Risk stratification lymphoma

 IPI and R-IPI

https://thehematologist.org/lymphoma-prognosis-scores/

FLIPI and FLIPI 2

https://thehematologist.org/follicular-lymphoma-international-prognostic-index-flipi-and-flipi-2/

MIPI

https://thehematologist.org/simplified-mipi-smipi-simplified-prognostic-index-for-advanced-stage-mantle-cell-lymphoma/

Mantle cell low risk:

SOX 11 neg

Ki 67 less than 10 %

Hypermutated IGHV

Stable karyotype

Mantle high risk:

TP53 mutated

Complex karyotype

Blastoid/pleomorphic

Ki 67 % greater than 30%

Who can you watch and wait in Mantle cell?

Leukemic or non nodal, no B symptoms, Ki 67 less than 10 percent, normal LDH, mutated IGHV. MIPI not useful.

Updates in MCL

1. BOVEN trial: zanubrutinib+ obin+len in TP53 mutated 1L

https://ash.confex.com/ash/2023/webprogram/Paper180069.html

2. TRIANGLE trial: FFT improved with ibrutinib front line with or without ASCT.

3. BRIDGE trial : frontline zanubrutinib in a triangle regimen

Relapsed refractory DLBCL

 

1. Tafasitamab - CD 19 Ab: approved with lenalidomide for patients with R/R DLBCL ineligible for ASCT. median OS 3 yr. 2L, ineligible for ASCT. CR 43%, ORR 60%, 1 yr  OS 74%. L-MIND study.

2. Loncasituximab- ADC against CD19: with revlimid or ibritunib with 50% ORR. 3L. LOTIS -2 trial. PFS 10 months. Neutropenia, tpenia, and increased GGT.

3. Polatuzumab- ADC against CD79b- 3rd line for R/R. in combo with BR. Can be 2nd line if not ASCT candidate or CAR-T candidate.

4. Selinexor- XPO1 inhibitor- approved 3L. SADAL study. Cytopenias, fever, fatigue. ORR 28%. median PFS 9 m.

Other agents:

1. Pembrolizumab - approved for R/R primary mediastinal B-cell lymphoma (PMBL) based on the results of KEYNOTE-170 which demonstrated an ORR of 41.5% (CR 20.8%), with median PFS and OS of 4.3 and 22.3 months

2 Brentuximab +/- Rituxan in CD 30+ DLBCL . Works even without CD 30 positivity. 

2025 update: BV 1.2 mg/kg q 3 weeks+ rituxan q 3 weeks+ Lenalidomide 20 mg daily- 3rd line versus R2 as the comparator. Median OS 13.8  m versus 8.5 months. ( JCO March 2025) ECHELON-3. The PFS was low. Therefore may be a bridging therapy to ASCT or CAR-T. This regimen worked even in those who relapsed after CAR-T and high IPI.

3. Revlimid and other CELMods: single agents with < 30% ORR.

Reference

Myeloma

 1. Frontline transplant eligible: VRD dara for younger patients stringent CR, depth of response and MRD all higher with quadruplet. Translates to better PFS. Trend toward better OS.

CASSIOPEIA ( VTD-dara) and GRIFFIN ( VRD-Dara).

2. Relapsed MM:  First relapse: ( second line)

Bortezomib is suboptimal at the time of the first relapse for len-refractory patients based on CASTOR study results

Len refractory ( progression on len or within 60 days of last dose): Dara or Isatuximab ( anti CD 38 antibody) with second gen PI ( Karfilzomib) with low dose dex

a. Dara- Kd--> CANDOR --> PFS 29 months ( for all comers, 1/3 len refractory)

b. Isa-Kd--> IKEMA--> PFS 36 months ( all comers, 1/3 len refractory). Kd arm PFS 15 m

Lenalidomide sensitive patients at the time of first relapse: POLLUX study-- Dara - len-dex-- median PFS 4 yr.

3. Relapsed myeloma: second relapse: ( third line)

 Pom/dex backbone with CD 38 antibody: ICARIA and APOLLO

a.  Istatuximab + Len/dex: ICARIA:  PFS, 11.5 months, versus 6.5, with a hazard ratio of 0.6. So that’s a 40% reduction in the risk of death of progression with isatuximab/pom/dex versus pom/dex alone

b. Dara-Pom dex- APOLLO: Median PFS 12 months for triplet versus 7 for Pd alone. Of note Dara was used subcut not IV.

4.  What is Iberdomide? It is a CELMoD. Cerebron ligase modulators have more affinity in binding and degrading substrates needed by the myeloma cell. 10-20 times more potent than Lenalidomide.

5. If you progress on an anti CD 38, how long should the patient be off the antibody before you retreat? Ans: at least 6 months for the CD 38 to get expressed again on the myeloma cells.

6. MAIA study elderly non transplant eligible: the median progression-free survival was 44.5 months in the daratumumab group, as compared with 17.5 months in the control group.

Metastatic breast cancer- CCO

 

1. Based on current indications and clinical guideline recommendations, patients with hormone receptor (HR)–positive/HER2-negative MBC can receive a CDK4/6 inhibitor with either an AI or fulvestrant as first-line treatment for MBC. PARP inhibitors, immunotherapy, and antibody–drug conjugates (ADCs) can be use din subsequent lines of treatment, including after chemotherapy.

