Leukemias Flashcards
1
Q
Leukemia - intro
A
Classified as:
- acute or chronic
- myeloid or lymphoid, B cell or T cell
Diseases:
Acute - AML, ALL
Chronic - CML (myeloproliferative disorder), CLL
2
Q
AML (acute myeloid leukemia) - diagnosis/prognosis
A
Presentation
- fatigue/wt loss
- coagulopathy - easy bleeding/bruising, or clotting
- organ involvement (CNS
- infection/sepsis
- features of MI (esp in elderly)
Organ involvement
- CNS involvement of AML in 1-7% cases. Risk fx inc high WCC, LDH, inv(16), 11q abnormalities, younger age
Diagnosis:
Blood film and BMAT (bone marrow aspirate and trephine)
- AML blasts with Auer rods are present in myeloid leukemia (AML and APML)
- morphology of acute leukemia shows >20% blasts in blood or bone marrow.
- cytochemistry shows cells are myeloperoxidase (MPO) positive
- flow cytometry (immunophenotyping) shows myeloid antigens CD13, CD33
Prognosis:
- Age >60yrs is the strongest adverse prognostic factor
- Cytogenetics inc karyotype - reveal translocations that correspond to their prognosis:
- good prognosis: t(15,17) APML inv(16). Also t(8;21) CBF AML (Core Binding Factor AML Has 69% 5yr survival, from 1998 study AML10 trial)
- intermediate prognosis: patients with normal karyotype, and Y-
- poor prognosis: patients with del7, del5q, inv(3), t(3;3), t(6;9), t(9;22), 11q23 abnormalities. Also patients with complex cytogenetics >or=3 abnormalities
https: //www.nejm.org/doi/pdf/10.1056/NEJMoa1112304 (NEJM - prognostic relevance of genetic profiling AML, 2012, Patel) - Molecular markers
- NPM1 + mutation conveys good prognosis
- Flt3 + receptor mutation conveys poor prognosis.
- NPM1+ Flt3- co-occurance conveys highly favourable prognosis in AML
https: //ashpublications.org/bloodadvances/article/1/19/1546/15693/Co-occurrence-of-FLT3-TKD-and-NPM1-mutations (Blood Advances: FLT3-TKD and NPM1 defines highly favorable prognostic AML. 2017)
3
Q
AML (acute myeloid leukemia) - treatment/therapy
A
Prognostic factors influence therapy.
Curative intent:
- Chemotherapy
- induction and consolidation chemotherapy commonly with cytarabine and anthracytline - allogeneic bone marrow transplant
- only curative therapy available for relapsed AML, if there is an appropriate donor + if patient is appropriate
Demethylating agents inc azacitidine.
Targeted therapies include:
- Flt3+ (either ITD or TKD) –> treat with Midostaurin (pan-kinase inhibitor i.e. multitargeted protein kinase inhibitor) for incremental benefit along with chemotherapy (7&3 cytarabin & idarubicin for induction; HiDAC for consolidation). These patients have improved clinical remission (CR) and overall survival (OS)
FLT3 internal tandem duplication (FLT3/ITD) mutation is found in approximately 25% of patients with de novo AML and conveys a generally poor prognosis. It can be successfully treated into remission with intensive chemotherapy, but patients have more aggressive disease and it routinely relapses.
The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or allogeneic hematopoietic cell transplantation (HCT) during their first remission, if there is a suitable donor, and the patient is fit enough.
- venetoclax (ABT-199) with azacitidine/low dose AraC (cytarabine)
- IDH2 mutations
Prognostic factors that influence treatment:
- Age >60yo. Chemotherapy has not been shown to improve survival. Depending on functional status, can offer chemotherapy vs supportive care.
- Adverse cytogenetics/karyotype
- Normal karyotype but adverse mutations (e.g. FLT3-ITD/TKD)
- consider allogeneic BM transplant in their first remission, if there is a suitable donor, and the patient is fit/appropriate
Treatment refractory AML
- patients who fail to enter complete remission or relapse within 6months of therapy completion
- MEC chemotherapy may be indicated to obtain disease control prior to HSCT, or as 1’ treatment for relapsed disease in pts who aren’t elegible for transplant anymore. MEC therapy has variable response, but some prev studies have shown unacceptably low overall response and short median OS.
