INTERVENTION:

Product Name: acalabrutinib Product Code: ACP‐196 Pharmaceutical Form: Capsule, hard INN or Proposed

INN:

ACALABRUTINIB CAS Number: 1420477‐60‐6 Current Sponsor code: ACP‐196 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Trade Name: Gazyvaro Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

INN:

obinutuzumab CAS Number: 949142‐50‐1 Other descriptive name: OBINUTUZUMAB Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1000‐ Trade Name: MABTHERA Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

INN:

RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐ Trade Name: Endoxan Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed

INN:

CYCLOPHOSPHAMIDE CAS Number: 50‐18‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐ Trade Name: Fludarabine Pharmaceutical Form: Concentrate for solution for injection/infusion INN or Proposed

INN:

FLUDARABINE PHOSPHATE CAS Number: 75607‐67‐9 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Trade Name: Venclyxto Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

VENETOCLAX CONDITION:

Previously untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation ; MedDRA version: 21.0 Level: LLT Classification code 10009310 Term: CLL System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04]

SECONDARY OUTCOME:

; Secondary end point(s): 1.Progression‐free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment, respectively. ; 2. Event‐free survival (EFS), defined as the time from randomization to the first occurrence of disease progression, initiation of subsequent anti‐CLL therapy, or death from any cause per IRC assessment and the investigator assessment, respectively. ; 3.Objective response rate (ORR), defined as the proportion of subjects with a CR, CRi, or PR per the investigator or and IRC assessment, respectively as per IWCLL 2018 criteria at or before initiation of subsequent anticancer therapy. ; 4.Duration of objective response (DOR), defined as the time from the first documentation of objective response to the earlier time of disease progression (assessed by the investigator and IRC, respectively, per IWCLL 2018 criteria) or death from any cause. ; 5.Time to next treatment (TTNT), defined as the time from randomization to institution of non‐protocol specified treatment for chronic lymphocytic leukemia (CLL). ; 6.Overall survival (OS), defined as the time from randomization to death from any cause. ; Final analysis: 64 months after the first subject is randomized;

INCLUSION CRITERIA:

1. Men and women =18 years of age.

PRIMARY OUTCOME:

; Main Objective: To evaluate the efficacy of acalabrutinib/venetoclax (AV; Arm A) compared with chemoimmunotherapy; (fludarabine/cyclophosphamide/rituximab [FCR]/ bendamustine/rituximab [BR]; Arm C); ; Secondary Objective: To evaluate the efficacy of acalabrutinib/venetoclax/obinutuzumab (AVG; Arm B) versus FCR/BR (Arm C); ; To evaluate the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B) versus FCR/BR (Arm C); ; Timepoint(s) of evaluation of this end point: Interim analysis: 42 months after the first subject is randomized; Final analysis: 64 months after the first subject is randomized; Primary end point(s): Progression‐free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria. ; 7.Minimal residual disease (MRD) negativity rate (determined as the proportion of subjects with MRD‐negativity) measured in the peripheral blood by flow cytometry at the start of Cycle 9 (in Arm A), the start of Cycle 10 (in Arm B), and 12 weeks after the start of Cycle 6 (in Arm C).; ; Timepoint(s) of evaluation of this end point: Interim analysis: 42 months after the first subject is randomized 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 3. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018): Monoclonal B‐cells (either kappa or lambda light chain restricted) that are clonally co‐expressing B‐cell marker (CD19, CD20, and CD23) and CD5. Prolymphocytes may comprise <55% of blood lymphocytes. Presence of =5x109 B lymphocytes/L (5000/µL) in the peripheral blood (at any point since the initial diagnosis). 4. Active disease per IWCLL 2018 criteria that requires treatment (see Section 4.5.6). 5. Meet the following laboratory parameters: a) Adequate bone marrow function independent of growth factor or transfusion support within 1 week of Screening, as follows: i.ANC =750 cells

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INTERVENTION:

Product Name: pinatuzumab vedotin Product Code: DCDT2980S Pharmaceutical Form: Powder for infusion INN or Proposed

INN:

pinatuzumab vedotin Other descriptive name: DCDT2980S Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: polatuzumab vedotin Product Code: DCDS4501A Pharmaceutical Form: Solution for infusion INN or Proposed

INN:

polatuzumab vedotin Other descriptive name: DCDS4501A Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Trade Name: Mabthera Product Name: . Product Code: . Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

INN:

RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Trade Name: Gazyvaro Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

INN:

obinutuzumab CAS Number: 949142‐50‐1 Other descriptive name: OBINUTUZUMAB Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1000‐

CONDITION:

