Chronic lymphocytic leukemia

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  • [CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. B-cell chronic lymphocytic leukemia is the most common chronic leukemia in adults in Western countries. Most cases involve blood and bone marrow with or without involvement of lymph nodes, spleen, liver, and other organs. The neoplastic lymphocytes are small but slightly larger than normal small lymphocytes and show scant cytoplasm and round to slightly irregular nuclei containing clumped chromatin (three arrows). Nucleoli are small to indistinct. A characteristic morphologic feature is the presence of “smudge” or “basket” cells (two arrowheads) which are essentially neoplastic cells that got “smudged” during slide preparation because of the fragile nature of these cells. Compare the cell size of CLL cells with a single large granular lymphocyte (curved arrow).
  • [CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. This smear shows the presence of four small neoplastic lymphocytes and three smudge cells (arrowheads). The diagnosis on blood smear is suspected based on characteristic morphology and confirmed using flow cytometric analysis of blood and/or bone marrow which usually shows a characteristic immunophenotype. The neoplastic cells generally show expression of CD19, dim CD20, monoclonal immunoglobulin kappa or lambda light chain, and co-expression of CD5 and CD23. The cells do not express CD10 or bcl-6. The dim expression of CD20 and surface immunoglobulins is very common.
  • [CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Compare the size of this neoplastic lymphocyte with red blood cells. A CLL cell is only slightly larger than a red blood cell and shows clumped chromatin, sometimes likened to a “soccer ball.” However, atypical CLL cells may not show this chromatin clumping and diagnosis can only be made using immunophenotyping.
  • [CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Atypical morphology may manifest by irregular nuclei showing clefts and deep grooves similar to cells of follicle center cell lymphoma and mantle cell leukemia. The CLL cells with nuclear clefts, indentations, and deep grooves are termed “Rieder cells.” Diagnosis must be established using immunophenotyping showing expression of CD20, CD19, CD5, CD23 but no expression of CD10 and cyclin-D1.
  • [CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Note three “Rieder” CLL cells with nuclear indentations and notches. These cells are larger than typical CLL cells. About 80% of all CLL cases show detectable chromosomal abnormalities most commonly deletion of 13q14.3 and less commonly trisomy 12, and deletions of 11q22-23, 17p13, and 6q21 regions. About 40-50% of cases show an unmutated IgH variable gene whereas the rest show somatic hypermutations.
  • Histologic patterns of trephine biopsies from bone marrow reveal patterns that can be useful in assessing patient risk.
    Nodular patterns are made up of mature lymphocytes. The nodules are larger-than-normal lymphoid follicles and lack clear centers. There is no interstitial infiltration. Fat cells are preserved. Nodular patterns are associated with low-risk disease.
    Interstitial patterns show some degree of replacement of normal hematopoietic tissue by mature lymphocytes, but fat cells and bone marrow structure are preserved. Interstitial patterns are also associated with low-risk disease.
    Diffuse patterns show diffuse lymphoid infiltration with massive replacement of normal hematopoietic tissue as well as replacement of fat cells. Diffuse patterns are associated with high-risk disease.
    Biopsy patterns may reflect variations in the amount of lymphoid accumulation during the course of the disease.
  • Until recently, B-CLL cells were differentiated from other B-cell lymphoproliferative diseases by immunophenotyping with 5 cell membrane protein markers: SmIg (Surface Membrane-bound Immunoglobulin), CD5 (T1 antigen), CD23 (The Fc Receptor for IgE), FMC7 (a specific conformation of CD20, possibly multimeric and possibly associated with membrane cholesterol), and CD22 (gp135; a B-cell adhesion molecule).
    CD79b (a signal transduction molecule that associates with SmIg) is now preferred to CD22, a change that has significantly increased the ability to discriminate between B-CLL and other B-cell disorders.
    An immunophenotyping scoring system was developed that gives a value of 1 or 0 according to whether it is typical or atypical for CLL. Total scores range from 5 (typical of CLL) to 0 (atypical of CLL).
  • Because of the limitations of the Rai and Binet systems in predicting the progression of CLL, other prognostic criteria are being considered; for instance, advanced disease stage, male gender, CD38 expression >30%, and atypical morphology predict relatively poor outcomes in CLL. Additionally, karyotyping and molecular biology techniques reveal that the behavior of certain genetic markers in CLL may offer insights into the molecular mechanism of the disease and predict treatment outcome.
    In a study of 205 patients with CLL, 69% were found to have an abnormal karyotype. Genetic abnormalities included:
    structural abnormality of chromosome 13q14
    trisomy 12
    11q23 deletion
    17p13 abnormalities; loss or mutation of the p53 gene
    13q14 deletion carries a better prognosis than deletion of 11q13 or 17p13.
    Deletion of 11q23 is associated with bulky lymphadenopathy and a high incidence of residual disease following autologous transplantation.
    17p13 abnormalities that result in mutation or loss of the p53 gene correlate with resistance to purine analogs.
  • Patients with a low level of CD38 expression tend to have a more favorable clinical course than those with a high level.
    In a study where the positivity status for CD38 was set at 30% of examined cells staining for CD38, median survival among those with CD38 expression <30% was 288 months (24 years), comparedwith approximately 163 months (13.5 years) for those with CD38 expression >30%.
    Some investigators have suggested using CD38 expression as a correlate for the VH gene status. However, in about a third of patients, the CD38 level does not predict the VH mutation status.
  • Lymphocyte doubling time (LDT) is clearly related to prognosis in patients with CLL.
    In a study of 100 untreated patients, LDT correlated partially with clinical stage and with bone marrow patterns, but it also had a clear prognostic significance by itself.
    Patients with an LDT 12 months were likely to have a poor prognosis, whereas those with an LDT >12 months had a good prognosis, with a long treatment-free period and survival.
  • Döhner et al evaluated 325 cases of CLL to assess the frequency and clinical relevance of genomic aberrations.1 Of the 325 patients, 248 had received no prior treatment, 39 had received 1 chemotherapeutic agent, and 38 had received 2 or more chemotherapeutic regimens before the cytogenetic analysis was conducted.1
    Of the 325 patients, 268, or 82%, exhibited abnormalities. The primary endpoint for this study was survival from time of diagnosis. All cases were evaluated by interphase cytogenetics. On the basis of regression analysis, the investigators constructed a hierarchical model of 5 genetic categories for evaluation as prognostic factors: 17p deletion; 11q deletion but not a 17p deletion; 12q trisomy but not a 17p or 11q deletion; normal genome; and 13q deletion as the sole aberration. Of the 325 patients, 300 could be assigned to one of these 5 subgroups; 25 with various chromosomal abnormalities could not.