- FLAG chemotherapy (re-induction) + allograft may be considered for pts <60yo
Sources:
DeltaMed notes 2017.
Further read:
(NEJM, midostaurin plus chemo for FLT3, 2017) https://www.nejm.org/doi/pdf/10.1056/NEJMoa1614359?articleTools=true
(Sorafenib in FLT3 positive AML) https://acsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/cncr.32387
(IDH inhibitors AML) https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(19)31172-3/fulltext
(BCL2 inhibitors AML) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235069/
4
Q
APML (acute promyelocytic leukemia) - description, morphology, diagnosis
A
Description
- Acute promyelocytic leukemia is a rare clinicopathological variant of acute myeloid leukemia (AML).
- It has characteristic morphologic, genetic and clinical features
- Unique treatment strategies with unique complications
Morphology
- Classical morphology on BM or peripheral blood smear shows large atypical promyelocytes with high N:C ratio, bilobed nucleus, prominent nucleoli, violet granules in cytoplasm, and typically have Auer rods clustered together, which is pathognomonic for APML.
- Hypergranular and microgranular variants
- Typically pancytopenic with low-ish WCC
- Bone marrow typically “packed”
Genetics
- Diagnostic hallmark (genetic testing) is reciprocal translocation between the long arms of chromosome 15 and 17 t(15;17) –> generating “PML-RARA” fusion gene –> leading to abnormal gene product.
APML diagnosis
- “Spot diagnosis” on blood film/marrow aspirate is required to ensure immediate treatment due to high early complications (coagulopathy)
- Confirmation of diagnosis requires demonstration of chromosomal translocation (t(15;17)) or fusion transcript (PML-RARA)
5
Q
APML (acute promyelocytic leukemia) coagulopathy
A
AMPL coagulopathy
- APML is characterised by life threatening coagulopathy. Early recognition of this is imperative to prevent catastrophic bleeding events and early haemorrhagic death.
- Early haemorrhagic death manifests mainly as CNS & pulmonary. Pre-2007 stats (before current treatment regimens and supportive care) EHD seen in 17-25% APML cases.
- Multiple pathways and contributing factors to coagulopathy
- Tissue factor (TF) and cancer procoagulant (CP) expressed by APML cells –> DIC
- Annexin-II is highly expressed –> mediates hyperfibrinolysis
- Marrow infiltration by APML cells –> thrombocytopenia
- Laboratory tests
- Low fibrinogen, prolonged PT/APTT, elevated INR, raised D-Dimer, thrombocytopenia
- APML cells overexpress tissue factor (TF) which promotes a procoagulant state, leading to low grade DIC.
- These cells also overexpress annexin A2 (ANA2), which leads to an anticoagulant state and hyperfibrinolysis
- APML coagulopathic mechanisms aren’t fully understood, though hyperfibrinolysis usually predominates.
- Hyperfibrinolysis is driven by the high expression of annexin II, increased activity of tissue plasminogen activator (tPA) and therefore plasmin formation (and subsequent clot breakdown), increased activity of urokinase plasminogen activator, and deficiency of PAI-1 and alpha2 antiplasmin. This is also compounded by the patient being thrombocytopenic, due to bone marrow invasion by APML cells
- Procoagulant mechanisms are driven by high expression of tissue factor expression leading to activation of clotting cascade, as it binds to factor 7 and activates factor10 and 9, triggering eventual formation of fibrin clot.
- In APML, hyperfibrinolysis is driven by the high expression of annexin II, increased activity of tPA and therefore plasmin formation (and subsequent clot breakdown), increased activity of urokinase plasminogen activator, and deficiency of PAI-1 and alpha2 antiplasmin.
