Review for the GPO. Rajat Kumar CancerCare Manitoba

Transcription

1 Chronic Lymphocytic Leukemia: A Review for the GPO Rajat Kumar CancerCare Manitoba

2 Objectives Chronic Lymphocytic Leukemia (CLL) Diagnosis and investigations Common clinical presentations Treatment options, expected benefits and toxicities Follow-up care

3 Conflicts of interest Research support Celgene for MDS Employee Nil Consultant Nil Stockholder Nil Speaker bureau Nil Scientific advisory board Celgene for MDS

4 In 2010 Manitoba CLL Clinic Number of Pts registered in Clinic: 609 Details available as per Registry: 551 Newly Diagnosed Pts seen in Clinic / year: 50 Total Pts added to Clinic per year: 100

5 Diagnosis and Investigations

6 Chronic Lymphocytic Leukemia (CLL) Most common leukemia (Incidence 8/100,000/yr 000/yr in Manitoba) Seftel MD. Leuk Res 2009, 33: Median age at diagnosis i is 72 years 10% <50 yrs 30% <65 yrs Diagnosis by peripheral blood and flow cytometry

7 CLL cells in peripheral blood Monoclonal B cells CD19+, CD5+, CD23+ Smudge cell

8

9 Differential for CLL by Flow Cytometry CD19 CD5 CD23 CD10 CD25 CD79b FMC7 CD103 CLL Prolymphocytic leukemia Mantle cell lymphoma Marginal zone lymphoma Follicle centre cell lymphoma /- - -/ /+ ++ -/+ -/ / / /+ -/ Waldenstrom s / macroglobulinemia Hairy cell leukemia

10 CLL and Variants CLL SLL MBL B cell count in blood Lymphadenopathy/ splenomegaly >5 x 10 9 /L <5 x 10 9 /L <5 x 10 9 /L Maybe Yes No MBL: Monoclonal B cell lymphocytosis CLL: Chronic lymphocytic leukemia SLL: Small lymphocytic y lymphoma Hallek et al. Blood, 111:5446, 2008

11 Case #1 Asymptomatic 62, M, No abnormal findings Annual CBC: Hb 152 g/l, Platelets 276 x10 9 /L WBC 12.8 x10 9 /L, Lymph 6.4 x10 9 /L Flow Cytometry: 50% of Lymphocytes monoclonal kappa +ve, CD5+, CD19+, CD23+, CD20+(dim) Monoclonal B cells: 3.2 x10 9 /L Diagnosis: MBL

12 Relevance of MBL? 1-2%/year MBL CLL/SLL 3.5% in general population 2%, yrs 5%, >60 yrs 13.5% in familial CLL Landgren et al. NEJM, 360:659, Rawstron et al. NEJM, 359:575, 2008.

13 Initial Evaluation for CLL Physical examination CBC Flow cytometry of blood: CD38, ZAP70 Marrow aspirate and biopsy (?) Immunoglobulin levels Serum electrophoresis Coomb s testt Hepatitis screen β2-microglobulin c obu level e

14 Bone Marrow in CLL CLL CLL Marrow Normal Marrow Normal Marrow

15 Diagnosis of B-CLL Bone Marrow Examination International Workshop on CLL 2008 Marrow exam NOT required at Diagnosis Marrow examination remains indicated Before treatment: to determine cause of cytopenias If unclear cytopenia (of any lineage) For definition of a complete remission (CR) Persisting cytopenias after therapy to differentiate between disease vs therapy related

16 Common Clinical Presentations Asymptomatic lymphocytosis Lymphadenopathy p y Splenomegaly Anemia Thrombocytopenia

17 Lymphadenopathy and Splenomegaly

18 Rai Staging for CLL Stage Modified Stage Features Median Survival (yrs) 0 Low-risk Lymphocytosis >10 I Intermediate-Risk Lymphadenopathy 7-9 II Splenomegaly l III High-Risk Hgb <110 g/l 2-5 IV Platelets <100 x 10 9 /L 85% present with Rai stages 0/I disease

19 Binet Staging for CLL Stage Blood Counts Number of Sites Median Survival (yrs) A Hgb >100 Platelets > sites >10 B Hgb >100 Platelets > sites 7 C Hgb <100 Platelets <100 Any number 5 Sites: Enlarged nodes in neck, axilla or inguinal areas, clinically enlarged spleen or liver

20 Manitoba CLL Clinic

21 Predicting Disease Progression CLINICAL Marker Poorer Prognosis Better Prognosis Sex Male Female Age >65 <65 Lymphocyte doubling <6 months >6 months time Lymphocyte <30% smudge cells >30% smudge cells morphology PLASMA β2-microglobulin High Low LAR CELLU ZAP-70 20% cells +ve 19% cells +ve IgVH Mutation Status Unmutated Mutated CD38 20% cells +ve 19% cells +ve FISH Del 17, del 11 Del 13 trisomy 12