    This slide illustrates the percentage of surviving patients by genetic aberration over 168 months. Median survival times for the groups were: 17p deletion, 32 months; 11q deletion, 79 months; 12q trisomy, 114 months; normal genome, 111 months; and 13q deletion as the only abnormality, 133 months. As the slide shows, patients with 17p deletions had by far the worst prognosis.1
  • A complete remission according to NCI criteria requires that bone marrow contain fewer than 30% CLL lymphocytes; the criteria recommend that the clinical significance of lymphoid nodules be assessed prospectively.
    The criteria for the confirmation of a complete remission are similar for both sets of guidelines although the IWCLL allows focal infiltrates or nodules in bone marrow while the NCI group specifies “no nodules.”
    The criteria for partial remission according to IWCLL are limited to a downshift in clinical stage, whereas the NCI group provides more specific hematologic requirements similar to those specified for a complete response.
  • With the purpose to answer the question, if F is alos better in the elderly pts, we included in our CLL5ptocol pateients,older than 65. They were randomized to receive F or Clb. Patients in the F-arm were treated withthe same dose as the younger pts. Within the Clb-arm pts received clb in a dose of o.4mg/kg bodyweight on day 1 and 15. The dose was planned to be increased up to o.8 mg/kg BW if tolerable
  • Moreover, in tendency F treated pts had a shorter survival time which was 46 months in comparison to 64 months in the Clb arm, but these18 months difference were statisticall ynot significant.
  • Looking for a reason for this fact, causes of death of both arms were evaluated: in both arms most death were CLL-related, but 4 treatment-associated deaths occurred in the F-arm and one in the Clb arm, which were all related to infectious complications. Secondary disease was the cause of death in one third of the patients.
  • European Phase III ‘Intergroup’ CLL Study: progression-free survival
    The median observation time was 35 months (range 1–68) at the time of this analysis. The median progression-free survival was significantly longer in the bendamustine group (21.6 months) compared with the chlorambucil group (8.3 months) (p< 0.0001).
    Reference:
    Knauf W et al. J Clin Oncol 2009; published online August 3.
  • Summary
    Patients with CLL are mostly elderly, with more than one co-morbidity,1,2 and a large proportion of patients will therefore not be suitable for intensive chemotherapy. Studies with bendamustine as first-line therapy for CLL show that it provides significantly greater efficacy than chlorambucil, with a manageable toxicity profile.3 It may, in the future, be a possible treatment option for elderly patients and those who are not suitable for treatment with chemotherapy. However, bendamustine is currently only indicated for first-line treatment of chronic lymphocytic leukemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
    References
    1. Horner M et al. (eds). SEER Cancer Statistics Review, 1975–2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006/, based on November 2008 SEER data submission, posted to the SEER web site, 2009.
    2. Yancik R. Cancer 1997;80:1273–83.
    3. Knauf W et al. J Clin Oncol 2009; published online August 3.
  • BR, bendamustine/rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete blood count recovery; FCR, fludarabine/cyclophosphamide/rituximab; IV, intravenously; OS, overall survival; PFS, progression-free survival; PR, partial response.
  • BR, bendamustine/rituximab; CLL, chronic lymphocytic leukemia; FCR, fludarabine/cyclophosphamide/rituximab.
  • Veronica: This should be the same blue as on other slides—appears to be more aqua. The client would prefer three dimensional bevel should be removed. Note font colors, sizes and styles throughout.
  • Veronica: Lose bevel throughout
  • AE, adverse event; BID, twice daily; CLL, chronic lymphocytic leukemia; IGHV, immunoglobulin heavy chain variable region; IRC, Independent Review Committee; LNR, lymph node ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
  • CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance score; IWCLL, International Workshop of CLL; SLL, small lymphocytic leukemia.
  • CR, complete response; MRD, minimal residual disease; NR, not reported; ORR, overall response rate; PR, partial response.
  • La lenalidomide possiede svariati mecchanismi d’azione. L’effetto di questa molecole sembra essere diverso a seconda della patologia.
    Il meccanismo e’ stato descritto nei particolari per quello che riguarda l’ inibiozione dei progenitori ertroidi nella del 5 MDS Numeri studi sono stati condotti nel MM e in una riview dei fratelli Mitsiades vengono descritti modificazione nel microenviroment, aumento dell’ apoptosis ecambiamenti nelle molecole di adesione.
    Nella LLC la ricerca e’ piu’ indietro ed I meccanismi d’azione non sono conosciuti.
    Personalmente io favorisco il meccanismo di immunostimolazione, attraverso il miglioramento delle sinapsi immunologiche e la stimolazione di T cell e NK cell. Altri effetti non possono pero’ essere esclusi.
    i The exact mechanism of action is not known, but is likely to be different from classic chemotherapeutic agents. It also appear to be different in different disease. In del 5q MDS thereis a direct effect on erythroid progenitors as shown by Pellagatti and coll. In MM the group in Boston as reviewed by Mitsides point to the relevance of changes to the microenviroment, in adhesion molecules and increased apoptosis.
    The mechanism of action in CLL is still under investigation. Here are some of possible activities and we looking at several of them at the present time. Personally I would favor the immunostimulatory effect with improve immunological synapses formation and increase activation of T and NK cells. The interference with the microenviroment option may end up being very relevant as well. Even if we initailly tested this agent because of its TNF inhibitory proprties and its anti-angiogenesis ability, the current data seem not to favor this mechanism, with the execption of changes in cytokine production (Th1 type of response) from the T cells. Similarly the pro-apoptotic effect of this agent may not be marked in CLL
  • Dopo vari tentativi (4 anni) siamo riusciti a condurre uno studio di fase II con lenalidomide in pazienti con malattia in ricaduta o refrattaria alla fludarabina. Abbiamo deciso di ammistrare il farmaco in maniera continuata (come era stato fatto nella MDS) perche’ volevamo ottenere un inibizione costante del TNF e del VEGF. La dose iniziale era di 10 mg e si poteva aumentare gradatament fino a 25 mg al giorno.
