- Email: [email protected]
Late-Onset Neutropenia After Rituximab-Containing Therapy for Non-Hodgkin Lymphoma
Original Study
Late-Onset Neutropenia After RituximabContaining Therapy for Non-Hodgkin Lymphoma David Aguiar-Bujanda, María Jesús Blanco-Sánchez, María Hernández-Sosa, Saray Galván-Ruíz, Samuel Hernández-Sarmiento, Salvador Saura-Grau, Uriel Bohn-Sarmiento Abstract The incidence of late-onset neutropenia resulting from rituximab among 183 patients with non-Hodgkin lymphoma was 6% (13 episodes in 11 patients). The median time to onset of neutropenia was 75 days, and the median duration was 100 days. Although infectious complications were uncommon, early recognition is required to avoid life-threatening complications. Background: Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON. Patients and Methods: We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy. Results: We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 109/L (range, 0.06-0.9 109/L). Two patients presented infectious complications, one with fatal outcome. Conclusion: In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Anticancer therapy, Anti-CD20, Chemoimmunotherapy, Haematological toxicity, Secondary effects
Introduction The anti-CD20 monoclonal antibody rituximab is part of the standard treatment of patients with B-cell non-Hodgkin lymphoma (NHL), including follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and small lymphocytic lymphoma/chronic lymphocytic leukemia. Other approved and off-label indications in
Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain Submitted: Apr 6, 2015; Revised: Jul 27, 2015; Accepted: Jul 28, 2015 Address for correspondence: David Aguiar-Bujanda, MD, Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Barranco de la Ballena s/n, 35020 Las Palmas de Gran Canaria, Spain Fax: þ34 928450079; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.07.635
several autoimmune diseases as well as in the setting of stem cell transplantation (SCT) are rapidly extending.1,2 With the increasing use of rituximab in the postmarketing setting, many adverse effects have been recognized, including, among others, late-onset neutropenia (LON).3,4 LON is defined as an unexplained neutropenia occurring at least 4 weeks after last dose of rituximab in a patient who had recovered from previous chemotherapy-induced neutropenia. The real incidence of LON and its clinical course remains unknown because of the lack of specifically designed prospective trials. The reported incidence of LON ranges 5.3% to 27.3%, with a median time to onset of 70 to 175 days.5-12 Furthermore, its predisposing risk factors and exact pathogenic mechanisms are also poorly understood. Our aim was to investigate the incidence of LON in a group of patients with B-cell NHL treated with rituximab, review its clinical
Clinical Lymphoma, Myeloma & Leukemia Month 2015
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Neutropenia After Rituximab-Containing Therapy course and complications, and evaluate the risk factors associated with LON.
Patients and Methods
Characteristic
We retrospectively reviewed the medical records of 183 consecutive patients attended at the Department of Medical Oncology of Hospital Universitario de Gran Canaria Dr Negrin with a diagnosis of B-cell NHL who were treated with rituximab either in combination with chemotherapy or as single agent from 2003 to 2013. Patients with a minimum follow-up of 1 year were included in the study. Treatment protocols and follow-up visits were performed in a daily care setting according to standard clinical practice guidelines during the study period. As a general rule, complete blood counts were performed at every follow-up visit; 1 month after the end of therapy; every 4 months for the first 2 years; every 6 months up to the fifth year; and yearly thereafter. LON was defined as a neutropenia grade 3 (absolute neutrophil count [ANC] of 0.5 and < 1.0 109/L) or grade 4 (ANC of < 0.5 109/L) according to the National Cancer Institute Common Toxicity Criteria v4.03 (2010) without an apparent cause, occurring at least 4 weeks after last dose of therapy and after ANC had previously recovered to normal. Time to onset of LON was measured from last dose of rituximab to detection of neutropenia grade 3/4. Duration of neutropenia was measured from detection of neutropenia grade 3/4 to ANC > 1.0 109/L. Occurrence of other alterations in blood cell counts, serum immunoglobulin levels, and infectious complications during LON episodes were also analyzed. The study was carried out according to the principles of the Declaration of Helsinki with its current amendments. Statistical analyses were performed by SPSS 19.0 (IBM, Armonk, NY).
Age (Years)
Results
2
-
Table 1 Patient Characteristics
We identified 11 (6%) of 183 patients fulfilling the defined criteria for LON. The main patient characteristics are outlined in Table 1. Clinical characteristics of LON episodes (n ¼ 13) are listed in Table 2. Interestingly, all patients developed LON after receiving a rituximab-containing regimen, with no case of LON observed among 34 patients who received rituximab as a single agent. The median time to onset of LON was 75 days (range, 30-198 days). The median time to recovery from neutropenia was 100 days (range, 21-324 days). Seven patients (63.6%) had neutropenia grade 3, and 4 patients (36.4%) had neutropenia grade 4 (rate of grade 4 LON ¼ 2.2%). The median neutrophil count nadir was 0.55 109/L (range, 0.06-0.9 109/L). Five patients received granulocyte colony-stimulating factor (GCSF) during LON episodes, leading to the resolution of neutropenia in all cases. All patients presented with concomitant lymphocytopenia during LON episodes (grade 3/4 in 7 patients), with a median of absolute lymphocyte count nadir of 0.52 109/L (range, 0.12-1.25 109/ L). Additionally, 4 patients showed thrombocytopenia and 5 patients presented anemia (grade 3/4 in 1 patient each, respectively). Data about serum immunoglobulin levels were available in 8 cases of LON. All showed normal values of IgA, while 4 and 2 patients had low levels of IgG and IgM, respectively.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Median (range)
All Patients (n [ 183) 62 (28-85)
Patients With LON (n [ 11) 60 (37-82)
60
109 (59.6)
6 (54.5)
<60
74 (40.4)
5 (45.5)
Sex Male
83 (45.4)
5 (45.5)
100 (54.6)
6 (54.5)
DLBCL
74 (40.4)
2 (18.2)
FL
64 (35)
7 (63.6)
MZL
34 (18.6)
1 (9.1)
MCL
8 (4.4)
1 (9.1)
SLL
3 (1.6)
0
Female Histology
Stage I
46 (25.1)
0
II
35 (19.1)
1 (9.1)
III
24 (13.1)
2 (18.2)
IV
78 (42.6)
8 (72.7)
BM Involvement Yes
64 (35)
5 (45.5)
No
119 (65)
6 (54.5)
No. of Therapies Median (range)
1.42 (1-4)
1.63 (1-4)
Data are presented as n (%) unless otherwise indicated. Abbreviations: BM ¼ bone marrow; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; LON ¼ late-onset neutropenia; MCL ¼ mantle cell lymphoma; MZL ¼ marginal zone lymphoma; SLL ¼ small lymphocytic lymphoma.
