Epidemiology of Chemotherapy-Induced Anemia in Patients with Non-Hodgkin Lymphoma


Kim Cannavale, MPH1; Hairong Xu, MD, PhD2; Lanfang Xu, MS3; Olivia Sattayapiwat, MPH1;
Roberto Rodriguez, MD4; Chet Bohac, MD5; John Page, MD, ScD6; Chun Chao, PhD1

Perm J 2019;23:18-252 [Full Citation]

E-pub: 06/27/2019


Introduction: Anemia is a common adverse effect of myelosuppressive chemotherapy, and the development of chemotherapy-induced anemia (CIA) is more common in patients with hematologic malignant tumors.
Objective: To assess the incidence and treatment pattern of CIA in patients diagnosed with non-Hodgkin lymphoma (NHL) from a large managed care organization in California.
Methods: Patients diagnosed with NHL between 2010 and 2012 were studied to provide an updated picture of CIA in current hematology-oncology practice. Trends in anemia treatment patterns were examined from 2000 to 2013. All data were collected from Kaiser Permanente Southern California electronic health records.
Results: Of 699 chemotherapy-treated patients with NHL diagnosed between 2010 and 2012, 36.9% and 11.6% developed moderate (hemoglobin < 10 g/dL) and severe (hemoglobin < 8 g/dL) CIA during chemotherapy, respectively. Proportions of moderate CIA events treated with erythropoiesis-stimulating agents (ESAs) decreased from 2000 to 2013: 34% in phase 1 (January 1, 2000, to December 31, 2006), 22% in phase 2 (January 1, 2007, to March 24, 2010), and 6% in phase 3 (March 25, 2010, to June 30, 2013). An increasing trend of red blood cell transfusion was observed: 12% in phase 1, 22% in phase 2, and 27% in phase 3. Similar calendar trends were observed for management of severe CIA events.
Discussion: In contrast to previous European reports, we note a higher incidence of CIA in patients with NHL in this US community practice setting.
Conclusion: Moderate to severe CIA is common in patients with NHL receiving chemotherapy. Multiple ESA-related policy changes occurred from 2000 to 2013. A large proportion of CIA episodes were currently not treated with ESA, and transfusions have become more common. Further studies are needed to determine associations between CIA symptom burden and CIA treatment as they relate to patient outcomes and quality of life.


Anemia is a common adverse effect of myelosuppressive chemotherapy. Compared with patients with solid tumors, the development of chemotherapy-induced anemia (CIA) is more common in patients with hematologic malignant tumors.1,2 Anemia can have a negative effect on a patient’s quality of life, causing symptoms that include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.3,4 Prior studies suggest a link between the occurrence of anemia and inferior survival in patients with cancer treated with chemotherapy.5-7

Several previous studies reported the incidence of anemia in patients with non-Hodgkin lymphoma (NHL).5,8-10 Coiffier et al10 conducted a retrospective medical record survey of anemia among both solid tumor and hematologic cancers at 24 centers in France. They reported that 37.1% of the patients had baseline hemoglobin (Hb) levels indicative of some degree of anemia, and by cycle 3, the prevalence of anemia (defined as the cumulative proportion of patients with moderate [Hb 8 to < 10.5 g/dL] to severe [Hb < 8 g/dL] anemia any time after the start of chemotherapy) increased to 54.1% of patients and remained > 50% through cycles 4 to 6. There are no comparable studies that document the occurrence of anemia in NHL in current hematology-oncology practice in the US, especially anemia episodes associated with chemotherapy treatment.