2. Current guidelines and expert recommendations suggest testing peripheral blood and metastatic TNBC biopsy samples for PD-L1, BRCA1/2 mutation, and HER2 status to assess patient eligibility for available treatment options. Patients with a PD-L1 CPS score of ≥10 are eligible for chemotherapy plus pembrolizumab, whereas patients with germline BRCA1/2 mutations should receive a PARP inhibitor (olaparib or talazoparib) or platinum-based chemotherapy. HER2 expression testing may be recommended in patients with previously diagnosed TNBC who have progressed on chemotherapy with or without pembrolizumab to determine optimal ADC-based therapy: Patients with HER2-low disease should receive T-DXd, and those with HER2-zero disease could consider sacituzumab govitecan.

Discussion regarding frontline choice of CDK4/6 inhibitors in MBC:

In MONALEESA-2 and MONALEESA-7, ribociclib in combination with ET yielded a statistically significant improvement in OS compared with ET alone (hazard ratios in both trials: 0.76).^7,8 MONALEESA-3 included a first-line cohort evaluating ribociclib plus fulvestrant and showed significantly improved OS with ribociclib plus fulvestrant compared with fulvestrant alone (median OS: 67.6 vs 51.8 months; hazard ratio: 0.67).⁹

MONARCH-3, the trial evaluating abemaciclib as part of first-line therapy, has not yet shown a statistically significant improvement in OS. An interim analysis of survival has been reported for abemaciclib plus AI compared with AI alone (median OS: 67.1 vs 54.5 months; hazard ratio: 0.754), which looks very promising based on what we have seen in MONALEESA-2.¹⁰ However, we are awaiting the final statistical analysis from MONARCH-3, which is anticipated by the end of 2023. 

Unfortunately, the PALOMA-2 trial with first-line palbociclib plus letrozole did not yield a survival advantage compared with letrozole alone (median OS: 53.9 vs 51.2 months; hazard ratio: 0.956).¹¹ Nonetheless, certain subsets of patients do very well with palbociclib-based treatment, including older women, patients with bone-only disease, and patients with more ET-sensitive disease. As such, palbociclib is not an unreasonable choice for patients when ribociclib and abemaciclib are not ideal options.

RIGHT Choice trial- use Ribo with ET front line for aggressive MBC. PFS 24 m compared to 12 m with chemo even in the first 3 months.

Impending liver failure would be the only reason to use traditional chemo

Gem carbo ( Gem D1,8 dose reduced 800), carbo ( AUC 4 or5) or 50% dose reduced vinorelbine if bili > 2.

Taxol dose reduced unless Bili > 7.5 and AST/ALT> 10 ULN

Monitoring for CDK4/6 inhibitors

Monitoring plan for antineoplastic therapy

Monitor labs for neutropenia and LFT abnormalities for all 3. CBC, CMP q 2 weeks for first 2 month, then monthly for next 2 months. Then q 3 m . LFT issues less likely with palbo.

Clinical monitoring for PE/DVT ( abema) and ILD with all 3.

Diarrhea with abema:

 For either grade ≥3 diarrhea or persistent grade 2 diarrhea that does not resolve within 24 hours, we want to suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at a reduced dose.¹For grade 2 diarrhea that does not resolve within 24 hours with antidiarrheal agents, suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at the same dose level. For grade 1 diarrhea, no dose modifications are required, and I often tell patients they can take one half to a full dose of loperamide once per day and continue therapy without suspending treatment.

LFT abnormality with abema:

with abemaciclib, no dose modification is required for grade 1 or 2 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation without increase in bilirubin above 2 times the upper limit of normal (ULN). Patients who experience persistent or recurrent grade 2 ALT/AST elevation or grade 3 ALT/AST elevation without an increase in bilirubin should hold abemaciclib until the toxicity resolves to grade 1 or baseline levels and then resume with a dose reduction. Patients with ALT/AST elevation >3 times the ULN with an increase in bilirubin or those with a grade 4 ALT/AST increase should discontinue the CDK4/6 inhibitor

Neutropenia with ribo

In patients receiving ribociclib, the prescribing information recommends monitoring complete blood counts every 2 weeks for the first 2 cycles, after the subsequent 4 cycles, and as clinically indicated.¹⁵ No dose adjustments are required for grade 1 or 2 neutropenia. If grade 3 neutropenia develops, suspend treatment until neutropenia resolves to grade ≤2, and then resume at the same dose. If there is recurrent grade 3 neutropenia or febrile neutropenia (with single episode of fever of >38°C or above 38°C for more than 1 hour and/or concurrent infection), stop treatment until neutropenia resolves to grade ≤2, and then resume at the next lower dose level. If grade 4 neutropenia develops, stop treatment until neutropenia resolves to grade ≤2, and then resume treatment at the next lower dose level.

Metastatic TNBC

1. Keynote 355: 

The final efficacy data from KEYNOTE-355 are summarized on this slide.²⁰ Although the trial enrolled all-comers, approximately 40% of patients were PD-L1 positive based on a CPS score ≥10. If we look at median OS on the left, we can see approximately 7-month improvement with the addition of pembrolizumab to chemotherapy in patients with a CPS score of ≥10, with median OS of 16.1 months without pembrolizumab vs 23.0 months with pembrolizumab (1-sided P = .0093). In addition, 14% more patients were alive at 2 years in the pembrolizumab-containing arm.