    We therefore explored the activity of lenalidomide in patients that had received prior treatment. All patients had been treated with purine analogue-based combination. Standard inclusion criteria were used in this study, pat with any neutrophil or PLT count were eligible. The starting dose was 10 mg. Modeled on the regimen used in MDS, but Lenalidomide was given daily without interruptions (since we were aiming at long-term suppression of TNF and inhibition of neoangiogenesis). The dose was increased by 5 mg every 28 days up to 25 mg daily. The first response assessment was performed after 3 months of treatment.
  • In questa tabella vengono riassunte le caratteristiche dei pazienti. Si trattava di un gruppo intensamente pretrattato. I pazienti avevano svariati fattori prognostici sfavorevoli: b2m elevata, linfoadenopatie “bulky”, VH unmutated a 11q e 17p deletions.
    The patients characteristics are illustrated in this table. The median number of prior treatment was five and two patients had received ten or more lines of therapy. The advanced nature of this population is reflected by the high median b2M value and the high number of patients with poor prognostic features. 66% of the cases had unmutated Vh and 59% of the patients carried a poor prognostic genomic abnormality. 27% were refractory to fludarabine
  • I risultati sono stati pubblicati l’anno scorso. Risposte obbiettive sono state ottenute nel 32% dei pazienti. Abbiamo imparato durante questo studio che le risposte richiedo svariati mesi di trattamento e che possono migliorare in qualita’ se la terapia viene continuata. Abbiamo anche imparato che e’ molto difficile valutare le risposte quando si usa un farmaco che viene dato tutti I giorni e non una classica combinazione di chemoimmunoterapia in cui la risposta migliore viene determinata quando I 6 cicli sono stati amministrati.
    The responses are summarized here. 14 patients achieved a response according to NCI-WG criteria for an OR rate of 32%. Two patients achieved a CR, one a nodular PR and ten a PR. Minimal residual disease was detectable by flow cytometry at a level of 0,01% in one of the CR and was not dectable by flow and only revealed as low positivity by PCR in the other patients. eleven additional patients had either stable disease are therefore contiued on treatment. nineteen patients experienced disease progression. Two early deaths (within 30 days from initiation of therapy) occurred. One was a 86 y/o patient that developed pneumonia and an intracranial hemorrhage on day 11, another was a 76 years old patient that died of disseminated mucormycosis on day 22 of treatment.
    Three patients are still on treatment more that 2 years out
  • Queste sono le conclusioni derivate dai due studi di fase II pubblicati fino ad ora. Attualmete la maggior parte degli studi nella LLC utilizza trattamento continuo e dosi bassi inizialmente.
    In our experience low-dose, continuous lenalidomide shows activity as salvage treatment in CLL. As anticipated myelosuppression is common.
    Our impression is that the management is different than with chemoimmunotherapy, patients require a prolonged treatment to reach their response, as long as 9-12 months
    Similarly we believe that the most active dose and schedule in CLL need to be yet define and clear responses are seen at doses lower than the one used in Multiple Myeloma
  • Chronic lymphocytic leukemia

    1. 1. The Chronic Lymphocytic LeukemiaThe Chronic Lymphocytic Leukemia (CLL)(CLL) Dr.manoj toshniwalDr.manoj toshniwal
    2. 2. • B-CLL is a neoplastic disease characterized by proliferation and accumulation of small, mature, long- living lymphocytes in blood, marrow and lymphoid tissues (lymph nodes, spleen) • IWCLL 2008 criteria- an absolute malignant b lymphocyte count >5000 The B-CLL - definition
    3. 3. • SLL- ALC <5000, LN/Spleenomegaly • MBL-precursor to CLL, immunophenotypicaly consistent LN<1.5cm, ALC<5000, no cytopenias, Rate of progression 1.1% / yr • PLL-  prolymphocytes exceed 55% of lymphoid cells in peripheral blood
    4. 4. • Most common adult leukemia in Europe and North America (in USA incidence of about 3/100.000 population) • predominantly, CLL is a disease of elderly • 40% of leukemias in patients over 60 years old • men affect twice as often as women; 2:1 ratio of male to female • CLL morbidity rapidly increases with age (especially between 50 and 60 years of age) B-CLL epidemiology ≥ 65 years 55–64 years 20–54 years 72 % 25 % 3%
    5. 5. • the cause of CLL is unknown • there is increased incidence in farmers, rubber manufacturing workers and tire repair workers • genetics factors have been postulated to play a role in high incidence of CLL in some families (10%) B-CLL etiology & pathogenesis
    6. 6. • often none! - 40% of patients are asymptomatic and the diagnosis is typically accidental • unspecific: night sweats, fever, weakness (many patients have fatigue, reduced exercises tolerance or malaise, weight loss) • recurrent infections (bacterial, viral – Herpes Zoster, fungal) – they are the most common cause of death • bleeding and symptoms of anemia and thrombocytopenia • Lymphadenopathy (lymph node enlargement) – at diagnosis - nontender in 80% of patients – later - may become very large • splenomegaly - mild to moderate in 50% of patients • hepatomegaly • some organs infiltration (lungs, pleura, skin and soft tissue) B-CLL clinical symptoms
    7. 7. CLL – Initial symptoms • Approximately 40% are asymptomatic at diagnosis – discovered by a CBC • In symptomatic cases the most common complaint is fatigue • Well’s syndrome – increase sensitivity to insects bites • B symptoms – fever, sweats, weight loss • Less often the initial complaint are enlarged nodes or the development of an infection (bacterial)
    8. 8. B-CLL clinical symptoms Cervical limfadenopathy in patient with B-CLL
    9. 9. B-CLL clinical symptoms The CLL patient can have splenomegaly
    10. 10. Diagnosis…Diagnosis…
    11. 11. B-CLL laboratory features • Bone Marrow smear (cytological examination) – extensive replacement of marrow element by mature lymphocytes (more than 30%)
    12. 12. Prognosis: histological bone marrow patterns Interstitial (low risk) Diffuse (high risk) Nodular (low risk)
    13. 13. – CD5+/CD19+/CD23+/ dim CD20+ – 90% of the patient have a very weak expression of surface immunoglobulin (kappa or lambda light chain, IgM, IgD) – sometimes also CD38+, – Dim expression of CD20, CD25, CD11c; – lack expression of CD 10, CD 103, CD79a, FMC7 Immunophenotyping
