Axicel versus tiso cel:
Axi cel with better PFS, and OS than tiso cel when compared in patients who did not go on trial. More grade 3 ICANS with Axicel.
https://www.nature.com/articles/s41591-022-01969-y
Lisocel has a better toxicity profile than Axicel, although premed with steroids helps reduce the incidence of CRS with axicel.
RTP Pan Pacific 2022
https://www.researchtopractice.com/UNMCPanPacific22CART/Video/1?playlistIndex=0#t=3m46s
Three main considerations:
1. Surgery upfront or NACT followed by interval surgery
2. Choice of front-line chemo
3. Molecularly targeted therapy: HRD, BRCA
Primary surgery depends on patient's clinical condition and the possibility of complete cytoreduction.
If NACT 3 cycles chemo--> surgery--> 3 cycles chemo
Choice of chemo
Standard: carbo taxol 3 week. Total 6 cycles
Molecular therapy:
Bevacizumab: improves PFS
The biggest change has been in BRCA improves OS as maintenance.
In the maintenance setting:
BRCA mutated: niraparib ( PRIMA), Olaparib with or without avastin
BRCA WT but HRD: Niraparib, olaparib
BRCA WT, HRD p: niraparib, avastin
Antibodies in X linked hemophilia
These are alloantibodies acquired after prior plasma-derived or recombinant factor 8. It can start as early as within 20 exposure days. Bypass agents are formally indicated and patients are treated with immune tolerance therapy. Occasionally immunosuppression is used. Spontaneous remission is rare, and mortality is high due to bleeding risk.
Antibodies in acquired hemophilia ( AHA)
These are autoantibodies. 50% of these are idiopathic, but look for cancer, autoimmune conditions, drug-induced and postpartum. Interestingly, postpartum acquired hemophilia can go into remission in 20-30% cases. Bypass agents can be used but not formally indicated as with X linked. In contrast, immune suppression ( IST) is indicated, but ITI is not typically used.
A word about immune tolerance therapy ( ITI)
More successful in Hemophilia A versus Hemophilia B. 70% versus 30%.
Small doses of factor 8 are introduced daily in those with high titers of inhibitor. High dose is preferred to low dose based on a 2012 study which showed faster improvement in high dose cohort and higher bleeding in low dose cohort.
ITI typically in good prognosis patients, IST in poor prognosis patients.
IST treatment in acquired hemophilia
High risk or low risk.
High risk: Inhibitor > 20 BU, factor 8 less than 1%
Low risk : inhibitor < 20 BU, factor 8> 1%
Mortality in acquired hemophilia: 20% in those over 65 yr.
CV complication, risk of infection and risk of bleeding. Also prognosis is determined by the underlying condition responsible for AHA.
Alloantibodies in VWD are always in type 3. Difficult to treat. Routine testing is not done. Inhibitors may cause anaphylaxis when VWF is infused. Suspect this if a loss of response to VWF Infusions.
Acquired VWD: MGUS, malignancies, aortic stenosis etc.
Treat underlying condition.
Combination of VWF/factor 8 concentrates, IVIG, IST, DDAVP.
1. KN 522 Early TNBC : 8% EFS benefit and 8% Distant met free survival benefit over 3 yr. OS data are not statistically significant at 3 yr with the addition of Keytruda to carbo taxol- AC. My personal comment on this is that I would not use the 3 week AC dose as in this trial just to accommodate keytruda regimen. We know that DDAC is better in high-risk patients. Unanswered questions include: whether should Keytruda be continued if path CR is achieved. What if path CR is not achieved in BRCA + patients? PARP or Capecitabine +/- keytruda?
2. Monarch- E High risk node positive ER+- Ki 67 prognostic but not predictive of abema benefit. Inclusion criteria N2 disease. If N1 disease, had to have either T3, G3, or ki67 20% or higher disease. absolute improvements in 3-year IDFS and distant relapse-free survival rates of 5.4% and 4.2%, respectively, for the ITT population
3. Brightness trial TNBC: This was an interesting trial presented at ESMO 2021. The key questions were to determine if adding carboplatin and/or veliparib to standard AC-T improved outcomes. Veliparib made no difference even in BRCA germline mutated patients. Carboplatin improved EFS and path CR in all comers.
4. Olympia BRCA 1/2 : 1 yr adjuvant olaparib for high risk HER 2 neg patients BRCA 1/2.
TNBC 80% or ER+ 18%. 50 % received neoadjuvant. 7% DDFS benefit in 3 yr. 9% IDFS benefit.
OS data 3 yr OS improvement 3.8%
CPS EG 3 or higher indicates high risk of relapse in ER+ patients.