22 Treatment options, expected benefits and toxicities

23 Indications for Initiating Treatment Progressive marrow failure: RAI stage III or IV Anemia, thrombocytopenia Massive or progressive lymphadenopathy or splenomegaly Spleen > 6cm BCM, LN > 10cm or progressive Rapid lymphocyte doubling time Doubling time <6M; >50% increase over 2M (Absolute lymphocyte count >30, unrelated to infections) Constitutional symptoms referable to CLL Wt loss >10% in 6M; fever >2 weeks; Fatigue, night sweats Autoimmune cytopenias: poorly responsive to steroids

24 Cases # 2 and # 3 84 M CLL for 5 yr WBC: 150, Lymph 144 Hb 120 Platelet l t 110 LN: Bulky up to 10cm Energy +++?? Rx 54 F CLL for 6 M WBC 50, Lymph 48 Hb 124 Plat 189 No LN, Spleen ve Intense fatigue: 2yr?? Rx

25 Approaches to Initial Treatment Low doses of chlorambucil Higher doses of chlorambucil or fludarabine Amou unt of CL LL Drug combinations eg, FC, FR or FCR Marrow transplant Time from treatment

26 Chlorambucil (CBL) For patients ineligible for intensive chemo Action: Alkylating agent Adverse events: Myelotoxic, prolonged action, secondary MDS/AML Autoimmune hemolytic anemia (AIHA) in 10% Regimens British 10mg/m 2 /d x 7, rpt every 28 d German 0.5mg/kg on days 1 & 15, rpt every 28d If unable to tolerate bolus: CBL 0.1mg/kg/d or 4-6 mg/d Monthly CBC: If ANC <1.0, Plat <100 or Hb<100, delay Rx till count recovery No evidence that Prednisone increases effectiveness and should be avoided

27

28

29

30 Cyclophosphamide Less marrow toxic than chlorambucil Immunosuppressive, a treatment for autoimmune cytopenias. Good alternative to CBL in Pts with history of immune cytopenias, or +ve DAT

31 Fludarabine IV and Oral Adverse events: Myelosuppression Fever, Nausea, Vomit Auto immune hemolytic anemia (AIHA) (maybe fatal) Pulm, CNS Opportunistic infections

32 Fludarabine vs Chlorambucil in Previously Untreated CLL Patients (N=509); Intergroup Ph 3 Trial Rai KR. N Engl J Med 2000; 343: day Rx cycles, up to 12 months Therapy arms Fludarabine (F) 25 mg/m 2 x 5d Chlorambucil (CBL) 40 mg/m 2 on day1 Fludarabine 20 mg/m 2 /d x 5d + Chlorambucil 20 mg/m 2 on day1 Crossover permitted for non-responsive or early relapse

33 Fludarabine vs Chlorambucil for Previously Untreated CLL: Progression-Free Survival Rai KR. N Engl J Med 2000; 343: P<

34 Fludarabine vs Chlorambucil for Previously Untreated CLL: Overall Survival Rai KR. N Engl J Med 2000; 343:

35 Fludarabine + Cyclophosphamide (FC)

36

37 UK CLL4 Trial: F vs FC vs CBL in Prev Untreated Pts Catovsky D. Lancet 2007 Responses CBL (n=366) F (n=181) FC (n=182) CR 7% 15% 38% PR 65% 65% 57% 5-Yr Progression Free Survival (p< ) 10% 10% 36% 5-Yr Overall Survival 59% 52% 54% Auto Immune 12% 11% 5% Hemolytic Anemia

38 Progression Free Survival (OS) Overall Survival (OS)

39 Activity of Rituximab in CLL Antibody-dependent cellmediated cytotoxicity (ADCC) FcγR Direct Induction of Cell Death Complement-Dependent Cytotoxicity (CDC) CLL Cell Rituximab CD52 CD20 CD20 Mossner et al. Blood, 116:4393, Patz et al. Br J Haematol, 152:295, 2010

40 Rituximab (R) IV Infusion. Infusion reactions: more common with high lympho counts. fever, chills dyspnea Severe reactions- ARDS, usually in 24h of 1 st dose Tumor lysis syndrome Viral reactivation: Hep B, JC virus (PML)