- APML cells also cause damage to endothelial cells and release products when they die [such as extracellular chromatin and phosphatidylserine] which increase the production of thrombin and fibrin
- coagulation studies in APML, including low fibrinogen, often profound thrombocytopenia, prolonged INR and aPTT, high fibrinogen degradation products, high D-Dimer
- Derangement of these parameters doesn’t tend to correlate with degree of haemorrhage
6
Q
APML (acute promyelocytic leukemia) treatment
A
Aggressive correction
- Aggressive blood product replacement to correct the coagulopathy is essential. Most early deaths from APML are due to early catastrophic bleeding
- Target platelet count >50, fibrinogen level >1.5g/L, INR <1.5, normal aPTT.
- Early administration of ATRA is essential, as it decreases bleeding risk
APML - treatment
- Once APML is suspected based on clinical or cytologic criteria (microbiologist calls saying these cells just look like possible APML), have a low threshold to treat, don’t wait for confirmation before initiating treatment.
- Initial treatment is with differentiation agent ATRA (active metabolite of vitamin A).
- ATRA bind to PML-RARA gene product, leading to its degradation, inducing differentiation and apoptosis of promyelocytes. This leads to clinical remission in the majority of patients.
- In rare cases, patients may have APML associated with variant gene rearrangements, and they have experienced different responses to ATRA doses.
- Arsenic trioxide is commenced once APML diagnosis is confirmed (genetic testing/ cytogenetics)
- Long term therapy incorporates arsenic +/- chemotherapy agents, mainly idarubicin (esp for high risk pts who present with WCC >5.0)
- This is required as remission is not sustained with ATRA alone.
- Long term survival of early treated APML is excellent for patients who have managed to survive without catastrophic bleeding events. Majority of patients are cured.
APML treatment outcomes
- Patients with APML have exceptional long-term outcomes with current therapy (90-95% long term survival)
- For high risk (WCC >5): induction therapy includes ATRA, arsenic trioxide, idarubicin –> consolidation therapy involves ATRA, arsenic trioxide –> followed by maintenance therapy on ATRA [2yrs]
- Standard risk (WCC <5): treated with ATRA & arsenic (for induction & consolidation therapy) à continued on ATRA as maintenance therapy (for 2yrs)
- Kaplan Meier curves
- used to show survival over time
- APML4 study in 2015 published in lancet. Study found that high risk patients treated with this combination therapy (mentioned above) had 95% overall survival after 5yrs.
- Phase 2 trial. Looked at 124 patients with APML.
- Assessed new treatment protocol ‘APML4 protocol’ compared it to old treatment protocol (APML3). APML4 protocol involved combination of arsenic trioxide + idarubicin for induction chemotherapy, and arsenic + ATRA for consolidation therapy
- Observed outcomes of disease-free survival, event-free survival, time free from relapse over 4-5yr period
- Phase 2 trial. Looked at 124 patients with APML.
- 2016 study published in NEJM. This study showed that standard risk patients treated with atra-arsenic had 99% survival at 2yrs compared, vs 91% survival on atra-chemotherapy regimen.
- The main mortality/risk occurs initially. If patients survive the initial coagulopathy and risk of haemorrhagic death, their outcomes on treatment are excellent.