    14. 14. CLL - Immunophenotype scoring system (Matutes score) Scoring system for B-CLL Membrane marker Points 1 0 Smlg Weak Moderate/strong CD5 Positive Negative CD23 Positive Negative FMC7 Negative Positive CD79b (SN8) Negative Positive 1. Matutes E, et al. Leukemia. 1994;8:1640-1645. 2. Moreau EJ, et al. Am J Clin Pathol. 1997;108:378-382. In 1994, Proffessor E. Matutes proposed a scoring system range between 5 (typical B-CLL cases) and 3 (less typical B-CLL cases)
    15. 15. • Conventional metaphase cyto difficult d/t very low proliferation activity of leukemic cells • Cytogenetic examinations - clonal chromosomal abnormalities are detected in approximately 30- 50% of CLL patients – deletion 13 (13q14.3) – trisomy 12 – structural abnormalities of chromosomes 11 (11q-), 14, 17 B-CLL laboratory features
    16. 16. FISH • FISH positive in 80% of cases • m/c del13 q (55%), f/b del 11q (18%), trisomy 12(16%), del17p(7%), del 6q(7%) • Good- 13q • Neutral- normal, 12+ • Bad- 17p, 11q • Addition of an alkylating agent to fludarabine may help to overcome adverse prognostic sign of 11q
    17. 17. CLL - Genetic abnormalities Genetic abnormality Incidence (%) Median survival (months) Clinical correlation 13q14 55-62 133-292 Typical morphology Mutated VH genes Stable disease + 12 16-30 114-122 Atypical morphology Progressive disease del 11q23 18 79-117 Bulky lymphadenopathy Unmutated VH genes Progressive disease Early relapse post autograft p53 loss/mutation 7 32-47 Atypical morphology Unmutated VH genes Advanced disease Drug resistance 1. DÖhner H, et al. N Engl J Med. 2000;343:1910-1916. 2. Oscier DG, et al. Blood. 2002;100:1177-1184.
    18. 18. CLL genomics: Recurrently mutated genes and survival • TP53: major negative effect, short OS. • ATM: Little or no effect on OS. • NOTCH1: conflicting data, additional prospective evaluations are needed, association with Richter’s transformation. • SF3B1: likely minor effects on PFS but further research is needed. • Others: unknown.
    19. 19. Diagnosis of B-CLL Blood test lymphocytosis ≥ 5G/l Morphology monoclonal population of small mature lymphocyte B-cell CLL phenotype clonal CD5+/CD19+ population of lymphocyte Markers of clonality κ/λ light chain restriction; cytogenetical abnormalities Bone marrow infiltration > 30% of nucleated cells on aspirate Lymph node diffuse infiltrate of small lymphocytes
    20. 20. Staging…Staging…
    21. 21. Rai’s clinical staging system Stage Clinical Features at Diagnosis Median Survival (years) 0 Low risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% >12,5 I Intermediate risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and enlarged lymph nodes 8 II Intermediate risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and enlarged spleen and/or liver 6 III High risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and anemia (Hb < 11g/dl) 1,5-2 IV High risk Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and thrombocytopenia(< 100 000 /ul) 1,5-2
    22. 22. CLL – Rai stages
    23. 23. Binet’s clinical staging system Stage Clinical Features at Diagnosis Median Survival (month) A Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and less than 3 areas of palpable lymphoid-tissue enlargement Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia > 120 month B Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% and 3 and more areas of palpable lymphoid-tissue enlargement Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia 60 month C Blood lymphocytosis>5G/l, Bone marrow lymphocytosis>30% with anemia (Hgb <10g/dL) or thrombocytopenia (Plt <100.000/uL) 24 month
    24. 24. CLL – Binet’s stages
    25. 25. Prognostication…Prognostication…
    26. 26. Major phenomena underlying CLL clinical behavior • CLL has a highly varied clinical course. • Phase 1: Diagnosis to need of first therapy (TTFT). • Short TTFT independently associates with expression of ZAP70, IgVH-UM status, INSR expression/del11q, TP53 mutations/del17p and elevated genomic complexity. • Phase 2: Time from first therapy to death (Survival). • Short survival is determined by TP53 mutations/del17p, del11q status and most comprehensively SNP array-based elevated genomic complexity. • Most CLL markers are unstable longitudinally necessitating outcome analysis from the dates of marker measurements.
    27. 27. Prognostic factor Good prognosis Bad prognosis Clinical stage according to Binet Rai A 0 B, C I, II, III, IV Bone marrow infiltration in - bone marrow biopsy - cytological examination Leucocytosis Prolymphocytes in peripheral blood Leukemia cell doubling time Non-Difussed infiltration <=80% lymphocytes <= 50 x 109/l <= 10% > 12 months Difussed infiltration > 80% lymphocytes > 50 x 109/l >10% <= 12 months New prognostic indicators in B-CLL (1)
    28. 28. Prognostic factor Good prognosis Bad prognosis Serum markers: - lactate dehydrogenase activity (LDH) - ß2-microglobulin activity - lymphocyte’s thymidine kinase activity (TKA) - sCD23 expression Normal range Elevated Clonal chromosomal abnormalities Normal karyotype isolated del (13q) Del (11q) Del (17p) CD 38 expression <= 30 % > 30% New prognostic indicators in B-CLL (2)
    29. 29. Prognostic factor Good prognosis Bad prognosis The mutational status of immunoglobulin variable region of heavy chain genes (IgvH) mutated unmutated ZAP–70 expression low (< 20%) high ( > 20 %) Survivin absence presence New prognostic indicators in B-CLL (3)
    30. 30. • clinical stage • bone marrow histology (diffuse replacement carries worst prognosis) • leukemia cell doubling time (less than 1 year - worse prognosis) • percentage of prolymphocyte • high cell-surface expression of CD38 • ZAP-70 expression • serum level of: B2-microglobulin; thymidine kinaze, LDH, sCD23 • IgVH mutational status • genetic features - FISH cytogenetic – low-risk: normal kariotype; isolated del(13q) – high-risk: del(17p0, del(11q), trisomy 12 New prognostic indicators in B-CLL - summary
    31. 31. CLL : ZAP-70
    32. 32. CLL : CD38 Expression Months 1. Orchard JA, et al. Lancet. 2004;363:105-111. Percentsurviving(%) CD38 ≥30% Mean = 163.2 months CD38 <30% Mean = 288 months N=162 P=.008 100 80 60 40 0 20 90 70 50 30 10 0 100 200 300 400 500
    33. 33. CLL: lymphocyte doubling time Survival time according to LDT (all stages) Months Probabilityofsurvival 1600 20 40 60 80 100 120 140 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Doubling time ≤12 months Doubling time >12 months 1. Montserrat E, et al. Br J Haematol. 1986;62:567-575.
