Outcomes of Diffuse Large B-Cell Lymphoma in Elderly Patients—Real-World Experience from a Middle-Income Country Setting

Outcomes of diffuse large B-cell lymphoma in elderly patients—real-world experience from a middle-income country setting

Chandrayee Sarker1, Vivek S Radhakrishnan1,a , Payal Mandal1, Jeevan Kumar1, Saurabh Bhave1, Rimpa Achari2, Debdeep Dey3, Indu Arun3, Zameer Latif3, Neeraj Arora4, Deepak Mishra4, Mammen Chandy1 and Reena Nair1

1Department of Clinical Hematology, Tata Medical Center, 14 Main Arterial Road (EW), Newtown, Kolkata 700160, India 2Department of Radiation Oncology, Tata Medical Center, 14 Main Arterial Road (EW), Newtown, Kolkata 700160, India 3Department of Pathology, Tata Medical Center, 14 Main Arterial Road (EW), Newtown, Kolkata 700160, India 4Department of Hemato Pathology, Tata Medical Center, 14 Main Arterial Road (EW), Newtown, Kolkata 700160, India ahttps://orcid.org/0000-0001-9484-5669

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of lymphoma in the elderly and poses unique challenges in this group of patients. There is a need for more information on real-world outcomes across economic disparities.

Methods: Electronic Medical Record of 3,087 lymphomas (>18 years) were evaluated retrospectively, of which 842 (27%) patients were ≥65 years. Two hundred and twelve patients who were ≥65 years received first line treatment for DLBCL between May 2011 Clinical Study and Dec 2016. Demography, clinical features, associated co-morbidities, first line treatment outcomes and hospital costs were analysed. Patients were followed up till March 2020.

Results: The median age at presentation was 71 years. Gender ratio was 2.5:1. 38% patients presented with early-stage disease, 37% with low and low-intermediate Inter- national prognostic index, 49% with nodal disease. One or more co-morbidities were Correspondence to: Dr Reena Nair present in 58%. The commonest extra nodal site was gastro-intestinal (29%). Two-thirds Email: [email protected] of the patients presented with non-Germinal centre B subtype. The overall response (OR) ecancer 2021, 15:1242 to treatment was 72.5%. Patients who received anthracycline-based therapy (n = 124) https://doi.org/10.3332/ecancer.2021.1242 and rituximab-based therapy (n = 159) had a median progression free survival (PFS), not Published: 03/06/2021 reached and 47.0 months, respectively, versus 10 months and 7.9 months, respectively, Received: 28/08/2020 for patients receiving non-anthracycline and non-rituximab therapies. At a median fol- Publication costs for this article were supported by low-up of 24 months, the 5-year overall survival and PFS are 44% and 41%, respectively, ecancer (UK Charity number 1176307). for the entire cohort. Copyright: © the authors; licensee Conclusions: DLBCL is a curable lymphoma in elderly patients with standard anthracy- ecancermedicalscience. This is an Open Access cline and rituximab-based therapies. Improvement in outcomes largely depends on social article distributed under the terms of the Creative Commons Attribution License (http:// and financial support to complete the scheduled treatments. creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and Keywords: diffuse large B-cell lymphoma, elderly, anthracyclines, rituximab, dose intensity reproduction in any medium, provided the original work is properly cited.