Calculator:
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt
5. Rx PONDER
Recurrence score 0-25 Post menopausal women with 1-3 LN, no chemo benefit
Premenopausal women: 5% benefit in IDFS and 2.5 % benefit in distant recurrence free survival.
Benefit was seen in pre-menopausal women with micro mets and macro mets.
6. TEXT and SOFT trials:
OFS: 13 yr follow up 3.3% OS benefit with exemestane with OFS compared to tamoxifen with OFS
1. Stage IB through IIIA --> if resectable--> surgery then 4 cycles adjuvant chemo.
If margins positive--> repeat resection ( preferred) or RT
Recent updates:
Add adjuvant atezo for 1 yr after 4 cycles adjuvant chemo if PDL1= or>1% for a DFS benefit
If EGFR mutant, add osimertinib for 3 yr after 4 cycles chemo
OR if able to use neoadjuvant chemo io do 3 cycles nivo with carbo taxol--> surgery---> 6 months nivo--> OS benefit.
My take on this:
Early stage resectable, do NGS to identify EGFR/ALK mutations. If positive, plan for surgery, adjuvant chemo, and then osimertinib for 3 years. This may change once the results of the NeoADAURA trial become available. ADAURA showed a DFS benefit with 90% patients with no disease progression at 5 yr and median DFS of 5.5 yr.
If no driver mutations, and resectable do neoadjuvant nivo with carbo taxol. High rate of path CR 37% and OS benefit.
ALK mutations: ongoing trials using alectinib
2. A side note on KRAS mutated versus wild type patients: best rx available now is chemo IO even if PDL1 > 50% do not use single agent IO.
3. Seribantumab trials in those with NRG1 mutations ( rare mutations) is a HER 3 antibody ( similar to Perjeta) and has a 33% response in this population comparable to chemo. Diarrhea.
TDxd in exon 19 or 20 insertions - ongoing trials
3. IIIB/IIIC unresectable
concurrent chemo RT followed by 1 yr durva in all comers irrespective of EGFR mutation status. Although in Europe, these patients are not given durva. Ideally enroll in a clinical trial after concurrent chemo RT.
NRG Lung 004 trial: in patients with PDL1> 50% omit chemo and use concurrent IO RT followed by maintenance IO ( durva). Bottom line, this was safe. Efficacy data pending.
What is VEXAS syndrome: A syndrome with a mix of inflammation and hematologic disorder.
Often associated with MDS Or MGUS.
UBA1 gene inactivating mutations
Most effective rx so far to date: Jakafi ( Blood Aug 2022)
Adult-onset syndrome that links seemingly disparate hematologic and autoimmune symptoms. The first description of the disorder, called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, was published in The New England Journal of Medicine (NEJM) in December 2020
https://www.nejm.org/doi/full/10.1056/NEJMoa2026834
https://ashpublications.org/ashclinicalnews/news/5960/The-Vexing-VEXAS-Syndrome?searchresult=1
1. Non critically ill hospitalized patients: use rx dose heparin
2. Critically ill hospitalized patients: use trophy dose heparin
Avoid rivaroxaban
Except for NICE guidelines, which recommend 7 days post-discharge prophylaxis
Blood Aug 2022
Smoldering myeloma work up
Blood Aug 2022
Baseline tests:
CBC, B12, folate, iron studies
Creatinine, calcium, ALKP
UPEP, SPEP, IFE, FLC
NT-pro BNP
PET CT or whole body low dose CT or MRI spine and pelvis
Repeat in 3-6 months: creatinine, Calcium, CBC, SPEP IFE, FLC
Anemia labs if Hb drops
24 hr urinary protein, NT BNP every 12 months
Imaging and bmbx when progression suspected
1. Anemia and Von Willebrand factor levels
Anemia can falsely elevate levels of VWF and factor 8, which can affect diagnosis. This applies only to type 1 disease. So correct anemia and recheck levels in suspected VWD.
2. Prophylaxis with recombinant VWF in severe VWD ( 3 or more spontaneous bleeds in prior 12 months) Vonicog alpha, phase 3 trial
VWF: Ristocetin level < 20, so patients with severe disease were included.
Vonicog alpha was better than on-demand prophylaxis ( previously using plasma product) and reduced the annualized bleeding rate. It was as good as plasma product in those who were on plasma-based routine prophylaxis with no new adverse events.
3. New guidelines for diagnosis and management of VWD
AML over 60 yr
1. Secondary AML increasingly resistant to frontline chemo , worse RFS but not increased TRM
2. TP 53 mutated AML and MDS EB similar in outcomes
Mechanism: Binds to the non-kinase domain of BCR-ABL where ATP binds.
