FLT 3 mutation and inhibitors in AML

Type 1 inhibitors good against TKD and ITD FLT3 ( ITD is the one associated with shorter DOR and higher relapse rates)

Type 2 ( quizartinib and sorafenib) are only useful against FLT 3 ITD.

Reference

The efficacy of quizartinib appears comparable to midostaurin, which resulted in the same HR of 0.78 when evaluated in the RATIFY trial compared to placebo, although the analyzed population in RATIFY also included patients with FLT3-TKD (tyrosine kinase domain) mutations and restricted inclusion to patients aged 18 to 59 years.

Secondary factors may therefore influence the decision to use midostaurin or quizartinib. For example:

• Quizartinib is the only FLT3i approved for maintenance treatment after alloHCT.

• The pretreatment QT interval using Fridericia's correction (QTcF) must be less than 450  ms for quizartinib and equal to or less than 500  ms for midostaurin (midostaurin dose must be reduced for QTcF of 471-500  ms).

• Quizartinib is inactive against FLT3-TKD (D835) and Y842 mutations and must not be used in these patients.

• Quizartinib works even if FLT 3 mutations are associated with DNMT3 A or NPM1 mutations.

• Quizartinib leads to worse outcomes if FLT 3 mutations are combined with ASXL1 mutations. So do not use Quizartinib if you see both these mutations together.

• The AMLSG 16-10 trial reported a high efficacy of midostaurin in younger and older patients (61-70 years old), while the effect of quizartinib was most pronounced in patients aged less than 60 years.

• It is not understood why subgroup analyses showed a better efficacy of quizartinib in female and midostaurin in male patients. 

• FLT3i maintenance treatment after alloHCT is recommended in all FLT3-mutated patients.

• The prognostic effect of FLT3-ITD MRD is established for the time point after 2 cycles of chemotherapy and before alloHCT using either bone marrow or peripheral blood. The proportion of MRD-positive patients after 2 cycles of chemotherapy ranges from 29% to 56%.

• The most discriminatory threshold for MRD is a VAF of 0.01%, although MRD detection below this threshold is also associated with a higher relapse rate

• Sorafenib improves OS when given in the maintenance setting irrespective of MRD status before or after allo HCT.

• Quizartinib and gliteritinib showed improved OS if FLT 3 MRD positive by NGS before or after allo-HCT. Duration of maintenance 2-3 yr.

AML- Ven AZA VIALE study

 VIALE study criteria for those ineligible for 7+3

Age: > 75

ECOG 2 or higher

CHF EF 50% or less, chronic stable angina, COPD FEV1< 65% or DLCO< 65%

 Median OS 15 months versus 9 months with addition of Ven to AZA

NPM1 mutated AML without signaling mutations (TP53, FLT3, NRAS , KRAS) median OS 39 months

Genetic signature with high benefit, intermediate benefit and low benefit to the above rx:

1. Low benefit: TP 53 mutated, median OS 5.5 months ( there was no benefit to adding ven to this group compared to placebo)

2. Intermediate: FLT3/KRAS/or NRAS mutated but with NO TP 53 mutation ( or wildtype TP 53): median OS 12 months

3. High benefit: none of the above mutations. Cr+Cri 77%. Median OF 26 months

DLBCL front line and relapsed

 

Front line:

The frontline treatment for diffuse large B-cell lymphoma (DLBCL) is rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This regimen is the standard of care and has been shown to cure more than 60% of patients with DLBCL. The National Comprehensive Cancer Network (NCCN) guidelines also endorse R-CHOP as the first-line treatment for DLBCL.

For elderly patients, the treatment approach may be adjusted based on their fitness and comorbidities. A comprehensive geriatric assessment can help tailor the treatment, and dose-reduced regimens such as rituximab-miniCHOP may be used for very old or frail patients.

Recent advancements include the POLARIX trial, which suggests that adding polatuzumab vedotin to R-CHP (pola-R-CHP) may improve progression-free survival and could potentially replace R-CHOP in eligible patients. In  non GCB subtype, with IPI 3 or higher, this may provide a better PFS.

Relapsed or refractory: Reference

Second line EGFR mutated lung ca stage 4

 ASCO recommends: Amivantamab+ carbo +pemetrexed

MARIPOSA 2 trial

PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively.

Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively.

PFS 8 months amivantamab+ chemo with or without lazertinib.

Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy.

CHRYSALIS -2 second line without chemo- ami+ laz

Amivantamab and lazertinib has demonstrated promising efficacy as a second-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed on osimertinib. The CHRYSALIS-2 study reported an overall response rate (ORR) of 36% (95% CI, 23-51) in the target population, with a clinical benefit rate (CBR) of 58% (95% CI, 43-72) and a median duration of response (mDOR) that was not reached at the time of reporting. This study also highlighted the manageable safety profile of the combination, with the most common adverse events being infusion-related reactions, paronychia, rash, and stomatitis.

The response rate of amivantamab+ lazertinib is similar to chemo alone in the second line setting ie 36%.

NTRK inhibitors

 1. Larotrectinib is more specific. Entrectinib can be used for ROS1 mutations as well.

2. ORR 73%, median OS 3 yr in NTRK mutated lung adenocarcinoma ( 0.1 to 0.3%)

3.  Unique se: dizziness, wt gain, neuropathy or myopathy withdrawal pain if a dose is missed, LFT elevations. Use meclizine for vertigo and midodrine for orthostatic hypotension.

Metastatic castration resistant prostate cancer- HRR m versus BRCA mutated

Metastatic castration resistant prostate ca has a life expectancy of 2 yr to 4 yr after onset of castration resistance. 20-30% of mCRPC pts have HRR mutations.