In the first-line metastatic setting in KEYNOTE-355, we saw that those patients receiving pembrolizumab experienced modestly higher levels of colitis (1.8% vs 1.4%) and pneumonitis (2.5% vs 0%), and the most common events were hypothyroidism (15.8% vs 3.2%) and hyperthyroidism (4.3% vs 1.1%).²⁰ These just occur at lower incidences than in the neoadjuvant and adjuvant curative setting.

2. However, if a patient is PD-L1 positive with CPS of ≥10, then I would hold the PARP inhibitor until after progression on first-line chemotherapy plus pembrolizumab. PARP inhibitors show PFS but no OS benefit in gBRCA. So even in such patients, if CPS>10, use Keynote 355 regimen.

Subsequent lines

NCCN adjuvant and NACT lung

 For stage II and IIIA- get PDL1, EGFR, ALK

If EGFR neg--> NACT platinum doublet with nivo 3 cycles

Adjuvant 

If EGFR, ALK neg, and PDL1 0- after adjuvant chemo, pembro

If EGFR positive, after chemo, osimertinib for 3 yr

If EGFR and ALK neg, PDL1 > 50, can consider atezo although pembro would be fine

For ALK mutation positive--> after 4 cycles chemo, no IO. Can consider clinical trial.

Counseling patients with prostate cancer starting ADT

 All patients with metastatic CSPC should receive ADT, with the addition of other modalities depending on patient-specific factors and the extent of disease.  Choices include orchiectomy, Gnrh agonists or antagonists. Gnrh agonists are commonly administered as monthly, 3 month or 6 month injections.

Relugolix is a GNRH antagonist. Compared to ADT it is associated with less major adverse cardiovascular events. This difference is more pronounced in patients with past hx of a major CV event.

Leuprolide and Eligard are the most commonly used ADT meds. These are given intramuscularly.

ADT is associated with metabolic, cardiovascular, musculoskeletal, cognitive, and neuropsychiatric issues, as well as sexual dysfunction.

1. Osteoporosis prevention: Bisphosphonates do not reduce skeletal related events in newly diagnosed castrate sensitive met prostate cancer based on CALGB 90202 study and STAMPEDE trial. However, a baseline DXA scan is indicated to identify underlying osteoporosis or high risk osteopenia which may worsen with ADT. Calcium and vitamin D supplementation are indicated.

Recommended:

DXA scan

Calcium 1000 mg with vit D3 1000 units daily

If DXA shows  high risk osteopenia ( T score less than neg 2) or osteoporosis ( T less than neg2.5), then will discuss bisphosphonates q 6 m.

2. Sarcopenia and risk of falls : These are well known side effects. I recommended strength training at least 20 min a day 3 days a week along with stretching exercises.

3. Cardiovascular risk factors: The patients cardiac risk factors were evaluated.

No hx of ongoing angina or exertional dyspnea. Can climb 2 flights of stairs without stopping. No CP at rest. No hx of MI or cardiac stents. Has a hx of controlled hypertension being managed by PCP. Current meds include:

He is on aspirin but not on an anticoagulant.

4. Fatigue is also extremely common with ADT. Exercise can help with this.

 Hot flashes and gynecomastia: discussed these side effects. Gabapentin, acupuncture and effexor can help.

5. We will monitor lipid panel annually as well as weight gain since ADT increases risk of metabolic syndrome.

6. Erectile dysfunction is a common side effect. 

;

Ovarian ca PARP flowchart

 

Frontline is platinum based chemo with or without bev.

 Germline BRCA or HRD, negative-- Observation is ok, Niraparib cat 2A based on PRIMA. Also PRIME trial showed benefit in all comers ( stage III was included, therefore good risk patients). HR 0.72 with a 16 month versus 8 month PFS benefit in HRP versus placebo. 

HRD positive BRCA WT PAOLA-1 data

In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation

Germline or somatic BRCA mutations POSITIVE

Niraparib and olaparib are NCCN category 1 recommended options for those with germline or somatic BRCA1/2 mutations who are in complete or partial remission after surgery and platinum-based first-line chemotherapy

EGFR antibodies skin toxicity Canadian recommendations

 Reference

Rash lasts the first 6 weeks. 

Intensity of rash correlates with efficacy

STEPP trial was the first prospective trial which showed a benefit with 6 weeks of doxycycline or minocycline to prevent grade 2 or higher rash.

CTC criteria using BSA may not apply. Another risk stratification is used specific for EGFR Ab.

Flowchart for grades of toxicity and management

Grade 1 : mild pustular with no other symptoms.

Rx: topical clinda 2% with hydrocortisone 1% apply BID lotion ( although generally speaking refrigerated emollient alcohol free cream is better for the rest of the body).

Grade 2: Moderately symptomatic, moderate pustular with erythema, may or may not interfere with ADL

As with grade 1 + oral doxy until rash resolution+ for scalp lesions clinda with triamcinolone

Grade 3:  Moderate to severe intolerable rash, interferes with ADL

"Several situations warrant patient referral to a dermatologist. Clinicians may wish to refer if the skin toxicity does not improve within 1–2 weeks of treatment. Referral is also recommended if the patient is severely symptomatic (for example, if necrosis, blistering, or petechial or purpuric lesions are present) or if multiple hair, nail, and skin issues emerge 29. In general, if the skin toxicity has an uncharacteristic appearance or distribution (it just doesn’t look “right” or familiar), it is advisable to refer the patient to a dermatologist."

DVT prophylaxis in Myeloma

 IMPEDE or SAVED score can be used.