Follicular Non‐Hodgkin’s Lymphoma (FL); Diffuse Large B‐Cell Lymphoma (DLBCL) ; MedDRA version: 18.0 Level: LLT Classification code 10012857 Term: Diffuse large cell lymphoma (Diffuse large B‐cell lymphoma) (Working Formulation) refractory System Organ Class: 100000004864 ; MedDRA version: 18.0 Level: LLT Classification code 10012855 Term: Diffuse large cell lymphoma (Diffuse large B‐cell lymphoma) (Working Formulation) System Organ Class: 100000004864 ; MedDRA version: 18.0 Level: LLT Classification code 10012856 Term: Diffuse large cell lymphoma (Diffuse large B‐cell lymphoma) (Working Formulation) recurrent System Organ Class: 100000004864 ; MedDRA version: 18.0 Level: LLT Classification code 10067070 Term: Follicular B‐cell non‐Hodgkin's lymphoma System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04]

SECONDARY OUTCOME:

Secondary end point(s): Safety ; 1. Incidence of anti‐therapeutic antibodies (ATAs) against DCDT2980S and DCDS4501A or obinutuzumab; ; ; Activity Outcome measures for obinutuzumab ‐containing arms/cohorts ; 2. Objective response (OR; CR or partial response [PR]) at end of treatment based on PET alone as determined by the investigator and IRC) ; 3. CR at end of treatment based on computed tomography (CT) only, as determined by the investigator and IRC ; 4. OR (CR or PR) at end of treatment based on CT only as determined by the investigator and IRC ; 5. Best objective response (BOR; CR or PR) while on study based on PET alone or CT only, as determined by the investigator ; ; Pharmacokinetics ; 6. Total exposure (area under the concentration‐time curve [AUC]), maximum plasma and serum concentration (Cmax), clearance (CL), terminal half‐life (t1/2), volume of distribution at steady state (Vss) ; Timepoint(s) of evaluation of this end point: 1: Up to 6 months after treatment completion visit for rituximab‐containing cohorts; up to 24 months after treatment completion visit for obinutuzumab‐containing cohorts ; 2‐5: Up to 24 months ; 6: Up to approximately 1 year; up to 18 months for obinutuzumab‐containing cohorts ;

INCLUSION CRITERIA:

‐ Life expectancy of at least 12 weeks; ‐ Age > or = 18 years; ‐ History of histologically documented relapsed or refractory Grades 1‐3a FL, or relapsed or refractory DLBCL; ‐ Must have at least one bi‐dimensionally measurable lesion; ‐ Adequate hepatic, renal and cardiopulmonary function;

PRIMARY OUTCOME:

Main Objective: Safety, tolerability and anti‐tumor activity of DCDT2980S combined with rituximab and DCDS4501A combined with rituximab or obinutuzumab Primary end point(s): Safety; 1. Incidence of adverse events;; 2. Nature of adverse events;; 3. Severity of adverse events;; ; Activity Outcome measures for rituximab‐containing arms/cohorts; 4. Objective response rate;; 5. Duration of response;; ; Activity Outcome measures for obinutuzumab ‐containing arms/cohorts; 6. Complete response (CR) at end of treatment (6‐8 weeks after Cycle 6 Day 1 or last dose of study medication) based on positron emission topography (PET) alone, as determined by the Institutional Review Committee (IRC); Secondary Objective: Incidence of anti‐therapeutic antibodies (ATA) against DCDT2980S, DCDS4501A and obinutuzumab; comparison of the anti‐tumor activity of DCDT2980S combined rituximab and DCDS4501A combined with rituximab or obinutuzumab; pharmacokinetics of DCDT2980S combined with rituximab and DCDS4501A combined rituximab or obinutuzumab Timepoint(s) of evaluation of this end point: 1‐3: Up to 12 months for rituximab‐containing cohorts; up to 24 months for obinutuzumab‐containing cohorts; 4‐5: Up to 12 months; 6: Up to 24 months; ‐ For all men and women of childbearing potential use of adequate methods of contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 61 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 185

Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.

