By Clinical Content Hub

Follicular lymphoma (FL) is the most common indolent lymphoma diagnosed in the United States.1 With approximately 14,000 cases per year, it accounts for about 35% of all non‐Hodgkin lymphomas (NHLs) and 70% of indolent lymphomas.2-4 While still considered an incurable disease, improvements in diagnosis and therapeutic advances have improved outcomes. The development of anthracycline-containing chemotherapy and use of the anti-CD20 monoclonal antibody rituximab, along with the newer phosophatidylinositol-2-kinase-delta (PI3Kδ) inhibitors (idelalisib, copanlisib, and duvelisib), have steadily extended survival.5,6 The median survival is now close to 20 years.

The mortality rate for patients with FL remains at 0.5 per 100,000 persons (2013-2017 cases and deaths)and the clinical heterogeneity of the disease is still poorly understood.7 FL can remain indolent for decades in some patients while in others it will follow an aggressive clinical course. Approximately 10% to 15% of patients with FL will experience an aggressive disease trajectory with a shortened lifespan, while others with an indolent course may survive for decades with minimal impact on their lives.8 Most patients, however, will experience a pattern of relapse and remission and require numerous lines of treatments throughout their lifetime. Early recurrence following frontline chemoimmunotherapy consistently occurs in 20% of all patients, and has emerged as a predictor of poor survival.9

FL is defined as a lymphoma of follicle center B-cells, which typically manifest with follicular pattern and originates in the lymph nodes.10 Many adult patients will initially present with asymptomatic lymphadenopathy, which can fluctuate for years, and at least 70% will have bone marrow involvement. This reflects stage IV disease at diagnosis but variability in tumor burden can be significant.8 The involvement of other organs is uncommon, although a rare extranodal variant of FL can present in the intestines. Involvement of the gastrointestinal tract tends to follow a particularly indolent course with a much better prognosis.11

About 90% of FL cases are characterized by the recurrent chromosomal translocation t(14;18)(q32;q21), which results in the influence of IgH promoter on BCL2, ultimately leading to the overexpression of the antiapoptotic BCL2 protein in cells of the FL microenvironment.12 FL is also associated with a characteristic immunophenotype that includes CD20+, CD10+, BCL2+, CD23+/-, CD43-, CD5-, CCND1-, and BCL6+, while cases may occasionally be CD10- or BCL2-.13 Aggressive disease can result in the histologic transformation of FL to diffuse large B cell lymphoma (DLBCL), which occurs in 15% of patients with a risk of 2% to 3% per year, and is associated with a poor prognosis. Transformation is often associated with rapid progression of lymphadenopathy, extranodal disease aside from bone marrow, systemic symptoms, hypercalcemia, elevated serum lactate dehydrogenase (LDH), and a limited response to initial therapy.14 MYC abnormalities are also associated with transformation to a clinically aggressive and chemorefractory disease state, and other genetic aberrations associated with a poor prognosis include 1p36 deletions (usually in association with mutations of TNFRSF14), TP53 mutations, MLL2 and EZH2 mutations, and CDKN2A deletions.8

Risk Stratification

Defining a patient’s individual risk can be difficult due to the significant biologic heterogeneity in FL at the histologic, genetic, epigenetic, and proteomic levels. Tools and models have been developed to help inform treatment decisions and to allow clinicians to evaluate individual patient risk. One model is the FL international prognostic index (FLIPI), which was developed to stratify patients by risk and to predict survival (Table). FLIPI has been validated as a diagnostic model for patients treated in both the pre- and post-rituximab eras.15 The endpoint of the model is overall survival, and 5 parameters are used: age (>60 vs ≤60), serum LDH level (>upper limit of normal [UPLN] vs ≤UPLN), number of nodal areas (>4 vs ≤4), hemoglobin level (<120 vs ≥120g/L) and Ann Arbor state (III-IV vs I-II). Three risk groups were identified: low, intermediate and high.

