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Hematology Review in Myeloid and Lymphoid Disease

Hematology Review in Myeloid and Lymphoid Disease. Veteran General Hospital 洪英中. Indication of Allo-HSCT in AML in 1st CR. Intermediate risk: If matching sibling donor available( normal karyotype with NPM1- or FLT3+, +8, +6, -Y ) High risk( chromosome 5, 7or complex ). Appelbaum, ASCO 2008.

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Hematology Review in Myeloid and Lymphoid Disease

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  1. Hematology Review in Myeloid and Lymphoid Disease Veteran General Hospital 洪英中

  2. Indication of Allo-HSCT in AML in 1st CR • Intermediate risk: If matching sibling donor available( normal karyotype with NPM1- or FLT3+, +8, +6, -Y ) • High risk( chromosome 5, 7or complex ) Appelbaum, ASCO 2008

  3. Indication of AlloHSCT in ALL • Matching sibling donor: all risk group adult ALL in 1st CR • Matching unrelated donor: high risk group t( 4,11 ), complex. Ph+ in 1st CR and all disease beyond 1st CR Appelbaum, ASCO 2008

  4. Donor Lymphocyte Infusion • Most promising in CML CP • Myeloma, Low grade NHL and Hodgkin’s lymphoma: modest effect • AML and high grade NHL: not satisfied • ALL: disappointing Mackinnon, ASCO 2008

  5. Reduced Intensity HSCT • Graft-versus leukemia/lymphoma • Lower toxicity of conditioning regimen but higher relapse rate • Extend to older age people • Risk of GVHD: similar to conventional dose HSCT but pattern of onset is different • Onset of aGVHD may be delayed by weeks to months Antin 2007 Hematology

  6. Reduced Intensity HSCT • Not a very effective cytoreductive therapy • Performed in reasonable control of the disease • Immune mechanism “GVL” • Tumors could not provide co-stimulatory signals may be poor targets • Proliferative rapidly may be difficult for the immune system to control • Extensive disease more resistant than minimal disease Antin 2007 Hematology

  7. Reduced-Intensity HSCT • Less aggressive course and lower proliferative rates • CML, CLL, low grade NHL: excellent rates of disease control • High grade NHL and Hodgkin lymphoma: wait for further study • AML/MDS: successful especially in CR status • ALL: much less amenable to GVL and best in CR status • MM: Good candidate for immunologic control Antin 2007 Hematology

  8. Graft versus Host Disease • Multifactorial pathogenesis • Conditioning regimen toxicity that exposes neoantigens • Enhances cytokines release • Augments APC presentation of alloantigen to incoming donor T cells • Initiates immunologic storm • Donor T cells activated by alloantigen expand and migrate to lymphoid organs and expansion • Cytokine and cytolytic apoptotic injury Weisdorf, Hematology 2007

  9. Graft versus Host Disease • Skin, liver, and gut, probably lung • aGVHD 30-50% in sibling donor • Higher incidence in MUD • Dierct organ injury requiring immunosupressive therapy • Secondary risks of infection • Hightened risks of cGVHD • Enhanced antitumor effect Weisdorf, Hematology 2007

  10. Graft versus Host Disease • Cytotoxic T cells and inflammatory cytokines produce injury to GVHD target organs through direct cytolytic effect and induction of apoptosis • Antibody-mediated B-cell responses may be involved in GVHD as well Weisdorf, Hematology 2007

  11. Presentation of Acute GVHD • Erythematous skin rash progressing to bullae in most severe form • Predilection for dorsal surfaces of extremities, malar regions, tops of the ear, back of neck and involvement of palms and soles • GI tract involvement: nausea, anorexia, vomiting( UGI ); watery, protein-rich, secretory diarrhea that can progress to bloody diarrhea or ileus • Hepatic involvement: targets the biliary epithelium with cholestasis and Alk-P elevation • Few case with GI tract or liver involvement only without skin rashes Weisdorf, Hematology 2007