    34. 34. Effect of genetic abnormalities on survival 1. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.
    35. 35. Treatment…Treatment…
    36. 36. • We have to remember: – B-CLL – indolent lymphoma, but incurable – Elderly patients – risk of additional diseases – Course of the disease can be very long, indolent for many years, patient can die because of another reason which is not connected to B-CLL. • Decision about treatment depends on clinical stage, prognostic factors and patient’s condition CLL – treatment
    37. 37. CLL Therapy 1960-2014 Many things have changed… • From chlorambucil (<10% CR) to chemoimmunotherapy (60%-70% CR) • Chemoimmunotherapy new gold-standard for CLL therapy • MRD- negativity CRs correlates with better outcome • Improved PFS and OS
    38. 38. Indications to treatment: • leukemia cell doubling time <6 (12) months • Grade 2 or greter fatigue • B symptoms for >2weeks • Lymph nodes of >10 cm • Symptomatic liver or splenic enlargement • Anemia hb <11 gm% • Thrombocytopenia <1 lac platelets • Wbc count >3 lac on 2 occasions 2 weeks apart • Severe paraneoplastic process related to CLL
    39. 39. • Watch and wait • Monotherapy – Glucocorticoids (autoimmunological complications) – alkylating agents (Chlorambucil, Cyclophosphamide) – purine analogues (Fludarabine, Cladribine, Pentostatin) • Combination chemotherapy – Chlorambucil/Cyclophosphamide + Prednisone – purine analog (Fludarabine) + Cyclophosphamide +/- Mitoxantrone – CVP, CHOP (Cyclophosphamide, Doxorubicin, Vincristin, Prednisone) • Monoclonal antibodies (monotherapy and in combination) – Alemtuzumab (anti-CD52) = CAMPATH – Rituximab (anti-CD20) = Mabthera – antiCD23 etc. – monoclonal antibodies conjugated with radionuclides = Ibritumomab tiuxetan = Zevalin CLL – treatment
    40. 40. • Hematopoietic stem cell transplantation – autologous - still no cure with auto-SCT – allogenic with reduced intensity conditioning • Even RIC-SCT is still a risky procedure - indicated only in high-risk disease • New and novel agents – Oblimersen – bcl2-directed antisense oligonucleotide – Lenalidomide – Flavopiridol – Anti-CD23 – Anti-CD40 • Vaccine strategies • Supportive therapy (allopurinol, G-CSF, blood and platelet transfusion, immunoglobulins, antibiotics) CLL – treatment
    41. 41. • Complete response (for at least 2 months) – clinical features – normal – morphology – normal (Hb>11 g/dl; Pt>100 000 /ul, lymphocytes <4000 G/l; neutrofiles >1500 G/l)) – bone marrow - lymphocytosis less than 30% • Partial response • Stable Disease • Progressive Disease: at least 50% increse in ALC/spleen/liver, new lesions, ds related cytopenias • Relapse: evidence of disease progression after 6 months or more of initial CR/PR • Refractory disease: failure to achieve a response or having disease progression in 6 months of last Rx Response criteria (NCI working group 1996)
    42. 42.   Partial response : A partial response (PR) is defined (NCI criteria) as presence of all of the following for two or more months:      - A reduction in previously enlarged nodes, spleen, and liver by at least 50 percent and  -Absolute neutrophil count   >1,500/µL or  -Platelet count   >100,000/µL or  -Hemoglobin concentration   >11 g/dL or      50 percent improvement over pretherapy reductions in hemoglobin concentration and/or platelet count
    43. 43. Complete remission : A complete remission in CLL requires all of the following to be present for two or more months       -Absence of symptoms attributable to CLL.   -Normal findings on physical examination.   -Absolute lymphocyte count <4,000/µL. -Absolute neutrophil count >1,500/µL.   -Platelet count >100,000/µL.   -Hemoglobin concentration >11 g/dL (untransfused).   -Bone marrow lymphocytosis <30 percent.   -No nodules (lymphoid aggregates) on BM biopsy.
    44. 44. 1. Cheson BD, et al. Blood. 1996;87:4990-4997. Variable NCI IWCLL Response criteria CR Physical exam Normal Normal Symptoms None None Lymphocytes (x 109 /L) ≤4 <4 Neutrophils (x 109 /L) ≥1.5 >1.5 Platelets (x 109 /L) >100 >100 Hemoglobin (g/dL) >11 (untransfused) Not stated Bone marrow lymphs (%) <30, no nodules Normal, allowing nodules or focal infiltrates PR Physical exam (nodes and/or liver, spleen) ≥50% decrease Downshift in stage Plus ≥1 of: Neutrophils (x 109 /L) ≥1.5 Platelets (x 109 /L) >100 Hemoglobin (g/dL) >11 or 50% improvement Duration of CR or PR ≥2 months Not stated
    45. 45. Professional Experience Required to “Tailor” CLL Therapy • Median age at diagnosis: 72 years1 • Elderly patients may be fit or have comorbidities 1 Ries LAG et al. SEER Cancer Statistics Review 1975–2005. 2 Yancik R. Cancer 1997; 80:1273–83. Age at CLL diagnosis (years) Patients 1 (%) Mean comorbidities2 (all cancer types, n) ≤54 11 n/a 55–64 19 2.9 65–74 27 3.6 75+ 43 4.2 Mean no. of co-morbidities 2.9 3.6 4.2 n/a
    46. 46. Gribben JG. Blood 2009;114:3359-60; Balducci L, Extermann M. Oncologist 2000;5:224-37. Classification of Patients by a Comprehensive Geriatric Assessment (CGA) GO SLOW NO Suitable for standard treatment Suitable for reduced treatment Suitable for supportive care Cumulative Illness Rating Scale
    47. 47. CLL7 protocol of the GCLLSG/FCLLSG Patients at Binet stage A or B without symptoms Assessment of 4 prognostic factors: • 11q- or 17p- deletion • Unmutated IgVH-Status • Serum thymidine kinase > 10 U/L • Lymphocyte doubling time < 12 months Low risk: < 2 factors positive High risk: 2 or more factors positive FCR watch and wait watch and wait Aim and Rationale: Complete (MRD-) eradication of early high risk disease 2/3 of patients 1/3 of patients
    48. 48. Comparison of Fludarabine (F), Bendamustine (Ben), Alemtuzumab (Al) and Chlorambucil (Chl) as Single Agents Rai 20001 Hillmen 20072 Knauf 20093 Regimen N F Chl 179 193 Al 149 Chl 148 Ben 157 Chl 157 Median age, years 64 62 59 60 63 66 Rai Stage III-IV or Binet C, % 39 41 34 33 29 29 Grade 3/4 ↓ ANC, % 27 19 41 25 23 10.6 CR, % 20 4 24 2 31 2 OR, % 63 37 83 55 68 31 Med. PFS (mo) 20 14 14.6 11.7 21.6 8.3 1 Rai KR et al. N Engl J Med 2000;343:1750–57. 2 Hillmen P et al. J Clin Oncol 2007;25:5616– 23. 3 Knauf W et al. J Clin Oncol 2009;27:4378-84.