Anemia during chemotherapy was historically treated using red blood cell (RBC) transfusions. In 1993, erythropoiesis-stimulating agents (ESAs) were approved for correcting mild to moderate anemia in the US and reduced the need for RBC transfusions in patients with nonmyeloid malignant tumors.11 Beginning in 2003, studies suggested that ESA use was associated with decreased overall patient survival and/or tumor progression or recurrence in patients with breast, lymphoid, cervical, head and neck, and non-small cell lung cancers.12 These findings led to a series of changes in the US regarding how to prescribe ESAs in patients with cancer,13-16 including the implementation of the Risk Evaluation and Mitigation Strategy (REMS) program in March 2010. Several studies have reported decreased use of ESAs immediately after policy changes in the setting of CIA in numerous cancer types.13 In addition, Hb concentrations are typically lower among patients with cancer receiving myelosuppressive chemotherapy.17 Additional data are needed to evaluate the long-term effects of these policy changes on clinical management of CIA.18-20

In this article, we report the patterns of occurrence of CIA in patients diagnosed with incident NHL in a large managed care organization in California. Patients diagnosed with NHL between 2010 and 2012 and treated by June 2013 were included to provide an updated picture of CIA in current hematology-oncology practice. We also evaluated how management of CIA episodes changed over time, from 2000 to 2013, as the recommendations for ESA use evolved.


Study Setting Population

Kaiser Permanente Southern California (KPSC) is an integrated managed care organization that provides comprehensive health services for more than 4 million racially/ethnically and socioeconomically diverse enrollees who broadly represent the population in southern California.21 KPSC maintains electronic records of health care received by their members. These electronic databases include laboratory data, diagnosis codes, medical procedures, pharmacy files, and disease registries, such as the cancer registry. KPSC’s Surveillance, Epidemiology, and End Results-affiliated cancer registry routinely collects information on age, sex, race/ethnicity, cancer type, histologic type, and stage at diagnosis. All data for this study were collected from KPSC electronic health records. All KPSC health record data became electronically available in all service areas for both inpatient and outpatient settings by the end of 2008.

For the examination of incidence of CIA, patients were included if they 1) were diagnosed with incident NHL at age 18 years or older at KPSC between March 25, 2010 (ie, after the implementation of REMS), and December 31, 2012; 2) initiated chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and 3) had at least 1 laboratory measurement of Hb during the first course of chemotherapy. Of those who met the inclusion criteria, patients were excluded if they 1) had less than 12 months of KPSC membership before the start of chemotherapy; 2) had missing information on cancer stage or chemotherapy regimen or agents; 3) had a diagnosis of myelodysplastic syndrome before chemotherapy initiation assessed with International Classification of Diseases, Ninth Revision (ICD-9) codes; 4) had a diagnosis of inherited anemia; 5) had an Hb concentration < 10 g/dL within 3 months before chemotherapy initiation (ie, had baseline anemia for any reason, including nutritional deficiency); 6) had a transfusion within 2 weeks before chemotherapy initiation; 7) received radiotherapy within 4 months before chemotherapy initiation; and 8) received bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria ensure the patients evaluated had sufficient clinical information and anemia events (if any) that were most likely related to chemotherapy.

To examine changes in the treatment pattern of patients with CIA over time, we included patients with NHL who were 1) diagnosed at age 18 years or older and treated in the 3 KPSC medical centers in San Diego, Orange County, and Fontana between January 1, 2000, and December 31, 2012 (we restricted the sample to these 3 medical centers because of their completeness of outpatient and inpatient chemotherapy data before 2007); 2) initiated chemotherapy before June 30, 2013; and 3) developed anemia in the first course of chemotherapy. The same exclusion criteria described above were applied to this secondary study population.

This study was approved by the KPSC institutional review board.

Data Collection

Data on patient demographic characteristics, cancer stage, length of KPSC membership, chemotherapy information, and Hb concentrations were collected using the KPSC cancer registry and clinical databases. History of comorbidities was assessed using ICD-9 diagnosis codes noted in the 12-month prechemotherapy period. Information on body mass index and chemotherapy regimens and cycle were collected from the KPSC oncology pharmacy dispensing systems. For CIA treatment, we considered RBC transfusion, ESA use, and prescription nutritional supplements, including iron (intravenous or oral), folate (intravenous or oral), and B12 (intravenous or oral) prescriptions. Use of RBC transfusion was captured using ICD-9, Current Procedural Terminology 4, and KPSC internal procedure codes. Use of ESA and prescription nutritional supplements was captured using the KPSC oncology drug dispensing systems and general pharmacy databases.