ecancer 2021, 15:1242; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1242 1 ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 Burkitts’ andBurkitt-like lymphoma. and immunohistochemistrybcl-2 Ki-67, (IHC)/fluorescenthybridizationin situ C-myc (FISH) were undertaken to differentiate DLBCL from centre Bcell (GCB)or histochemistrybased on animmune non-GCB approach usingtheHan’s algorithm [18]. Tests for Proliferative index diagnosis was reviewed atcentrethe (subjecttoavailability) slideandblock prior to startof therapy. DLBCLs were classifiedinto germinal This information was obtained fromelectronic thehospital records medical (EMRs). In patients reporting post-biopsy, thehistopathological Details collected atpresentation, diagnosisincludedclinical history, medical co-morbidities, laboratory tests, treatment andrelated toxicity. Disease assessment for consent was granted. line treatment. The audited data hasbeenapproved for presentation by review theinstitutional board (Hospital Ethics committee). A waiver forty-twoand patients(27%) were≥65 years. Twohundredtwelve and treatment naiveDLBCL patients wereconsidered evaluable for first definite treatment prescribed at our centre, were considered assecond opinionseekers and were not analysed Eight inthisaudit. hundred followed up at our centre and 1,068 (34%) registered for a second opinion. Patients with less than four visits in the outpatient clinic with no received frontline therapy for their disease,101(3%) were treated for relapsed or refractory disease,299(10%) were treated elsewhere and Between May 2011 and December 2016, 3,087 patients (>18 years) with adiagnosis of lymphoma were registered at our centre, 1,617 (52%) Methodology a in outcomes real-world the at middle-income countrylook setting, identify thechallenges inpractice andlookat potential for solutions us thefuture. helped This institute. our at treated years, 65 ≥ DLBCLs of audit retrospective a conducted We and Rituximab), butnodefinitive ‘bestregimen’ hasbeendefined. native regimensCEOP-Rinclude (cyclophosphamide, etoposide, vincristine andprednisolone along Rituximab)with or(Bendamustine BR remains themost widely usedandstandard-of-care regimen. In patients with cardiac insufficiency andother associated co-morbidities, alter potentially outcomes impact intheelderly. CHOP-R(cyclophosphamide, adriamycin, vincristine andprednisolone along Rituximab)with frailty anddisproportionate toxicityolder inthe patientstend to reduce lessintensive doseanduse or abbreviated regimens. These practices due to anunder-representation of theelderly inlargetrials. Most clinical cliniciansinabusy practice setting with concerns of comorbidities, Current therapeuticoptions for elderly DLBCL have largely beenextrapolated from treatment results in younger patients, predominantly to implement inabusy clinicalpractice. and acomprehensivemorbidities geriatricassessment (CGA) are valuable tools inassistingphysicians [17].However, thesescalesare difficult to bebetter tolerated [2].Mosthavetrials clinical focused onpatients between 60and80 years with DLBCL [15,16]. An assessment of co- comorbiditieshave beenobserved [5,9]. The shorter survival couldalso relate to atrend intheprescription of weaker treatments assumed of toxicity of chemotherapy. Very significantchanges in weight, statusnutritional andeasy fatigability, accompanied by poorly controlled of thenon-Germinalcentre (non-GCB) B phenotype are attributed to thepoor outcomes [13,14].Elderly patients are atan increased risk 12]. The difference remains significant after adjustment for related non-lymphoma deaths. Aggressive diseasebiology andahigher incidence When paired for histologicalcharacteristicsand clinical of thesurvival lymphoma, isshorter intheelderly patients compared to younger [11, approach, aggressive diseasebiology, higher toxicity, compromised dosingandearly curtailment of treatment [5,8–10]. significantsocioeconomic dependence, under-representationin prospective clinicaltrials,scanty literature andlackof anevidence-based these patients remains achallenge dueto thefollowing reasons: presence of significant co-morbidities andfrailty, delayed access to care, above theage of 65 years [6]. The average life-expectancy inIndia is66.6 years for menand69.4 years for women [7].Management of response, shorter disease-free survival andoverall survival (OS)rates [2–5]inolder patients. ‘Elderly’ isdefined by the asanyoneWHO Diffuselarge B-cellfrequentmost is the (DLBCL) lymphoma subtype of lymphomaintheelderly [1].Numerous have studies describedlower Introduction 2 -