The National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on FL patients treated in community practices, evaluated the FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens.15 The results showed that it was able to predict distinct outcomes for both overall and progression-free survival (PFS), and that it remained a valid and important prognostic tool for patients receiving contemporary immunochemotherapy regimens.

An updated model, the FLIPI2, was designed to evaluate newly diagnosed patients treated with contemporary therapies, and it also incorporated PFS as an endpoint. The final prognostic model included age, hemoglobin levels, longest diameter of largest involved lymph node, β2-microglobulin levels, and bone marrow involvement, and it was shown to be highly predictive of treatment outcomes. It also stratified patients into 3 distinct risk groups with 3-year PFS rates ranging from 51% to 91%, and 3-year overall survival rates ranging from 82% to 99%.16

A higher FLIPI score may suggest that treatment should be initiated rather than a “watch and wait” approach, but other factors need to be determined when assessing risk, including tumor burden. There are various criteria that are used to evaluate tumor burden, such as the Groupe d’Etude des Lymphomes Folliculaires (GELF).17 Data show that a high tumor burden, as defined by GELF criteria, was associated with worse overall survival and PFS in patients treated with first-line R plus chemotherapy.18

The World Health Organization has also classified FL into grade 1, grade 2, and grade 3, which has been further divided into grades 3a and 3b. Grade 3a is indicated by the presence of centrocytes, while grade 3b is indicated by the presence of sheets of centroblasts. Because grade 3b is clinically and biologically similar to DLBCL, it is also treated similarly.19

First-Line Treatment

Less than 10% of patients present with stage I/II disease, and most will have disseminated disease at diagnosis.13,19 Guidelines from the National Comprehensive Cancer Network (NCCN) only offer treatment recommendations for FL grade 1-2 and consider grade 3a to be an “area of controversy.”13 In addition, the NCCN guidelines noted that grade 3b FL is commonly treated as DLBCL.

The preferred first-line therapy is chemotherapy in combination with an anti-CD20 antibody such as rituximab. These combinations include bendamustine plus rituximab; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); or rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). The NCCN also recommends rituximab as monotherapy or combined with immunomodulator lenalidomide.13 An update of the FOLL05 trial (ClinicalTrials.gov Identifier: NCT00774826) showed that among patients with advanced FL, treatment with R-CVP, R-CHOP, or rituximab plus fludarabine and mitoxantrone resulted in similar 8-year overall survival; however toxicity profiles varied.20 Compared with patients who received R-CHOP, patients who were initially treated with R-CVP had a higher risk for lymphoma progression and risk of requiring additional therapy. Of the 3 regimens, the investigators of the study suggested that R-CHOP should be the preferred option.

Combination rituximab plus lenalidomide represents a nonchemotherapy option for patients, and results of the RELEVANCE trial (ClinicalTrials.gov Identifier: NCT01476787) found it comparable to standard regimens.21 The phase 3 superiority trial compared rituximab plus lenalidomide with rituximab plus chemotherapy in treatment-naive patients and demonstrated that overall response rate (ORR) was comparable between groups. The 3-year PFS was 77% and 78% for rituximab plus lenalidomide and immunochemotherapy arms. A higher rate of grade 3 and 4 neutropenia (32% vs 50%) and febrile neutropenia (2% vs 7%) was observed in the chemotherapy group.

Extended dosing or consolidation with rituximab is an option for patients initially presenting with high tumor burden, and radioimmunotherapy can also be given following induction with chemotherapy or chemoimmunotherapy.13 Studies have reported a benefit with extended dosing including data from the phase 3 ECOG (E1496) study which showed a PFS benefit with rituximab maintenance in patients with advanced indolent lymphoma who had responded to first-line CVP regimen.22 The subgroup of FL patients who received maintenance therapy had a PFS of 64% vs 33% for those who didn’t. However, the 3-year overall survival rate did not significantly differ between groups (91% vs 86%, respectively).