SOC: AR receptor blockers ( abiraterone, darolutamide, Enza)+ ADT, triplet with chemo, docetaxel with ADT. 2L-Rad 223, SipT, PARP inhibitors for HRR m ( olaparib) or BRCA ( rucaparib), pembro MSI high, Lu 177 3rdline.

 1. Front line CRPC- olaparib+ abiraterone only for BRCAm whereas talazoparib+ enza is for all HRRm in the front line.

2. Olaparib single agent  later line for all HRRm; rucaparib single agent later line for BRCA m.

3. Talazoparib+ Enza approved for 1st line HRR m CRPC. OS HR in HRR m population 0.69

4.  TALAPRO study SE: 36% required prbc. Other se: fatigue, nausea, anorexia, neutropenia. 0.4% AML/MDS

Systemic therapy HCC ASCO update

1. Child's pugh A-- durva treme or atezo - bev. Screen for esophageal varices. Screen for autoimmune diseases.

2. First line: If cannot do durva treme or atezo bv, consider lenvatinib, sorafenib or durvalumab. Len is non inferior to sorafenib but with more SE.

3.  After first line as above, 2L- sorafenib, lenvatinib, cabozantinib, ramucirumab if AFP > 400. Ipi+nivo 2L based on case series. No high quality data, but durva treme can be used 2L following 1st line atezo bev.

4. 2L following 1st line TKI- cabozantinib, regorafenib. Can do single agent IO pembro or nivo or front line IO combinations if no contraindications.

5. Child Pugh class B- benefit is modest at best with standard rx as listed above. Shared decision making encouraged. Sorafenib in non SHARP trial pt is similar to best  supportive care. The toxicity of sorafenib was similar whether Child's A or Child's B.

6. Prognosis: Durva treme HIMALAYA median OS 16 months; Atezo bev median OS 13 months.

7. Main side effects  : hand foot syndrome higher with TKI. HTN. elevated AST. Diarrhea. All more common with sorafenib except HTN with atezo bev. Proteinuria. Elevated lipase and bilirubin. Alopecia with sorafenib.

8. Most studies exclude macrovascular portal vein invasion and > 50% hepatic disease burden.

9. Lenvatinib with TACE 1st line, China only, superior OS and PFS compared to len alone. LFT elevation more common with the combination.

10. Ramucirumab in REACH, REACH -2 studies showed OS benefit if AFP> 400 compared to placebo. HTN, hyponatremia were SE.

11. Regorafenib FDA approved 2L for those who progressed on sorafenib baased on RESORCE trial. Only try this if pt is Child Pugh A and was able to tolerate sorafenib 400 mg for 3 weeks or longer. This is not a good drug for those who were intolerant to sorafenib due to greater toxicities. On the other hand cabozantinib is an option if intolerant to sorafenib.

12. Cabozantinib , CELESTIAL trial can be used in 3rd line. 

13. Factors to consider when choosing rx for advanced HCC: performance status, Child's Pugh score, bleeding risk, portal hypertension, esophageal varices, tumor burden, extra hepatic spread and major vascular invasion.

14. Checkmate 040- nivo child Pugh B OS 7.6 months

Immunotherapy skin toxicity

  Dermatologic adverse events to immunotherapies are of topmost importance because they are usually the first to appear, within approximately 3 weeks of the patient starting therapy. They are also among the most common: about 30% to 40% of all patients treated with immunotherapies will develop some type of dermatologic side effect. Some of the most common include rash, itching, skin color changes, and hair loss. However, the most common, by far, are itching of the skin without presence of a rash and rashes that can present in various ways. These generally occur within the first couple of months, but they can occur at any time during immunotherapy treatment, even years after the patient has finished therapy

1. Grade 1 or 2 rashes, high-potency, topical steroids are used—strong topical steroids, not an over-the-counter solution. Some topical steroids are now available as a spray.
2. Grade 3 rashes, of course, oral prednisone at approximately 0.5 to 1 mg/mg/kg per day, tapered over a course of 4 weeks. If the rash recurs after that, you should consider using a steroid-sparing agent, usually a biologic agent.
3. Late skin toxicity- vitiligo, alopecia areata, autoimmune blistering conditions like bullous pemphigoid

 How is the rash of immunotherapy different from Osimertinib rash?

• Osimertinib causes acneiform rash, usually affects the face and chest,
•  immunotherapies can cause an acneiform rash very infrequently. Immunotherapy rashes affect mainly the trunk and extremities.
• immunotherapy rashes differ in appearance from acneiform—they present more like psoriasis, like eczema, or like hives

Underutilized treatments for skin toxicity:

• pruritus- pregabalin, omalizumab, doxepin, dupixent

General advice for patients on immunotherapy

fragrance-free detergents and soaps, protective clothing, sunscreen when outside

Reference : 

Metastatic GIST

 All pt with advanced GIST--> check for KIT and PDGFRA mutations. 70-80% have either of these.

KIT exon 9---> needs higher dose of imatinib 800 mg daily, 

exon 11 standard dose

PDGFRA also responds to imatinib

SDH deficient--> resistant to imatinib. Other options--> sorafenib, vandetinib, pazopanib, regorafenib, temodar

High risk Mantle cell lymphoma

 Mantle cell lymphoma

ASH education book 2024

1. Identify biologic MIPI( MIPI+Ki67), aggressive biology( blastoid, pleomorphic), high risk genetics ( 17p, TP 53 mutations, complex cytogenetics). 