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 administeredtreatmentthe during and follow up. This cost-analysis was restricted to Group3, where thetreatment intention was essentially and costs of medications for management of other intercurrent illness. The bloodbankexpenses includedcosts of any component therapy 2020. The pharmacy costs costs include of allchemotherapy, immunotherapy, supportive treatments, antimicrobial therapy for infections management. These includedcosts duringhospitalisation andoutpatient treatment andfollow-uptill the date of auditanalysis, in March The hospitalcosts were calculated under theheaders of investigations, procedures, imaging,pharmacy, bloodbankservices andinfection Hospital costs and survival curves were compared usingthelog-rank test. validation of the cohort were gender, stage, IPI and previous co-morbidities. PFS data was computed by the Kaplan–Meier analysis method OS was calculatedfrom asthetime registration to thelast followor up death. The predictive covariates of survival analysed for internal Statistical analysis anthracycline) therapy. The DI was calculated asmg/m Dose intensity (DI) was calculated for patients receivedwho anthracycline-based or etoposide-based (in theCHOP like regimen, instead of and availability of multipleaffordable generic brands. responseInclusion(PR). of chemotherapyin the rituximab regimen increased over time with improvements inpatientaccess programmes, Advanced stage disease was treated six cycleswith of therapy followed by radiotherapy to thesite of initialbulky tumour or for partial as miniCHOP-R.Early-stage patientsreceived four cyclesof chemotherapy followed by radiotherapy, if they achieved anearly response. or (EPOCH-R)] adriamycin-Rituximabcyclophofamide, prednisolone,vincristine, therapy[etoposide, infusional as (CHOP+/−R), doses dard cytarabine basedtherapy orwith without brainwhole radiotherapy. Group3 received multiagentregimens anthracyclinewith instan- reportson echocardiography evaluationand/or prior significantcardiac history. Patients lymphomareceived CNS with methotrexate and adverse with patientsfor factor limiting a cardiotoxicityconsideredphysiciansas chemotherapy(CVP/CEOP+/−R, combinationwhen B-R) (steroids, cyclophosphamideand etoposide), along supportivewith care inthefrail elderly patients. Group2 received non-anthracycline given to patients > 2atPS with presentation,and advanced highLDH stage disease. The Group1 received low doseoral chemotherapy feasibilitying onfinancial of thepatient. Pre-phasechemotherapy steroidswith aloneor with cyclophosphamide and vincristine (CVP) was social support. Treatment decisions were physician determined asina‘real-world’ situation andRituximab was addedto theregimen depend- In elderly DLBCL patients,choicethe of therapy was dependenton thepatient’s general condition, co-morbidities, financialconstraints and Treatment, response andsafety Reasons for death have beenclassifiedinto three groups asfollows: progressive disease(PD), treatment toxicity andother causes. is reportedFollow-up intheaudit. information of eachpatient was obtained from theEMRrecords, or by contacting thepatient or family. was calculated forpatient each [11].Responseassessments were donemidcycle and at theendof treatment. The endof treatment response (0–1 ori.e., PS >1), Ann Arbor stage (localised versusextensive), extranodal site (0,1 versus(normal 2)andLDH versus upper normal value) level <3.5gm/dL. Theoff cut for haemoglobin was 10gm/dL. The International prognostic index (IPI)onthebasisof thefollowing criteria, recorded were absolute bloodcounts,creatinine, and lactatealbumin dehydrogenase Hypoalbuminaemia (LDH). was defined asanalbumin (CSF)fluid cytology atdiagnosis was donefor patients high riskofwith central nervous system (CNS) involvement.Laboratory test results phy-computerized tomography (PET-CT) or CT imaging of the thorax and abdomen along with bone marrow biopsy was done. Cerebrospinal done atbaseline for allpatients, andatinterim/end of treatmentpatients.in most As partof stagingevaluation, positron emissiontomogra- weight loss(>10%of body weight in6months) and Ann Arbor stage. Pre-existing co-morbidities were alsorecorded. Echocardiography was Clinical variables recorded fromage,included EMR the gender, Eastern co-operative oncology groupperformance status fever (PS), (>38.6°C), tion (physical/telephonic) after progression were considered deceased. talisation and reported in the EMR were analysed. Patients in remission were censored at last follow-up. Patients with no follow-upinforma - Cancer Institute-sponsored International Working Groupcriteria establishedin1999[12]. Treatment-related toxic effects leadingto hospi- Nationalefficacy the dose. ofaccordingThetreatment to planned assessed was <80% and 80%, ≥ forcalculatedDI (PFS) survivalfreewas 2 /week of adriamycin (or etoposide) andcyclophosphamide. Impact onprogression 3

