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