2. p53 accumulates in the cell in TP53 mutations > 30-50%. Stain by IHC. CIT ( Chemo/ASCT) can overcome neg impact of p53 mutations. Unclear significance of TP53 in the leukemic, non nodal variant.

3. Blastoid has a 5 yr OS of 35%. LYMA study high MIPI 5 yr OS 47%.

4. Approach to pt with p53 mutations: avoid benda in 1st line or second line, they do not do well even with intensive CIT or BTK and should be planning CAR-T. 

5. Allogeneic stem cell transplantation, as consolidation during the first CR or at first relapse, is a consideration for select eligible patients, particularly where CAR T-cell therapy is not available.

6. Two main strategies have been pursued to improve outcomes in MCL, including in high-risk patients: (1) incorporating novel agents with CIT and (2) substituting CIT with a combination of novel agents.

7. There were 2 trials that evaluated BTKi ( ibrutinib or acala) with BR in elderly. No OS benefit although PFS improved. High toxicity. p53 group did not benefit in the SHINE trial (ibrutinib).

8. TRIANGLE study: younger, ASCT eligible pt. 3 yr FFS in both ibrutinib groups 88% including high p53 > 50%.

9. Chemo free regimens upfront can involve a BTKi+ Ven+ CD 20 antibody. Acala+ Lenalidomide+ Obin or Ven+ R2 have shown excellent PFS and 2 yr OS in phase 2 trials.  boVEN Zanubrutinib+ Obin+ Ven 

10. An Ara-C-containing intensified induction therapy followed by ASCT remains a highly effective treatment strategy in younger MCL patients, inducing long-lasting remissions. However, no randomized trial has shown an OS benefit with ASCT when modern rituximab-based regimens are used.

 Summary:

Frontline- TP53 aberrant( high p53, 17p, TP53 mutations)---> options clinical trials or BTKi-CIT followed by 3 yr rituxan maintenance or BTKi+BCL2i+CD20 Ab. No benefit to intensive CIT and ASCT in TP53mutated.

Other high risk- trial, or CIT+ BTK+rituxan maintenance

Non high risk- Intensive CIT followed by ASCT in fit younger pt < 66 yr or TRIANGLE regimen without ASCT.

Anticoagulation in brain tumors

 Blood journal Oct 2024

ICH risk factors in pt with brain tumors receiving anticoagulation(ACN)-Table 1

1. High risk: plt count < 50K, large vol ICH (> 10 ml)

2. Intermediate risk: High grade glioma, plt < 100K, combining antiplatelet therapy with anticoagulation.

3. Uncertain risk: SRS( except melanoma) VEGF inhibitors, CKD

Other useful tips

1. 4 types of ca with high risk of ICH even without ACN- melanoma, RCC, thyroid, choriocarcinoma

2. VEGF inhibitors can increase risk of bleeding in gliomas. 

3. Use DOAC for ACN in glioma, not LMWH.

4. Antiplatelets alone do not increase risk of ICH in  brain tumors 

5. Pre-existing intratumoral hemorrhage

Case scenarios:

1. Pt with high grade glioma, new PE, recent tumor related ICH in the last 30 days ( yes or no): what are the risk factors for bleeding and progressive thrombosis. 

Estimate risk for bleeding: concurrent antiplatelet use, reduced plt count, type of tumor, high grade glioma, large vol or multifocal ICH, recent SRS ( esp melanoma), what does the most recent brain imaging show ( stable hemosiderin deposition is good)

Assessment: The brain mets are stable or tumor risk of bleeding is high/ intermediate. Other risk factors that increase risk of bleeding include: 

While these risk factors increase risk of ICH, the risk is not prohibitive, start LMWH ( or DOAC for glioma), monitor in neuro ICU, repeat CT in 24-48 hr.

If risk is prohibitive because of high risk of bleeding, and the thrombotic risk is high ( PE or proximal DVT)--> place a filter

2. Recent tumor related ICH in the last 30 days

If isolated subsegmental PE ( neg b/l DVT), then OK to withold AC until stable, then repeat US in 1 week and 2 weeks. If propagation, consider ACN if bleed has stabilized.

If proximal VTE, PE and high risk of ICH expansion ( high vol > 10 ml ICH), IVC filter, hold ACN

If intermediate risk ICH expansion--> LMWH or DOAC 50% dose start typically after 2-4 days.

Discuss risk benefit ratio with healthcare proxy and document discussion.

Metastatic GEJ carcinomas

 

HER 2 neg: FOLFOX pembro Keynote 859: improved OS 13 months versus 11.5 months with and without pembro. OS, PFS , ORR benefit. Across all PDL1 groups, benefit noted.

HER 2 positive CapeOX with trastuzumab- median OS 17 months. Add pembro to the triplet, OS 20 months if CPS > 1. Keynote 811. There was an OS benefit. Patients with a PD-L1 CPS ≥ 1 experienced a 21% reduction in the risk of death and a 28% reduction in disease progression with pembrolizumab, whereas the CPS < 1 subset (15% of the population) derived no benefit 

T cell lymphoma- pearls

 Reference: 

1. T cell lymphomas- nodal, cutaneous, leukemic. T cell lymphomas comprise 10-15% of mature lymphomas from post thymic T cells.

2. Nodal approximately 60%. 3 main groups- PTCL NOS, Anaplastic (ALK positive and ALK neg), T follicular helper cell nodal ( includes angioimmunoblastic).

3. Standard of care for CD 30+ T cell lymphoma is BV+ CHP based on ECHELON 2 which showed OS and PFS benefit over previous SOC which was CHOP.

4. 5 yr OS for all PTCL with CHOP= 30%, ALK+ anaplastic is the best with 5 yr OS 70%. This group also did the best with CHOEP and BV- CHEP. PFS 48 months versus 20 months BV- CHP versus CHOP in ECHELON 2.