Clinical Study CHOP+/−R, miniCHOP+/−R andEPOCH-R. curative. The mediancosts were calculated separately for private and subsidised categorythe of patients, and therapeutic subgroups of ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 bidity records were available, hypertension was thecommonestco-morbidity in 89(71%),followed by diabetes in60(48%),hypothyroidism Dataavailable andrecordedshowedEMR inthe oneor more co-morbidities in125patients (58%).In thecohort of patients where co-mor Co-morbidities and significant pattern, as shown inFigures 3aandb. CI: 37.0–83.0),respectively (p<0.0001),asshownin Figure 2c. Thefor median OS the treatment groups1, 2 and 3 was 3 months (95%CI:1.0–7.0), 14 months (95% CI:11.0–29.0)and83months (95% 49 patients who received a DI ≥ 80%, and 42 months in 85 patients who received DI of <80% (95% CI: 16.0–58.0), respectively (p =0.1388). months (95%CI:5.0–20.0)for those who didnot receive Rituximab (p<0.0001),asshown in Figure. 2b The medianPFS was not reached in anthracycline basedtherapy (p<0.0001). The medianPFS for patients receiving Rituximab was 47months (95%CI:25.0–58.0) and7.9 median PFS for patients receiving anthracycline was not reached as compared to 10 months (CI: 4.9–20.0) in patients who did not receive and 3are 1monthCI: 0.0–44.0),20months(95% CI: 6.1–25.0)andnot(95% reached, respectively (p<0.0001)asshown in Figure 2a.The The 5-year PFSfor entire the cohort(Figureis 41% 1a constraintsin seven patients;undetermined forcause early discontinuation infour andcontinuation of treatmentelsewhere infour patients. tumour lysis inoneeach);severe morbidity leadingto early cessation of treatmentin five patients; treatment discontinuation dueto financial be evaluated for response. This wasto due early treatment-related mortality inseven patients (Infections infive patients, haemorrhage and ment.Progression ontreatment wasin groupsand 8% 18% seenin37%, 1,2and3,respectively. Twenty-seven (14%)patients could not 7%, 72%and81%,respectively. The CRrates were 3.5%,47%and68%,respectively. Thirty-one patients (14.6%)hadPDonfirst linetreat - patientsafterdisease in8(4%), in 31(15%)andstable (54%), PR first linechemotherapy. The ORrates for treatmentGroups 1,2and3 were (2011–2013) of thisstudy. This increased to 90%of thepatients inthe years following 2013.Complete response (CR) was observed in115 treatmentsaccording topredefined the subgroups in is summarised Eight patients did not receive further therapy. Patients received a median of six cycles (range: 0–6) of chemotherapy. The ofdistribution Pre-phasechemotherapy was administered in114patients (53%)to stabilisethepatient(s) prior to theplannedchemotherapy protocol. Treatment efficacy nodal presentation didnot impactthe OS.GCBsubtype Data from age, stage, extranodal site and IPI were well validated for OS, as shown in patients (28%)andanendof treatment PET was donein89(41%). The remaining patients hadevaluation done with CT scans. row biopsy was available in129(60%)andCSF cytology in17(8%). A repeat PET scanfor treatment mid response evaluation was donein60 Staging evaluation by PET-CT was available in 57 patients (27%),and CT thorax and abdomen in the remaining. Information from bone mar available for 144patients: 47 were GCB(32%)and97non-GCB(67%). of cyclin D1positive,rich and plasmablastic T-cell richB-cell lymphoma. The cell of origin(COO) onblockreview (by Hans-algorithm) was included tourinaryand others(7%) CNS bone (9.5%), (12.5%), (15.5%),lung (para-vertebral, breast,soft tissue, etc.). DLBCL subtypes onmorphology and 2), 37% with low IPI and 49% with nodal disease. The common extra nodal sites were gastro-intestinal (29%), head & neck (16.5%), geni- was 2.5:1. The medianduration of symptoms was 3months (range: 15days to 18months) 38%patientswith presenting with early stage (1 Thecharacteristics clinical of elderly DLBCL patients are in summarised Results de novo DLBCL in178,highgrade DLBCL in23,transformed follicular or low-grade lymphomain6,Grey zone in3andoneeach ), the 5-yearwhile OSis44%(Figure 1b hadamediansurvival of 29months subtype andnon-GCB 14months. IPI was prognostic for survival outcomes, both OSand PFS, inanexpected Table 3.Only 50%of thepatients received Rituximab intheinitialperiod Table 1. The medianage was 71 years for thecohort. The gender ratio Table 2. While age, stage and IPI had an impact, extra- ). The medianPFS for treatment groups 1,2 4 - -

