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Editorials
3. Santarone S, Natale A, Olioso P, et al. Pregnancy outcome following hematopoietic cell transplantation for thalassemia major. Bone Marrow Transplan. 2017;52(3):388-393.
4. Santarone S, Pepe A, Meloni A, et al. Secondary solid cancer following hematopoietic cell transplantation in patients with thalassemia major. Bone Marrow Transplant. 2018;53(1):39-43.
5. Angelucci E, Pilo F. Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major. Ann NY Acad Sci. 2016;1368(1):115-121.
6. Ferrari G, Cavazzana M, Mavilio F. Gene Therapy Approaches to Hemoglobinopathies. Hematol Oncol Clin North Am. 2017;31(5): 835-852.
7. Lucarelli G, Clift RA, Galimberti M, et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood. 1996;87 (5):2082-2088.
8. Angelucci E, Pilo F, Coates TD. Transplantation in thalassemia: Revisiting the Pesaro risk factors 25 years later. Am J Hematol. 2017;92 (5):411-413.
9. Bernardo ME, Piras E, Vacca A, et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood. 2012;120(2):473-476.
10. Poomthavorn P, Chawalitdamrong P, Hongeng S, et al. Gonadal func- tion of beta-thalassemics following stem cell transplantation condi- tioned with myeloablative and reduced intensity regimens. J Pediatr Endocrinol Metab. 2013;26(9-10):925-932.
11. Anurathapan U, Pakakasama S, Mekjaruskul P, et al. Outcomes of tha- lassemia patients undergoing hematopoietic stem cell transplantation by using a standard myeloablative versus a novel reduced-toxicity con- ditioning regimen according to a new risk stratification. Biol Blood Marrow Transplant. 2014;20(12):2066-2071.
12. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and com- plications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187-1193.
13. La Nasa G, Caocci G, Efficace F, et al. Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia. Blood. 2013;122(13):2262-2270.
14. Coates TD, Carson S, Wood JC, Berdoukas V. Management of iron overload in hemoglobinopathies: What is the appropriate target iron level? Ann NY Acad Sci. 2016;1368(1):95-106.
15. Shenoy S, Angelucci E, Arnold SD, et al. Current Results and Future Research Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease and Thalassemia: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23(4):552-561.
16. Shenoy S, Gaziev J, Angelucci E, et al. Late Effects Screening Guidelines after Hematopoietic Cell Transplantation (HCT) for Hemoglobinopathy: Consensus Statement From the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant. 2018 Apr 10. [Epub ahead of print].
17. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018;378(16):1479-1493.
18. Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology Am Soc Hematol Educ Program. 2010;2010:456-462.
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Still a role for second-line chemoimmunotherapy in chronic lymphocytic leukemia?
Jennifer R Brown
CLL Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
E-mail: jennifer_brown@dfci.harvard.edu doi:10.3324/haematol.2018.196014
In this issue of the Journal, Cuneo et al. report a retro- spective observational study of the efficacy of ben- damustine rituximab (BR) given as first salvage therapy for chronic lymphocytic leukemia (CLL) patients within the GIMEMA and ERIC networks.1 Among 237 patients, the median progression-free survival (PFS) was an excel- lent 25 months and the median time to next treatment 31.3 months. Predictors of shorter PFS in multivariable analysis included del(17p), unmutated IGHV and advanced stage. Cuneo et al. further performed a matched adjusted comparison of overall survival (OS) between the subset of BR-treated patients without del(17p) who had received front-line chemoimmunotherapy (CIT), and sim- ilar patients who had received ibrutinib second-line in named patient programs in the UK and Italy. Interestingly, there was no difference in OS, with 63% alive in the ibru- tinib group at 36 months, as compared to 74.4% in the BR group.1
At first glance these data may seem surprising, as ibruti- nib has had OS benefit in both the RESONATE trial,2 com- paring ibrutinib with ofatumumab in relapsed refractory CLL, and in the RESONATE-2 trial,3 comparing ibrutinib with chlorambucil in previously untreated CLL. It is important to note that the control arms of both of these trials did not unfortunately represent particularly effective
therapy, especially in comparison to the BR presented here; they were also both relatively small studies. A US Intergroup trial comparing ibrutinib to ibrutinib rituximab to BR for front-line therapy of CLL in older patients has completed accrual and results are awaited.
While these data from randomized trials are invaluable, they often do not capture the full picture of a new therapy, hence the value of observational studies like that of Cuneo et al.1 Eligibility, particularly for phase III trials, is typically strict, resulting in a selected healthy patient population. This may be particularly true of the ibrutinib randomized studies. For example, although the median age of patients receiving ibrutinib in RESONATE-2 was 73 years, only 31% had a cumulative illness rating score (CIRS) over 6, indicating a very low level of comorbidity for their age.3 Why does this matter? Although ibrutinib is often said to be well-tolerated among older patients with comorbidi- ties, the data supporting this claim are actually quite lim- ited, and a recent multicenter retrospective study has found that a CIRS score of over 6 was in fact associated with inferior event-free survival and OS, as well as increased risk of dose reduction or discontinuation, among ibrutinib-treated patients.4
Other real-world analyses with ibrutinib, as well as longer follow up of the prospective trials, have also made
haematologica | 2018; 103(7)