Bone marrow biopsies were performed in 4 patients, all of which revealed decreased cellularity; granulocytic hypoplasia with myeloid maturation arrest was found in 3 patients. Retreatment with rituximab was attempted in 4 patients after resolution of LON, with 3 patients developing recurrent episodes of LON. Two patients developed grade 2 LON (ANC 1.0-1.5 109/ L) and 1 patient developed 2 episodes of grade 4 LON, the first after 45 days of rituximab retreatment (resolved in 13 days with GCSF support) and the second spontaneously after 6 months of the last rituximab dose (resolved in 120 days without GCSF therapy). There were 2 infectious complications among 11 patients with LON (18.1%). One patient had acute bronchitis, which resolved with oral antibiotics. The other patient (refractory mantle-cell lymphoma in the fourth line of chemotherapy) died from bilateral pneumonia.
Discussion The true incidence of LON in patients with NHL receiving rituximab therapy is not well defined. Our study shows an incidence of recognized LON of 6% among 183 patients, which is, to our knowledge, the largest series published to date. This is in line with other previously published series, which presented incidences varying from 5.3% to 27.3% (Table 3)5-12 and is much higher than the 0.02% calculated in the postmarketing reporting rates of
David Aguiar-Bujanda et al Table 2 Clinical Characteristics of Late-Onset Neutropenia Episodes Patient No.
Age/Sex
Stage
Histology
1
67/M
IV
MCL
2 3 4 5 6 7 8 9 10 11-1 11-2 11-3
54/F 71/M 44/M 37/M 49/F 75/M 51/F 69/F 82/F 64/F
IV II III IV IV IV III IV IV IV
FL DLBCL FL MZL FL FL FL DLBCL FL FL
Previous Therapy RCHOPdd, FMDR, TEM, BR RCHOP, BR RCHOP RCHOP RCHOP-RM RCHOP-RM RCVP RCHOP, BR RCHOP RCVP, RCNOP, BR RCHOP RR RR
Days to Onset Nadir of ANC
Duration of LON
Infectious Complication Pneumonia, sepsis, exitus Bronchitis e e e e e e e e e e e
58
0.06
73
85 189 80 31 30 32 31 198 42 40 45 180
0.60 0.72 0.80 0.90 0.39 0.60 0.35 0.80 0.79 0.1 0.33 0.44
124 30 21 41 107 35 22 324 99 230 13 120
Abbreviations: ANC ¼ absolute neutrophil count (109/L); BR ¼ bendamustine rituximab; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; FMDR ¼ fludarabine, mitoxantrone, dexamethasone, rituximab; LON ¼ late-onset neutropenia; MCL ¼ mantle cell lymphoma; MZL ¼ marginal zone lymphoma; RCHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RCHOPdd ¼ RCHOP dose-dense (every 14 days); RCNOP ¼ rituximab, cyclophosphamide, mitoxantrone, vincristine, prednisone; RM ¼ rituximab maintenance; RR ¼ rituximab retreatment; TEM ¼ temsirolimus.
rituximab.4 However, all these studies, including our own, have a number of limitations and pitfalls as a result of its retrospective nature, the lack of a control group, and the use of different definitions of LON. Some authors include in their reports only patients with grade IV neutropenia, while others include grade III-IV or even grade I-IV (ANC of < 2.0 109/L). In the series of Fukuno et al,7 the rate of LON was 5.6% (grade IV neutropenia), while in the series of Rozman et al,12 the rate of LON was 26.9% (grade I-IV neutropenia). Another important characteristic of LON is that most cases are asymptomatic and short-lived, and hence cases of LON that are not detected in routine follow-up may go unnoticed. Dunleavy et al6 reported a LON (grade IV) incidence of 8% among 76 patients. On the basis of a statistical model to estimate the true incidence of LON with data from other published studies, the authors concluded that the real incidence of LON in their series could be higher than 8%, with an estimated true rate of LON after rituximab therapy of 35.5%. Another important issue regarding the
actual incidence of LON after rituximab therapy is the fact that not all patients received rituximab as a single agent, and many patients had received several lines of chemotherapy, including high-dose therapy in some cases. An important observation in our study is the absence of LON among 34 patients who had been previously treated only with rituximab as a single agent. The same limitations can be taken into account when interpreting the duration of LON episodes. Blood tests performed more than 3 months apart can miss asymptomatic neutropenia. In our study, the median duration of LON episodes was 100 days (range, 21-324 days) with the limitation of a lack of strict follow-up criteria. Similar reports show variable median duration of LON ranging from 6 to 77 days (median duration, 44 days), but with single cases with durations of 4 days up to 349 days. Median time to onset of LON from last rituximab dose is also extremely variable among series, ranging from 70 to 175 days (median, 105 days), also with extremes: from 21 days up to 384 days.
