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