This is the only CML TKI that works in this way.
Asciminib is preferred to ponatinib in those with intolerance or lack of response to first and second-line TKI.
However, ponatinib may be preferred if BCR ABL> 10% at 6 months.
Both ponatinib and asciminib may be acceptable in T315 mutation or non-T315I kinase domain mutations.
Omacetaxine is another drug approved for T315 I mutations.
2024 update
https://www.nejm.org/doi/full/10.1056/NEJMoa2400858
How to counsel pt: Imatinib was the first generation TKI. It is still the standard of care. The second gen TKI can induce deeper molecular remission and greater chance of going into TFR, but the OS is not different. The MR3 at 48 weeks is 40% imatinib, 45% second gen and 68% asciminib.
The drug that induced the highest MR3 was ponatinib but the front line trial EPIC was aborted due to concern for vascular events.
Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).
In conclusion, asciminib is much better tolerated and induces deeper responses that imatinib. The MR3 for asciminib was not statistically superior to second gen TKI.
Adverse events ( G3 or higher):
Asciminib 38%, Imatinib 44%, Second gen TKI 55%
Discontinuation:
Asciminb 4.5%, Imatinib 11%, Second Gen TKI 10%
PNH
Loss of CD55 and CD59 due to loss of PIGA coded proteins which bind these proteins using GPI anchors--> alternative pathway for complement activation --> RBC hemolysis.
-C5 inhibitor Ravulizumab
-C3 inhibitor Pegcetacoplan: FDA approved, given subcut twice a week. Main AE infection with encapsulated bacteria. black box warning meningococcal d/s
Cold Agglutinin disease
Ig M binds to RBC and brings along C3b as a companion in lower temp.
In warmer temp, Ig M dissociates from the RBC, leaving C3b on the RBCs --> hemolysis.
Current rx: avoid cold, rituxan front line, relapsed disease fludarabine rituxan, velcade, BR therapy
-FDA approved sutimlimab--> inhibits classical complement C1
Caution: vaccinate against encapsulated bacteria before starting the treatment.
Initially weekly for 2 doses then every other week.
Transplantation-associated microangiopathy:
thrombocytopenia, microangiopathic hemolytic anemia, organ damage
Current rx: stop the calcineurin inhibitor, PLEX, rituxan, steroids eculizumab
Lectin pathway and complement inhibition are being investigated in those resistant to eculizumab ( narsoplimab and conversion)
ITP: Sutimlimab being investigated for ITP resistant to prior therapies
Ref: Blood June 2022
Standard of care for RR HL--> salvage chemo followed by ASCT
Standard chemo yields 54 to 73% PET neg CR which is the most imp predictor of outcomes.
BV with nivo ( no chemo) salvage--> 67%
However, BV is now being used frontline.
Nivo monotherapy --> 27 to 43% CR without chemo.
PET adapted sequential nivo followed by nivo with ICE
Nivo q 2 weeks up to 6 doses. If CR-->ASCT
If not CR after 6 cycles or PD at any point, then 2 cycles ICE+ nivo--> ORR over 90%
2 yr PFS all comer 72% 2 yr OS 95%
1. Neoadjuvant nivolumab with platinum doublet: 3 cycles
Checkmate 816: NEJM
Stage IB to IIIA. HR 0.63 for a reduction in progression, death, recurrence
Path CR 24% versus 2% standard arm.
Pearl: the tumor, when it shrinks, does NOT move away from the mediastinum or vital structures
NADIM II- neoadjuvant nivo with carbo taxol 3 cycles in resectable IIIA without EGFR/ALK--> surgery-->adjuvant nivo for 6 months. Improved path CR, PFS and OS. First trial to show OS benefit.
2. Adjuvant atezo after chemo in non small cell lung ca: IMpower 010 JCO:
Stage II to IIIA
DFS benefit with atezo 1 yr given after 4 cycles of platinum doublet
In those with PDL1 1% or higher, DFS not reached with atezo, 35 months with BSC after 4 cycles chemo.
Pearl: Which staging system( AJCC 7) was used in the study and how does it compare to the current AJCC ( 8 now)
3. EGFR mutated localized disease
Should osimertinib be continued when switching to chemo for progression:
Ans: yes, if CNS mets, otherwise there is an ongoing study looking to answer that question
1. CD 10 positive: Follicular or Burkitt's
2. CD5 positive: CLL, Mantle cell [ FMC7, SOX11 positive in Mantle, neg CLL].
3. FMC7 positive: Mantle cell, Hairy cell
4. CD 23: positive in CLL
5. TDT positive: lymphoblastic lymphoma [ if CD 20+, then B cell, if CD 20 neg, then T cell]
Definition and complications in ABO-mismatched HSCT
Major ABO-mismatched HSCT
Major ABO-mismatched HSCT can cause hemolysis of donor’s erythrocytes by recipient’s IHAs10. In bone marrow derived grafts, hemolysis is more common than PBSC due to the high amount of erythrocytes in bone marrow11.