Table 3 LON in Selected Retrospective Studies of Rituximab-Containing Chemotherapy for Non-Hodgkin Lymphoma
Study (Year) 5
Chaiwatanatorn (2003) Dunleavy6 (2005) Fukuno7 (2006) Cattaneo8 (2006) Nitta9 (2007) Tesfa10 (2008) Lai11 (2009) Rozman12 (2012) Current study (2014)
No. of Patients
Rate of LON (n)
53
13.2% (7)
76 54 72 107 113 121 160 183
8% 5.6% 27.3% 21.5% 7% 13.2% 26.9% 6%
(6) (3) (21) (23) (8) (16) (43) (11)
Definition of LON Time to LON by Neutropenia Rate of LON Grade (Days), Median Grade IV (n) (Range) IV IV IV II-IV III-IV II-IV III-IV I-IV III-IV
13.2% (7)
122 (32-168)
8% 5.6% 11.6% 9.3% 5.3% 3% 3.8% 2.2%
175 73 70 124 88 129 90 75
(6) (3) (9) (10) (6) (4) (6) (4)
(77-204) (34-111) (21-161) (46-384) (30-295) (39-277) (28-327) (30-198)
Duration of LON (Days), Median (Range) 9 (4-148) 14 (11-16) 6 (5-16) 77 (7-161þ) 28 (5-84) 54 (10-120) 69 (3-349) Not reported 100 (21-324)
Abbreviation: LON ¼ late-onset neutropenia.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
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Neutropenia After Rituximab-Containing Therapy
4
-
The exact pathogenesis of LON after rituximab treatment has not been fully elucidated, and many hypotheses have been proposed. The 2 most frequently suggested are immunologic reactions and disturbance in hematopoiesis. Production of autoantibodies against neutrophils has been proposed to occur after rituximab induced B-cell depletion, resulting in neutropenia.5 Proliferation of T-cell large granular lymphocytes induced by rituximab has been involved in the apoptosis of mature neutrophils via the production of large amounts of Fas and Fas ligands.13 B-cell depletion can also induce variations of growth and retention factors, including B-cell activating factor and stromal derived factor 1 (SDF-1). During lymphocyte recovery, the increased secretion of SDF-1 impairs neutrophil egress from the bone marrow to the peripheral blood, causing neutropenia.6 Risk factors for LON have been assessed in several retrospective and small studies, which have not permitted definitive conclusions to be drawn. Higher rates of LON are reported in patients with lymphoma after allo-SCT, but these studies lacked a clear definition of LON and included few patients for incidence calculation.14-16 Different risk factors were identified in 2 retrospective studies, but patient populations were heterogeneous, including patients receiving first-line therapy or patients with relapsed disease, as well as different patterns of chemotherapy and rituximab therapy. In the study of Cattaneo et al,8 only previous treatment with chemotherapy and more than 4 rituximab doses were found to be significantly associated with a high risk of postrituximab delayed cytopenia in multivariate analysis. In contrast, Nitta et al9 reported in their multivariate analysis that the use of treatment regimens with higher intensity (including allo-SCT and high-dose methotrexate-containing regimens) was an independent risk factor for LON. More recently, 2 larger retrospective studies reported by Lai et al11 and Rozman et al12 with a more homogeneous population of patients with DLBCL failed to identify any significant predisposing factor for LON after first-line RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) therapy. Factors analyzed included age, gender, clinical stage, serum lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status, bone marrow involvement, International Prognostic Index score, B-symptoms, extranodal disease, aggressive treatment, and irradiation. The small number of patients in our study and the low incidence detected preclude an analysis of LON risk factors; in addition, the retrospective nature of our review means that certainly there may be many cases of LON that were not captured, invalidating any such statistical analysis. The absence of a common risk factor profile in the literature is in part explained by the nature of the studies themselves, but it also may indicate that genetic traits of the host may play a role in LON development. Three recent studies in rituximab-treated lymphoma patients have reported a correlation between a higher rate of LON and a specific polymorphism in the immunoglobulin G Fc receptor FcgRIIIa 158 V alleles.17-19 The FcgRIIIa 158 V/V and V/F polymorphisms were highly associated with development of LON in a cohort of 80 newly diagnosed B-cell lymphoma patients who were consecutively treated with rituximab-containing chemotherapy (without allo-SCT).17 In another study, 33 patients with recurrent or refractory B-cell NHL who received rituximab in the posttransplantation setting were analyzed to determine whether FcgRIIIa polymorphisms were correlated with clinical outcome.18
Clinical Lymphoma, Myeloma & Leukemia Month 2015
