What you got in those genes?
AML with inv (16); What is the risk category?
Favorable risk.
inv(16) is one of the core-binding factor mutations. Typically demonstrates monocytic and granulocytic differentiation with abnormal eosinophils in the bone marrow. Others include t(26;26), t(8;21).
BONUS: what is the preferred consolidation therapy for AML with inv(16), w/o c-kit, with post induction CR, ie absence of blasts or cyto-genetic identification of inv(16)?
58 y/o M s/p &+43 induction and allo transplant from his brother for de novo AML. He is on cyclosporine and methotrexate for acute GVHD prophylaxis. On day +25, he is noted to have an erythematous rash involving < 25% of BSA. What therapy do you recommend?
Topical steroids. Patient has grade 1 cutaneous GVHD.
For most patients with grade I cutaneous GVHD (< 25%) recommendation is topical steroids and prophylactic measures.
Grade II or higher recommended is systemic steroids +/- topical steroids. Most common is methylprednisolone 2mg/kg/day in divided dose. Generally for several weeks followed by prolonged taper.
Patient receiving HIDAC consolidation. Develops nystagmus, slurred speech. What is the etiology and appropriate management?
Cerebellar toxicity from Ara-C.
Stop therapy with HiDAC. Should not re-challenge. Need to find alternative therapy.
More common in patients with renal insufficiency.
55F presented with WBC 23,000, blasts 56%, cytogenetic t(6;9) without FLT3 or NPM1 mutations. She is now s/p induction therapy with cytarabine and daunorubicin with complete response. Her sister is a matched donor. What is the most appropriate therapy for consolidation in this patient?
Allogeneic transplantation
t(6;9) = poor risk
Patient < 60, poor risk, with CR after induction. Allogeneic transplant with matched related or unrelated donor is preferred post-remission therapy.
55 y/o M is planned to start induction therapy with traditional "7+3" using cytarabine & daunorubicin. What dose do you recommend?
Age <60: Cytarabine 100-200 mg/m2 and Daunorubicin 60-90 mg/m2.
Age >60: Cytarabine 100-200 mg/m2 and Daunorubicin 45-90 mg/m2
CALGB established 3 days of daunorubicin and 7 days cytarabine were more effective than 2 & 5 respectively, and that 10 days cytarabine was not superior to 7. Also, 100 mg/m2 cytarabine was as effective as 200 mg/m2 for same duration. Daunorubicin 30 mg/m2 was inferior to 45 mg/m2 and more recently 45 mg/m2 show to be inferior to 90 mg/m2. UK study showed daunorubicin 60 mg/m2 was equivalent to 90 mg/m2
Patient presents with 60% peripheral blasts on outpatient CBC. WBC 11.5k, plt 65k, hgb 8. Patient is clinically stable. t(15;17) identified in all metaphases on BM biopsy. What is diagnosis? Risk category?Initial therapy recommendation?
Patient has APML.
WBC > 10k confers high risk disease. Higher risk of differentiation syndrome with ATRA.
High risk APML patients should receive ATRA + chemotherapy.
Standard risk: ATRA and ATO preferred
52 y/o M s/p &+3 and allo transplant for AML with multi-lineage dysplasia. On day +180 he is overall doing well except for grade I chronic GVHD of liver and skin. 4 days later he develops 102.3 fever and is admitted to ICU. Blood cultures show gram positive lancet shaped diplococci. What is the most likely infectious organism?
Strep Pneumo
Patients with chronic GVHD can develop hypo-splenia or compromised splenic macrophages leading to susceptibility from encapsulated organisms (E Coli, H Flu, Strep Pneumo, Salmonella, Klebsiella, Neisseria meningitidis).
Patients also commonly have hypogammaglobulinemmia which limits ability to respond to infection.
Patient should be considered for lifelong penicillin prophylaxis.
52 y/o patient receiving induction therapy with idarubicin & cytarabine continuous infusion develops acute hypoxia on day 4 of therapy. CXR shows bilateral dense pulmonary infiltrates with near white out of lungs. CBC & coags are normal. Patient afebrile. What is the most likely etiology?