    49. 49. CLL5 protocol for elderly patients with advanced CLL 6 x Fludarabine phosphate F 25 mg/m², Days 1– 5 q 28 days Chlorambucil (up to a maximum of 12 months) Clb 0.4 mg/kg body weight increasing 0.1 mg up to 0.8 mg/kg body weight q 15 days CLL, > 65 years, untreated, Binet stage C or symptomatic A/B
    50. 50. CLL5 protocol Overall Survival (OS) Median OS: F 45.8 months; Clb 63.6 months Overall survival in months 908478726660544842363024181260 CumSurvival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 CLB-censored F-censored CLB F random p = 0.15
    51. 51. CLL5 protocol Cause of death 66%3% 25% 6% CLL related Treatment related Secondary disease Unknown Clb arm: 32 patients died 54% 10% 31% 5% CLL related Treatment related Secondary disease Unknown F arm: 42 patients died
    52. 52. Chlorambucil (Chl) plus Rituximab (R) in Older CLL Patients Hillmen et al, ASH 2010 Foa et al, ASH 2010 Trial Therapy n Response CR OR SD/PD Chl-R (Foa) A 54 (of 98) 16.7% 81.4% 7.4% Chl-R (Hillmen) B 100 9 (9%) 82 (82%) 15 (15%) UK CLL4 (Chl only) C 200 12 (6%) 132 (66%) 60 (30%) A) CLB 8 mg/m2 d1-7 q28d up to 8x + R 375 mg/m2 c1-2, 500 mg/m2 c3-8, followed by R-maintenance 375 mg/m2 q 2 m for 2 yrs B) CLB 10 mg/m2 d1-7 q28d up to 6x + R 375 mg/m2 c1, 500 mg/m2 c2-6 C) CLB like B without R
    53. 53. FC Improves Overall Survival in Non-High Risk CLL GCLLSG CLL4 protocol - 375 patients (<66 years) with advanced CLL were randomly assigned to fludarabine 25 mg/m2 x 5d IV q28d vs FC (fludarabine 30 mg/m2 and cyclophosphamide 250 mg/m2 x 3d IV q28d) - Complete remission rate, 24% vs 7% (p < 0.001) - Overall response rate, 94% vs 83% (p = 0.001) - Progression-free survival, 48 mo vs 20 mo (p = 0.001) - Treatment-free survival, 37 mo vs 25 mo (p < 0.001) Eichhorst BF et al. Blood 2006;107(3):885-91.
    54. 54. Outcome n 6-year OS p-value F 190 54% F + (M or C) 140 59% R-FC 300 77% p = 0.37 p < 0.001 Improved Efficacy by Combining FC Chemotherapy with Rituximab (MD Anderson, historical comparison) Tam CS et al. Blood 2008;112:975–80. F = fludarabine; M = mitoxantrone; C = cyclophosphamide; R-FC = fludarabine, cyclophosphamide and rituximab
    55. 55. The CLL-8 trial: R-FC vs. FC in previously untreated CLL R A N D O M I S E R-FC q4wk × 3 FC q4wk × 3 R E S T A G E R-FC q4wk × 3 FC q4wk × 3 SD, PD off study CR, PR Rituximab Cycle 1: 375mg/m2 Cycles 2–6: 500mg/m2 Fludarabine 25mg/m2 iv, day 1–3 Cyclophosphamide 250mg/m2 iv, day 1–3  Untreated B-CLL  Binet B requiring treatment or Binet C  ECOG PS 0–1  n=817 Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174 ECOG PS = Eastern Cooperative Oncology Group performance status; q4wk = every 4 weeks SD = stable disease; progressive disease
    56. 56. FC FCR Evaluable patients 409 408 ORR (%) 80 90 CR (%) 22 44 PFS (median) ~33 m. ~ 52 m. OS @ 5 yrs 60% 75% The CLL-8 trial: R-FC vs. FC in previously untreated CLL Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174
    57. 57. Bendamustine in CLL therapy • Reference Phase Regime Pat. prev. ORR CR n= ther. (%) • Kath et al., 2001 II B 5x60mg/m2 23 10/23 75 30 • Bremer et al., 2002 II B 5x60mg/m2 15 yes 77 7 • Aivado et al., 2002 II B 2x100mg/m2 23 yes 67 29 • Köppler et al., 2004 I/II BM 2x75mg/m2 22 yes 86 27 • Bergmann, 2005 I/II B 2x70mg/m2 16 yes 56 12,5 • Lissitchkov, 2005 I/II B 2x100mg/m2 15 yes 60 27
    58. 58. Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans- Joerg Fricke, Francoise Huguet, Ilaria Del Giudice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, and Marco Montillo Journal of Clinical Oncology 27:4378-4384
    59. 59. European Phase III ‘Intergroup’ CLL Study: progression-free survival Median progression-free survival: bendamustine 21.6 months; chlorambucil 8.3 months; p<0.0001 Survival distribution function Bendamustine (n=162) Chlorambucil (n=157) Censored observations 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 42 48 54 60 Time (months) • Median observation time: 35 months (range, 1-68) at the time of the analysis
    60. 60. 1st-line therapy with single- agent bendamustine in CLL • Most patients with CLL are aged over 65 years and have at least 2 co-morbidities • A large proportion of patients are therefore not suitable for intensive chemotherapy • Studies with bendamustine as first-line therapy for CLL show that it: – Provides significantly greater efficacy than chlorambucil both in terms of RR and PFS – Has a manageable toxicity profile
    61. 61. Bendamustine plus Rituximab Fischer et al, ASH 2009;Abstract 205. Response N % ORR 100 90.9 CR 36 32.7 nPR 3 2.7 PR 61 55.5 SD 10 9.1 PD - -
    62. 62. Recommended doses for bendamustine in CLL Pre-treated Patients: Bendamustine 70 mg/m2, day 1+2 every 4 weeks BR – Rituximab 375 mg/m2 day1 (2nd+ cy 500 mg/m2) + bendamustine 70 mg/m2 day 1+2 q4 weeks Primary therapy: Bendamustine 100 mg/m2, day 1+2 q4 weeks
    63. 63. CD20 Targeting RITUXIMAB OFATUMUMAB GA101 STATUS Licensed Licensed Phase III TYPE Chimeric Humanized Humanized EPITOPE Type I Type I Type II ADCC + + +++ CDC + ++ – CELL DEATH + ± +++ 0
    64. 64. 3rd generation of trials of the GCLLSG: Risk, stage and fitness adapted W& W Inactive Binet A Active disease + all Binet C, not del(17p) CLL12 CLL10 CLL11 Go Go Slow go Which is the best score to define high risk? yesno CLB CLB + RBR FCRtreatW&W Disease (MRD) eradication? Longer survival? Symptom control? longer disease-free survival?
