytic lineage

4. ATRX loss is mutually exclusive from 1p/19q co-deletion in oligodendroglioma

5. IDH WT has a worse prognosis

Reference:

1. https://www.sciencedirect.com/science/article/pii/S0716864017300603?via%3Dihub

2. 4 prognostic categories based on molecular markers

Hemophilia prophylaxis

Severe hemophilia - < 1% factor level

Moderate 1-5%

Mild 5-40%

 Three types of prophylaxis

1. Primary: anyone with factor level <1% even before a bleed

2. Secondary: anyone with more than 1 bleed into a target joint irrespective of factor level

3. Continuous and intermittent: mild factor def with levels close to 5% rather than 40% prior to high impact activities, surgery etc

Choice of therapy

The bispecific monoclonal antibody emicizumab is approved for prophylaxis in adults and children (including newborns) who have hemophilia A with or without FVIII inhibitors.

Emicizumab is not derived from plasma and thus is not associated with infectious risk

It should not be used for acute bleeding.

It can be used for prophylaxis in patients with or without inhibitors.

It is a bispecific monoclonal antibody that scaffolds IXa and factor X bringing them together, a function normally carried out by factor 8.

Pancreatic neuroendocrine tumors

NET classification

• foregut (bronchial, gastric, duodenal, pancreatic)

• midgut (ileal, jejunal, caecal)

• hindgut (distal colonic, rectal).3

Pancreatic NET

1. Typically are well differentiated

2. FDA approved treatment: somatostatin analogs, everolimus, sunitinib, and peptide receptor radionuclide therapy

3. Contrast enhanced EUS differentiates pan NETs from pancreatic adenocarcinoma

4.  68Ga-dotatate PET/CT had the highest detection rate for pancreatic lesions (95% CI, 89.4 to 98.1). Standard first line imaging.  68Ga-dotatate PET/CT has become the first-line modality of choice for detecting SSTR  ( somatostatin receptor) expression in PanNETs.

5. 5 types of F-Pan NET- insulinoma, glucagonoma, Gastrinoma, VIPoma, somatostatinoma

6. NF Pan NET < 2 cm observe, > 2 cm resect ( non functional)

7. F-Pan NET ( functional)- resect at any size if resection feasible.

8. In advanced pan-NET, resection is controversial.

9. Poorly differentiated pan-NET treated with chemo- temodar or streptozocin ( +5FU or doxorubicin, the latter preferred)

However temodar is preferred- CAPTEM 

CAPTEM resulted in median OS of 24 months (95% CI, 17.1% to 30.8%) as well as a 2-year OS of 42%

10. Everolimus in grade1/2 pan-NET- RADIANT III trial

median PFS with everolimus treatment (11 months v 4.6 months; HR, 0.35)

AE-stomatitis, rash, diarrhea, and fatigue

11. Sunitinib in advanced pan-NET-median PFS of 13.2 months and an overall response rate of 24.5% in patients given sunitinib treatment. AE  neutropenia, diarrhea, erythrodysesthesia, hypertension, and thrombocytopenia

12. PRRT- 2 trials ERASMUS ( GEP)  and NETTER ( mid gut NET).

177Lu had an overall response rate of 16% and a median duration of response of 35 months.40 However, approximately 1%-2% of patients reported acute leukemia and myelodysplastic syndrome.

13. Cabozantinib after sunitinib or everolimus in phase II:

A phase II study of cabozantinib demonstrated a 15% response rate and a median PFS of 21.8 months in patients with grade 1 and 2 PanNETs who had a treatment history of everolimus or sunitinib.44 An ongoing phase III CABINET trial 

Liver directed therapy

Liver mets are important in prognosis.

40% 5 yr survival in liver mets versus 100% OS in non liver mets

Liver debulking if > 70% hepatic mets resection or tumor clearance. Threshold lowered from previously used cut off of 90%.

Radiofrequency ablation- 5 yr OS 48%, median OS 4 yr. Improves survival for tumors < 3 cm ideally but can be done up to 5 cm.

HAE- transarterial embolization, TACE, Transarterial radioembolization ( TARE).

TARE has 89% disease control in the short term but concern for long term toxicity.

CLARINET Trial- metastatic foregut -lanreotide versus placebo

PROMID trial- metastatic mid gut- octreotide vs placebo

Reference: Understanding the management of Pancreatic NET