SAVED score 3 or higher --> use Lovenox 40 mg daily, OR Warfarin INR 2-3, Rivaroxaban 10 mg or Eliquis 2.5 mg  BID

Otherwise Aspirin 325 mg or 81 mg

SAVED score

• Prior VTE= 3
• High dose dex ( > 160 mg per cycle)= 3
• Prior surgery in the last 3 m= 2
• Low dose dex( 120-160/ cycle)= 2
• Age > 80 yr= 1
• Asian race= negative 3

Does the patient have cytopenias? Bleeding risk? Renal or liver dysfunction? Already on anticoagulation or another reason to be on anticoagulation? Hx of HIT. Any drug interactions with DOAC or Lovenox?

Cancer care symptom management

 This post will be continuously updated.

1. Constipation

-types of meds: stool softeners ( docusate), stimulant laxatives ( senna), bulking agents ( psyllium), osmotic laxatives ( milk of magnesia, laculose).

For opiate induced constipation--> stimulants may be needed. Softeners and  bulking agents do not work on their own.

-conside Lubiprostone for chronic IBS associated constipation.

-naltrexone can reverse opiate constipation.

2. Cancer related fatigue:

• Onset and progression:
• Baseline functioning and current interference with ADL:
• Alleviating and aggravating factors:

Assessment:

1. Anemia
2. Sleep: CBT category 1 intervention
3. Anxiety/Depression
4. Endocrine disturbances: thyroid, adrenal insufficiency
5. Alcohol and substance abuse
6. Pain control
7. Physical activity program: category 1, yoga
8. Systems based:

• Liver
• Kidney
• GI
• cardiac
• Neurologic
• Pulmonary

Pharmacologic rx: phase II data for methylphenidate. No convincing evidence for modafinil or ginseng.

Thrombocytopenia

 Outpatient

.fname has been referred for further evaluation and management of thrombocytopenia.

On review of records, he/she had a normal platelet count until -date. OR We have no record of last known normal platelet count.

On- date- platelet counts were (low/normal) at *. Since then there has been a gradual drop over a period of * months. The most recent platelet counts are *.

Hemoglobin and white count are normal.

Clinically, the patient denies bleeding from nose, mouth, gums or cutaneous bleeding. There is no history of rectal bleeding or melena. No history of vaginal bleeding or hematuria.

No constitutional symptoms such as weight loss, weight gain, fever, chills, abnormal lumps. Full 13 system review was as noted below. No recent vaccinations.

No history of infections such as hepatitis C or Helicobacter pylori. No history of risk factors for HIV such as unprotected sexual intercourse or needle sharing. He is agreeable to testing for these 3 infections as part of the work up.

No history of liver disease. LFT are normal. Prior abdominal imaging in *date showed no evidence of splenomegaly, or liver cirrhosis on ultrasound. The platelet count at the time of the imaging was low at *. History of alcohol intake:

No history of tobacco or recreational drug use. Marijuana* 

The patient is not pregnant. There is no family history of blood disorders or bleeding history. No family members with a history of splenectomy. No history of blood transfusion, heparin exposure, cardiac or other surgical procedures in the last 3 months.

All medications were reviewed. He was not temporally initiated on a new medication prior to the onset of thrombocytopenia.  Over the counter medications were reviewed.*

There is no history of malignancy or autoimmune condition personally or in the family.

Clinical exam:

Conjunctival bleeding

Skin petechiae/ purpura

Oral mucosa: wet purpura

Abdomen: palpable liver and or spleen

Signs of chronic liver disease

A/P:

.age yo .gender with isolated thrombocytopenia of gradual onset since *. No clinical evidence of bleeding. No associated anemia or WBC abnormalities. No hx of drug use, excess alcohol use. No hx of malignancy, autoimmune disease, new medication or liver disease. No hx of infections, recent blood transfusion, cardiac or surgical procedures.

Ddx: ITP, drug induced thrombocytopenia.

Investigations:

• CBC, peripheral smear review, quantitative immunoglobulin, B12 level
• Infection testing: hepatitis C, HIV, H. pylori
• Bone marrow exam: if older 60 yr, treatment with steroids planned, rapid down trend in platelet count, anemia or WBC count issues to rule out MDS.
• US abdomen -
• If anemia- baseline anemia work up, B12 level, ferritin, retic count 
• ABO, DAT

Inpatient: reference

.fname was admitted to the hospital on * for complaints of *.  Information was obtained by review of records. 

Last normal platelets:

Sudden or gradual drop in platelets since: 

Prior to this, the patient was started on * medication/ chemotherapy. hx of antibiotic or heparin ( 4T score)

No history of recent surgery, cardiac procedure, or blood transfusion. No hx of vaccination.