Statistical Analysis

Distributions of demographic characteristics, cancer characteristics, and number of chemotherapy cycles were calculated to describe the study cohort. Anemia was defined as an Hb level < 14 g/dl for men and < 12 g/dl for women. Following the National Cancer Institute’s Common Terminology Criteria for Adverse Events,22 CIA events were classified by severity: Grade 1 (10 g/dl to lower limit of normal; ie, 14 g/dl for men and 12 g/dl for women), grade 2 (8.0-9.9 g/dl), grade 3 (6.5-7.9 g/dl), and grade 4 (< 6.5 g/dl). An anemia episode was defined to start when an Hb measurement met the definition of anemia and to end when the anemia was resolved (a single measurement of Hb reached normal), when the Hb measurement reached a more severe anemia grade (eg, a grade 2 anemia became a grade 3 anemia), or 60 days after the last dose of chemotherapy.

The incidence proportions of CIA (of different severities) and corresponding 95% confidence intervals (CIs) were estimated by cancer stage at diagnosis, chemotherapy regimen, and cycle. Incidence proportion of CIA at the patient level was calculated as the proportions of patients who ever experienced a CIA event during the first course of chemotherapy. Incidence proportion of CIA at the chemotherapy cycle level was calculated as the proportions of patients in a specific cycle of chemotherapy who had experienced a CIA episode during that cycle of chemotherapy. Related 95% CIs for each incidence proportion were estimated using normal approximation. For the patient-level and cycle-level incidence proportion calculation, the most severe grade of CIA a patient experienced was used for the calculation of incidence proportion by CIA severity. This same anemia event was then characterized for its morphologic characteristic using mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH): Microcytic anemia (MCV < 80 fL), normocytic anemia (MCV 80-100 fL), macrocytic anemia (MCV > 100 fL), hypochromic anemia (MCH < 27 pg/cell), normochromic anemia (MCH 27 - 31 pg/cell), and hyperchromic anemia (MCH > 31 pg/cell).23

To describe anemia treatment patterns in patients with NHL, the following calendar periods were evaluated: January 1, 2000, to December 31, 2006 (before the issue of the ESA black box warning) (period 1); January 1, 2007, to March 24, 2010 (before REMS implementation) (period 2); and March 25, 2010, to June 30, 2013 (after implementation of REMS) (period 3). Distributions of demographic characteristics were calculated separately for patients who were diagnosed in the 3 calendar periods.

For the analysis of calendar trends in CIA management, the proportions of anemia episodes treated with ESA, RBC transfusion, other prescription medications, or no treatment were calculated in each of the 3 calendar periods (by the calendar period in which the anemia episode took place). Because more than 1 treatment approach can be used for the same anemia episode, proportions of mutually exclusive combinations of the above-mentioned treatment strategies were also evaluated. Proportions of anemia episodes treated with different management strategies were calculated for any anemia and by the severity of anemia. These analyses were repeated for patients with stage 4 NHL, in whom the burden of CIA may be greater.

A logit model, using generalized estimating equations, was used to evaluate the trends in CIA management pattern across calendar periods while accounting for potential changes in the population characteristics (ie, age, sex, race, and comorbidities). The independent error structure was used with this model.

All analyses were conducted using SAS statistical software, version 9.2 (Statistical Analyses System Inc, Cary, NC, USA).


Incidence of Chemotherapy-Induced Anemia

A total of 1675 incident cases of NHL diagnosed between March 25, 2010, and December 31, 2012, at KPSC were identified. Of these, 1255 patients met the exclusion criteria, leaving a total of 699 patients for the examination of the incidence proportion of CIA. The mean (standard deviation [SD]) age at diagnosis was 61.1 (13.9) years (Table 1). More than half the patients were men and of non-Hispanic white race/ethnicity. Most patients were diagnosed with stage III (22.6%) or IV (38.9%) disease. The mean (SD) Hb level before chemotherapy was 12.9 (1.5) g/dl. The mean (SD) number of chemotherapy cycles received was 5 (2.4). The most common comorbid conditions before starting chemotherapy were hypertension (46.4%), diabetes (22.6%), and renal disease (11.2%). The most common regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (58.7%), followed by bendamustine with or without rituximab (11%).