APML principles of management
- Early / low threshold for diagnosis of APML
- Followed by immediate administration of ATRA (don’t wait for confirmation via FISH / RT-PCR/karyotyping), as well as aggressive blood product replacement (set targets)
- And finally commencement on ATRA/arsenic trioxide therapy +/- chemo
This prevents early haemorrhagic death and leads to high probability of long-term survival
7
Q
Differentiation syndrome
A
Differentiation syndrome aka ATRA-syndrome
- ATRA & arsenic trioxide are differentiating agents –> release the “maturation block” caused by RARA abnormality
- Large release of pro-inflammatory cytokines from blasts as they differentiate from promyelocytes into mature cells
- Occurs ~ 25% of APML cases, usually within 7-10 days of treatment initiation. Characterised by:
- dyspnoea
- hypoxia
- bilateral pulmonary infiltrates
- fever
- hypotension
- peripheral oedema, weight gain
- serositis –> pleural/pericardial effusions
Treatment of differentiation syndrome
- Principles of treatment involve routine prophylaxis with 1mg/kg pred in all patients, OR if they are high risk with WCC > 5 (depending on hospital protocol)
- High dose corticosteroids commenced at first sign of syndrome (dexamethasone 10mg BD)
- Management of leukocytosis
- Hydroxyurea
- Idarubicin
- Consider temporary cessation of arsenic trioxide
8
Q
thrombotic complications of APML
A
- Thrombotic complications do occur, but less common, less well recognised and under-reported. Occurs in 5-10% pts at presentation, may appear pre-treatment, during induction, or maintenance phase
- Reported events inc DVT, PE, hepatic and portal vein occlusion, ischemic stroke, MI
- Microvascular thromboses (major feature of DIC) have been rarely reporting, manifesting as skin necrosis and multiorgan failure
- Features associated with higher risk of thrombosis
- WCC >10
- Expression of certain gene transcripts [[CD2, bcr3 PML-RARA transcript (the “short” isoform). And presence of FLT3-internal tandem duplication (FLT3-ITD)]]]
- Case series of thrombotic presentations of APML
- PETHEMA LPA96 and 99 trials (Sanz et al, 1999, 2004)
- Of patients with APML who died prior to starting chemo, 23% were due to thrombotic complications
- PETHEMA LPA96 and 99 trials (Sanz et al, 1999, 2004)
9
Q
ALL (acute lymphoblastic leukemia) - diagnosis, prognosis, MRD
A
Diagnosis:
- morphology
- >20% blasts in blood or bone marrow (as with any acute leukemia)
- NO Auer rods - immunophenotyping (flow cytometry)
- Lymphoid antigens inc CD10 TdT; CD19 CD20 (B cell ALL); CD2 CD3 CD4 CD8 (T cell ALL)
Prognosis
Different prognostic factors for adult vs paeds ALL (paeds does not = adult ALL … refer to image attached).
- Age
- paediatric group (young age) is good prognostic factor - Cytogenetics
Good prognosis:
- Paediatric B-ALL: >50 chromosomes (high hyperdiploid). t(12;21) TEL-AML1, +4, +10, +17
- T cell ALL: cortical on immunophenotyping is better prognosis than ETP
Poor prognosis:
- Paediatric B-ALL: 11q23 KMT2A/MLL translocations
- Adult B-ALL: t(9;22), 11q23 translocations. BCR-ABL and Ph-like translocations. Ikaros deletion
- T cell ALL: ETP on immunophenotyping
Further read:
(ALL improved survival younger patients. 2009. Blood) https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2008-06-164863
- Survival has improved for patients with ALL over the time period studied, but treatment of older patients remains a difficult issue.
(Ph-like ALL) https://www.nejm.org/doi/full/10.1056/NEJMoa1403088
-Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors.
(Philidelphia like ALL and other mutations, MRD and poor prognosis) https://www.nejm.org/doi/full/10.1056/NEJMoa1403088
- Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
MRD (minimal residual disease)
- MRD status is one of the most powerful predictors of disease-free and overall survival for children and adults with ALL. However, not all patients with MRD positivity will relapse clinically, and some patients relapse despite negative MRD studies
(MRD is an important predictor of relapse in paediatric ALL) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424148/
- Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy.
10
Q
ALL(acute lymphoblastic leukemia) - treatment
A
Prognostic factors at diagnosis influence therapies.