41 FR

42 P<0.0001

43 P=0.0006

44 Hallek et al. Lancet, 376:1164, 2010

45 CLL8 Study Design and Treatment Untreated, active CLL R 6courses FCR FC C1 C2 C3 C4 C5 C6 Follow up FC FCR Fludarabine FC + 25 mg/m 2, i.v., d 1-3 Rituximab Cyclophosphamide Cycle 1: 375 mg/m 2, d mg/m 2, i.v., d 1-3 Cycles 2-6: 500 mg/m 2, d 1 Hallek et al. Lancet, 376:1164, 2010

46 Patient Responses FC FCR CR* 21.8% 44.1% PR 66.6% 51.0% Overall response rate 88.4% 95.1% SD 7.8% 3.9% PD 3.8% 1.0% *According NCI WG Criteria, confirmatory BM assessment performed up to 6 months after P < 0.01 final restaging

47 Overall Survival in All Patients FCR FC

48 FCR FC Progression Free Survival FCR FC

49 Rituximab-Containing Treatments Reference Treatment Number Previous CR (%) npr (%) PR (%) Treatment Byrd et al F 178 No % Byrd et al FR 104 No (2003) Kay et al (2010) PR 33 No Kay et al PCR 64 No (2007) O Brien OBrien et al FC 34 No (2001) Keating et al (2005) Hallek et al (2010) 84% 75% 91% 95% FCR 224 No % FC 371 No % FCR 388 No % P, pentostatin

50 Typical duration: 6months Principles of Therapy except for Cbl where Rx Contd for 12 m if response +ve at 6m Type of Rx depends on ECOG, co-morbidities (CIRS)* and renal function. If previously treated, consider BM reserve. If response poor: less than 50% decrease in Lymph counts or reduction in LN, Spleen after 2 m Rx re-evaluate *CIRS: cumulative index rating scale

51 First Line Therapy (for Fit Pts) Rituximab containing: FCR, FR, PCR

52 FCR In Manitoba: 1/3 receive FCR as 1 st line Dose reduction in 50%, only 75% complete 6 cycles If Infections develop, or ANC, Plat not recovered to baseline by week 5: reduce dose of FC by 20-40%, Keep R same Avoid G-CSF for count recovery: AML/MDS more common with FCR than with FR, risk > with G-CSF FCR overcomes poor prognosis with del11, but not with del17

53 FR In Manitoba: half receive FR as first line Well tolerated, no apparent risk of AML/MDS

54 Second Line and Subsequent therapies

55 Drug Sensitive Drug Sensitive defined as : If Relapse occurs > 2yr after FCR or >1yr after other regimens Likely sensitive to initial therapy, can be tried again

56 Drug Refractory/Resistant Drug refractory: Not responding to treatment within 2m Drug resistant: Relapsing within 2 yr of FCR or 1 yr of other regimens Fludarabine regimen resistant: t 40% will have del 17p, require Alemtuzumab regimen or High dose steroids BMT If not del17p: Ofatumumab, Bendamustine or lenalidomide Chlorambucil resistant: alternative Rx as per clinical status and Physician/Pt preferences

57 Alemtuzumab Humanized MoAb against CD52 (present on surface of B and T Lymphos, Mono and NK cells) Indication: Refractory to FLU regimens, LN <5cm diameter Route s/c. If used alone: 3 times/week, min 12 wk SE: mainly in 1 st 2 wk, local skin reaction (use ice packs) Main problem: Infections, CMV reactivation Combinations: CFAR, FluCam

58 High Dose Steroids High dose methylprednisolone + Ritux or Alemtuzumab Response in 2/3 cases

59 New Agents Ofatumumab: IV, Anti-CD20 MoAb. Effective in 50% Pts resistant to FR Bendamustine: recently licensed in Canada IV, combination alkylating + nucleoside analogue. Can be used in moderate renal or liver impairment. 1 st line instead of CBL, 2 nd line as BR Myelosuppression, Infections, Secondary malignancies Lenalidomide: Oral, as 1 st and 2 nd line

60

61

62

63 Blood and Marrow Stem Cell Transplantation

64 Biol Blood Marrow Transplant 2009; 15: 53-58

65 B J Haem 2012, 158,

66 Survival after allobmt for CLL: Manitoba Censored Death/Relapse Survival % year OS 56.7% [ ] Number of Years

67 Follow-up care

68 Monitoring for Cytopenias during Therapy Neutrophils to be >1.5 x 10 9 /L before cycle Platelets > 100 x 10 9 /L before chemo Ignore these if baseline counts are lower, for the first 2 cycles. If there is no recovery, delay, reduce dose or discontinue If AIHA or AITP develop, remove from therapy

69 Supportive Therapy

70 Immune deficiency Due to abnormalities of B and T cells in CLL, value of immunization is sub-optimal Recommend: Yearly Influenza and Pneumococcal vaccination at diagnosis i and once in 5yr Shingles vaccine NOT recommended IVIG: for recurrent bacterial infections not shown to be cost effective