Current medications including antibiotics with start date:

Summary of initial work up:

• DIC panel: fibrinogen, D dimer, FDP ( use ISTH scoring system)
• Peripheral smear : Examine smear- 
• clumping, giant plt--> true thrombocytopenia
• RBC: schistocytes, spherocytes,  nucleated RBC, RBC clumping, 
• WBC: blasts, toxic granulations, atypical lymphocytes, neutrophilia
• B12, ferritin
• PT, PTT
• Blood cultures
• Hepatitis C, HIV
• ABO DAT

A/P Top diagnosis:  sepsis, drug-induced thrombocytopenia, immune thrombocytopenia, or surgery

Rule out life threatening conditions:  Identify if actively bleeding, new thrombosis, multiorgan failure, neurologic dysfunction, DIC,  post op or on dialysis

Ddx: Life threatening diagnosis

• Sepsis-induced thrombocytopenia (check blood cultures and lactate)
• Heparin-induced thrombocytopenia
• Thrombotic thrombocytopenia purpura or hemolytic uremic syndrome (which leads to fragmented red blood cells and an increased LDH)
• Drug-induced immune thrombocytopenia
• Primary immune thrombocytopenia (ITP) with bleeding (very unusual in a hospitalized patient who doesn’t have a previous diagnosis of ITP)
• Acute leukemia
• Posttransfusion purpura (very rare)

ASCO guideline Hormone sensitive metastatic prostate cancer

 

1. Compare PEACE 1 trial with ARASENS trial?

Abiraterone added to docetaxel and ADT improved rPFS and OS. Hypertension was higher in abiraterone but neutropenia, fatigue, neuropathy, and sepsis were not increased. This was for patients with high volume disease and data are immature for low vol disease.  The median OS in Chaarted trial with docetaxel +ADT was 55 months which is 4.5 years, the same as in the SOC arm ( docetaxel with ADT). The median OS was not reached in the triplet arm.

• Median progression-free survival was 4.46 in the triplet abiraterone arm vs 2.03 years, and median overall survival was not reached vs 4.43 years.

ARASENS: Darolutamide median OS not reached versus 45 months ( shy of 4 yr). Clear improvement in OS and all secondary factors such as rPFS, time to first skeletal event, time to next antineoplastic therapy. AE coincided with docetaxel administration.

2. Compare ARCHES versus ENZAMET trial?

Arches compared enzalutamide versus placebo in hormone sensitive met prostate ca. Although OS was not improved, multiple other factors including radiographic progression, PSA rise and initial skeletal events, pain progression were all less with enza compared to placebo with ADT. Prior docetaxel use was permitted. Low volume disease patients also benefited. Approx 24% grade 3 or higher AE.

Enzamet was similar to Arches trial but had a triplet arm with docetaxel.

3. CHAARTED trial OS: docetaxel with ADT 55 months OS, 13 months more than ADT alone in high volume disease.

4. What adverse effects should you be concerned in patients on AR inhibitors?

 These include fatigue, falls, fractures, mental impairment, rash, hypertension, and cardiovascular events. 

Darolutamide dose needs to be reduced for Child Pugh's B and Cr Cl 15-29. The dose is 300 mg BID.

During counseling for darolutamide: ask for symptoms of uncontrolled ischemic heart disease and other CV risk factors. Counsel about risk of seizures.

Apalutamide has an incidence of rash of 25%. This is more than for other AR inhibitors. Typically seen at 2.5 months.

Management: reference

Prostate cancer in the elderly ASCO education 2023

1. Geriatric assessment screen- G8

https://www.mdcalc.com/calc/10426/g8-geriatric-screening-tool

The G8 ranges from 0 to 17, with lower numbers associated with increasing frailty. In patients with cancer, scoring below 14 has an 85% sensitivity and 64% specificity for detecting frailty.

2. Life expectancy calculator

eprognosis by UCSF

https://eprognosis.ucsf.edu/calculators.php

3. Cognitive screening: Mini Cog Score of 3 or less indicates impairment with 89% specificity

Remember 3 objects, draw a clock face

4. My CARG chemo toxicity calculator:

https://www.mycarg.org/?page_id=2405

4. Bone health

DXA on initiation of ADT

- newly diagnosed castrate sensitive Prostate ca patients do not need antiresorptive therapy unless:

- prior fracture

-osteoporosis

-high risk osteopenia with FRAX showing greater than 20% risk of any fracture or 3% risk of hip fracture in 10 yr

Triple negative breast cancer Early stage

 1. Dose dense regimen

Use of DDAC followed by taxol- EFS and OS benefit shown in the CALGB/intergroup trial 2003 82% versus 75% DD group versus 3 week dose at 4 yr cut off.

2. Weekly taxol:

ECOG 1199 study demonstrated that once weekly paclitaxel 80 mg/m2 improved disease-free survival (DFS; HR, 0.69; P = .001) and OS (HR, 0.69; P = .019) compared with once every 3-weeks paclitaxel 175 mg/m2 administration.

3. Adjuvant after pembro based regimen Keynote 522

- if path CR--> ct pembro

-if no path CR, capecitabine if no germline BRCA, otherwise olaparib. If pre op pembro ct pembro.

CREATE-X trial as adjuvant treatment with capecitabine (1,250 mg/m2 PO twice a day days 1-14, 6-8 cycles) improved OS of patients with TNBC and residual invasive disease after NAC when compared with observation (HR, 0.52)

Olympia trial : After a median follow-up of 2.5 years, the 3-year DDFS was 87.5% in the olaparib group and 80.4% in the placebo group (7.1% difference)

Lung cancer stage 4

1. EGFR: Osimertinib, dacomitinib 1L

2. Afatinib (1L) with or without cetuximab ( after progression on Osimertinib)

3. ALK :Alectinib, Brigatinib, Lorlatinib all 1L, Lorlatinib can be 2L

4. Dabrafenib Trametinib can do 1L in BRAF  V600E mutated

5. 2nd line EGFR exon 20- amivantamab, mobocertinib

6.  KRAS G12 C 2L Sotorasib/ adagrasib

7. MET exon 14: 1L ok tepotinib, capmatinib, crizotinib

8. ROS 1: 1L Entrectenib ( better if brain mets) crizotinib, ceritinib. Lorlatinib can be used 2L.

9.  NTRK- 1L entrectenib, larotrectinib

10. HER 2 mutated- TDxd 2L

11. RET-1 L selpercatinib/ pralsetinib

Stage 4 lung cancer and IO

Cemiplimab monotherapy PDL1 50% or higher- median OS 26 m vs 13 months 

Cemiplimab with chemotherapy median OS 22 m vs 13 m. 