Paeds ALL treatment:
1. Induction chemotherapy
- trials are ongoing
2. Maintenance chemotherapy (up to 2yrs)
- oral + intermittent IV agents
3. Allogeneic BMT
- indicated with poor prognostic cytogenetics or relapsed disease
Adult ALL treatment:
1. Induction chemotherapy
- ongoing trials
- if Ph+ ALL, then use BCR-ABL inhibitor such as imatinib, dasatinib
2. Maintenance chemotherapy (up to 2yrs)
- oral + intermittent IV agents
3. Allogeneic BMT
- indicated with Ph+ ALL in their 1st complete remission, or with relapsed disease
- remains the most effective curative therapy for adult ALL for its Graft vs leukemic effect
Targeted immunotherapies for ALL
- Complement mediated (inc Rituximab for CD20+ ALL)
- T cell mediated (inc CAR-T cells ~ Chimeric Antigen Receptor modified T cell infusions; or BiTE antibodies ~ Bispecific T cell engaging antibodies such as Blinotumomab CD19/CD3)
- refer to image for targeted therapies and their surface antigens
(Novel targeted therapies ALL, Portell, 2013) https://www.tandfonline.com/doi/full/10.3109/10428194.2013.823493?scroll=top&needAccess=true
- Chemotherapy alone cures only 25–45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate, inotuzumab ozogamicin, and the anti-CD19 BiTE® antibody, blinatumomab, have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL. Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy.
11
Q
Adverse effects + limitations of chemo & HSCT of acute leukemias
A
Adverse effects of chemotherapy for acute leukemias:
Myeloablative
- induces GI toxicity (mucositis, diarrhoea); BM suppression (cytopenias requiring transfusion, increased risk of bleeding, neutropenia leading to bacterial/fungal infection, neutropenic enterocolitis); hair loss
Specific agents:
- cytarabine causes neurotoxicity
- anthracycline causes cardiac toxicity
- asparagine causes liver toxicity
- vincristine causes neuropathy
Limitations of allogeneic transplant in acute leukemias:
- Need appropriate donor and recipient (HLA matched donor; related vs unrelated; cord blood; recipient suitability in regards to age, ECOG, remission status)
- treatment related morbidity/adverse outcomes inc acute and chronic GVHD; infections; treatment toxicity
- treatment related mortality is up to 30% in MUD (matched unrelated donor), 10% in MRD (minimal residual disease); mortality secondary to infections (esp opportunistic); 50% mortality due to acute GVHD
- relapse post transplant (early vs late. Patient is not guaranteed cure)
12
Q
Blinotumumab for B cell ALL (acute lymphoblastic leukemia)
A
Recent advances on blinatumomab for ALL https://ehoonline.biomedcentral.com/articles/10.1186/s40164-019-0152-y
- patients with relapsed/refractory ALL still have dismal outcome
- CONCLUSION: Blinatumomab has been approved for patients with R/R B-ALL and MRD + B-ALL. Blinatumomab is being studied for use in frontline therapy of newly diagnosed B-ALL. Adding blinatumomab to the low intensity miniHCVD + INO regimen in the consolidation and maintenance phases appears to be promising. The mechanisms of blinatumomab resistance and predictive biomarkers for response remain uncertain. Blinatumomab in maintenance therapy appears to be promising to minimize chemotherapy and reduce therapy duration. More BiTE antibodies are coming to clinical applications. New regimens incorporating blinatumomab may lead to new therapy modalities for ALL. Combination of blinatumomab with TKIs or with immune checkpoint inhibitors are ongoing and may result in chemotherapy-free regimens for ALL.
(EXTRA:)
- Tyrosine kinase inhibitors, antibody–drug conjugates and chimeric antigen receptor T cell therapy are changing the therapy landscape for B- ALL. Blinatumomab, a bi-specific T cell engager, has been approved for patients with relapsed/refractory and minimal residual disease positive B-ALL
- Chemotherapy combined with targeted therapies and improved supportive care has enhanced complete remission (CR) rate of newly diagnosed B cell acute lymphoblastic leukemia (B-ALL) to 85–90%, and long-term survival rate to 40–45%
- However, about a third of standard-risk and two-thirds of high-risk patients experience recurrence. Relapsed and refractory (r/r) ALL has low rates of CR and poor long-term survival
- In a phase 2 clinical trial of blinatumomab for R/R B-ALL, The CR/CRh rate was 69% (25/36) after the first two cycles. Among the responders, 88% (22/25) achieved a molecular remission. The MRD-negative response rate was 69%. After longer follow-up (median 33 months), 80% MRD-negative response rate was reported. This study with long-lasting complete remission in R/R B-lineage ALL patients laid foundation for further expanded clinical investigation.