5. Consolidation in CR1 is standard with auto SCT and in first relapse after salvage with allo- SCT. Anaplastic ALK+ low risk do not need auto SCT in CR1.

6. ALK neg anaplastic but with DUSP22 mutation acts like ALK+ anaplastic.

7. GATA 3 mutation is a bad prognostic indicator

Metastatic pancreatic cancer

 Initial evaluation: 80% metastatic at the time of diagnosis

1. Imaging: CT CAP,  port placement

2. Labs: CBC, CMP, CA 19-9, INR, albumin. CA 19-9 may be negative in Lewis antigen neg individuals ( false neg) and falsely elevated in infection or obstruction of the biliary tract. Therefore CA 19-9 should only be measured after biliary obstruction relieved.

3. Germline and somatic tumor profiling: 3-5 % may have germline BRCA or PALB2 alterations. If insufficient tissue, ct DNA can be used for somatic tumor profiling for other  HRD gene alterations. These HRD alterations can be present in upto 40% of pt with pancreatic cancer stage 4. Comprehensive somatic tumor NGS helps identify : ALK, NRG1, ROS1, FGFR2, KRAS, HER2, and high tumor mutational burden (TMB-H). Such alterations either have clinical relevance in second- and later-line therapy .

Treatment:  The approach to initial systemic therapy for metastatic exocrine pancreatic cancer is based on the presence or absence of specific germline pathogenic variants and/or actionable molecular alterations in the tumor. Clinical factors that also influence selection of therapy include patient performance status (PS) and comorbidities, laboratory values (including serum total bilirubin levels), symptom burden, and goals of care.

• Performance status:
• Geriatric assessment: 
• Comorbidities:
• Symptom burden: high/low
• Goals of care: palliative. Patient's goals: 
• Labs influencing initial choice: LFT, renal function

1. Systemic therapy: Gemcitabine was established as the cornerstone of treatment in 1996. Subsequently, the four-drug combination ­FOLFIRINOX assumed that position when the PRODIGE 4/ACCORD 1 ­trial established it as the standard of care for fit patients. Disease control and survival are identical with FOLFIRINOX and mFOLFIRINOX. mFOLFIRNOX has 25% less 5FU and irinotecan. Other front line options include NALIRIFOX which has a 2 month survival benefit over Gem- Abraxane.

FOLFIRINOX median OS 1 yr

IMPACT study Gem Abraxane median OS 9 months

Gemcitabine1L- CONKO001- median OS 22 months. Fixed dose rate gem 10 mg/m2 /minute better than standard 30 minute infusion.

-We do not offer gem-cis to unselected patients without known germline or somatic HRD mutations either core or non-core. The core HRD mutations are BRCA and PALB2. 

-While awaiting results of the germline and somatic profiling, a safe bet is to start mFOLFIRINOX if good PS.

Targeted agents used in first line: NTRK, RET

2. Maintenance Olaparib 300 mg BID ( germline BRCA only) improved PFS by 12% over 2 yr, no OS benefit. Rucaparib can be used for germline and somatic HRD.

3. Supportive care:

- biliary obstruction

-cancer pain

-cachexia, loss of appetite

-pancreatic exocrine insufficiency

4. Prognosis: median OS with platinum regimen and core HRD mutations: 25 months. 

If no HRD mutations, platinum based agents-- meian OS 15 months

If no HRD and non platinum 1st line- 13 months 

5. Counseling regarding side effects:

The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups (MPACT trial)

FOLFIRINOX- neutropenia 45%, febrile neutropenia 5%, deaths occurred. Alopecia 11%, low blood counts10%, neuropathy , fatigue 23%, GI toxicity 15%, blood clots 6%.

6. Evaluating need for prophylactic DOAC: Khorana score 2 or higher. ONKOTEV-2 trial

A note on oligometastatic pancreatic cancer

EXTEND phase II trial with metastases directed therapy for oligometastatic pancreatic ca 5 or less sites of mets, treated with SBAR with PFS of 10 months versus 2.5 months.

Reference: JCO Nov 2024

Acute hematological emergencies: inpatient

 1. HLH:

Reference: https://pmc.ncbi.nlm.nih.gov/articles/PMC8094004/

2. Catastrophic APS : https://ashpublications.org/blood/article/126/11/1285/34367/How-I-treat-catastrophic-thrombotic-syndromes

3. ITP : https://ashpublications.org/thehematologist/article/doi/10.1182/hem.V21.3.202434/515735/Not-So-BenignImmune-Thrombocytopenia-New-and

https://ashpublications.org/hematology/article/2023/1/254/506436/How-to-manage-ITP-with-life-threatening-bleeding

4. HITT

5.  Purpura fulminans

6. Thrombotic microangiopathies

7. Acute promyelocytic leukemia

8. Warm and cold hemolytic anemias:

Pearls in anticoagulation

 

1. When and in whom should thrombophilia testing be done? Are the results going to change management? Why does the pt want the testing? Test at the appropriate time.

2. Middle of Stephan Moll's pyramid in whom testing is valuable- minor provoking factors--> travel, OCP ( recent start or change)

3. Estrogen and blood clotting

ASH strong recommendation : do not do blanket testing for thrombophilia just because they are about to start OCP. But if first degree family member with a VTE, recommend progestin based OCP.

Pregnancy planning: miscarriage, recurrent pregnancy loss ( other than APL) not improved with heparin for any other thrombophilia.