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 BSC, Best supportive care; PCNSL,Primary central nervous system lymphoma;COO, Cell of origin a Table 1.Clinicalcharacteristics of the212DLBCL patients at presentation. Missing data IPI score Haemoglobin 4 3 2 Stage: 1 Female Other: soft tissue Non-GCB GCB COO subtype #144 Gender: male Albumin PCNSL >Normal ≥75 ≥10.0 gm/dL Bone Normal <75 Age median(range) <10.0 gm/dL Lung <3.5 gm/dL (range) Low-intermediate Genitourinary LDH High-intermediate Head andneck Sites: >1 High 61 Extranodal a : median(range) gastrointestinal a a : median : low : nil a : median(range) 703 (192–12,978) 11.3 (4.7–15.7) 71 (65–95) (2.0–5.0) Number # 212 151 178 166 147 105 3.8 73 59 49 31 61 12 97 47 65 12 30 44 16 70 31 43 20 73 21 38 25 53 82 9 Percent 12.5 15.5 16.5 35 9.5 9.5 34 28 23 15 29 67 32 71 85 31 79 15 69 21 16 21 34 29 12 26 38 49 7 885 (368–4,291) Oral therapy or 10.6 (7.0–15.7) 75 (67–95) BSC #27 (2.1–4.4) 3.4 10 17 19 21 14 21 13 12 10 15 7 5 5 8 1 1 3 1 1 6 2 2 2 3 1 8 5 2 5 Non-anthracycline 668 (360–3,456) 11.7 (6.7–15.4) 72 (65–89) (2.0–5.0) # 61 3.9 19 29 47 18 13 11 14 11 55 17 50 44 16 15 26 24 32 16 1 5 3 7 9 5 4 7 9 4 3 Anthracycline based 647 (192–12,978) 11.1 (4.7–15.6) 70 (65–87) (2.1–4.8) # 124 102 3.7 44 10 51 85 34 31 15 39 35 34 95 22 90 29 14 22 11 42 25 46 27 20 41 58 32 1 8 9 5

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 Table 2.Outcomes of theelderly DLBCL patients. IV III II I Stage ≥75 years <75 years Age group OS High High-intermediate Low-intermediate Low IPI High High-intermediate Low-intermediate Low IPI PFS Yes No Co-morbidities Non-GCB GCB COO No Yes Extranodal site <80% ≥80% DI Overall Yes No Rituximab Overall Yes No Anthracycline basedtherapy Overall based 3. Anthracycline 2. Non-anthracycline 1. Oral therapy &BSC Treatment groups Median 17.0 15.0 27.0 10.0 45.0 10.0 15.0 33.0 17.0 49.0 14.0 29.0 14.0 29.0 42.0 33.0 47.0 34.7 10.0 33.0 20.0 7.9 1.0 NR NR NR NR NR 11 18 42 — 95% confidence interval 18.000–45.000 10.000–49.000 10.000–83.000 13.000–29.000 11.000–45.000 14.000–49.000 10.000–33.000 14.000–29.000 11.000–83.000 14.000–45.000 11.000–83.000 14.000–49.000 20.000–58.000 25.000–58.000 21.900–58.000 20.000–58.000 19.000–44.000 16.000–58.000 6.000–83.000 6.000–15.000 5.000–20.000 4.900–20.000 6.100–25.000 0.000–44.000 3.600–33.000 7.000–58.000 — — — — — — p =0.0005 p =0.7008 p =0.0007 p =0.1266 p =0.0910 p =0.2368 p =0.0023 p <0.0001 p <0.0001 p =0.0107 p =0.1388 p value 6