Approximately 90% of patients with NHL developed CIA (any grade) during the first course of chemotherapy. Of these patients, 58.9%, 28.2%, 11.2%, and 1.8% had grades 1, 2, 3, and 4 as the most severe grade, respectively (Table 2). Morphologically, 90%, 6%, and 4% of these CIAs were normocytic, macrocytic, and microcytic, respectively; and 53%, 41%, and 6% were normochromic, hyperchromic, and hypochromic, respectively. When we examined the incidence proportion of moderate CIA (Hb < 10 g/dL)
by stage at diagnosis, the incidence proportion increased from 27.3% in stage I NHL to 44.5% in stage IV NHL. The incidence proportion of severe CIA (Hb < 8 g/dl) increased from 6.1% in stage I NHL to 14.0% in stage IV NHL.

Figure 1 shows the cycle-level incidence proportion of CIA by chemotherapy cycle in patients receiving the CHOP/R-CHOP regimens. The incidence proportion of overall CIA events and moderate CIA events increased from cycles 1 (13%) to 5 (21%) and decreased in cycle 6 (14%). The incidence proportion of severe CIA (Hb < 8 g/dl) continued to increase through cycle 6 (1% in cycle 1 to 6% in cycle 6).

Treatment Pattern of Chemotherapy-Induced Anemia

There were 1560 patients with incident NHL who initiated chemotherapy in the KPSC medical centers in San Diego, Orange County, and Fontana between January 1, 2000, and June 30, 2013. After applying the exclusion criteria, 989 patients with NHL were included in the treatment pattern analyses. Their demographic and clinical characteristics were similar to the patient population used to evaluate the incidence of CIA (Table 3). The numbers of observed CIA episodes were 914 in phase 1, 441 in phase 2, and 506 in phase 3. The numbers of moderate anemia episodes were 313 in phase 1, 144 in phase 2, and 140 in phase 3. Among moderate CIA, proportions of episodes with ESA use decreased from 2006 to 2013: 34% in phase 1, 22% in phase 2, and 6% in phase 3 (ESA use without transfusion: 29% in phase 1, 15% in phase 2, and 3% in phase 3 [Figure 2A]). An increasing trend of RBC transfusion use was observed: 12% in phase 1, 22% in phase 2, and 27% in phase 3. Similarly, among severe CIA (Hb < 8 g/dL), proportions of episodes with ESA use decreased from 2006 to 2013: 44% in phase 1, 27% in phase 2, and 5% in phase 3 (ESA use without transfusion: 33% in phase 1, 11% in phase 2, and 0% in phase 3 [Figure 2B]). An increasing trend of RBC transfusion use was observed: 26% in phase 1, 62% in phase 2, and 62% in phase 3. Use of iron, folate, or B12 supplement was uncommon across all calendar periods. The proportion of untreated anemia episodes increased from 57% in phase 1 to 70% in phase 3 for moderate anemia. The proportion of untreated severe anemia episodes decreased from 38% in phase 1 to 27% in phase 2 and then increased back to 38% in phase 3.

The observed number of anemia episodes in patients with stage IV NHL was 316 in phase 1, 153 in phase 2, and 199 in phase 3. The number of moderate anemia episodes in patients with stage IV NHL was 114 in phase 1, 56 in phase 2, and 56 in phase 3. We observed similar trends in CIA treatment patterns in these patients with stage IV NHL as in the overall patients with NHL. Although the proportion of untreated moderate CIA episodes increased from 59% in phase 1 to 63% in phase 3 (Figure 2C), the proportion of untreated severe CIA episodes decreased 42% in phase 1, 38% in phase 2, and 27% in phase 3 (Figure 2D).

In adjusted logistic regression analyses (using generalized estimating equations), the decreasing use of ESA was statistically significant compared with phase 1 (Table 4), whereas an increasing use of RBC transfusion was not statistically significant. For ESA use, the odds ratio was 0.59 (95% CI = 0.37-0.93) for phase 2 and 0.08 (95% CI = 0.04-0.18) for phase 3. For RBC transfusion, the odds ratio was 1.54 (95% CI = 0.93-2.56) for phase 2 and 1.56 (95% CI = 0.96-2.54) for phase 3.