Diffuse alveolar hemorrhage (DAH)
Can occur during induction therapy. Fatal if not recognized. When blasts are killed in the lung they can cause marked inflammation and alveolar bleeding. Most common in M4 & M5 (monocytic differentiation; may see gingival infiltration)
58M dx with AML. BM shows 45% blasts & genomic analysis shows FLT3-ITD (high allelic ratio) mutation. Performance status is excellent, however he declines allogeneic transplantation. He is planned to start induction with 7+3 followed by HIDAC for consolidation therapy. What additional FDA approved therapy can be integrated into his treatment which will improve OS?
Midostaurin - oral multikinase inhibitor which is active in patients with FLT3 mutation.
Phase III study of patients 18-59 y/o with new dx AML and FLT3 mutation were randomly assigned to induscion followed by consolidation with HIDAC + midostaurin 50 mg BID day 8-21 or placebo. Those in remission received maintenance with either midostaurin or placebo.
Included FLT3-ITD (internal tandem duplication) and -TKD (tyrosine kinase domain). In primary analysis and analysis where data for patients who underwent allo transplant were censored, the benefit of midostaurin was consistent across all FLT3 subtypes.
Name 3 treatment options for patients > 60 who are not candidates for intensive therapy, and who have been diagnosed with de novo AML, in the absence of IDH1, IDH2, or FLT3 mutation.
Venetoclax + decitabine or azacitidine (preferred) or Venetoclax + low dose cytarabine (preferred)
Single agent decitabine or azacitidine
Glasdebig (100 mg PO days 1-28) + low dose cytarabine
Low dose cytarabine (category 3)
Gemtuzumab ozogamicin (if CD33+) (category 2B)
Best supportive care
Name 4 poor-risk cyto-genetic findings for AML.
complex cytogenetis (> 3 clonal abns), monosomy, -5q/5q-, -7q/7q-, 11q23, inv(3)/t(3;3); t(6;9), t(9;22)
55F s/p allogeneic transplant; day +50 is travelling in the caribbean when she develops 102.5 fever. During hospital admission she received Levaquin for presumed pneumonia and receives 1 unit PRBC for hemoglobin 8.7 (post transplant baseline ~10) prior to d/c. 2 weeks later, after returning home to Philadelphia, she develops diarrhea, rash, and admitting labs noted elevated bilirubin. What is most likely etiology of these findings?
transfusion related GVHD
T-lymphocytes in donor PRBC can mount an immune response against recipient. More common when immuno-compromised and donor has same HLA haplotype (b/c donor t cells not rejected by recipient).
Transplant patients should receive gamma irradiated PRBC!
84M diagnosed with AML. WBC 53,000 with 85% blasts at diagnosis. Cytogenetics shows no FLT3 mutation, but IDH1 mutation is identified. He is felt ot be too frail for intensive chemotherapy or even venetoclax/HMA, so he is started on single agent ivosidenib. 6 days later he develops dyspnea and bilateral infiltrate on CXR. He is started on azithromycin but continues to worsen after 3 days. Repeat CBC shows WBC 61,000 with blasts 76%. What is likely diagnosis and what therapy should you recommend?
Dexamethasone 10 mg BID
IDH1/2 inhibitors can cause differentiation syndrome. They are approved for patients > 75 who are not candidates for other therapy.
Criteria for differentiation syndrome (2 of following): dyspnea, fever, weight gain, hypotension, AKI, pulm infiltrate or pericardial effusion. Patients with at least 4 of criteria considered severe differentiation syndrome.
Some recommend stopping drug also, but in APL, ATRA may be continued as long is condition is not severely worsening with organ dysfunction, so this is a matter of some debate.
58 y/o M with new dx AML. BM biopsy shows 35% blasts and molecular shows FLT3-ITD mutation with allelic ratio < 0.5 (low) & NPM1 mutation. What is this patients risk category and what consolidation therapy should be offered?