Both are category 1.

Cemiplimab with chemo: The most common (≥15%) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

The recommended cemiplimab-rwlc dose is 350 mg IV every 3 weeks. 

What subgroup of patients did the cemiplimab not benefit even though the overall population benefited? PDL1< 1%, women and non smokers. Underpowered to test the benefits.

Multiple myeloma treatment decisions

 Transplantation eligible

Ref: Blood May 2022

10-15% of heme malignancies are myeloma

SOC- induction, high dose melphalan followed by aSCT, consolidation, then len maintenance

Why is transplantation under question? OS benefit has not been convincingly proved, even though PFS better with transplant in eligible patients.

Delayed ASCT can be done in  younger individuals with standard risk disease if patient prefers due to social obligations. There is a risk of secondary primary malignancies. Updated IFM trial results report 8% secondary primary tumors over 8 yr and less than 2 percent AML, not different from non ASCT arm.

Choice of induction regimen: VRD ( PETHEMA/GEM 12, CR 33%) or D-VTD ( Cassiopeia tria)

D-VRD Griffin trial 

Peripheral neuropathy rates: 9 percent ( D-VTD), 4 % VRD, D-VRD-7%

4-6 cycles of D-VRD or VRD followed by ASCT. After ASCT if standard risk__> len maintanance or consolidation followed by len maintenance

After ASCT, if high risk, tandem ASCT ( done within 6 months of ASCT -1) or VRD maintenance

High risk myeloma:

In 2016, the International Myeloma Working Group (IMWG) made an attempt to find a consensus for the definition of HR cytogenetics MM,³ identifying patients with t(4;14), t(14;16), t(14;20), del17p, gain 1q, nonhyperdiploid karyotype, del13q at conventional karyotype, and HR signature at GEP as HR and all the others being standard risk

• t(4;14) FGFR3, MMSET
• t (4;16) cMAF
• t( 14;20)
• 1p32 unfavorable
• 1q gain if  4 or more, unfavorable
• Double hit- biallelic inactivation of TP53 ( very unfavorable)
• Single hit 17p

bortezomib-based treatments have improved, or even overcome, the poor prognosis imparted by t(4;14)

Discussion:

1. In designing a treatment plan, patient factors ( age, performance status and comorbidities) were taken into consideration. Additionally disease factors indicating disease burden ( beta 2 microglobulin, LDH, renal impairment, low albumin) and disease biology ( high risk GEP, cytogenetics, FISH) and organ dysfunction. He does not have > 20% circulating plasma cell or evidence of extramedullary disease both of which are suggestive of more aggressive disease.

2. We discussed the induction chemotherapy regimen RVD-Dara. We reviewed the side effects including but not limited to cytopenias, neuropathy, risk of blood clots, infusion reactions, need for blood transfusion support and rarely, death.

3. Anticoagulation risk mitigation:≤3 Points by IMPEDE Score or <2 Points by SAVED Score--> aspirin. Otherwise 10 mg xarelto or 2.5 mg BID apixaban.

4. Bone support: 2-3 yr Bisphosphonates. This can be administered q 3 months or q 4 weekly. In patients with significant bone disease or bone pain, q monthly for 1 y r can be considered. After discussing the options, we decided on q 3months. We reviewed the side effects including hypocalcemia, renal dysfunction and osteonecrosis of jaw among the most concerning se. Ocular toxicity is also associated with significant morbidity and the patient was advised to contact our office with any vision symptoms. I recommended a baseline dental exam and clearance by dentist as well as eye exam.

5. Hypercalcemia: bisphoshphonates as per #4.

6. Anemia: ESA not indicated. Correct nutritional deficiencies. Blood transfusion support per parameters.

7. ID prophylaxis: acyclovir

Rx of high risk disease:

Quadruplet induction (MoAb + PI + IMiD + dex)
Double ASCT
Quadruplet consolidation
Two-drug maintenance (PI + IMiD) for ≥2-3 y if sustained MRD⁻ 

Template:

Diagnosis: IgG kappa myeloma, RISS- stage

Transplantation eligibility

FISH

Cytogenetics

Date of diagnosis and initial presentation:

Presentation: details

CRAB

FLC

LDH

PET

BMBX:

Treatment history:

1. Date: RVD-dara

Date of progression

Comorbidities:diabetes mellitus, hypertension, heart failure, cardiac arrhythmias, hyperlipidemia, chronic renal failure, and other cancers

Geriatric/ frailty assessment:

End organ damage: renal failure, back pain, baseline neuropathy

CML 2023

Chronic Myeloid Leukemia

CML

• Chronic phase/ Accelerated/ Blast
• Baseline : BCR-ABL % IS
• Sokal score:
• Eutos Score:

Presentation:

Date: WBC at presentation, spleen palpable below costal margin, total spleen size, symptoms, anemia or thrombocytopenia

Date	Timeline	IS %	Goal	BMBx/CBC
	Baseline		NA
	3 months		<10%
	6 months		<10%
	9 months		<1%
	12 months		<0.1% ( for TFR) otherwise < 1%

Pearls:

1.  30% of blast crisis in CML can be lymphoid rather than myeloid.