4. Do not test for thrombophilia during an acute clot or while inpatient.

5. Antiphospholipid inpatient testing: young patients with cryptogenic stroke. infection, pregnancy, malignancy can affect cardiolipin and beta2 microglobulin. Lupus anticoagulant is affected by all anticoagulants.

6. Valvular disease and anticoagulation: 

-oral anticoagulation : fresh bioprosthetic valve 5 % risk of clot over 3 months. 

- assess bleeding risk: CKD, NSAID

Rx oral VKA or DOAC 1-3 months. Followed by low dose ASA.

If high risk bleeding--antiplatelet rather than anticoagulant.

Historically aortic and mitral valve replacement risk was considered differently ( mitral higher risk). Antiplatelet only if high risk bleeding, otherwise even aortic bioprosthetic valve should get an anticoagulant.

RIVER Trial ( afib): In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin

ENBALV trial edoxaban non afib population. Edoxaban was comparable to warfarin in preventing stroke or systemic embolism and intracardiac thrombus in patients with non-valvular atrial fibrillation (AFib) within three months after bioprosthetic valve surgery, 0.5% of patients receiving edoxaban experienced a stroke or systemic embolism compared with 1.5% of patients receiving warfarin. The incidence of major bleeding and clinically relevant bleeding was numerically higher in patients assigned to the edoxaban group compared with the warfarin group, however, no fatal bleeding or intracranial hemorrhage was observed with edoxaban. One fatal intracranial hemorrhage occurred in the warfarin group.

  Valvular versus non valvular: or rheumatic versus non rheumatic

In rheumatic valvular Afib-- use VKA not DOAC- Reference NEJM 

Muscle invasive bladder cancer

 1. General principles: Neoadjuvant cisplatin based chemo followed by radical cystectomy plus pelvic LN dissection is the standard of care for cisplatin eligible patients with muscle invasive bladder cancer.  In patients with residual disease after surgery, who have a PDL1 of 1% or more, should be treated with nivolumab  q 2w for 1 yr. 

2. Prognosis: Median OS in NAC+ cystectomy--> 102 months versus 82 months if no NAC

5 yr OS 60% versus 50%( for cystectomy alone), 14% improvement in OS over 5 yr with NAC before cystectomy.

3. Choosing the right chemo option: 

In the neoadjuvant setting, ddMVAC is preferred if patient is fit.

Medically fit cisplatin eligible patients may be treated with  6 cycles of DDMVAC ( VESPER trial)

Another option is 4 cycles of Gemcitabine cisplatin with split dose cisplatin. This is preferable for those with co-morbidities especially where cisplatin eligibility may be questionable e.g CKD with GFR 40-60.

While there appears to be a higher path CR rate with DDMVAC 42% versus 36% GC group.

4. After cystectomy, PDL1 testing will be done. If PDL1 1% or higher, 1 yr nivolumab if no contraindications to immunotherapy. DFS 22 months versus 13 months nivo versus placebo.

5. Side effects of cisplatin: hearing loss, need for hearing aids, neuropathy, kidney damage usually reversible, high risk of emesis and need to take prophylactic nause meds. 

Side effects of gemcitabine- abnormal blood counts, fatigue, risk of infection and sepsis. Liver functio abnormality.

5-year analysis of the French phase III VESPER trial showed no improvement in overall survival with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) vs gemcitabine and cisplatin (GC) in the total perioperative (intention-to-treat [ITT]) population of patients with muscle-invasive bladder cancer. Improvement in overall survival with dd-MVAC was observed among patients treated in the neoadjuvant setting, who constituted the majority of the study population.

Reference: VESPER trial update ASCO post

Gem-Cis- Durvalumab-- 2 yr OS 82% versus 75% without durva. Path CR with durva 37% versus 27%

Cisplatin ineligible

Per NCCN--> proceed to cystectomy, consider adjuvant nivolumab
Other options:
1. Neoadjuvant enfortumab: path CR 36%, EFS 2 yr 62%. Pts received 3 cycles of neoadjuvant EV (1.25mg/kg) on Days 1 and 8 of each 3-week cycle followed by RC+PLND and then 6 cycles of adjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3 week cycle starting 8 weeks post-RC. Primary endpoint is pathological CR (pCR) per central pathology review; secondary endpoints include pathological downstaging (pDS) rate per central pathology review, safety and tolerability. Here we present initial results from the neoadjuvant/RC+PLND phase + 30 days post surgery.
2. Neoadjuvant pembrolizumab: PURE -01 trial- 3 courses neoadjuvant pembro then cystectomy. The PURE-01 study tested the activity of preoperative pembrolizumab (pembro) in patients (pts) with muscle-invasive bladder (MIBC), resulting in 38.5% pathologic complete responses (pT0N0). As a result of this study, pembrolizumab is often considered in patients who are cisplatin-ineligible with MIBC

Low risk MDS with anemia

 low-risk MDS patients with anemia warranting treatment options:

No Ring Sideroblasts

Is Epo level <100?

• First Line: ESA
• Second Line: Either add lenalidomide or switch to Luspatercept
• Third Line: Luspatercept if not already used
• Fourth Line: Imetelstat

Is Epo level >100 <500?

• Consider first-line Luspatercept here (given ESA is less likely to work)
• Move to Imetelstat if failure with Luspatercept

Ring Sideroblasts

• First Line: Luspatercept. There is much clearer data for efficacy here.
• Second Line: Move to Imetelstat

If failure/lack of response despite further moving down this list, then hypomethylating agents as are used for higher-risk MDS.