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 hospitalisation) andchanges inmedication dueto complications were analysed. Eighty-six patients (40%) were for hospitalised grade 3or 4 There was paucity of information regarding grade 1–2toxicity intheEMR.In thisbackground, only theseriousadverse events (requiring Complications HIV inone. The co-morbidity status of thepatient didnot have animpactontheoutcomes, asshown in available in159patients. Hepatitis Bsurface Antigen (HBsAg) reactive status was observed ineight patients, HCV infive andaconfirmed in 16(12%),chronic obstructive lungdiseasein13(10%)andischaemicheart33(26%).Blood borne virus screening reports were Figure 1.(a): PFS for Elderly DLBCL patients. (b): OS for theelderly DLBCL patients. Table 3. da EPOCH-R#12 CHOP+/−R, #76 miniCHOP+/−R, #36 Group 3#124 Anthracycline based MVP+/−R #5 CVP+/−R, #9 CEOP+/−R #39 Bendamustine-Rituximab, #8 Group 2#61 Non-anthracycline Others #10(Steroids SA Rituximab, RT) CEPP/PEP-C, #17 Group 1#27 Palliative therapy Treatment groups Response rates after first linetreatment for 212elderly DLBCL patients. (a) #115 (54%) CR 54 24 85 21 29 7 4 1 3 0 1 1 #31 (14.5%) PR 16 15 2 8 6 0 3 9 3 0 1 1 Stable disease # 8(4%) 0 2 1 3 0 2 3 5 # 31(14.5%) PD 10 11 10 (b) 1 6 3 1 0 8 2 2 8 Table 2. Non-evaluable # 27(12%) 10 10 0 5 1 0 6 2 6 2 6 4 7

Clinical Study Figure 2.(a): PFS for thethree treatment groups. (b): PFS intheRituximab andno-Rituximab groups. (c): OSfor thethree treatment groups. ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 blastine was recorded infour patients. two andacute myocardial infarct in two. Peripheral neuropathy grade 3,requiring drug withhold and/or replacement of vincristine to vin- interventionfor intestinaland perforation. obstruction Four patients developeddisease, ischaemicheart with congestive cardiac failure in four patients (one at thetracheostomy site andthreehaemorrhage) gastric and were managed conservatively. Two patients required surgical intestinalresulted obstruction inhospitalisation ineight patients, hyponatraemia inthree andtumour lysis inone.Haemorrhage occurred in tract infection in 4 and Cytomegalovirus, Herpes zoster, Hepatitis and acute cholecystitis in 1 patient each. Vincristine induced subacute nia wascommonest the ofcause hospitalisation(n =29)followed by respiratory tract infection in12,gastrointestinal infection in4,urinary toxicity. Nine (12%)patients weremore hospitalised thanonce. The mediandays of hospitalisation were 6(range: 1–40).Febrile neutrope- (a) (c) (b) 8