The FcgRIIIa 158 V allele dose was correlated with a higher incidence of rituximab-induced neutropenia, showing that each additional V allele tripled a patient’s risk of developing neutropenia. In a third report, 115 DLBCL patients treated with RCHOP were compared with 105 healthy controls with regard to FcgRIIIa 158 V/F and C1qA-A276G polymorphisms.19 The FcgRIIIa 158 V/V genotype was associated with LON compared with V/F (P ¼ .028) and F/F genotypes (P ¼ .005). Most cases of LON are self-limited and even asymptomatic, and the incidence of serious infectious complications is reported to be low. In the series of Lai et al11 and Rozman et al,12 there were no serious episodes of sepsis, and only 1 patient (of 59 LON patients among both studies) experienced an episode of infection, which was not life threatening. Similarly, only 1 of 6 patients in the report of Dunleavy et al6 developed an oral infection. Factors that can be associated to an increased risk of infectious complications are the duration of neutropenia and the coexistence of lymphocytopenia and hypogammaglobulinemia. This can be specially challenging in lymphoma patients under SCT and in the setting of autoimmune diseases, where infections seem to be more frequent and severe.20,21 In our series, 2 patients of 11 with LON developed infectious complications; one of them (refractory mantle-cell lymphoma in the fourth line of chemotherapy) died of pneumonia. In both cases, low levels of IgM and lymphocytes were present. Whether GCSF support is needed in the setting of LON is another unanswered question, although data from other reports and our own suggest that it is effective and safe. GCSF could be justified in patients with grade IV neutropenia and associated risk factors such as elderly age, clinical evidence of bacteremia or septic, shock, severe comorbidities, patients under allo-SCT, or those with associated severe lymphocytopenia or hypogammaglobulinemia. Once the episode of LON is resolved, the decision of whether to administer rituximab retreatment may be reasonable if deemed clinically justified and should be made on a case-by-case basis. It is known that LON can present as recurrent episodes upon repeated treatments with rituximab, but also without reexposure. On the other hand, the survival benefit of adding rituximab to chemotherapy is some patients may overcome the risk of development of LON, which is in most of cases asymptomatic. Finally, the possible role of LON as a predictor of good prognostic for survival among lymphoma patients has been hypothesized. In a review of 9 retrospective studies and case series reporting patients with LON, only 1 of 92 patients experienced relapse.22 However, data from the series of Lai et al11 and Rozman et al12 showed that overall survival did not differ between patients who developed LON and those who did not. In the same way, another study of 115 DLBCL patients treated with RCHOP assessing FcgRIIIa 158 V/F polymorphisms showed that although none of the 7 patients with LON experienced relapse, this did not translate into improved event-free or overall survival.19 The meaning of all these observations needs to be confirmed in prospective trials.
Conclusion In our experience, the incidence of recognized LON is low (6%). However, its real incidence may be greater than noticed because of its asymptomatic course and quick patient recovery. Infectious complications are unusual, but in our opinion the coexistence of
David Aguiar-Bujanda et al lymphocytopenia and other immunosuppressive treatments put these patients at risk of developing life-threatening complications. Many questions remain unanswered, including the actual incidence, clinical course, risk factors, and optimal management of LON. The answer to all these questions will be obtained only after the incorporation of specific end points in prospective trials. In the meantime, we stress the importance of LON recognition as a possible adverse effect of rituximab treatment, and we suggest that all patients be carefully evaluated in order to avoid infrequent but potentially life-threatening complications.
Clinical Practice Points The real incidence of LON in NHL patients receiving rituximab
is unknown, varying across studies between 5% and 30%, depending of patient selection and criteria for LON definition. Median duration and time to onset of LON are extremely variable among series, ranging from 6 to 77 days and 70 to 175 days, respectively. A complete blood count should be performed for any patient treated with rituximab who displays infection symptoms, particularly during the first year after completion of rituximab, in order to exclude LON. Several risk factors for LON have been identified so far, but they are not consistent across studies. A possible correlation between a higher rate of LON and a specific polymorphism in the IgG Fc receptor FcgRIIIa 158 V alleles has been suggested. Most cases of LON are asymptomatic, and patients recover spontaneously. However, a careful evaluation of all cases of LON is warranted in order to avoid life-threatening complications. Specific end points should be incorporated in prospective trials in order to explain the actual incidence, clinical course, risk factors, and optimal management of LON.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Coiffier B. Rituximab therapy in malignant lymphoma. Oncogene 2007; 26:3603-13.