- In a separate large, multicenter, phase II trial (MT103-211, NCT01466179), 189 adult patients with Ph-negative R/R B cell ALL were enrolled to further assess the clinical activity of blinatumomab. Findings implied that blinatumomab has the potential to be better than salvage chemotherapy.
- To confirm the efficacy of blinatumomab for R/R ALL, a phase III randomized trial (the TOWER trial, NCT 02013167) was done to compare blinatumomab versus salvage chemotherapy. Compared with salvage chemotherapy, blinatumomab monotherapy had better OS (7.7 m vs 4.0 m, P = 0.01), CR rate (34% vs 16% in 12 weeks, P < 0.001) and EFS rate (31% vs 12% at 6 m, P < 0.001) in r/r B-ALL patients.
- Blinatumomab became the first FDA-approved treatment for MRD + B-ALL in 2018
- Clinical trials have been initiated to characterize the activity of blinatumomab in Ph+ R/R ALL patients.
- Some studies have shown the combination of blinatumomab with TKI was well tolerated. The chemotherapy-fee regimen appears to be promising to serve as a bridge therapy prior to allo-HSCT.
13
Q
CAR-T cell therapy for R/R B-ALL
A
Novartis receives first FDA approval for CAR-T cell therapy (https://www.novartis.com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy-kymriahtm-ctl019-children-and-young-adults-b-cell-all-refractory-or-has-relapsed-least-twice)
- First-in-class therapy showed an 83% (52/63) overall remission rate in this patient population with limited treatment options and historically poor outcomes
- Novel approach to cancer treatment is the result of pioneering CAR-T cell therapy collaboration with University of Pennsylvania
- Reproducible, flexible and validated manufacturing process builds on years of global clinical trial experience at our facility in New Jersey, US
- Novartis also announces innovative collaboration with the US Centers for Medicare and Medicaid Services
Novartis’ CAR-T therapy gets second FDA approval (2018)(http://www.pharmatimes.com/news/novartis_car-t_therapy_gets_second_fda_approval_1233967)
- The FDA has approved Novartis’ CAR-T therapy Kymriah (tisagenlecleucel) for intravenous infusion for its second indication - the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia (2016) https://www.ncbi.nlm.nih.gov/pubmed/27098534
- CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for relapsed/refractory acute lymphoblastic leukemia (ALL).
- Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control.
14
Q
CLL (chronic lymphocytic leukemia)
A
Most common haematologic malignancy and lymphoproliferative disorder.
Immunophenotyping:
- CD5+ CD19+ B cells which show clonality (are kappa or lambda light chain restricted)
Clinical associations:
- lymphadenopathy, immune haemolysis (spherocytes), thrombocytopenia, BM failure
Prognostic factors: clinical, immunophenotypical, cytogenetic, molecular characteristics predict whether a patient is likely to progress or remain stable
Clinical stages of CLL
- Stage I: lymphocytosis only
- stage II: lymphadenopathy
- stage III: cytopenias (non-immune. More significant BM replacement)
Cytogenetics
- FISH >90% abnormal
- good prognosis: 13q deletion
- poor prognosis: 11q and 17p deletion (rapidly evolving, therapy resistant)
Molecular testing (important for prognosis)
- unmutated IgVH genes (advanged stage, adverse cytogenetics, therapy resistant)
Immunophenotyping (important for prognosis)
- CD38+ZAP-70 expression (correlates to unmutated IgVH status).
ZAP-70 is assessed by flow cytometry. It is a surrogate marker of IgH mutational status. A higher level of ZAP-70 is associated with IgH unmutated. Correlates with decreased overall survival / progression-free survival
ZAP-70 testing is not standardised and there is uncertainty in its prognostic utility.
Fludarabine for patients who remain symptomatic despite treatment (therapy resistant)
Transformation
Richter’s transformation (Ritcher’s syndrome):
- complication of CLL in 2-9% patients. Associated with poor prognosis. Median survival 8months.