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 alternative lower-intensity regimens,accompanied by appropriate supportive measures andfrequent toxicity monitoring canbemore than nor3-year the (69% OS versusdiffers72%) respective inthe treatment arms.In the very elderly, thefrail or inthoseunfit for R-CHOP-21, studyLNH03-6B compared R-CHOP-21and R-CHOP-14 the role of sixor eight cycles of CHOP-14 or R-CHOP-14. Outcomes were not better for eight cycles of chemotherapy [26].Further, the and 27.6%,respectively. Deaths dueto second cancers, late relapses andother causes wereRicover-60 comparable [25].The Trialexamined eightcycles of R-CHOP or CHOP therapy. The CRrates were 76%and63%, with a10-year PFS of 36.5%and20%, and10-year OSat 43.5% nied by appropriate supportive care [15,24].In theGELA study, treatment naïve DLBCL patients, aged 60–80 were randomised to receive In thelasttwo decades, R-CHOP administered every 3 weeks has been established as the standard-of-care for older fit patients, accompa- has beendemonstrated earlier inolder patients [23]. and mortality fromintercurrent illnesses [19–22]. The feasibility of delivering fulldoseCHOP therapy with myeloid growth factor support of patientsreceiving standard doseanthracycline-basedchemotherapy were similar to younger patients associated but with higher toxicities 40% inthoseover 75 years of age. Median remission duration was 16months andcure rates were intherange of 25%–30%. The outcomes In thetreatment ofCR rates DLBCL, reported CHOPwith chemotherapy intheolder patients have been50%inthoseaged 65–75 years, and Discussion 322,500 ($4300)andRs 422,500($5600),bloodproducts andinfection management costs were Rs 20,000($250)and Rs 66,500($850). tive mediancosts of investigation (procedure andimagingincluded) were Rs 158,875($2200)andRs 385,810($5000),Pharmacy costs Rs account of bloodproductsand infection management were Rs 15,000($200). Among patients receiving miniCHOP therespec andEPOCH, investigations inclusive of procedures andimaging was Rs 80,000($1000),pharmacy costs Rs 138,900($2000)andsupportive care costs on accounted for Rs 20,000 ($ 250), from diagnosis to the lastfollow In up. patients who received standard therapy with CHOP, the cost of Ingroup, thesame themedianexpenditure onpharmacy costs was Rs 181,500($2500), while Blood bankandinfection management costs In thegroup3 patient cohort, themedianexpenditure oninvestigations, procedures andimagingservices combined was Rs 109,500($1500). Hospital costs Figure 3.(a): IPIandPFS. (b): IPIandOS. (a) [27]. Ata medianfollow of up 56months, neither the 3-year PFS (60% versus 62%) (b) 9 -

Clinical Study under-emphasised. Continuous assessment duringthecourse of treatment andfollowhas apositive up impactonoverall outcomes [36]. portive care interventions for symptom control and improvement of physical, emotional, and cognitive function amongelderly cannot be Robustsingle domaingeriatric assessment tools andMobile healthtechnology may provide potential [37,38]. solutions The role of sup ability of aneasy-to-usetool,and quick especially incentres adedicatedwithout geriatrician or ageriatric care service, remains achallenge. for allpatients. CGA isnow increasingly considered anessential tool indetermining treatment pathways for elderlyavail patients- [36].The therapy,of use pre-phasetherapy of anduse ageappropriate andfitness treatment regimens basedonamulti-disciplinary team discussion co-morbidityassessment, andPS cross-consultation specialitywith colleagues regarding comorbidity status prior to thestartof definitive DLBCL patients at our centre. This hasenabledusto streamline thecare of elderly patients by adopting thefollowing approaches: careful This retrospective studyto enabledus understandmagnitude oftrue the thechallenges we experience with themanagement of elderly fitness andmobility are significant determinants of outcomes. outcomes in this setting [35] . In an out-of-pocket healthcare system, socio-economic dependence on other earning family members, overall economicreasons. Access to healthcare, good supportive care (includingintensive care), good andaffordability nutrition broadly determine Patients labelledas‘second opinion-seekers’ could potentially belongto agroup which lacktheability to pursue treatment for socialand supportive care requirements duringtreatment andhigher hospitalisation rate for adverse event management. very elderly patientstreated miniCHOP.with These patientsneeded more frequent interventions ascentral such lineinsertions,increased penia andinfection. This was especially seeninpatients treated regimenwith EPOCH for highgrade andadvanced stage DLBCLs, andinthe regimens, adverse events requiring hospitalisation were also high(40%). The mostcommon causes for hospitalisation were Febrile neutro- anthracycline basedregimen significantly improved CR,PFS andOS. Though highresponse rates were observed with anthracycline based survivors. Mostpatients groupsin the 2 and3received curative treatment. The availability of generic [31]anditsadditionto rituximab an and advanced disease were treated with oral chemotherapy or steroid monotherapy, and the response rate was 7% with no long-term neutropenia duration,tumour lysis andtherapy associated mortality with R-CHOP therapy [32].In group1, patients with poor performance ment’ with prednisolone for 7days aloneor with 1 mg vincristine which decreases thefirst cycle effects of deepneutrophil nadir, longer Fifty-three percent (53%)patients received someform of pre-phase therapy. In practice, many centres administer aninitial‘pre-phase treat- the FIL Criteria [33]. A malereferral biasinour dataset isconsistent with experience from other Indian tertiary care[34]. hospitals dedicated speciality servicesituations. inmost A more realisticscale wouldbe PS,age, comorbidities andaneasier-to-use scoring system like comprehensiveapplying CGAin abusy scales centre. They are consuming, time require caregivers andphysicians to enter information anda determined predominantly by eyeballing,assessment, PS comorbidity review andcliniciangroupdecisions. This highlights theconstraints of profilethat presents to atertiary care centre inamiddle-income Asian country. A CGA at diagnosis was not undertaken, andfrailty was sification for subtypingDLBCL was available in 144 patients, of which 67% had a non-GCB subtype and 32% GCB. This reflects the disease stage IIIor IV disease,51%demonstrated extra-nodal diseaseandover 60%hadaprognostic score of high-intermediate or high.COO clas- In our study 212 with patients and a median age of 71 years, 58% (n = 125) presented with one or more comorbidities, 63% presented with with afavourable toxicity profile [31,32]. or etoposide [28–30]. The BendamustineRituximab combination hasbeenexamined insmallseriesandhasdemonstrated anORof 69% doxorubicin,liposomal and include Rmini-CHOP, infusionalregimens, R-CVP or replacement of Adriamycin with mitoxantrone, gemcitabine palliative in outcomes, and could potentiallyquality/quantity add meaningful of life. These approaches have been explored in phase 2 trials ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 No relevant funding. Funding desirable outcomes. The care of theelderly remains achallenge indeveloping economies. of the elderly patient needs close attention to medical, socio-economic, and emotional in ordersupport to complete treatment and achieve DLBCL isacurable diseaseintheelderly byage using andcomorbidity appropriate treatments with chemo-immunotherapy. Management Conclusions 10 -