71 Infection Prophylaxis Immunocompromized due to disease and treatment Treatment with Purine analogs or Alemtuzumab Prophylaxis against Pneumocystis jiroveci, till 6 months after stopping Rx. For HSV, VZV: if h/o shingles or recurrent cold sores Alemtuzumab: Prophylaxis against CMV: Valganciclovir prey g g emptive therapy for increased CMV PCR

72 Granulocyte Colony Stimulating factor (G-CSF) No role in Prophylaxis to raise ANC May use in neutropenic fever.

73 Irradiated blood products For patients who received Alemtuzumab or Fludarabine regimens or BMT Irradiated blood products for life Aim: prevent transfusion related graft-versus host disease (TA-GVHD)

74 Complications

75 Case # 4 54 M, CLL Rai Stage IV On FCR x 3 rd cycle Hb after 1 week? Cause No Bleeding Inv : Retics low, Bilirubin- normal, LDH marginal increase. DAT +ve BM: Adequate erythroid precursors

76 Autoimmune Cytopenias in CLL in Manitoba Total 72 (Of 609 patients) = 11.8% Frequency of different Cytopenias AIHA : 60% ITP : 29% PRCA : 7% AIN :4%

77 Prevalence of Autoimmune Cytopenias in CLL Cumulative Risk: 5-10% Time of AIC All stages of CLL Often precipitated by drugs: purine analogs or alkylating agents

78 Therapies for AIHA or ITP in CLL Isolated Autoimmune Cytopenias First line: corticosteroids Second line: Cyclosporine IVIG Rituximabi Splenectomy Azathioprine Disease + Autoimmune Cytopenias / Refractory CLL Chemotherapy directed at CLL : RCD

79 Rituximab Cyclophosphamide Dexamethasone (RCD) Highly effective for immune cytopenias, also effective for CLL Myelosuppression is mild Useful in Pts with history of Immune Cytopenias Regimen: Rituximab 375 mg/m 2 IV (D-1) Cyclophosphamide 750mg/m 2 IV (D-1) Dexamethasone 12 mg IV D-1 and oral day 2-7

80 Second malignancies Two-fold increase in second malignancies compared to age and sex matched controls

81 Second Malignancies in Manitoba CLL Patient Population (551Pts) Type of Cancer % Skin (basal cell, squamous) 25 In - situ 8.5 Prostate 5.6 Breast 4.7 Lung 3.8 Colon 3.6 Lymphoma Melanoma

82 Case #6 54 M CLL Rai Stage 1 Wait and Watch 3yr Developed wt loss, sweats, anemia, increase in LN size. Hb 98, Plat 557, WBC 10.5, Lymph 2.5 BM: consistent with CLL PET scan: increased SUV in axillary LN Biopsy: Classical Hodgkin s lymphoma

83 Richter s transformation Transformation of CLL to high grade disease in 10% Usual transformation: DLBCL, Hodgkin s, Prolymphocytic leukemia Clinical: Fever, Wt loss, High LDH, PET scanhigh SUV, Biopsy

84 General Measures Vitamin D Green Tea??

85

86 Chronic Lymphocytic Leukemia (CLL) Most common leukemia Median age at diagnosis is 72 years Elevated Lymphocyte count, in itself, is NOT an indication for treatment Chemotherapy NOT curative. Only cure is with an allogeneic marrow stem cell transplant Death usually related to: Progressive disease Infections Second cancers

87

88 Treatments for CLL in Manitoba Fit (CIRS 6) Less fit AIC Frail FCR FR RCD Chlorambucil Fludarabine Resistance High-dose solumedrol ± rituximab ± alemtuzumab Alemtuzumab alone Marrow transplant (<65 yrs) Ofatumumab Bendamustine Lenalidomide F, fludarabine; C, cyclphosphamide; R, rituximab; D, dexamethasone CIRS, Cumulative Illness Rating Scale AIC, autoimmune cytopenias

89 Monitoring Progression of CLL Physical exam and CBC every 3-12 months Ig levels and Coombs yearly Infections Prophylaxis for selected patients Immunize except for live vaccines Treat infections promptly Second malignancies Ensure screening guidelines

90 Manitoba CLL Clinic Clinic Nurses Research Nurses Erin Elphee Jayne Kopala Translational Research Nurse Pat Benjamison Jamie Vaughn Pharmacist Marc Geirnaert Donna Hewitt Data Manager Courtney Edworthy Physicians Dr James Johnston Dr V Banerji Dr Rajat Kumar