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18 252a

18 252c

18 252e


In this study, we examined the patterns of severe CIA incidence in patients diagnosed with NHL in a large, integrated health care system. We found in the first course of chemotherapy that 37% of patients with NHL developed moderate CIA, whereas more than 10% developed severe anemia. These incidence patterns largely reflected patients who received CHOP-based therapy because most patients received CHOP/R-CHOP therapy. Consistent with previous studies,9 we found an increase in severe CIA in patients whose cancer was diagnosed at advanced stages, who may have had greater myelosuppression because of the treatment as well as the disease. As patients progressed with their chemotherapy cycles, a steady increase in overall CIA incidence was observed between cycles 1 and 5, but this incidence decreased afterward, in part because of discontinuation of chemotherapy. The highest incidence proportion of severe CIA was noted in cycle 6. We also evaluated how CIA management changed as the recommendations for ESA use, in the CIA setting, evolved. We found limited use (ie, < 3% of CIA) of ESAs after the implementation of REMS, even among patients with stage IV NHL (≤ 5% of CIA) for whom ESA is more likely to be indicated. RBC transfusion use increased significantly. Although the proportion of untreated severe CIA episodes did not increase over time (and in fact decreased in patients with stage IV NHL), a significant proportion of severe CIA (approximately 40%) episodes remained not actively treated.

previous studies have examined the incidence of anemia in patients with NHL in European populations. In a prospective study, Birgegard et al5 conducted a survey of patients with lymphoma and multiple myeloma in European cancer centers and reported anemia prevalence, incidence, treatment patterns, and risk factors. In their study, of the patients (with lymphoma and multiple myeloma) who were not anemic at enrollment, 55.4% of those who began their first chemotherapy and underwent at least 2 chemotherapy cycles during the survey became anemic (Hb < 12 g/dl). In patients with NHL specifically, Birgegard et al5 found that 62.3% had developed anemia by cycle 6. Haioun et al8 conducted an observational study in 14 European countries and Australia of anemia management in patients with NHL receiving CHOP/R-CHOP. They found that overall 11% were anemic (Hb < 10 g/dl) at the start of chemotherapy, whereas 33% of patients were anemic during chemotherapy. Compared with these studies conducted in Europe and Australia, we found a significantly higher incidence of overall CIA as well as moderate CIA among patients with NHL. These differences may be attributable to evolution of chemotherapy regimens used to treat NHL or differences among countries and regions and differences in standards of care for treating anemia. Thus, in contrast to previous understanding of the occurrence of CIA based on European studies, our estimates indicate a higher incidence of CIA in patients with NHL in this US community practice setting.

Several previous studies have examined CIA treatment in all tumor types before and after the 2007 Centers for Medicare & Medicaid Services release of the national coverage determination (NCD).18-20 We were not able to find any studies that looked specifically after the REMS program pertaining to ESA use in CIA was launched in March 2010. In a study conducted by Henry et al18 among patients with solid tumors, the post-NCD patients reached significantly lower Hb levels during chemotherapy and had higher odds of receiving a transfusion. Hess et al19 compared the frequency of myelosuppressive chemotherapy treatment, ESA administrations, and RBC transfusions before and after the NCD in patients with CIA in several cancers. Although exposure to myelosuppressive chemotherapy was not different, ESA administrations significantly decreased and blood transfusions significantly increased after implementation of the NCD. Although our study looked at the periods before and after the 2007 Centers for Medicare & Medicaid Services release of the NCD, we also included the period after the REMS program was launched in March 2010. We found a steady decrease of ESA use after the implementation of the NCD and REMS. There was little use of ESAs after the implementation of REMS, including for patients with stage IV NHL for whom ESAs may be indicated. Along with the increased use of transfusion, the proportion of untreated CIA did not increase from phase 1 to phase 3 for severe CIA events. However, there appears to be an increase in untreated moderate CIA events across the calendar periods in patients with NHL. The clinical implications for this increase in untreated moderate CIA are unclear.