    65. 65. R Fludarabin Cyclophosphamid Rituximab (FCR) Bendamustin Rituximab (BR) CLL 10 protocol Fludarabine 25 mg/m² i.v., days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab: 375 mg/ m2 i.v. day 0, cycle 1 Rituximab: 500 mg/m² i.v. day 1, cycle 2-6 Bendamustine 90mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycyle 1 Rituximab 500 mg/m² day 1, cycyle 2-6 Similar efficacy of BR in comparison to FCR? Lower toxicity rate of BR?
    66. 66. • Median observation time: 27.9 mos • Median PFS: – FCR: NR versus BR: 44.9 mos (P = .04) • 2-yr OS – FCR: 94.2% v. BR: 95.8% (P = .59) Response, % FCR (n = 274) BR (n = 273) CR (CR + CRi) 47.4 38.1 CR 40.1 36.3 CRi 7.3 1.8 PR 50.4 59.7 ORR 97.8 97.8 CLL10: Ph3 FCR v BR in Frontline Eichhorst B, et al. ASH 2013. Abstract 526
    67. 67. Adverse Events, % FCR BR P Value All 90.8 78.5 < .001 Hematologic 90.0 66.9 < .001 Neutropenia 81.7 56.8 < .001 Anemia 12.9 9.7 .28 Thrombocytopenia 21.5 14.4 .03 Infection 39.0 25.4 .001 CLL10: Ph3 FCR v BR in Frontline Eichhorst B, et al. ASH 2013. Abstract 526
    68. 68. CLL11 Protocol for Unfit, Slow Go Patients Chlorambucil combined with GA101 GChl Randomization Chlorambucil Chl Chlorambucil combined with rituximab RChl
    69. 69. CLL11 Trial Goede V, et al. ASH 2013. Abstract 6.; Goede V, et al. NEJM 2014
    70. 70. Grade ≥ 3, % Obinutuzumab + Chlorambucil, n = 336* Rituximab + Chlorambucil, n = 321* Any 70 55 Infusion-related reaction 20 4 Neutropenia 33 28 Anemia 4 4 Thrombocytopenia 10 3 Infection 12 14 Pneumonia 4 5 *Includes 5 patients randomized to who mistakenly received obinutuzumab-chlorambucil. CLL11 Trial Goede V, et al. ASH 2013. Abstract 6.; NEJM 2014 [Epub ahead of print]
    71. 71. Implications for Practice? • CR more common after FCR v. BR for tx-naïve CLL – ORR are similar – PFS significantly longer with FCR – Acute (and long-term?) toxicity greater with BR • Obinituzumab (now approved) + chlorambucil is an effective, well-tolerated therapy for tx-naïve CLL – Most appropriate for elderly – Begs question of whether obinituzumab is superior to rituximab in other clinical contexts
    72. 72. CLL Treatment Binet Stage Fitness First line treatment GCLLSG trial A, asymptomatic B Irrelevant None CLL7CLL12 C, symptomatic B Go Go FCR (BR, FR, FCA) Del(17p): FCA AlloTx CLL10 Slow Go CLB, Bendamustine F (+C? +R?, reduced dose) CLL11 Relapse Fitness Second line GCLLSG trial Early (< 1 year) = refractory disease Go Go Alemtuzumab, FC-A Allo Tx CLL2O, CLL2L, CLLX2 Slow Go Alemtuzumab (17p-), Bendamustine (+R), R-CHOP, lenalidomide? CLL2O, CLL2P Late (> 1 year) Go Go & Slow Go Repeat first line
    73. 73. What's New……What's New……
    74. 74. • Ibrutinib - Specifically target and selectively inhibit BTK • Irreversible inhibitor, oral, once daily. • Idelalisib - is a first-in-class, oral small molecule that is a highly selective inhibitor of the delta isoform of phosphatidalyinositol-3-kinase (PI3K- δ) -
    75. 75. Ibrutinib in Treatment-Naïve CLL
    76. 76. Ibrutinib for Untreated CLL: Toxicity Treatment Naive (n=31) Grade 3Grade 1 Grade 2 Grade 4 SM O’Brien et al. Lancet Oncol 2014; 15:48-58
    77. 77. Ibrutinib for Untreated CLL: Response PR w/ lymphs SM O’Brien et al. Lancet Oncol 2014; 15:48-58
    78. 78. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)
    79. 79. Idelalisib + Rituximab in Frontline CLL Nodal Response at 8wks Best Nodal Response SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)
    80. 80. Idelalisib + Rituximab in Frontline CLL SM O’Brien et al. J Clin Oncol 31, 2013 (suppl; abstr 7005)
    81. 81. *Patients with disease progression continued on idelalisib Extension Study 117. † Rituximab schedule: 375 mg/m2 , then 500 mg/m2 every 2 wks x 4, then 500 mg/m2 every 4 wks x 3. Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print] Rituximab† (6 mos) Patients with heavily pretreated, relapsed CLL Placebo BID n = 110 Idelalisib 150 mg BID n = 110 Disease progression,* death, or discontinuation due to AE Primary Study 116 Extension Study 117 Rituximab† (6 mos) Idelalisib 300 mg BID Idelalisib 150 mg BID Stratified by del(17p)/TP53 mutation, IGHV mutation status Planned interim analyses at 50% and 75% of events Clinical Endpoints Primary: PFS as assessed by IRC Events: Disease progression or death Secondary: ORR, LNR, OS Idelalisib and Rituximab for Relapsed CLL
    82. 82. R-Idelalisib for Relapsed CLL: Survival Furman R, et al. ASH 2013. Abstract LBA-6; Furman R et al. NEJM 2014 [Epub ahead of print]
    83. 83. Ph2 Ibrutinib+Rituximab for High-Risk CLL • Rituximab 375 mg/m2 – Cycle 1 (Mo 1), Days 1, 8, 15, 21 – Cycle 2 (Mos 2-6), on Day 1 of each mo • Ibrutinib given 420 mg orally once daily – Continually for duration of trial – If patients benefited after 12 cycles, they could continue ibrutinib alone • Eligibility criteria: – High-risk CLL/SLL previously treated with ≤ 3 courses or previous therapy – Presence of del(17p) or del(11q) or TP53 (treated or untreated) – Remission duration of < 3 yrs after previous frontline chemoimmunotherapy treatment indicated per 2008 IWCLL – ECOG PS 0/1 – Adequate renal and hepatic function Burger J, et al. ASH 2013. Abstract 675.