- it involves development of new aggressive large B cell lymphoma, clonally related to underlying CLL or arises from de novo mutations.
- Characterised by large nodes/masses (progressive LN), type B symptoms, elevated LDH, monoclonal gammopathy, extra-nodal involvement.
- prev treatement with alkylating agent and nucleoside analog increases risk of transformation
Treatment:
Is guided by symptoms and prognostic factors
Asymptomatic patients –> watchful observation
Symptomatic:
- oral –> chlorambucil
- IV chemo –> Fludarabine/cyclophosphamide/Rituximab (gold standard)
- monoclonal antibodies (for p53 mutation) –> note, Alemtuzumab isn’t used for CLL anymore
- allogeneic stem cell transplant –> in suitable patients who have poor prognosis, and have suitable donor
- trials –> Bcl2 inhibitors (venetoclax ABT-263 inhibitor), and Bruton TKI (ibrutinib)
Sources:
(ibrutinib & venetoclax 1st line CLL) https://www.nejm.org/doi/full/10.1056/NEJMoa1900574
- patients with either: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older.
- ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily).
- With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease
- conclusion: combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL
(ibrutinib as initial therapy for CLL) https://www.nejm.org/doi/full/10.1056/NEJMoa1509388
- ibrutinib vs chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.
- Ibrutinib was superior to chlorambucil as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables
(Ritcher’s transformation in the era of targeted therapy) https://austinpublishinggroup.com/hematology/fulltext/hematology-v3-id1093.php
- man with CLL, co-expression of CD5 and CD23. IgVH was mutated and FISH analysis showed only a 13q14 deletion. The CLL continued to respond to Ibrutinib while the patient developed an aggressive clonally related transformation lymphoma. Based on poor performance status it was decided not to pursue further chemotherapy.
15
Q
Hyperleukocytosis and leucostasis
A
Hyperleukocytosis:
- total leukemic blood cell count > 50 or 100 x 10^9/L
- Occurs in AML (10-20% new diagnoses), ALL (10-30% new acute cases), CLL (but leucostasis is rare), CML (common). Esp with AML variants (APML, myelomonocytic leukemia, monocytic leukemia)
Leucostasis
- symptomatic hyperleukocytosis, esp with WCC >100
- medical emergency. Prompt treatment. 20-40% 1-week mortality (worse symptoms correlates with worse outcome)
- common in pts with blast crisis in AML and CML.
- high WCC and symptoms of decreased tissue perfusion due to white cell plugs in microvasculature
- present with respiratory distress (dyspnoea, hypoxia, diffuse alveolar infiltrates); or neurological distress (headaches, dizziness, tinnitus, gait instability, confusion, somnolence, coma. High risk ICH); fever (80% patients, due to the inflamm response). Less commonly MI, AKI, limb ischemia, bowel ischemia
- pathophys not well understood. Due to increased blood viscosity, WCC plugs in microvasculature, impeding blood flow, local hypoxia. Leads to cytokine release, endothelial damage, haemorrhage
- exaccerbated by transfusions and diuretics (increases viscosity), IV contrasts (affects kidneys)
- paO2 falsely low, spO2 appropriately low, platelet count falsely high (so requires manual count), hyperK, DIC (in up to 40% pts, esp after chemotherapy starts), spontaneous TLS
Management
Cytoreduction:
- hydroxyurea (Hydroxyurea (2-4g bd until WCC <50) is for pts with asymptomatic hyperleukocytosis who are unable to receive immediate induction chemo)
- Leukopheresis: for symptomatic hyperleukocytosis who can’t receive immediate chemo, except in pts with APML (can worsen their coagulopathy)
- remission induction chemo: essential. Rapid WCC reduction in 24hrs.
TLS prophylaxis - allopurinol; or treatment with rasburicase
IVF resuscitation to maintain good u output.
Refrain from RBC transfusions (can increase blood viscosity), but give platelet tranfusion to target plt 20-30.
