Systematic Reviews in Hematological Malignancies

Transcription

1 Systematic Reviews in Hematological Malignancies Pia Raanani, MD Davidoff Cancer Center Rabin Medical Center, Israel 1

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3 Disorder CHMG Systematic review* Title Protocol Full Review Myelodysplastic syndrome Acute myeloid leukemia (including APL) Chronic myeloid leukemia Myeloproliferative disorders Acute lymphoblastic leukemia Chronic lymphocytic leukemia Non Hodgkin lymphoma (T cell; follicular; aggressive) Hodgkin lymphoma Multiple myeloma Waldenstrom macroglobulinemia Aplastic anemia Hematopoietic cell transplantation ESA / CSFs / supportive care * Some reviews may appear under >1 disorder category, e.g underhodgkin & HCT

4 Super-view of Systematic Reviews and Meta-analyses in Hemato-oncological Disorders Systematic reviews involved in the primary treatment of hematological disorders Systematic reviews associated with the supportive care of hematological disorders 4

5 Requirements A critical review on the systematic reviews & meta-analyses published in the field Authors were asked to relate to the following issues: The main meta-analyses published in the field Their strengths and weaknesses Their contribution to patients' management The necessity for further systematic reviews and meta-analyses on the subject and their focus 5

6 Systematic Reviews Involved in the Primary Treatment of Hematological Disorders 6

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8 Issues Addressed by Systematic Reviews Issue 1: Treatment for early-stage MM does not offer survival benefit Issue 2: Combination chemotherapy does not offer survival benefit vs. melphalan / prednisone Issue 3: High-dose therapy with single autologous transplant is associated with better EFS but not OS Issue 4: Tandem vs.single autologous transplant does not prolong survival Issue 5: Thalidomide is associated with better OS, but more AE Issue 6: Interferon-α is associated with better PFS and OS but more AE Issue 7: Bisphosphonates reduce pathological fractures but do not prolong survival 8

9 Conclusions & Future Perspectives Few systematic reviews address the treatment options in multiple myeloma Data do not appear to be incorporated in treatment guidelines Research synthesis of data on the novel agents has to be done 9

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11 Systematic Reviews Assessing Survival Induction Consolidation Maintenance Rituximab 2-2 IFNα 2-1 Radioimmunoconjugates

12 Conclusions & Future Perspectives Closed issues Rituximab should be added to induction treatment IFNα-2b is an alternative added therapy during induction if rituximab is not tolerated Open issues The role of IFNα-2b in induction The role of radioimmunoconjugates in maintenance Patients with relapsed/refractory disease should be treated with rituximab maintenance Various issues regarding rituximab in maintenance 12 Rituximab and autologous HCT QOL issues

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14 14 Herbst et al., Haematologica 2009 *No information on long-term outcomes

15 Conclusions & Future Perspectives The move from radiotherapy alone to combined modality treatment was supported by meta-analyses More information on long-term outcomes such as the risk of secondary malignancies is needed Current discussions on treatment of early stage Hodgkin include: 15 Reduction of treatment intensity The role of PET/CT in patients management Jul-11

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17 Issues Investigated HCT for AML HCT for ALL allohct -specific considerations Donor selection Conditioning regimens Conclusions AlloHCT best Rx. for high risk pts. AlloHCT has survival benefit in CR1 allohct - specific considerations Further studies needed to assess best donor OS and disease-free survival were better with Cy/TBI than with Bu/Cy Graft source Supportive care GVHD prophylaxis 17 OS and DFS were better in PMHC as compared to BM See below No difference in survival between regimens

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20 Issues Supported by Evidence Based Medicine The role of allohct AlloHCT for first-line treatment Conditioning regimens Graft source AlloHCT for second-line treatment The role of combination IST The role of HGFs The role of supportive care 20 *Limitation: Paucity of RCTs & small sample size due to rarity

21 Future Perspectives Patients younger than 40 years Best 1 st line Rx. for young patients w/o sibling donor Best 2 nd line Rx. for young patients w/o sibling or MUD donor Patients older than 40 years Is sibling donor allohct better than IST as 1 st line Rx. The best graft source 21

22 Systematic Reviews Associated with the Supportive Care of Hematological Disorders 22

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24 ESAs Effectively Reduce the Risk for RBC Transfusions But Increase the Risk for Thrombovascular Events RBC transfusions Thrombovascular events 24

25 ESAs Increase the Risk for Mortality 25

26 Conclusions & Future Perspectives The role of iron supplementation with ESAs Different ESAs management schedules The improvement of QOL in cancer patients treated with ESAs 26

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28 The Role of Myeloid Colony Stimulating Factors Acute myeloid leukemia primary prophylaxis Priming Acute lymphoblastic leukemia Adult ALL Childhood ALL Lymphoma Aplastic anemia Hematopoietc cell transplantation Autologous Allogeneic Febrile neutropenia 28

29 Effect on survival Future Perspectives For AML more subgroup analyses (age, risk, stage) For ALL larger cohorts in adults Stem cell transplantation separate studies in order to standardize recommendations 29

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31 Where Do Systematic Reviews Contribute? No benefit for β-lactam-aminoglycoside combination therapyvs. monotherapy in patients with neutropenic fever No benefit for antiviral prophylaxis for severely neutropenic hemato-oncological patients Antifungal prophylaxis in neutropenic cancer patients reduces mortality Empirical antifungal Rx. for breakthrough fever decreases invasive fungal infections but not mortality 31

32 Quinolone vs. control 16 studies, 3545 patients RR 0.55 (95% CI ) All-cause mortality Any antibiotic vs. control 42 studies, 5211patients RR 0.66 (95% CI ) 32 Gafter-Gvili et al, Ann Intern Med., 2005

33 Immunoglobulin Prophylaxis Raa Hematopoietic HCT e Raanani et al, JCO, 2009 CLL & M CLL & MM 33 Raanani et al. Leuk Lymph, 2009

34 Limitations of Systematic Reviews & Meta-analyses Pooling of biases of included studies Biases introduced by the process of selecting RCTs for inclusion (Publication bias) Heterogeneity between RCTs included Common practice not always examined Discordance between results of different metaanalyses on the same subject Oversimplification of complex data Lack of subject level data 34

35 Future Perspectives Conduct systematic reviews also in neglected areas, i.e. CML, HCL, MPD, rare plasma cell dyscrasias, etc. Draw to a close issues aborted at earlier stages, i.eat the stage of title/protocol Conduct more systematic reviews based on individual patient data Better adherence of the AMSTAR criteria Conduct systematic reviews evaluating the role of the novel agents Concentrate more on QOL issues Incorporate more data obtained from systematic reviews into practical guidelines 35

36 Acknowledgements Rabin Medical Center, Israel Ofer Shpilberg, MD Anat Gafter-Gvili, MD Ron Ram, MD Mical Paul, MD Ronit Gurion, MD Liat Vidal, MD Nicole Skoetz, MD Isaac Ben-Bassat, MD All authors of the Special Issue of Acta Haematologica 36