2. Abdulla NE, Ninan MJ, Markowitz AB. Rituximab: current status as therapy for malignant and benign hematologic disorders. BioDrugs 2012; 26:71-82. 3. Ram R, Ben-Bassat I, Shpilberg O, et al. The late adverse events of rituximab therapy—rare but there! Leuk Lymphoma 2009; 50:1083-95. 4. Benyunes M, Multani P, Saunders A. Neutropenia in patients treated with rituximab [response letter]. N Engl J Med 2003; 348:2691-4. 5. Chaiwatanatorn K, Lee N, Grigg A, et al. Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 2003; 121:913-8. 6. Dunleavy K, Hakim F, Kim HK, et al. B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood 2005; 106:795-802. 7. Fukuno K, Tsurumi H, Ando N, et al. Late-onset neutropenia in patients treated with rituximab for non-Hodgkin’s lymphoma. Int J Hematol 2006; 84:242-7. 8. Cattaneo C, Spedini P, Casari S, et al. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006; 47:1013-7. 9. Nitta E, Izutsu K, Sato T, et al. A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20positive B-cell lymphoma: a single-institution study. Ann Oncol 2007; 18:364-9. 10. Tesfa D, Gelius T, Sander B, et al. Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis. Med Oncol 2008; 25:374-9. 11. Lai GG, Lim ST, Tao M, et al. Late-onset neutropenia following RCHOP chemotherapy in diffuse large B-cell lymphoma. Am J Hematol 2009; 84:414-7. 12. Rozman S, Sonc M, Novakovic BJ. Late-onset neutropenia following primary treatment of diffuse large B-cell lymphoma with rituximab-containing therapy. Leuk Lymphoma 2012; 53:1945-8. 13. Liu JH, Wei S, Lamy T, et al. Chronic neutropenia mediated by fas ligand. Blood 2000; 95:3219-22. 14. Lemieux B, Tartas S, Traulle C, et al. Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin’s lymphoma. Bone Marrow Transplant 2004; 33:921-3. 15. Hirayama Y, Kohda K, Konuma Y, et al. Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab. Intern Med 2009; 48:57-60. 16. Cairoli R, Grillo G, Tedeschi A, et al. High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation. Haematologica 2004; 89:361-3. 17. Li SC, Chen YC, Evens AM, et al. Rituximab-induced late-onset neutropenia in newly diagnosed B-cell lymphoma correlates with Fc receptor FcgRIIIa 158(V/F) polymorphism. Am J Hematol 2010; 85:810-2. 18. Weng WK, Negrin RS, Lavori P, et al. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2010; 28:279-84. 19. Keane C, Nourse JP, Crooks P, et al. Homozygous FCGR3A-158V alleles predispose to late onset neutropenia after CHOP-R for diffuse large B-cell lymphoma. Intern Med J 2012; 42:1113-9. 20. Tesfa D, Ajeganova S, Hagglund H, et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum 2011; 63:2209-14. 21. Kato H, Yamamoto K, Matsuo K, et al. Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events. Ann Oncol 2010; 21:1699-705. 22. Hincks I, Woodcock BE, Thachil J. Is rituximab-induced late-onset neutropenia a good prognostic indicator in lymphoproliferatve disorders? Br J Haematol 2011; 153:411-3.
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Late-Onset Neutropenia After RituximabContaining Therapy for Non-Hodgkin Lymphoma David Aguiar-Bujanda, María Jesús Blanco-Sánchez, María Hernández-Sosa, Saray Galván-Ruíz, Samuel Hernández-Sarmiento, Salvador Saura-Grau, Uriel Bohn-Sarmiento Abstract The incidence of late-onset neutropenia resulting from rituximab among 183 patients with non-Hodgkin lymphoma was 6% (13 episodes in 11 patients). The median time to onset of neutropenia was 75 days, and the median duration was 100 days. Although infectious complications were uncommon, early recognition is required to avoid life-threatening complications. Background: Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON. Patients and Methods: We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy. Results: We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 109/L (range, 0.06-0.9 109/L). Two patients presented infectious complications, one with fatal outcome. Conclusion: In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Anticancer therapy, Anti-CD20, Chemoimmunotherapy, Haematological toxicity, Secondary effects
Introduction The anti-CD20 monoclonal antibody rituximab is part of the standard treatment of patients with B-cell non-Hodgkin lymphoma (NHL), including follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and small lymphocytic lymphoma/chronic lymphocytic leukemia. Other approved and off-label indications in
Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain Submitted: Apr 6, 2015; Revised: Jul 27, 2015; Accepted: Jul 28, 2015 Address for correspondence: David Aguiar-Bujanda, MD, Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Barranco de la Ballena s/n, 35020 Las Palmas de Gran Canaria, Spain Fax: þ34 928450079; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.07.635
several autoimmune diseases as well as in the setting of stem cell transplantation (SCT) are rapidly extending.1,2 With the increasing use of rituximab in the postmarketing setting, many adverse effects have been recognized, including, among others, late-onset neutropenia (LON).3,4 LON is defined as an unexplained neutropenia occurring at least 4 weeks after last dose of rituximab in a patient who had recovered from previous chemotherapy-induced neutropenia. The real incidence of LON and its clinical course remains unknown because of the lack of specifically designed prospective trials. The reported incidence of LON ranges 5.3% to 27.3%, with a median time to onset of 70 to 175 days.5-12 Furthermore, its predisposing risk factors and exact pathogenic mechanisms are also poorly understood. Our aim was to investigate the incidence of LON in a group of patients with B-cell NHL treated with rituximab, review its clinical
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-1
Neutropenia After Rituximab-Containing Therapy course and complications, and evaluate the risk factors associated with LON.
Patients and Methods
Characteristic
We retrospectively reviewed the medical records of 183 consecutive patients attended at the Department of Medical Oncology of Hospital Universitario de Gran Canaria Dr Negrin with a diagnosis of B-cell NHL who were treated with rituximab either in combination with chemotherapy or as single agent from 2003 to 2013. Patients with a minimum follow-up of 1 year were included in the study. Treatment protocols and follow-up visits were performed in a daily care setting according to standard clinical practice guidelines during the study period. As a general rule, complete blood counts were performed at every follow-up visit; 1 month after the end of therapy; every 4 months for the first 2 years; every 6 months up to the fifth year; and yearly thereafter. LON was defined as a neutropenia grade 3 (absolute neutrophil count [ANC] of 0.5 and < 1.0 109/L) or grade 4 (ANC of < 0.5 109/L) according to the National Cancer Institute Common Toxicity Criteria v4.03 (2010) without an apparent cause, occurring at least 4 weeks after last dose of therapy and after ANC had previously recovered to normal. Time to onset of LON was measured from last dose of rituximab to detection of neutropenia grade 3/4. Duration of neutropenia was measured from detection of neutropenia grade 3/4 to ANC > 1.0 109/L. Occurrence of other alterations in blood cell counts, serum immunoglobulin levels, and infectious complications during LON episodes were also analyzed. The study was carried out according to the principles of the Declaration of Helsinki with its current amendments. Statistical analyses were performed by SPSS 19.0 (IBM, Armonk, NY).