Clinical Study ecancer 2021, 15:1242; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1242 References Not applicable. Consent for publication Notwaived.applicable, Consent to participate Institutional Review Board (Ethics Committee) waiver. Retrospective study with nopatient personal identifiers. Ethics approval the manuscript. Manuscript finalisedby RNand VSR. NAIA, ZL, contributed andDM to laboratoryand edited studies themanuscript. VSR,DD, RN, SB, NA, DM, IA,ZL, RAJK, reviewed andMC acquisition was undertaken by CS, and costing data by PM. Data analysis was undertaken by RN, and literature search by VSR and RN. DD, conceivedRN andleadtheidea.RN, VSRand CS wrote themanuscript, contributed to thedesign andeditingthemanuscript. Patient data Authors’ contributions Not applicable. Code availability (software application or custom code) Yes, onareasonable request to thecorresponding author. Availability of data andmaterial (data transparency) work. Other authors declare norelevant conflicts of interest respectwith to thesubmitted work. personal feesfrom (institutional) ASTRA ZENECA, from support institutional non-financial Dr Reddy's Laboratories, thesubmitted outside grantsinstitutional fromgrantsinstitutional BMS, from support andnon-financial CIPLA Pharmaceuticals, grants institutional from EMCURE, fromsupport and non-financial INTAS Pharmaceuticals, grantsinstitutional from NATCO Pharmaceuticals, grants institutional from ROCHE, and Dr Reddy’s Laboratory. VSRreports advisory fees from support andnon-financialinstitutional (institutional) grants institutional PFIZER, has receivedRN researchgrants, advisory board fees as well asSpeaker fee from Cipla,Fresenius Kabi, Johnson and Johnson, Mylan, Novartis Conflicts of interest/competing interests 1. org/10.1053/j.seminoncol.2003.12.024 PMID: Yancikand RiesR LA (2004)Cancer inolderinternationalan persons: issueinanaging world 15112144 Semin Oncol 31(2) 128–136https://doi. 11

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Clinical Study