Risk category is favorable; strongly consider HIDAC rather than allo transplant in this patient. Consider adding midostaurin as well (only ~ 5% of patients in trial fit this group).
European Leukemia Net recommendation from 2017 stated that higher rate of relapse and poorer OS in FLT3-ITD patients is largely dependent on allelic ratio. Those with NPM1 mutation and FLT3-ITD (low) have similar outcome (favorable) as those with NPM1 alone.
NPM1 mut and FLT3-ITD (high) is considered intermediate risk
NPM1 wt and FLT3-ITD (low) is considered intermediate risk
NPM1 wt FLT3-ITD (high) is considered high risk
68 M recently diagnosed with AML. He is not a candidate for intensive induction therapy due to multiple medical co-morbidity. Patient is found to have IDH2 mutation. What targeted agent may be considered based on this finding?
Enasidenib; seems to work by inducing differentiation of myeloblasts, thus must monitor for signs of differentiation syndrome.
Also could consider HMAs or Venetoclax + HMA.
For IDH1 can use Ivosidenib
Name 1 common genetic abnormality associated with therapy related AML associated with exposure to topoisomerase II inhibitors.
11q23 (MLL gene) or 21q22 (RUNX1)
t-AML associated with topo-II inh accounts for 20-30# of patients with t-AML, latency period 1-5 years (can be as short as months). Less often preceded by MDS phase.
t-AML related to exposure to alkylating agents / radiation therapy - risk increases with age; typically 5-10 year latency period, unbalanced loss of genetic material from chromosomes 5 or 7, or TP53 mut.
For what condition is the use of peripheral blood stem cells (as opposed to bone marrow stem cells) NOT generally recommended for allo-transplant in adults?
Aplastic anemia (also in children adolescents with acute leukemia)
PBPC are associated with faster engraftment of neutrophils and platelets, higher rate of overall and chronic GVHD. There is theorized to be a superior graft vs tumor effect with use of PBPC, but this is not needed in aplastic anemia.
76F dx with AML with (+) FLT3-ITD mutation. Not felt to be a candidate for intensive therapy or stem cell transplant. She is treated initially with decitabine and achieves partial response which lasts for 6 months before relapse. What therapy is recommended for relapsed/refractory AML in this setting?
FLT3-ITD mut: Gilteritinib (category 1) or HMA + sorafenib
Other:
FLT3-TKD mut: Gilteritinib (category 1)
IDH1 mut: Ivosidenib
IDH2 mut: Enasidenib
CD33+: gemtuzumab
In absence of mutation, non-candidates for aggressive therapy may consider venetoclax + HMA or low dose ARA-C. Arguably could consider venetoclax in this patient as well.
52M with newly diagnosed AML with cytogenetic finding of t(9;22). APL is ruled out. What do you recommend for induction therapy?
Standard dose cytarabine x 7 days with daunorubicin x 3 days PLUS a tyrosine kinase inhibitor.
t(9;22) is a poor risk feature. Patient should be treated similar to CML blast crisis with induction chemo plus TKI.
What are indications for gemtuzumab ozagimicin?
Newly diagnosed AML that is CD33+ and for treatment of relapsed/refractory CD33+ AML
May be used in combination with daunorubicin and cytarabine or as stand alone for certain patients (not candidates for intensive therapy).
ALFA-0701 trial: de novo AML age 50-70 randomized to 7+3 +/- gemtuzumab. EFS (failure to reach CR, relapse, or death due to any cause, including drug toxicity) 17.3 mo vs 9.5 mo favoriing gemtuzumab (p=0.0002). Benefit primarily confined to the favorable/intermediate risk arm. OS 27.5 mo vs 21.8 mo (p=0.16)
AML-19 study: gemtuzumab vs best supportive care in patients > 75 or 60-75 with ECOG 2 or higher (or refuse chemo). OS 4.9 vs 3.6 months...