  12. Variant Presentation of GVHD • Umbilical cord: less frequent or less severe • RIC or nomyeloablative: later and slower in evolution of aGVHD but similar in cGVHD Weisdorf, Hematology 2007

  13. Infection Complication of GVHD • Immunosuppressive and further immunosuppressive therapy produced lymphopenia • Disrupted cutaneous and epithelium • CMV reactivation, invasive fungal infection, PCP, VZV, bacterial infection ( pneumococcal and H. influenzae) Weisdorf, Hematology 2007

  14. Treatment of aGVHD • Suppression of T-cell activation, cytokine release and re-establishment of donor-host immunotolerance • Blunt T-cell activation and facilitate Treg cell expansion • Initial therapy: 1-2 mg/kg/day prednisone, 30-50% response • Limited-severity, upper-GI-only GVHD: oral budesonide or beclomethasone with hlow dose prednisone Weisdorf, Hematology 2007

  15. Treatment of aGVHD • MMF • Etanercept( TNF-alpha receptor fusion protein ) • Denileukin diftitox( Ontak, IL-2 diphtheria toxin ) • Pentostatin • Daclizumab( IL-2R alpah receptor Ab ) • Infliximab( anti-TNF alpha Ab ) • ATG • Sirolimus, alemtzumab, mesenchymal stem cells Weisdorf, Hematology 2007

  16. Presentation of Chronic GVHD • Similar with aGVHD: skin, GI and Liver • Sicca syndrome • Obstructive broncholitis • Lichenoid or sclerotic skin change • Esophageal dysmotility, fasciitis, arthropathy and autoimmune manifestation Weisdorf, Hematology 2007

  17. Treatment of cGVHD • Extended duration of immunosuppressive therapy • Corticosteroid and calcineurin inhibitors • Newer agent: MMF, sirolimus, pentostatin, extracoporeal photophresis • Rituximab and thalidomide ? Weisdorf, Hematology 2007

  18. GVHD • Major risk factor for cGVHD: preceding aGVHD • Most important cause of nonrelapse mortality and limiting quality of life • Associated with protection against malignancy • The extent and severity do not directly correlate with protection against relapse Weisdorf, Hematology 2007

  19. Chronic Lymphocytic Leukemia • 80% CLL with cytogenetic lesions with FISH • Del 13q: most common • Trisomy 12 • Del 11q • Del 17p: poor response to standard C/T, inferior prognosis, lack functional p53, response to Alemtuzumab Kipps, ASCO 2008

  20. Chronic Lymphocytic Leukemia • Soluble CD23, thymidine kinase, beta2M, MMP9, IL-8, IL6, CD44: poorer survival or shorter PFS • Not capable of identifying patients at diagnosis who are at increased risk for PD Kipps, ASCO 2008

  21. IgHV somatic hypermutation and ZAP-70 in CLL • Aggressive clinical course in unmutated • Indolent course in somatic hypermutated • ZAP-70 express in unmutated • ZAP-70 enhance the signaling capacity of the surface Ig expressed in CLL derive more stimulation from self and environmental antigens increased proliferation and/or resistance to apoptosis Kipps, ASCO 2008

  22. MicroRNAs in CLL • Inhibit gene expression by causing either degradation or blocking the translation of target mRNA • Regulate gene expression in development and disease • miRNA gene in del 13q: miR15a and miR16-1 • Abnormal, low-level expression of miR15a and miR16-1 can lead to a disease of CD5-positive B cells in both mice and human Kipps, ASCO 2008

  23. Time to Treatment of CLL • NCI-working group criteria( revised 2008 ) • Should not be treated solely on the basis of prognostic markers except in clinic trial • Monitor without therapy in asymptomatic early stage disease( Rai 0 to 1, Binet A ) unless PD • PD: progressive BM failure worsening anemia and/or thrombocytopenia, progressive lymphocytosis with an increase > 50% over 2 months, lymphocyte doubling time< 6 months, massive or progressive LAP, massive or progressive splenomegaly • Intractable autoimmune anemia or thrombocytopenia Kipps, ASCO 2008