BMJ Society of Immunotherapy guidelines/ GI toxicity

 Reference:

BMJ/SITC guidelines 

MD Andersen guidelines

British Society of Gastroenterology guidelines

Diarrhea and colitis

• Diagnostic workup for grade 1 diarrhea or colitis symptoms should include CBC, CMP, and fecal lactoferrin.

• Additional workup should be performed for patients with diarrhea or colitis symptoms of grade ≥2, and these additional tests should include fecal calprotectin, and stool infectious analysis (stool ova and parasite, C. difficile and cytomegalovirus (CMV) testing via polymerase chain reaction (PCR) if available or if high index of suspicion is present, among other infectious studies (eg, COVID-19)). Serum TSH and celiac serologies (antitransglutaminase antibodies with total IgA level) may also be considered, if clinical suspicion of ICI-induced celiac disease is present.  Stool: lactoferrin and calprotectin; blood: ESR and CRP

• Fecal pancreatic elastase if steatorrhea or failure to respond to front line steroids in 24-48 hr

• Abdominal CT scan should be obtained in patients with signs and symptoms of colitis complications, such as bowel perforation or toxic megacolon. Flexible sigmoidoscopy and/or colonoscopy with biopsy should be performed for patients with diarrhea or colitis symptoms of grade ≥3 or with persistent (≥5 days) diarrhea or colitis symptoms of grade 2 . Contraindicated if acute abdomen such as toxic megacolon or perforation or if ANC < 1.0

• ICIs may be temporarily withheld (instead of discontinued) in patients experiencing grade ≥3 diarrhea or colitis symptoms. These patients may be re-challenged with ICIs if their symptoms are stable (grade ≤1 or baseline) with <10 mg/day of prednisone (or equivalent) 

• Prior to administration of infliximab or vedolizumab, patients should be tested for HBV, HIV, and TB. Administration of infliximab or vedolizumab should not be delayed if test results are pending.

• if there is severe ulcerative presentation on colonoscopy, 3 doses of infliximab (5 mg/kg) should be administered at 0, 2, and 6 weeks to reduce the risk of colitis recurrence

• If diarrhea or colitis symptoms persist after the second dose of infliximab treatment, the third dose should be held and 3 doses of vedolizumab (300 mg) should be administered at 0, 2, and 6 weeks.

• • If no clinical improvement is observed following immunosuppressive therapy in patients with grade ≥3 diarrhea or colitis, a repeat endoscopy with infectious workup (C. difficile and CMV) should be performed. Repeat endoscopy should be performed prior to resuming ICI therapy.

  • If diarrhea or colitis symptoms recur following corticosteroid taper, they should be evaluated and treated in the same manner as the first episode

Flexible sigmoidoscopy or colonoscopy on admission to the hospital if no evidence of acute abdomen:

An infectious cause for the diarrhea should be excluded in all patients. Patients with grade 1 symptoms are managed conservatively. Patients with grade 2 or higher symptoms should undergo a colonoscopy and are treated with systemic corticosteroids and, depending on their response, biologic therapy.

Perform colonoscopy and EGD only if ANC > 0.5 K/microliter

Examine biopsies for the presence of CMV and other opportunistic infections in immunosuppressed patients

Order EGD if there are signs and symptoms of concurrent nausea/vomiting and/or epigastric pain 

 Esophageal biopsies are strongly recommended if there is visible evidence of esophageal inflammation on endoscopy 

Although the British Society of Gastroenterology (BSG) recommends performing a colonoscopy on all patients with GI irAEs, the AGA reserves endoscopic evaluation for patients with grade 2 or higher GI irAEs.

 Endoscopy should be considered before initiation of high-dose systemic glucocorticoids, in patients with corticosteroid-refractory disease, and in those previously exposed to immunosuppressants to exclude the presence of opportunistic infections.

Because 98% of GI irAEs involve the left colon, a flexible sigmoidoscopy rather than a full ileocolonoscopy can be performed in most cases.

The presence of deep, large ulcers is a high-risk feature and associated with increased need for biologic therapy, increased need for hospitalization, and longer hospital stays. Colonic ulcers are the only identifiable predictor of response to treatment and need for biologic therapy.

In some situations, follow-up endoscopy is important to monitor response to therapy and determine the appropriate time to resume ICIs. Alternatively, recent evidence has demonstrated that fecal calprotectin is strongly associated with endoscopic severity in patients with immune-mediated colitis and may serve as a useful noninvasive marker of endoscopic and histologic remission. Fecal calprotectin > 116.

General guidelines

• Patients should receive dedicated education on irAEs by a medical professional and may receive additional materials such as informational booklets or reference cards.

• Patients should be encouraged to use contraception while receiving immunotherapy. Fertility should be discussed prior to treatment. Per NCCN use contraception for 6 months after the last dose.

• When beginning corticosteroid therapy, patients should be specifically counseled about potential toxicities, including hyperglycemia, mood disturbances, insomnia, gastritis, weight gain, and opportunistic infections (eg, Pneumocystis pneumonia)

• The following tests should be performed prior to beginning ICI therapy: complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), free thyroxine (fT4). Urinalysis should be considered to evaluate for baseline kidney disease.

• Consider performing a baseline electrocardiogram (EKG) on patients deemed at a higher risk for myocarditis (eg, cardiac comorbidities, diabetes mellitus, anti-PD-(L)1 with anti-CTLA-4 ICI combination therapy, etc). Baseline troponin testing may also be considered to provide information for evaluating potential future cardiac toxicity.