We evaluated the use of prescription iron, folate, or B12 supplement in the management of CIA. Although the National Comprehensive Cancer Network guidelines suggest evaluation of nutritional deficiency in the setting of cancer-induced anemia and CIA,24 the clinical guideline on the use of nutritional therapy for CIA still remains inconclusive because of insufficient evidence.25,26 Therefore, the use of nutritional therapy was likely limited in the setting of CIA in this KPSC population. Given the potential risks associated with the use of ESA and RBC transfusion, it may be worth exploring the potential benefit of these nutritional supplements for improving anemia in patients who had iron, folate, or B12 deficiency in this setting. Related to this notion is our finding on the morphologic subtypes of CIA. We reported that most (90%) CIA is normocytic. Almost all the CIA is characterized as hyperchromic (41%) and normochromic (53%), which is what we expected for CIA cases. Up to 10% of cases of CIA were of microcytic or macrocytic subtypes, and 6% were hypochromic subtype. The data suggest a possible role for nutritional deficiencies to a fraction of anemia during chemotherapy. Although these morphologic subtypes may not be strictly linked to nutritional causes, these data suggest nutritional causes for anemia should be routinely evaluated for and treated where appropriate.

our study has potential limitations that should be considered when interpreting the results. Given the retrospective, observational nature of this study, patients did not receive equal numbers of Hb measurements, and the Hb measurements were not obtained at equal intervals. Thus, CIA episodes in asymptomatic patients maybe missed because of a lack of Hb testing. The degree of this misclassification is likely small because 95% of the chemotherapy cycles evaluated in this study had at least 1 Hb measurement. We were unable to capture use of over-the-counter iron, folate, or B12 supplements because these can be purchased in any pharmacy outside the KSPC network. Another limitation was the varying number of chemotherapy cycles received by study patients. We were unable to distinguish those who had completed all planned therapy vs those who discontinued or switched because of adverse events on the basis of the electronic medical records. Therefore, our cycle-level estimates of CIA incidence may be a combined effect of natural progression in the incidence of CIA over cycles as well as a potential selection effect of patients who remained in the later cycles. However, these estimates represent what can be expected in real-life clinical practice. Another limitation is that we are unable to assess bone marrow involvement (which may trigger a different anemia management pattern) from existing databases. That said, all patients with NHL and bone marrow involvement would have stage IV disease. Finally, our estimates may not be generalizable to uninsured patients with NHL, who may be at poorer general health status at chemotherapy initiation.


We found that a higher percentage of patients with NHL in Southern California experience CIA during the first course of chemotherapy compared with that previously reported in patient populations from other countries. Lower Hb levels were more common in cases of NHL diagnosed with advanced-stage diseases. Despite the high incidence of CIA in patients with NHL, a large proportion of CIA episodes were not actively treated. Few patients received ESAs, and the most common method of CIA treatment observed was RBC transfusion. Future studies are needed to determine the associations between CIA symptom burden and CIA treatment, as well as whether CIA or its treatment modifies patient outcomes and quality of life.

Disclosure Statement

Chun Chao, PhD, receives research funding from and Chet Bohac, MD, owns stock in Amgen, Inc. John Page, MD, ScD, is both an employee and stockholder of Amgen, Inc.

The author(s) have no conflicts of interest to disclose.


Laura King, ELS, performed a primary copy edit.

How to Cite this Article

Cannavale K, Xu H, Xu L, et al. Epidemiology of chemotherapy-induced anemia in patients with non-hodgkin Lymphoma. Perm J 2019;23:18-252. DOI: https://doi.org/10.7812/TPP/18-252

Author Affiliations

1 Department of Research and Evaluation, Pasadena, CA

2 Atara Biotherapeutics, Thousand Oaks, CA

3 Medhealth Statistical Consulting Inc, Solon, Ohio 

4 Department of Hematology Oncology, Los Angeles Medical Center, CA

5 Immune Design Corporation, San Francisco, CA

6 Amgen Inc, Thousand Oaks, CA

Corresponding Author

Chun Chao, PhD (chun.r.chao@kp.org)

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Keywords: anemia, erythropoiesis-stimulating agents, lymphoma, non-Hodgkin lymphoma, transfusion

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