Long term follow-up results of the PRIMA study (ClinicalTrials.gov Identifier: NCT00140582) also demonstrated a benefit for extended therapy. Patients treated with rituximab maintenance had a median PFS of 10.49 years compared with 4.06 years for those who did not (P =.0001).23 However, no differences were seen in projected median overall survival, and in patients with a low tumor burden, the RESORT study (ClinicalTrials.gov Identifier: NCT00075946) showed similar results to rituximab maintenance and rituximab retreatment at the time of relapse.24

Transformation to Aggressive Lymphoma

Histological transformation of FL to an aggressive lymphoma will have a substantial effect on outcomes, and in the era before immunochemotherapy regimens, the risk was relatively high at 28% at 10 years.25 A more recent analysis showed that the inclusion of rituximab into first-line therapy has significantly reduced the risk of transformation to 7.7%.26 Advanced-stage and high-risk FLIPI and International Prognostic Index (IPI) scores at diagnosis correlate with a higher risk for histological transformation.

A subset of patients with indolent disease may be able to be cured by high-dose chemotherapy followed by autologous hematopoietic cell transplantation (ASCT), although it is unclear whether ASCT is preferable to immunochemotherapy.27 Some data suggest that ASCT following chemoimmunotherapy may improve outcomes as opposed to chemoimmunotherapy alone, with 5-year survival rates of 55% compared with 40%.28 However, other data showed better outcomes following R-CHOP without ASCT, with 5-year overall survival rates of 64.3%.29

Relapsed/Refractory Disease

Relapse is part of the disease trajectory in FL, but many treatment options are now available. Patients with relapsed or progressive disease following first-line therapy can sometimes benefit from a second period of observation, depending on individual characteristics including GELF criteria, presence of significant cytopenia secondary to lymphoma, bulky disease, splenomegaly, and experiencing steady disease progression over at least 6 months.

For second-line and subsequent therapy, NCCN guidelines recommend chemoimmunotherapy as per first-line therapy, rituximab alone; lenalidomide plus rituximab; radioimmunotherapy; idelalisib; fludarabine plus rituximab; and rituximab, fludarabine, mitoxantrone, and dexamethasone.13 Some patients may be treated according to the guidelines for DLBCL, depending on individual characteristics.

For second-line consolidation or extended dosing, the NCCN recommends rituximab maintenance, or high-dose therapy with autologous stem cell rescue or allogeneic stem cell transplant for highly selected patients.13

About a quarter of patients will be refractory to first-line immunochemotherapy and/or experience disease progression within the first 24 months. Early progression is associated with a poorer survival, as demonstrated by a combined analysis of 3 CALGB clinical trials, which showed an association with an increased risk of death.30 Those with early progression had a 2-year overall survival of 80% and 5-year overall survival of 74% compared to 99% and 90% for patients without early progression. Thus, disease progression within 24 months of remission is a prognostic marker for overall survival in patients treated with rituximab-containing immunotherapy.

The PI3Kδ inhibitors are a newer addition to the armamentarium for treating relapsed/refractory disease after 2 prior therapies and both idelalisib and copanlisib have demonstrated efficacy in a high-risk population with disease relapse less than or equal to 2 years after first-line therapy.31-35 A phase 2 trial comprised of 125 patients with rituximab- and alkylating agent–refractory indolent NHL (including 72 patients with FL) showed that treatment with idelalisib resulted in tumor reductions in 90% of the cohort, with an ORR of 57% (6% complete responses).31 A post hoc subgroup analysis of the 72 patients with FL showed an ORR of 55.6% (13.9% complete and 41.2% partial response) and the overall disease control rate was 87.5%.36

The phase 2 CHRONOS-1 (ClinicalTrials.gov Identifier: NCT01660451) found that treatment with copanlisib in patients with relapsed/refractory indolent NHL after 2 or more prior lines of therapy resulted in an ORR of 58.7% in the subgroup of 104 patients with FL (20.2% complete response and 38.5% partial response).35 Median duration of response was 12 months. Duvelisib was evaluated in the phase 2 DYNAMO study (ClinicalTrials.gov Identifier: NCT01882803) that included 129 patients with indolent NHL refractory to both rituximab and chemotherapy or radioimmunotherapy.33 The ORR was 47.3% (42.2% for the subgroup with FL), and estimated median duration of response and median PFS were 10 and 9.5 months, respectively.