Immunotherapy cardiotoxicity

ESC Guidelines

• Early toxicity typically inflammatory : ICI-associated myocarditis had early onset of symptoms (median of 30 days after initial exposure to ICI), and up to 50% died)
• > 90 days--> non-inflammatory HF,  MI, AV block, supraventricular and ventricular arrhythmias, new pulmonary artery hypertension, sudden death. Can be seen in association with ischaemic stroke, and VTE. Takotsubo-like syndrome, pericarditis, pericardial effusion, also described.
• Long term considerations in the clinic: progressive atherosclerosis, hypertension, 
• Highest risk of cardiac toxicity: ipilimumab+ nivolumab ( combination)

Class I recommendations:

-All patients on ICI treatment: CV risk assessment, troponin, BNP, NT-BNP, EKG

- pt on long term ICI management ( > 12 months) should have CV assessment every 6-12 months, particularly so for the high risk patient.

-High-risk patients should additionally have a TTE evaluation at baseline  and repeat if  symptoms. 

What falls under CV risk assessment:

• Physical examination, BP, NP (BNP or NT-proBNP), lipid profile, HbA1c, and ECG.

 

What is a high risk patient?

• Dual ICI
•  combination ICI-cardiotoxic therapy for example immunotherapy with herceptin, VEGF inhibitor or doxorubicin ( keynote 522); pembro + axitinib
•  ICI-related non-CV events
• prior Cancer therapy related cardiac dysfunction
•  known CAD.

Once started on therapy, ECG, cTn, and NP should be checked.

In patients who develop ECG abnormalities, new biomarker changes, or new cardiac symptoms at any time, prompt cardio-oncology evaluation is strongly recommended, including TTE for the evaluation of LVEF and GLS, and CMR when myocarditis is suspected.

Monitoring of cardiac function while on treatment for high risk:

-Serial ECG and cTn measurements should be considered before ICI doses 2, 3, and 4, and if normal, reduce to every three doses until completion of therapy to detect subclinical ICI-related CV toxicity

International cardio-oncology societ criteria for myocarditis

 Myocarditis diagnosis based on pathohistological findings i.e. “multifocal inflammatory cell infiltrates with overt cardiomyocyte loss by light microscopy”, or cardiac troponin elevation associated with 1 major criterion (cardiac MRI – CMR modified diagnostic Lake Louise criteria) or with 2 minor criteria after excluding acute coronary syndrome or acute infectious myocarditis . The five minor criteria include the “clinical syndrome”, ventricular arrhythmia +/− new conduction disease, decline in systolic function +/− regional wall motion abnormalities (non Takotsubo pattern), other IRAEs (myositis, myopathies) and “suggestive CMR”.

What treatment options are available in patients not responding to steroids in 24-48 hr?

1. TNF inhibitors: Infliximab is a monoclonal Ab, acts by blocking release of IL 1 and IL6. Typically single dose given 72 hr after steroids if symptoms not responding. Can repeat a second dose after 2 weeks. 5 mg/kg bwt single dose IV. Send quantiferon gold.

Effective in : colitis, ir rheumatologic AE

2. Vedolizumab: Integrin antagonist. Mostly ir GI enterocolitis.

Both agents equally effective in immune mediated diarrhea and colitis according to a small prospective trial. 

3. Mycophenolate: B and T cell suppression, widespread effectiveness in a variety of auotimmune conditions and transplant patients. Can be used for all immune mediated toxicities. But if colitis and diarrhea, prefer IV vedolizumab or infliximab.

4. IVIG: 2 gm per kg bwt daily for 1-3 days; broad spectrum use. Guillain-Barré syndrome (GBS), myasthenia gravis, neuropathies, rheumatologic conditions, blistering disorders, immune hematologic conditions, and many others (NCCN)

5. Plasmapheresis: GBS, myasthenia. Mixed results when used in all neuro irAE.

Hyperacute immunotherapy toxicity

 hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 

-9% developed toxicity at a median of 10 days; 82 patients studied retrospectively

-Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis)

-2% grade 5--> death

Reference

Fertility Counseling for immunotherapy

National Comprehensive Cancer Network guidelines advise that patients of reproductive age use effective birth control during and for at least 5 months after immunotherapy. Most clinical trials also required patients of reproductive age to use at least two anticonception methods while receiving anti‐PD‐1 or anti‐PD‐L1 agents up to 6 months after the last dose.

NCCN 2024 breast cancer

 Surgical updates:

1. Marker should be placed at tumor and LN prior to NACT

2. Post NAC MRI plus  mammogram can predict BCS eligibility in those not previously BCS eligible. MRI alone predicts in 88% versus 92% with bimodality. Mammogram is better at picking up calcifications which can be malignant in upto 40%. All post NACT calcifications should be excised.

3.  All multicentric and locally advanced ( skin, muscle infiltration) not eligible for downstaging after NACT

4. Ideal candidate for NACT is unifocal tumor which can be downstaged for BCS. 

5. Post NACT MRI eligible for downstaging only to assess accurate surgical planning. If you know she is going to get a post chemo mastectomy, there is no role for MRI.

6. Downstaging for BCS occurred in 75% ( 79% in HER 2 positive). Path CR is not required for downstaging.

7. Safety for downstaging with BCS: no difference in local or OS in those who were downstaged after NACT.

8. Management of axilla:

a. Clinically node positive getting NACT- clinical N1 disease. 4 studies showed false neg rate of > 10%. To bring it down below 10%, the following were done-- use a clip upfront on the node, remove more than or at least 3 SLNB, use dual tracers.

b. Nodal path CR is essential to omit ALND. Nodal recurrence of 1%.

c. Regional nodal radiation is indicated if SLNB is positive. However axillary XRT is not needed if pt undergoes axillary dissection

9. In clinically node negative early BC, if at the time of surgery only 1-2 SLNB are positive, ok to omit ALND and proceed with axillary XRT instead. This reduced lymphedema with XRT.