Age (Years)
Results
2
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Table 1 Patient Characteristics
We identified 11 (6%) of 183 patients fulfilling the defined criteria for LON. The main patient characteristics are outlined in Table 1. Clinical characteristics of LON episodes (n ¼ 13) are listed in Table 2. Interestingly, all patients developed LON after receiving a rituximab-containing regimen, with no case of LON observed among 34 patients who received rituximab as a single agent. The median time to onset of LON was 75 days (range, 30-198 days). The median time to recovery from neutropenia was 100 days (range, 21-324 days). Seven patients (63.6%) had neutropenia grade 3, and 4 patients (36.4%) had neutropenia grade 4 (rate of grade 4 LON ¼ 2.2%). The median neutrophil count nadir was 0.55 109/L (range, 0.06-0.9 109/L). Five patients received granulocyte colony-stimulating factor (GCSF) during LON episodes, leading to the resolution of neutropenia in all cases. All patients presented with concomitant lymphocytopenia during LON episodes (grade 3/4 in 7 patients), with a median of absolute lymphocyte count nadir of 0.52 109/L (range, 0.12-1.25 109/ L). Additionally, 4 patients showed thrombocytopenia and 5 patients presented anemia (grade 3/4 in 1 patient each, respectively). Data about serum immunoglobulin levels were available in 8 cases of LON. All showed normal values of IgA, while 4 and 2 patients had low levels of IgG and IgM, respectively.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Median (range)
All Patients (n [ 183) 62 (28-85)
Patients With LON (n [ 11) 60 (37-82)
60
109 (59.6)
6 (54.5)
<60
74 (40.4)
5 (45.5)
Sex Male
83 (45.4)
5 (45.5)
100 (54.6)
6 (54.5)
DLBCL
74 (40.4)
2 (18.2)
FL
64 (35)
7 (63.6)
MZL
34 (18.6)
1 (9.1)
MCL
8 (4.4)
1 (9.1)
SLL
3 (1.6)
0
Female Histology
Stage I
46 (25.1)
0
II
35 (19.1)
1 (9.1)
III
24 (13.1)
2 (18.2)
IV
78 (42.6)
8 (72.7)
BM Involvement Yes
64 (35)
5 (45.5)
No
119 (65)
6 (54.5)
No. of Therapies Median (range)
1.42 (1-4)
1.63 (1-4)
Data are presented as n (%) unless otherwise indicated. Abbreviations: BM ¼ bone marrow; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; LON ¼ late-onset neutropenia; MCL ¼ mantle cell lymphoma; MZL ¼ marginal zone lymphoma; SLL ¼ small lymphocytic lymphoma.
Bone marrow biopsies were performed in 4 patients, all of which revealed decreased cellularity; granulocytic hypoplasia with myeloid maturation arrest was found in 3 patients. Retreatment with rituximab was attempted in 4 patients after resolution of LON, with 3 patients developing recurrent episodes of LON. Two patients developed grade 2 LON (ANC 1.0-1.5 109/ L) and 1 patient developed 2 episodes of grade 4 LON, the first after 45 days of rituximab retreatment (resolved in 13 days with GCSF support) and the second spontaneously after 6 months of the last rituximab dose (resolved in 120 days without GCSF therapy). There were 2 infectious complications among 11 patients with LON (18.1%). One patient had acute bronchitis, which resolved with oral antibiotics. The other patient (refractory mantle-cell lymphoma in the fourth line of chemotherapy) died from bilateral pneumonia.
Discussion The true incidence of LON in patients with NHL receiving rituximab therapy is not well defined. Our study shows an incidence of recognized LON of 6% among 183 patients, which is, to our knowledge, the largest series published to date. This is in line with other previously published series, which presented incidences varying from 5.3% to 27.3% (Table 3)5-12 and is much higher than the 0.02% calculated in the postmarketing reporting rates of
David Aguiar-Bujanda et al Table 2 Clinical Characteristics of Late-Onset Neutropenia Episodes Patient No.
Age/Sex
Stage
Histology
1
67/M
IV
MCL
2 3 4 5 6 7 8 9 10 11-1 11-2 11-3
54/F 71/M 44/M 37/M 49/F 75/M 51/F 69/F 82/F 64/F
IV II III IV IV IV III IV IV IV
FL DLBCL FL MZL FL FL FL DLBCL FL FL
Previous Therapy RCHOPdd, FMDR, TEM, BR RCHOP, BR RCHOP RCHOP RCHOP-RM RCHOP-RM RCVP RCHOP, BR RCHOP RCVP, RCNOP, BR RCHOP RR RR
Days to Onset Nadir of ANC
Duration of LON
Infectious Complication Pneumonia, sepsis, exitus Bronchitis e e e e e e e e e e e
58
0.06
73
85 189 80 31 30 32 31 198 42 40 45 180
0.60 0.72 0.80 0.90 0.39 0.60 0.35 0.80 0.79 0.1 0.33 0.44
124 30 21 41 107 35 22 324 99 230 13 120
Abbreviations: ANC ¼ absolute neutrophil count (109/L); BR ¼ bendamustine rituximab; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; FMDR ¼ fludarabine, mitoxantrone, dexamethasone, rituximab; LON ¼ late-onset neutropenia; MCL ¼ mantle cell lymphoma; MZL ¼ marginal zone lymphoma; RCHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RCHOPdd ¼ RCHOP dose-dense (every 14 days); RCNOP ¼ rituximab, cyclophosphamide, mitoxantrone, vincristine, prednisone; RM ¼ rituximab maintenance; RR ¼ rituximab retreatment; TEM ¼ temsirolimus.