The use of either allogeneic or ASCT in FL has also been studied in numerous clinical trials, but a consensus on its use has not yet been established.37 Numerous phase 2 studies conducted before the introduction of rituximab found that about that about 40% of patients with good performance status and chemosensitive relapsed disease could experience prolonged PFS and overall survival following high-dose therapy and ASCT.38,39 More recently, studies have looked at the use of ASCT for high-risk patients with early relapse, with 1 reporting a 5-year overall survival rate of 70% following ASCT in this patient population.40 Other results from research conducted by the Center for International Blood and Marrow Transplant Research and the National LymphoCare Study, suggests ASCT in this population was associated with a higher 5-year overall survival as compared to patients without ASCT (73% vs 60%).41

Treatment with CD19 CAR-T cells is an emerging and promising therapeutic option for patients with FL, and there are currently 2 US Food and Drug Administration-approved products for patients with FL that is relapsed/refractory after 2 prior therapies: tisagenlecleucel and axicabtagene ciloleucel. One study reported a 71% response rate in 14 patients, and at a median follow-up of 28.6 months, 89% of the responders remained progression free.42 In another study, the rate of complete remission was 88%, and sustained remissions were achieved.43

Current first-line regimens for FL typically achieve high response rates, but for the most part, patients will be treated with multiple lines of therapies and/or different modalities throughout their lifetime. The outcome of these different regimens and their effect on patient survival are evolving, as new therapies come on the market and research continues into the underlying mechanisms of the disease.