2. All the TKIs except nilotinib are FDA approved in blast crisis.

How to differentiate between CML blast crisis and de novo ph+ ALL?

FISH studies can detect the isoforms of BCR-ABL oncogene and provide important clues. The p210 isoform is commonly seen in CML, whereas the p190 isoform occurs in the majority of Ph + ALL .

 Flow cytometry  for CD 26+ which are seen on myeloid stem cells.

Dasatinib 100 mg CP, 140 mg daily AP

Monitor for hematologic and non hematologic toxicities which may require drug management including dose adjustment, briefly interrupting therapy, change of therapy and symptomatic management.

Non hematologic toxicities include: fluid retention, pleural and pericardial effusion, GI upset, rash.

Look for other causes of anemia and thrombocytopenia.

Rash: topical, systemic steroids

Hold for  hepatotoxicity at thresholds Bili 3 times, transaminases 5 times

Imatinib cramps: calcium, magnesium, L carinitine supplements

EKG, echo, diuretics for fluid overload

Adjuvant endocrine therapy

 Ref: ASCO education book 2022

1. What is the correct duration of endocrine therapy?

• 10 yr if node positive, although 7 yr may be sufficient for AI
• 10 yr for tamoxifen based on ATTOm and ATLAS trials : absolute reduction in disease recurrence of approximately 3% to 4%, and in breast cancer mortality of 2.8%

2.  Benefit of endocrine therapy

-50% recurrences happen in the first 5 yr. 2% recurrence per year LN neg, 4% per yr if LN +

-MA-17 trial showed a 4.6% absolute reduction in recurrences for patients receiving 5 additional years of letrozole after 5 years of tamoxifen, with an improvement in disease-free survival (DFS) observed in lymph node–negative and –positive disease as early as 2 years

-But OS benefit only in LN + patients

3. Role of adjuvant CDK4/6 in the adjuvant setting: who and how long?

Abema 2 yr if high risk- high risk means 4 or more LN. If 1-3 LN, for tumors > 5cm or grade 3--> IDFS benefit of 7% at 4 yr in abema group ( 85 v 76%)

Ribociclib 3 yr- intermediate or high risk: stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC 

-3 yr IDFS 90% versus 87%. Overall, the addition of ribociclib reduced the risk for recurrence by 25%

4. Premenopausal women: choice of therapy

Tamoxifen versus Tamoxifen with OFS: OS benefit with the addition of OFS to tamoxifen: reduction of recurrence by 1.4% and risk of death by 2.3% at 12 yr, SOFT trial.

-12-year OS was more than 95% in pre-menopausal women with grade 1 or 2, less than 2 cm, node neg

-12 yr OS in women who got chemo: adding OFS to tamoxifen produced an absolute reduction in distant recurrence/death of 2.6%/4.7% at 12 years (OS improved from 78.9% to 83.6%).

- ER+ HER2-negative disease who received neoadjuvant chemotherapy or were younger than age 35, absolute survival improvement was in the range of 10% for either oral endocrine agent combined with OFS compared with tamoxifen alone

- AI versus Tamoxifen in addition to OFS: distant recurrence less with AI, no survival difference so far in premenopausal women

5. Males with breast cancer

Tamoxifen or AI with GnRH agonists

Need Germline testing.

Were included in the NATALEE trial

6. Role of bisphosphonates: ASCO and Cancer Care Ontario guidelines

- Strongly consider in post menopausal women - zoledronic acid q 6 months for 3-5  yr. Clodronate may be used. Not enough data to support denosumab. No conclusive evidence that 5 yr is better than 3 yr.

-Educate about risk of ONJ, renal failure, hypocalcemia and risk of ocular complications. Monitor calcium, renal function and ask for dental issues, ocular symptoms before each treatment.

- In women age ≤ 60 years with a previous hysterectomy and ovaries left in place, luteinizing hormone, follicle-stimulating hormone, and serum estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy to receive adjuvant bisphosphonates

-In postmenopausal women, the addition of bisphosphonates led to an absolute 2.2% reduction in the risk of bone recurrence (rate ratio, 0.72) and a 3.3% reduction in the risk of breast cancer mortality (rate ratio, 0.82) with a greater effect in older women, whereas no substantial effect was observed in premenopausal patients

- addition of bisphosphonates should be considered in women who were premenopausal at breast cancer diagnosis and who receive OFS as part of their endocrine therapy

7. De-escalation of endocrine therapy: When to use BCI

-in year 4 of planned 5 yr of AI, if patient is intolerant, do BCI to see if it would help to continue

- if HER 2+ and ER+, BCI can identify low risk patients who can stop AI at 5 yr

Melanoma management

Risk calculator

https://www.melanomarisk.org.au/

 Adjuvant

1. CheckMate 238: Adjuvant Nivolumab vs Ipilimumab in Stage III-IV High-Risk Melanoma

5 year update from this study demonstrated sustained long term improvement in median RFS with nivolumab at 61.0 months vs 24.1 months (HR: 0.72). The OS data remain immature.

50% vs 39% nivo versus ipi 5 yr RFS.

2. KEYNOTE-054: Adjuvant Pembrolizumab vs Placebo for Stage III Melanoma

The 5-year RFS rates were 55% with pembrolizumab and 38% with placebo (HR: 0.61).