rituximab.4 However, all these studies, including our own, have a number of limitations and pitfalls as a result of its retrospective nature, the lack of a control group, and the use of different definitions of LON. Some authors include in their reports only patients with grade IV neutropenia, while others include grade III-IV or even grade I-IV (ANC of < 2.0 109/L). In the series of Fukuno et al,7 the rate of LON was 5.6% (grade IV neutropenia), while in the series of Rozman et al,12 the rate of LON was 26.9% (grade I-IV neutropenia). Another important characteristic of LON is that most cases are asymptomatic and short-lived, and hence cases of LON that are not detected in routine follow-up may go unnoticed. Dunleavy et al6 reported a LON (grade IV) incidence of 8% among 76 patients. On the basis of a statistical model to estimate the true incidence of LON with data from other published studies, the authors concluded that the real incidence of LON in their series could be higher than 8%, with an estimated true rate of LON after rituximab therapy of 35.5%. Another important issue regarding the
actual incidence of LON after rituximab therapy is the fact that not all patients received rituximab as a single agent, and many patients had received several lines of chemotherapy, including high-dose therapy in some cases. An important observation in our study is the absence of LON among 34 patients who had been previously treated only with rituximab as a single agent. The same limitations can be taken into account when interpreting the duration of LON episodes. Blood tests performed more than 3 months apart can miss asymptomatic neutropenia. In our study, the median duration of LON episodes was 100 days (range, 21-324 days) with the limitation of a lack of strict follow-up criteria. Similar reports show variable median duration of LON ranging from 6 to 77 days (median duration, 44 days), but with single cases with durations of 4 days up to 349 days. Median time to onset of LON from last rituximab dose is also extremely variable among series, ranging from 70 to 175 days (median, 105 days), also with extremes: from 21 days up to 384 days.
Table 3 LON in Selected Retrospective Studies of Rituximab-Containing Chemotherapy for Non-Hodgkin Lymphoma
Study (Year) 5
Chaiwatanatorn (2003) Dunleavy6 (2005) Fukuno7 (2006) Cattaneo8 (2006) Nitta9 (2007) Tesfa10 (2008) Lai11 (2009) Rozman12 (2012) Current study (2014)
No. of Patients
Rate of LON (n)
53
13.2% (7)
76 54 72 107 113 121 160 183
8% 5.6% 27.3% 21.5% 7% 13.2% 26.9% 6%
(6) (3) (21) (23) (8) (16) (43) (11)
Definition of LON Time to LON by Neutropenia Rate of LON Grade (Days), Median Grade IV (n) (Range) IV IV IV II-IV III-IV II-IV III-IV I-IV III-IV
13.2% (7)
122 (32-168)
8% 5.6% 11.6% 9.3% 5.3% 3% 3.8% 2.2%
175 73 70 124 88 129 90 75
(6) (3) (9) (10) (6) (4) (6) (4)
(77-204) (34-111) (21-161) (46-384) (30-295) (39-277) (28-327) (30-198)
Duration of LON (Days), Median (Range) 9 (4-148) 14 (11-16) 6 (5-16) 77 (7-161þ) 28 (5-84) 54 (10-120) 69 (3-349) Not reported 100 (21-324)
Abbreviation: LON ¼ late-onset neutropenia.
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Neutropenia After Rituximab-Containing Therapy
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The exact pathogenesis of LON after rituximab treatment has not been fully elucidated, and many hypotheses have been proposed. The 2 most frequently suggested are immunologic reactions and disturbance in hematopoiesis. Production of autoantibodies against neutrophils has been proposed to occur after rituximab induced B-cell depletion, resulting in neutropenia.5 Proliferation of T-cell large granular lymphocytes induced by rituximab has been involved in the apoptosis of mature neutrophils via the production of large amounts of Fas and Fas ligands.13 B-cell depletion can also induce variations of growth and retention factors, including B-cell activating factor and stromal derived factor 1 (SDF-1). During lymphocyte recovery, the increased secretion of SDF-1 impairs neutrophil egress from the bone marrow to the peripheral blood, causing neutropenia.6 Risk factors for LON have been assessed in several retrospective and small studies, which have not permitted definitive conclusions to be drawn. Higher rates of LON are reported in patients with lymphoma after allo-SCT, but these studies lacked a clear definition of LON and included few patients for incidence calculation.14-16 Different risk factors were identified in 2 retrospective studies, but patient populations were heterogeneous, including patients receiving first-line therapy or patients with relapsed disease, as well as different patterns of chemotherapy and rituximab therapy. In the study of Cattaneo et al,8 only previous treatment with chemotherapy and more than 4 rituximab doses were found to be significantly associated with a high risk of postrituximab delayed cytopenia in multivariate analysis. In contrast, Nitta et al9 reported in their multivariate analysis that the use of treatment regimens with higher intensity (including allo-SCT and high-dose methotrexate-containing regimens) was an independent risk factor for LON. More recently, 2 larger retrospective studies reported by Lai et al11 and Rozman et al12 with a more homogeneous population of patients with DLBCL failed to identify any significant predisposing factor for LON after first-line RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) therapy. Factors analyzed included age, gender, clinical stage, serum lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status, bone marrow involvement, International Prognostic Index score, B-symptoms, extranodal disease, aggressive treatment, and irradiation. The small number of patients in our study and the low incidence detected preclude an analysis of LON risk factors; in addition, the retrospective nature of our review means that certainly there may be many cases of LON that were not captured, invalidating any such statistical analysis. The absence of a common risk factor profile in the literature is in part explained by the nature of the studies themselves, but it also may indicate that genetic traits of the host may play a role in LON development. Three recent studies in rituximab-treated lymphoma patients have reported a correlation between a higher rate of LON and a specific polymorphism in the immunoglobulin G Fc receptor FcgRIIIa 158 V alleles.17-19 The FcgRIIIa 158 V/V and V/F polymorphisms were highly associated with development of LON in a cohort of 80 newly diagnosed B-cell lymphoma patients who were consecutively treated with rituximab-containing chemotherapy (without allo-SCT).17 In another study, 33 patients with recurrent or refractory B-cell NHL who received rituximab in the posttransplantation setting were analyzed to determine whether FcgRIIIa polymorphisms were correlated with clinical outcome.18