References

  1. Sarkozy C, Maurer MJ, Link BK, et al. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of French and US cohorts. J Clin Oncol. 2019;37(2):144-152. doi:10.1200/JCO.18.00400
  2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443-459. doi:10.3322/caac.21357
  3. Batlevi CL, Sha F, Alperovich A, et al. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J. 2020;10(7):74. doi:10.1038/s41408-020-00340-z
  4. Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020;95(3):316-327. doi:10.1002/ajh.25696
  5. Casulo C, Barr PM. How I treat early-relapsing follicular lymphoma. Blood. 2019;133(14):1540-1547. doi:10.1182/blood-2018-08-822148
  6. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122(6):981-987. doi:10.1182/blood-2013-03-491514
  7. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: NHL – Follicular Lymphoma. https://seer.cancer.gov/statfacts/html/follicular.html. Updated September 14, 2020. Accessed September 14, 2020.
  8. Smith SM. Dissecting follicular lymphoma: high versus low risk. Hematology Am Soc Hematol Educ Program. 2013;2013:561-567. doi:10.1182/asheducation-2013.1.561
  9. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522. doi:10.1200/JCO.2014.59.7534
  10. Ma S. Risk factors of follicular lymphoma. Expert Opin Med Diagn. 2012;6(4):323-333. doi:10.1517/17530059.2012.686996
  11. Chouhan J, Batra S, Gupta R, Guha S. Gastrointestinal follicular lymphoma: using primary site as a predictor of survival. Cancer Med. 2016;5(10):2669-2677. doi:10.1002/cam4.763
  12. Kosmidis P, Mankel B, Fend F, Adam P. The t(14;18) translocation is absent from endothelial and follicular dendritic cells of follicular lymphoma (FL) and shows heterogeneous presence in preserved FL mantle zones. Diagn Pathol. 2018;13(1):25. doi:10.1186/s13000-018-0703-2
  13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) B-Cell Lymphomas Version 4.2020 – August 13, 2020. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed September 18, 2020.
  14. Freedman AS. Biology and management of histologic transformation of indolent lymphoma. Hematology Am Soc Hematol Educ Program. 2005;314-320. doi:10.1182/asheducation-2005.1.314
  15. Nooka AK, Nabhan C, Zhou X, et al. Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Ann Oncol. 2013;24(2):441-448. doi:10.1093/annonc/mds429
  16. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27(27):4555-4562. doi: 10.1093/annonc/mds429
  17. MD+CALC. Groupe d’Etude des Lymphomes Folliculaires (GELF) Criteria. https://www.mdcalc.com/groupe-detude-des-lymphomes-folliculaires-gelf-criteria. Accessed September 16, 2020.
  18. Kato H, Tange N, Iriyama C et al. Evaluation of tumor burden for predicting survival in patients with follicular lymphoma receiving first-line R-CHOP treatment: comparison of different definition of GELF criteria. Blood. 2017;130(Supplement 1):4063. doi:10.1182/blood.V130.Suppl_1.4063.4063
  19. Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020;95(3):316-327. doi:10.1002/ajh.25696
  20. Luminari S, Ferrari A, Manni M, et al. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018;36(7):689-696. doi:10.1200/JCO.2017.74.1652
  21. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi:10.1056/NEJMoa1805104
  22. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607-1614. doi:10.1200/JCO.2008.17.1561
  23. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51. doi:10.1016/S0140-6736(10)62175-7
  24. Williams ME, Hong F, Gascoyne RD, et al. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016;173(6):867-875. doi:10.1111/bjh.14007
  25. Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25(17):2426-2433. doi:10.1200/JCO.2006.09.3260
  26. Federico M, Caballero Barrigón MD, Marcheselli L, et al. Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis. Lancet Haematol. 2018;5(8):e359-e367. doi:10.1016/S2352-3026(18)30090-5
  27. Madsen C, Pedersen MB, Vase MØ, et al. Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation. Ann Oncol. 2015;26(2):393-399. doi:10.1093/annonc/mdu537
  28. Villa D, Crump M, Panzarella T, et al. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group. J Clin Oncol. 2013;31(9):1164-1171. doi:10.1200/JCO.2012.44.0693
  29. Gleeson M, Hawkes EA, Peckitt C, et al. Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013. Leuk Lymphoma. 2017;58(8):1805-1813. doi:10.1080/10428194.2016.1265114
  30. Lansigan F, Barak I, Pitcher B, et al. The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: a combined analysis of 3 CALGB trials. Cancer Med. 2019;8(1):165-173. doi:10.1002/cam4.1918
  31. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. doi:10.1056/NEJMoa1314583
  32. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648
  33. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi:10.1200/JCO.18.00915
  34. Gopal AK, Kahl BS, Flowers CR, et al. Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy. Blood. 2017;129(22):3037-3039. doi:10.1182/blood-2016-12-757740
  35. Dreyling M, Santoro A, Mollica L et al. Long-term efficacy and safety from the copanlisib CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma. Blood. 2019;10.1002/ajh.25711. doi:10.1002/ajh.25711
  36. Salles G, Schuster SJ, de Vos S, et al. Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study. Haematologica. 2017;102(4):e156-e159. doi:10.3324/haematol.2016.151738
  37. Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica. 2013;98(7):1014-1021. doi:10.3324/haematol.2013.084723
  38. Rohatiner AZ, Nadler L, Davies AJ, et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol. 2007;25(18):2554-2559. doi:10.1200/JCO.2006.09.8327
  39. Cao TM, Horning S, Negrin RS, et al. High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience. Biol Blood Marrow Transplant. 2001;7(5):294-301. doi:10.1053/bbmt.2001.v7.pm11400952
  40. Smith SM, Godfrey J, Ahn KW, et al. Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer. 2018;124(12):2541-2551. doi:10.1002/cncr.31374
  41. Casulo C, Friedberg JW, Ahn KW, et al. Autologous transplantation in follicular lymphoma with early therapy failure: a National LymphoCare Study and Center for International Blood and Marrow Transplant Research analysis. Biol Blood Marrow Transplant. 2018;24(6):1163-1171. doi:10.1016/j.bbmt.2017.12.771
  42. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-2554. doi:10.1056/NEJMoa1708566
  43. Hirayama AV, Gauthier J, Hay KA, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019;134(7):636-640. doi:10.1182/blood.2019000905

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Hematology Advisor had no role in this content’s preparation.

Reviewed October 2020