    84. 84. • Lymphocytosis peaked at 1 wk, decreased >50% from BL in ≤12 wks • Marrow lymphs decreased by approx 50% after 12 mo (P < . 00001) • Majority showed > 50% decreases in both spleen and node size • PFS at 18 mos: All patients: 78%; Del(17p): 72%; Others: 84% • OS at 18 mos: All patients: 84%; Del(17p): 78%; Others: 89% Burger J, et al. ASH 2013. Abstract 675. Best Response,* n (%) Patients (N = 40) CR† 4 (10) PR 34 (85) ORR 37 (95) NR 2 (5) Ph2 Ibrutinib+Rituximab for High-Risk CLL
    85. 85. Ibrutinib + Rituximab in High-Risk CLL Burger et al. ASH Annual Meeting 2012, Abstract 187
    86. 86. • del(5q) MDS Inhibition of del(5q) erythroid progenitors ( SPARC and↑ actinin)1 • Multiple Myeloma Changes in BM microenviroment, apoptosis, cell adhesion↑ ↓ 2 • CLL (??) ↑ immunological synapses formation ↑ T-cell and NK-cells function Interference with the microenvironment ↓pro-survival cytokines (TNF-α, VEGF, IL-8, IL-6) Pro-apoptotic effect Lenalidomide: Mechanisms of Action
    87. 87. Trial Design: Lenalidomide in Recurrent/Refractory CLL • Phase II • Previous treatment (purine analogue-based chemotherapy) • Lenalidomide 10 mg/day – titrate up by 5 mg every 28 days to 25 mg daily (minimum 5 mg, days 1–21) • Treatment continued until progression Ferrajoli A, et al. Blood. 2008;111:5291-7.
    88. 88. Characteristic N = 44 Median age (range), years 64 (49–86) Number (range) of prior therapies 5 (1–15) Serum β2-microglobulin (range), g/ml 4.3 (1.6–10.1) Rai disease stage III or IV, % 45 Fludarabine refractory, n (%) 12 (27) Alkylating-agent refractory, n (%) 11 (25) Bulky lymphadenopathy, n (%) 17 (39) Unfavourable cytogenetic features, n (%) del(11q23) 18 (41) del(17p) 8 (18) Unmutated VH, n (%)* 29 (66) * Not tested, n = 11. VH = immunoglobulin variable heavy chain. Lenalidomide in Recurrent/Refractory CLL: Patient Characteristics Ferrajoli A, et al. Blood. 2008;111:5291-7.
    89. 89. Response Patients, n (%) (N = 44) Complete response 3 (7) Nodular partial response 1 (2) Partial response 10 (23) Stable disease* 11 (25) Progressive disease‡ 19 (43) ORR 32% Responses evaluated according to 1996 NCI-WG guidelines Lenalidomide in Recurrent/Refractory CLL: Responses Ferrajoli A, et al. Blood. 2008;111:5291-7.
    90. 90. Lenalidomide in Recurrent/Refractory CLL: Conclusions • Responses seen with an immunomodulatory agent • Patients treated with oral therapy on a daily basis • Time to response is prolonged, best responses seen after 6-9 months • The toxicity profile is manageable and the treatment can be safely given as outpatient • Myelosuppression is frequent, requires dose reduction
    91. 91. Supportive care 1.Infections: antimicrobials, Serum IgG <500, Give prophylactic MONTHLY IVIG 0.5 g/kg 2.Vaccination 3.Prophylaxis drugs 4.Irradiated blood products
    92. 92. • is always the transformation of CLL into an aggressive Lymphoma – diffuse large cell lymphoma (DLCL) or Hodgkin‘s lymphoma • usually evolves after a long indolent course - • can occur as 1st manifestation of CLL: Primary Richter‘s - but still CLL • has a poor prognosis Richter’s Syndrome
    93. 93. Approach to CLL patients with del17p/TP53 mutations • Young and medically fit: Induction followed by RIC-SCT in first remission. • Regimens: FCR, other CIT combinations, alemtuzumab, high dose methylprednisone plus rituximab, high dose methylprednisone plus alemtuzumab, induction on a clinical protocol. • Ideal patient group for targeted clinical trials with novel agent acting through non-genotoxic pathways.
    94. 94. Indications for RIC-allo- PBSCT • Young (<65-70 years) and medically fit and • Del17p or • TP53 mutations or • Complex karyotype or even complex FISH or • Remission durations following chemoimmunotherapy (FCR, FR, BR, PCR) of <2 years.
    95. 95. THANK YOU……THANK YOU……

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