10. In patients who undergo NACT, we do not have data to safely assume that axillary dissection can be avoided in lieu of axillary XRT as in patients who did not get NACT. Risk of additional LN involvement is not predicted by SLNB findings and can be as high as 62%. Even if isolated tumor cells in the SLNB upto 20% can have additional nodal disease.

11. Regional nodal radiation reduced the risk of local and distant recurrence. Improved OS in 2 trials MA- 20 and EORTC 22922 in high risk patients.

12. RNI Oxford meta-analysis: cardiac sparing techniques--> cardiac toxicity was reduced. BC mortality was reduced.  DIBH--> deep inspiratory breath hold--> moves the heart away and inferiorly from the chest wall.

13. Margin of 1 mm is sufficient even after NACT.

14. TDM1 -KATHERINE study adjuvantly for residual disease after NACT--> 7 yr OS 5% difference and 7 yr IDFS benefit by 14%

15 Omitting regional nodal radiation if axillary path CR-- NSABP 51

Testicular cancer

 Reference: https://ascopubs.org/doi/10.1200/JCO.2014.56.0896

1. Seminomas were more radiation-sensitive. For patients with pure seminoma, orchiectomy was followed by RPLND or radiation to pelvic and para-aortic lymph nodes. Either approach resulted in similar survival; therefore, postorchiectomy radiation became standard practice. A 95% cure rate was reported in patients with seminoma treated with orchiectomy and radiation therapy. If distant metastases were found, radiation was given to the abdomen, mediastinum, supraclavicular area and even to lung metastases. 

-Today, the treatment options for stage I seminoma following orchiectomy include surveillance, 20 Gy radiation to the ipsilateral RPLN′s, or one to two cycles of carboplatin. Long-term survival is nearly 100%, irrespective of the initial option chosen.

-For patients with low volume (< 3 cm LN) stage II seminoma, 30 to 36 Gy radiation to the para-aortic and ipsilateral iliac lymph nodes remains standard.

-chemotherapy (regimen of bleomycin, etoposide, and cisplatin [BEP] × 3 or regimen of etoposide and cisplatin [EP] × 4) is preferred for patients with bulkier disease.

-residual mass > 3 cm after chemo--> PET--> SUV more than 4--> surgical resection

2.  Given the relative radiation-resistance of embryonal carcinoma, RPLND soon replaced radiation if nonseminomatous germ cell tumors (NSGCT) were present.

3. RPLND replaced radiation for patients with stage I or II NSGCT, achieving cures in nearly 50% of patients with nonmetastatic, lymph node (LN) –positive disease.

4. What can you find at RPLND and how does that affect the next steps? You may find:

-necrosis

- teratoma:  the presence of teratoma in the orchiectomy is predictive of teratoma in the RPLN

-or viable germ cell tumor (GCT)

-One area of management which remains unsettled is the role of PC-RPLND in patients with stage II or III disease achieving a serologic and radiographic complete response (CR). Proponents of observation at Indiana University cite the 15-year cancer-specific survival of 97% reported with this approach,29 while investigators at MSKCC recommend PC-RPLND in most patients, citing the presence of viable GCT and teratoma in some patients with normal-size RPLNs on CT

5.  Non seminomas Stage I: active surveillance, nerve-sparing RPLND or adjuvant chemotherapy, are standard for stage I NSGCT, resulting in 98% to 100% long-term cure rates.  Patients are characterized as high risk (relapse rates 50% with surveillance) versus low risk (15% relapse rates with surveillance) based on the presence of vascular invasion and embryonal predominant histology.

6. low volume stage II NSGCT (RPLN < 3 cm) and normal postorchiectomy hCG and AFP are generally managed with RPLND, while those with higher volume stage II disease or rising markers receive chemotherapy (BEP × 3 or EP × 4). Cures are achieved in approximately 95% of all patients

7. Seminoma has only good risk and intermediate. Intermediate BEP 4 or VIP.

8. Non seminoma has good, intermediate and poor risk. Intermediate and poor risk BEP 4.

No role for PET to assess post chemo masses in non seminoma ( can do in seminoma).

Examples of various stages of non seminoma

1. 30 yo M who underwent inguinal orchiectomy for left testicular mass. Post orchiectomy labs are normal. Path shows embryonal cell ca involving the spermatic cord. CT scan with no enlarged nodes or mets. What is his stage? 

T3N0M0 S0

Ans: stage I B, non seminoma.  Only if the tumor is limited to the testes and without any LVI, scrotal or spermatic cord invasion can it be stage IA. Otherwise T2, T3 or T4 tumors even if S0, N0, M0 should be considered IB. Predominant embryonal is also a high risk in stage I.

For stage IA-surveillance, RPLND or 1 cycle BEP are options

IB- get a CT within 4 weeks before 1 cycle BEP. RPLND or surveillance are also options.

2. 30 yo M left orchiectomy for choriocarcinoma. pT3. Persistent tumor marker elevation but no nodes, no mets. What is his stage?

Ans: stage I S ( any T stage, N0, M0 but with persistent tumor markers)--> IS

The management of IS is lumped with stage II and good risk III  ie IIIA

For non seminoma, if you have disease in the lymph nodes (N1-N3), but serum markers are still S0 or S1, you have stage II disease.

All patients undergo orchiectomy. Post orchiectomy get tumor markers and CT scan. If tumor markers are persistently elevated, BEP 3 cycles. Omit bleomycin if lung or kidney disease or over 50 yr. Within a month after chemo, get a CT CAP. No role for PET.  If residual mass 1 cm or bigger--RPLND.

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