  24. Time to Treatment of CLL • Symptomatic disease: unintentional BW loss > 10% in the past 6 months, significant fatigue( ECOG>=2, inability to work or perform usual activities ), fever > 100.5F or 38 C, for 2 weeks or longer without other evidence of infection, night sweats for 1 month or longer • Absolute lymphocyte count should not be the sole indicator for treatment as hypogammaglobulinemia, monoclonal or olgioclonal paraproteinemia Kipps, ASCO 2008

  25. HSCT in CLL • Incurable with standard treatment • Autologous HSCT: low treatment-related mortality but high relapse • Myeloablative allo-HSCT: high TRM with few late relapse Gribben, ASCO 2008

  26. Patient Selection for HSCT • Young patients with high risk disease • Unmutated IgHV, ZAP-70, del 17p, p53 abnormality • Failed to achieve CR, progressed within 12 months after purine analog, relapse within 24 months after response with purine analog or auto-HSCT Gribben, ASCO 2008

  27. AutoHSCT in CLL • Unclear role • Not recommended unless in clinical trial • Difficult collection of stem cell after purine analog • Secondary MDS or AML Gribben, ASCO 2008

  28. AlloHSCT in CLL • Significant morbidity and mortality from regimen-related toxicity, GVHD, and infection • Long term disease control in survivors • Induce durable remission even in refractory disease Gribben, ASCO 2008

  29. RIC AlloHSCT in CLL • Potential GVL effect • Decreased relapse with cGVHD • Increased relapse with T cell depletion • DLI generated GVL effect • Reducing short-term morbidity and mortality of alloHSCT • Allow transplantation in older patient • Alemtuzumab decreased GVHD but delayed post-HSCT immune reconstitution, increased infection risk and impaired GVL Gribben, ASCO 2008

  30. Treatment of CLL • Prognostic factors for time to treatment and survival : mutation status of IgHV, ZAP-70, CD38 expression, B2M, soluble CD23, del 17p, 11q by FISH • Early treatment with chemotherapy for patients without indications or based solely on prognostic factor status should be administered only in the context of a clinical trial • NCI-WG guideline revised 2008 ( Blood 2008 111: 5446-5456 ) Wierda, ASCO 2008

  31. Treatment of CLL • Alkylating agent based: chlorambucil, palliative, CR< 10% • Purine analog based: higher CR and longer remission duration, No different OS • Purine analog with alkylating agents: higher CR, OR, PFS with FC vs F; more myelosuppression in FC without increase of infection • No trial confirmed survival advantage • IVIG for recurrent infection with hypogammablobulinemia Wierda, ASCO 2008, Kay, Hematology 2007

  32. Treatment of CLL • Alemtuzumab: single agent activity in Flu refractory disease, sc better tolerated than iv, better response but no survival difference with chlorambucil, only drug with response to p53 abnormality( del17p ) • Rituximab: low CD20 expression in CLL, limited activity • FCR and PCR: waiting phase III result • No agent or combination have survival advantage Wierda, ASCO 2008, Kay, Hematology 2007 Wierda, ASCO 2008

  33. Treatment of CLL • 10-15% with autoimmune cytopenia • Purine analogs may aggravate autoimmune cytopenia • Immunotherapies and rituximab for AIHA, ITP • If failed with immunotherapies, use nonpurine analog chemotherapy • Richter transformation: DLBCL 1%/year Wierda, ASCO 2008, Kay, Hematology 2007

  34. Mantle Cell Lymphoma • 6% of newly diagnosed NHL • Worst 5-year OS of any lymphoma subtype in The Non-Hodgkin’s Classification Project • Median OS 3-4 years historically • Generally incurable with conventional C/T • Cyclin D1 overexpression • T(11,14)(q13, q32) Kahl, ASCO 2008