Clinical Lymphoma, Myeloma & Leukemia Month 2015
The FcgRIIIa 158 V allele dose was correlated with a higher incidence of rituximab-induced neutropenia, showing that each additional V allele tripled a patient’s risk of developing neutropenia. In a third report, 115 DLBCL patients treated with RCHOP were compared with 105 healthy controls with regard to FcgRIIIa 158 V/F and C1qA-A276G polymorphisms.19 The FcgRIIIa 158 V/V genotype was associated with LON compared with V/F (P ¼ .028) and F/F genotypes (P ¼ .005). Most cases of LON are self-limited and even asymptomatic, and the incidence of serious infectious complications is reported to be low. In the series of Lai et al11 and Rozman et al,12 there were no serious episodes of sepsis, and only 1 patient (of 59 LON patients among both studies) experienced an episode of infection, which was not life threatening. Similarly, only 1 of 6 patients in the report of Dunleavy et al6 developed an oral infection. Factors that can be associated to an increased risk of infectious complications are the duration of neutropenia and the coexistence of lymphocytopenia and hypogammaglobulinemia. This can be specially challenging in lymphoma patients under SCT and in the setting of autoimmune diseases, where infections seem to be more frequent and severe.20,21 In our series, 2 patients of 11 with LON developed infectious complications; one of them (refractory mantle-cell lymphoma in the fourth line of chemotherapy) died of pneumonia. In both cases, low levels of IgM and lymphocytes were present. Whether GCSF support is needed in the setting of LON is another unanswered question, although data from other reports and our own suggest that it is effective and safe. GCSF could be justified in patients with grade IV neutropenia and associated risk factors such as elderly age, clinical evidence of bacteremia or septic, shock, severe comorbidities, patients under allo-SCT, or those with associated severe lymphocytopenia or hypogammaglobulinemia. Once the episode of LON is resolved, the decision of whether to administer rituximab retreatment may be reasonable if deemed clinically justified and should be made on a case-by-case basis. It is known that LON can present as recurrent episodes upon repeated treatments with rituximab, but also without reexposure. On the other hand, the survival benefit of adding rituximab to chemotherapy is some patients may overcome the risk of development of LON, which is in most of cases asymptomatic. Finally, the possible role of LON as a predictor of good prognostic for survival among lymphoma patients has been hypothesized. In a review of 9 retrospective studies and case series reporting patients with LON, only 1 of 92 patients experienced relapse.22 However, data from the series of Lai et al11 and Rozman et al12 showed that overall survival did not differ between patients who developed LON and those who did not. In the same way, another study of 115 DLBCL patients treated with RCHOP assessing FcgRIIIa 158 V/F polymorphisms showed that although none of the 7 patients with LON experienced relapse, this did not translate into improved event-free or overall survival.19 The meaning of all these observations needs to be confirmed in prospective trials.
Conclusion In our experience, the incidence of recognized LON is low (6%). However, its real incidence may be greater than noticed because of its asymptomatic course and quick patient recovery. Infectious complications are unusual, but in our opinion the coexistence of
David Aguiar-Bujanda et al lymphocytopenia and other immunosuppressive treatments put these patients at risk of developing life-threatening complications. Many questions remain unanswered, including the actual incidence, clinical course, risk factors, and optimal management of LON. The answer to all these questions will be obtained only after the incorporation of specific end points in prospective trials. In the meantime, we stress the importance of LON recognition as a possible adverse effect of rituximab treatment, and we suggest that all patients be carefully evaluated in order to avoid infrequent but potentially life-threatening complications.
Clinical Practice Points The real incidence of LON in NHL patients receiving rituximab
is unknown, varying across studies between 5% and 30%, depending of patient selection and criteria for LON definition. Median duration and time to onset of LON are extremely variable among series, ranging from 6 to 77 days and 70 to 175 days, respectively. A complete blood count should be performed for any patient treated with rituximab who displays infection symptoms, particularly during the first year after completion of rituximab, in order to exclude LON. Several risk factors for LON have been identified so far, but they are not consistent across studies. A possible correlation between a higher rate of LON and a specific polymorphism in the IgG Fc receptor FcgRIIIa 158 V alleles has been suggested. Most cases of LON are asymptomatic, and patients recover spontaneously. However, a careful evaluation of all cases of LON is warranted in order to avoid life-threatening complications. Specific end points should be incorporated in prospective trials in order to explain the actual incidence, clinical course, risk factors, and optimal management of LON.
Disclosure The authors have stated that they have no conflicts of interest.
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