3. KEYNOTE-716: Adjuvant Pembrolizumab vs Placebo in High-risk, Resected, Stage II Melanoma

The 36-month RFS rate was 76.2% with pembrolizumab and 63.4% with placebo, and the median RFS was not reached in either arm. Although OS analyses remain immature, results from this study reinforce the SoC to consider adjuvant therapy with anti–PD-1 in this patient population.

4. CheckMate 76K: Adjuvant Nivolumab vs Placebo in Resected Stage IIB/IIC Melanoma

CheckMate 76K demonstrated an RFS benefit with nivolumab (HR: 0.42).

In patients with stage IIB melanoma, 12-month recurrence-free survival was 93% with adjuvant nivolumab therapy, and 84% in stage IIC melanoma (vs 84% and 72% in the placebo group).

5. COMBI-AD: Adjuvant Dabrafenib/Trametinib vs Placebo in BRAFV^600E/K-Mutant Melanoma

5 yr RFS 52% ( Dab Tram) vs 36% ( placebo)

Discussion:

Risks versus benefits of treatment, different options, duration of treatment, route of administration, chances of relapse with observation alone, patient preferences were all discussed.

Neoadjuvant

1. SWOG S1801: Adjuvant Pembrolizumab ± Neoadjuvant Pembrolizumab in Resectable Stage III-IV Melanoma

event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49%

2. OPACIN-Neo: 3 different doses of ipi nivo for stage 3 melanoma ; phase 3 ongoing. high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80% No difference between 3 arms.

3. Neoadjuvant Relatlimab + Nivolumab for Resectable Stage IIIB/C/D or IV Melanoma :phase 3 ongoing.

Metastatic 

1.  CheckMate 067: OS and PFS at 7.5-Year Follow-up

The 7.5 year follow-up of this trial found ongoing OS and PFS benefits in the nivolumab containing arms compared with ipilimumab.¹⁸ The median OS was 72.1 months, 36.9 months, and 19.9 months for nivolumab plus ipilimumab, nivolumab alone, and ipilimumab, respectively. These results reinforce the SoC for this patient population, which is using an anti–PD 1–containing regimen as upfront therapy.  

2. RELATIVITY-047: PFS by BICR

The study met its primary endpoint of an improvement in PFS with relatlimab plus nivolumab.²¹ At a median follow-up of 25.3 months, the median PFS was 10.2 months vs 4.6 months with nivolumab alone. OS not significant.

Discussion:

wild-type BRAF metastatic melanoma who is treatment naive: nivolumab in combination with either ipilimumab or relatlimab. While ipi nivo has not been compared head to head with nivo relatlimab, if the disease burden is low and patient frail,the latter combo has 10% grade 3 toxicity

3. BRAF V600 E mutated: Pooled Analysis of COMBI-d and COMBI-v Trials of Dabrafenib + Trametinib: 5-Year OS

5 year OS rate was 34% in this patient population, with a median OS of 25.9 months. The 5-year PFS rate was 19%, with a median PFS of 11.1 months

4. coBRIM: OS With Vemurafenib ± Cobimetinib in BRAF-Mutant Advanced Melanoma

Results from this study were similar to those seen with COMBI-d and COMBI-v, with a 5 year OS rate of 31% with the combination and a median OS of 22.5 months.

5. COLUMBUS:  phase III COLUMBUS study looked at encorafenib plus binimetinib in comparison with vemurafenib or encorafenib monotherapy in patients with unresectable stage IIIB/C/IV melanoma and a BRAF^V600E/K mutation.

Results similar to #3 and #4.

Metastatic melanoma treatment sequence : DREAMseq

This study established that the sequence beginning with combination nivolumab/ipilimumab resulted in a 20% absolute improvement in 2-year overall survival (72% v 52%) compared with the sequence beginning with dabrafenib/trametinib. A trend toward 2-year overall benefit was seen across all patient subsets, and other efficacy end points (progression-free survival and duration of response) also favored first-line immunotherapy

Clinical pearl: Dacarbazine is recommended in certain circumstances where patients are not eligible for immunotherapy or targeted therapy

How would you approach: BRAF wild-type melanoma who received first-line ipilimumab/nivolumab and now has progressive disease?

•  Relatlimab with Nivo
• Pembro with lenvatinib
• TIL therapy once approved or on clinical trial
• Dacarbazine

Melanoma with CNS mets

If asymptomatic -Ipi nivo

If symptomatic: steroids,local Rx and ipi nivo rather than combination BRAFMEK even for BRAF mutated melanoma

AE management BRAK MEK

• Derm: skin exam at baseline, q2 months, then upto after 6 months after stopping treatment
• Eye: baseline retinal exam, then as needed. Hold if grade 2 or higher
• Cardiac: EKG baseline, Echo baseline. At 2weeks- another EKG. At 1 month- echo. Then repeat EKG and echo q 3 m
• LFT monthly- hold if grade3 or higher
• Fever- hold, tylenol, steroids

Pearls:

1. BRAF mutant melanoma stage 4: symptomatic. Paraneoplastic are rare. Retinal manifestations may be seen. Use ipi nivo based on Dream seq data. 20% OS benefit in 2 yr.

2. MSLT II- therapeutic LND does not improve survival.

3. Steroids- small amount for short duration OK, more than 10 mg for longer term not good on IO.

4. Orthostatic hypotension in immunotherapy: rule out endocrine disturbances, but consider autonomic neuropathy. Could be directly drug induced although rare.