  35. Mantle Cell Lymphoma • CD5+CD23-, CD10-, CD20+ • FISH: t(11, 14) • Higher proliferation rat( CDC-2, ASPM, tubulin-alpha, CENP-F ), K-67: poor prognosis • Median diagnosis age: 63 • M/F 4:1 • Advanced stage • Extranodal with BM and GI tract involvement • 20-30% leukemic phase with poor outcome • Common splenomegaly Kahl, ASCO 2008

  36. Treatment of MCL • Induction therapy followed by some postremission therapy( consolidation or maintenance ) • R-CHOP + AutoHSCT • R-HyperCVAD • New postremission therapy: Y-90 ibritumomab tiuxetan, maintenance rituximab, bortezomib • New agents for relapse/refractory disease: temsirolimus, everolimus, thalidomide, lenalidomide Kahl, ASCO 2008

  37. Hodgkin Lymphoma • High cure rate • From extended field irridation and alkylating-based agents to anthracycline-based with involved filed irridation • ABVD preserved most fertility of men and women but should care pulmonary toxicity • PET a powerful functional imaging tool for restaging and response assessment • Highly predictive at the conclusion of chemotherapy Horning Hematology 2007

  38. Hodgkin Lymphoma

  39. Hodgkin Lymphoma

  40. Hodgkin Lymphoma • Second cancers are now the most common cause of mortality among long-term survivors of HL • Cardiac disease is secondary • Pulmonary disease • Endocrine dysfunction Travis Hematology 2007

  41. Hodgkin Lymphoma • Breast cancer: higher in R/T patients and decreases in received only alkylating agents( ovary ablation ? ) • Lung cancer: more in R/T Travis Hematology 2007

  42. Initial Therapy of Multiple Myeloma • Eligible to transplantation • All with phase III data • Thalidomide + Dexamethasone • Lenalidomide + Dexamethasone • Bortezomib + Dexamethasone • Bortezomib + Thalidomide + Dexamethasone Rajkumar ASCO 2008

  43. Initial Therapy of Multiple Myeloma • Thalidomide + Dexamethasone • Most used induction regimen in U.S. • More DVT than dexamethasone alone • Lenalidomide + Dexamethasone • Lower stem cell yield with small proportion of patient not collecting adequate amount • Bortezomib + Dexamethasone • Higher CR and VGPR than VAD • Bortezomib + Thalidomide + Dexamethasone • CR + VGPR > TD Rajkumar ASCO 2008

  44. Initial Therapy of Multiple Myeloma • Thalidomide and lenalidomide: higher incidence of DVT • Lenalidomide not suitable for renal failure • VTD most active regimen for renal failure who need a rapid response • In newly diagnosed MM, dexamethasone in combination should be low( < 40 mg/week ) • High dose dexamethasone is asociated with unfavorable survival Rajkumar ASCO 2008

  45. Initial Therapy of Multiple Myeloma • Not eligible for transplantation • Melphalan/prednosone/thalidomide (MPT) • Bortezomib/melphalan/prednisolone (VMP) • MPT and VMP demonstrate superior response rate and progression free even overall survival to MP • VMP overcome adverse cytogenetics but more neurotoxicity Rajkumar ASCO 2008

  46. Dose of Concomitant Corticosteroid • ECOG compared dexamethasone in low dose and high dose combined lenalidomide • Low dose is better than high dose in DVT and infection rate; higher overall survival, lower toxic and disease related death • Low dose steroid is safer and more effective in newly diagnosed MM Rajkumar ASCO 2008

  47. Goal of Therapy • Not response rate or CR rate • Failed to show a consistent association with overall survival in numerous trials • Most CR is temporary and inevitable relapse • IFM 99-06, Bologna 96, MAG trial, TT II all failed to showed correlation of CR with overall survival in MM • For non-transplant candidate, improve overall survival is the goal • For transplant candidate, safest, least-toxic regimen for pretransplant induction therapy Rajkumar ASCO 2008

  48. Duration of Therapy • Fixed duration as tolerated • MPT < 18 months • VMP < 12 months • LD indefinite but stop steroid after 1 year • VD, VTD, TD restrict to neurotoxicity Rajkumar ASCO 2008

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