AML is defined by > 20% blast cells in peripheral blood or bone marrow except in patients with certain cytogenetic abnormalities who are classified as having AML regardless of blast count. Name at least 3 of these cytogenetic abnormalities.
t(8;21)(q22;q22) = RUNX1, inv(16)(p13q22) =CBF, t(16;16)(p13;q22) = CBF & t(15;17)(q22;q12) = APL (PML/RARA)
All are associated with favorable outcomes.
cGVHD involving the lung or bronchiolitis obliterans syndrome (BOS) is an often asymptomatic disease leading to immune attack and fibrosis of small airways. What antibiotic therapy was shown to have a survival detriment when used as a means of prophylaxis against this condition?
azithromycin
Studies had suggested infections may contribute to BOS, including viral, fungal, bacterial. Prophylaxis with voriconazole or posiconazole may be considered. Also recommended is: PCP ppx with Bactrim, and strep prophylaxis with penicillin. Also GERD ppx or Rx recommended.
As azithromycin has immunomodulatory and anti-inflammatory effects, was tested as prophylaxis in ALLOZITHRO trial. Azithromycin 3x/week group (vs placebo) had increased mortality with 2-year OS 56.6% vs 70.1% (p=0.02). Azithro group had higher rate of hematologic relapse (33.5% vs 22.3% (p=0.002)
42M send to ED after abnormal CBC noted by PCP. WBC=34,000 with 40% blasts, HGB=6.0, PLT=25,000. In review of his history, it is found that he has 4 siblings, 3 of whom have been diagnosed in last 10 years with AML. What is the most likely germ-line mutation to be identified?
CEBPA; transcription factor CCAAT/enhancer binding protein alpha. Encoded on chromosome 19q13.1. Has an essential role in mediating granulocytic maturation and cellular growth arrest.
Somatic CEBPA mutations may occur in 10-15% of sporadic, normal karyotype AML. (CEBPA double mutation/bi-allelic have favorable outcome)
Autosomal dominant transmission has been observed in families harboring germ-line CEBPA mutation.
RUNX1A and GATA2 mutations also associated with leukemia predisposition syndromes.
34M found to have abnormal CBC on outpatient labs; WBC=23,000, HGB=6.2, PLT=72,000. Peripheral smear shows myeloblasts with auer rods. DIC panel is normal. BM biopsy shows 85% leukemic cells including promyelocytes and metamyelocytes with auer rods. Cytogenetics shows t(11;17)(q23;q21). What is the diagnosis, risk category, and effect of cytogenetics on expected response to treatment?
APL, high risk. ~ 1% of APL. Will have diminished response to ATRA (poorer prognosis).
Variant t(11;17) fuses RARa with promyelocytic zinc finger domain (PLZF). Treatment with ATRA in this setting does NOT induce terminal differentiation, and CR cannot be attained with ATRA alone. (some data supporting use of ATRA + GCSF to stimulate differentiation)
In general translocation partners STAT5B and ZBTB16 are RESISTANT to ATRA.
While NPM1 and NUMA FIP1L1 are SENSITIVE to ATRA.
67F with history of right sided breast cancer s/p mastectomy AC/T and radiation is noted to have leukocytosis with peripheral blasts on routine CBC. BM biopsy shows 45% blasts and cytogenetics reveals monosomy 7. No FLT3 mut noted. What therapy should be recommended?
For patients > 60. Liposomal encapsulated daunorubicin (44mg/m2)-cytarabine (100 mg/m2) (Vyxeos). For induction: Give via IV infusion over 90 minutes on days 1, 3, 5. If necessary, repeat same dose on days 1, 3.
Study CLTR0310-301 RCT comparing Vyxeos to standard 7+3 in 309 patients age 60 - 75 with t-AML or AML-MRC showed Vyxeos improved median OS (9.6 mo vs 5.9 mo; HR 0.69, p=0.005)
Per NCCN: patient >/= 60 with either t-AML, antecedent MDS/CMML, or cytogenetic findings c/w MDS, and is a candidate for intensive remission induction, Vyxeos is Category 1 recommendation.