In major ABO-mismatched HSCT, hemolysis can be prevented by removing erythrocytes from graft. Insignificant hemolysis can also occur during erythrocyte engraftment due to destruction of erythrocytes containing donor’s antigens by means of recipient’s IHAs12. Finally, these reactions cause pure red cell aplasia (PRCA) in the majority of patients who had major ABO-mismatched HSCT 13. Antibody titers can be diminished in major ABO-mismatched HSCT by plasma or whole blood exchange before engraftment8.
Minor ABO-mismatched HSCT (passenger lymphocytes syndrome)
About 7-14 days after the infusion of graft, hemolysis occurs due to donor’s IHAs against recipient’s erythrocytes14.
1. This immediate hemolysis can be more severe than major ABO-mismatched HSCT that usually decreases after 5-10 days. In this situation, direct antiglobulin test (DAT) is usually positive against recipient’s erythrocytes antigens.
2. Passenger lymphocyte syndrome: A second hemolytic reaction occurs due to immunization of donor’s B lymphocytes, which is called passenger lymphocytes (PL) and production of IHAs against recipient’s erythrocytes, which is called “delayed hemolysis”. An important factor in development of PL syndrome is PBSC-derived grafts due to high lymphocyte content15.
In minor ABO-mismatched HSCT, IHAs can be removed from the graft by various techniques. There is a significant association between minor ABO-mismatched HSCT and increased risk of acute graft-versus-host disease (aGVHD) in patients.
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375375/
Pearls in Stem cell transplant for the boards
Reference ASH
Know the indications for :
1. Allo SCT
AML: CR1 for intermediate or poor risk, CR2 for favorable risk, primary refractory, MDS or t-AML
ALL: Ph+ in CR1, any relapse, failure to achieve MRD neg after first induction, in AYA if high risk features such as iAMP 21 ( intrachromosomal amplification of chromosome 21), B cell with poor risk, 11 q 23
MDS: Intermediate or high risk, transfusion dependence, refractory cytopenias, moderate or severe fibrosis, therapy associated, adverse cytogenetics
CML: T3151 mutation, refractory or intolerant, accelerated or blast crisis
MF- DIPSS 2 or higher, DIPSS1 with other poor risk features, transfusion dependence, possibly triple neg MF
CLL: Richter's, second or higher progression
2. Auto transplant
a. Multiple myeloma
b. Chemosensitive Relapsed Hodgkin and NHL
c. Mantle cell
d. Autoimmune disease
e. Relapsed germ cell
f. T cell lymphoma ( not supported by phase 3 trials, but done in practice as for Mantle cell)
TYPES of transplant and stem cell sources
Auto
Allo- sibling donor
Haplo identical ( alternative donor)
MUD 10/10
Cord blood ( alternative donor)
Syngeneic - identical twin ( do not use when you want GVL effect, e.g AML)
Why syngeneic is not used in AML: We want the GVL effect, and you do not get that with an identical twin.
Stem cell sources
a. Umbilical- low risk of GVHD, prolonged time to engraftment
b. bone marrow: inconvenient to donors, no difference in survival compared to peripheral blood, less GVHD compared to peripheral SCT
c. Peripheral blood: higher CD 34 and T lymphocytes, so faster engraftment but higher GVHD
Preference of donors:
First: sibling, then second would be fully matched unrelated
Third- haplo, cord
Finally unmatched unrelated
HLA matching is important
Gender Female donor to male recipient higher GVHD because Y chromosome acts as a minor antigen
Biggest risk for GVHD: HLA mismatch
Calcineurin associated TMA- stop the drug
Calcineurin associated PRES ( altered mentation) in the peri transplant period- stop the drug
Hepatic VOD- defibrotide
GVHD rx in steroid refractory
Acute- Jakafi
Chronic- Ibrutinib, Belumosidil
Idiopathic pneumonia syndrome- steroids, etanercept
Castration sensitive, metastatic
Young patients with high vol disease start with chemo.
Castration resistant, metastatic
Nonmetastatic castration sensitive ( biochemical failure) ADT alone, intermittent
Nonmetastatic castration-resistant: salvage radiation, observation or daro/ apalutamide or enza ( if no contraindications)