Introduction: Several targeted agents have been introduced for CLL, including the CD20-antibody obinutuzumab (GA101, G) and the Bcl-2 antagonist venetoclax (ABT-1 99, A). Both agents show exciting efficacy which comes at the cost of an increased risk of TLS and IRRs and mandate several safety precautions especially during the first treatment cycles and in patients (pts) with a higher tumor load and/or renal insufficiency. Based on the theoretical "sequential triple-T" concept [Hallek M., Blood 2013; 122(23): 3723-34] of a tailored and targeted treatment aiming for total eradication of minimal residual disease (MRD), the GCLLSG designed the CLL2-BAG trial combining G and A in an induction and maintenance treatment. To reduce the risk of TLS and IRRs, G and A were started sequentially during the induction phase and patients with high tumor burden received bendamustine (B) as a debulking step before the induction treatment. Methods: This prospective, open-label, multicenter phase-II trial investigates the safety and efficacy of a sequential treatment with B, G and A in an all-comer population of physically fit and unfit, treatment-naïve and relapsed/refractory CLL pts requiring treatment, irrespective of high-risk genetics. Pts with an absolute lymphocyte count (ALC) ≥ 25.000/μ l and/or lymph nodes (LN) ≥ 5cm received 2 cycles of B as debulking treatment (70mg/m d1&2 q28 days). In the induction G was administered 3 times in cycle 1 (days 1/2, 8 & 15) and every 4 weeks in cycles 2-6. Daily intake of A started in cycle 2 with a slow dose ramp-up over 5 weeks and several safety precautions including blood sampling, hydration, allopurinol and rasburicase (depending on patient's TLS risk category). In the maintenance phase, A was continued and G administered every 3 months until achievement of a MRD-negative complete response or for up to 24 months. The primary endpoint was the overall response rate (ORR) at the end of induction therapy; secondary endpoints include safety parameters, MRD evaluations and survival parameters. Results: Between May 2015 and January 2016, 66 pts were enrolled, among them 35 with treatment naïve and 31 with relapsed/refractory CLL (median number of prior therapies: 2, range: 1-8). Median age was 59 (28-77) years and the median CIRS score was 2 (0-14). 12 of 48 pts (25%) had an impaired renal function at baseline with a creatinine clearance of 30-70ml/min. 11 of 62 pts (18%) had a del(17p) and 48 of 64 (75%) had an unmutated IGHV status. 47 (71%) pts received B debulking and 19 (29%) pts immediately started with G due to a low tumor burden (6), contraindications for B [known hypersensitivity or refractoriness] (4) and/or physicians decision (13). Median ALC was 52.3 (0.6-423.5) at baseline and 0.9 (0.2-102.0) after first induction cycle. Risk categories for TLS at baseline were: low (LR: ALC <25.000/μ l and LN <5cm): 9 pts (14%), intermediate (IR: ALC ≥ 25.000/μ l or LN 5-10cm): 37 (59%) and high risk (HR: ALC ≥ 25.000/μ l and LN 5-10cm or LN >10cm): 17 (27%), 3 missing. After debulking and/or 1st cycle with G risk categories were re-assessed in 19 pts and were LR in 13 (68%) and IR in 6 (32%) pts. As of July 20th2016, 76 serious adverse events (SAEs) were reported in 36 of the 66 pts, among them 64 (84%) related to study drug. 57 SAEs (75%) were CTC°3-4 and 3 deaths (septicaemias in heavily pretreated pts). So far 13 (17%) SAEs occurred during B debulking, 62 (82%) in the induction and 1 (1%) in the maintenance phase. Most common SAEs were infections (26 in 15 pts; among them 12 CTC°3-5) and hematological disorders (18 in 11 pts; 10 CTC°3-4); especially pneumonias (8 in 3 pts), sepsis (3 in 3 pts; all CTC°5) and neutropenias with/without fever (5 and 7 each; in 7 pts). Six serious IRRs occurred in 6 pts (4 CTC°3-4), 5 occurred during the first infusion of G; 3 of the affected pts had not received prior B. Five SAEs were laboratory TLS, which all resolved quickly; 1 occurred during the debulking with B and 4 during the induction therapy (1 in induction cycle 1 with G, 2 in cycle 3 and 1 in cycle 4 with G and A), all in pts without prior B debulking. Conclusion: The administration of B as a debulking step, followed by G helps to effectively reduce the patient's tumor load providing the ability to prevent serious IRRs and TLS. With this concept and the established safety precautions no clinical TLS occurred so far. Aside from 3 septicaemias with fatal outcome in heavily pretreated pts, the toxicity profile of this regimen is acceptable.

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INTERVENTION:

Product Name: Ublituximab Product Code: TG‐1101 Pharmaceutical Form: Solution for injection INN or Proposed

INN:

Ublituximab Current Sponsor code: TG‐1101 Other descriptive name: IgG1 immunoglobulins Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Product Name: TGR‐1202 Product Code: TGR‐1202 Pharmaceutical Form: Tablet INN or Proposed

INN:

TGR‐1202 Current Sponsor code: TGR‐1202 Other descriptive name: (S)‐2‐(1‐(4‐amino‐3‐(3‐fluoro‐4‐isopropoxyphenyl)‐1H‐pyrazolo [3, 4‐d] pyrimidin‐1‐yl)‐ethyl)‐6‐fluoro‐3‐(3‐fluorophenyl)‐4H‐chromen‐4‐one 4 methylbenzenesulfonate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Trade Name: Gazyvaro 1,000 mg concentrate for solution for infusion. Product Name: Gazyvaro 1,000 mg concentrate for solution for infusion. Product Code: Obinutuzumab Pharmaceutical Form: Solution for infusion INN or Proposed

INN:

Obinutuzumab CAS Number: 949142‐50‐1 Current Sponsor code: Obinutuzumab Other descriptive name: Obinutuzumab Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 25‐ Trade Name: Chlorambucil 2 mg tablets Product Name: Chlorambucil 2 mg tablets Product Code: Chlorambucil Pharmaceutical Form: Tablet INN or Proposed

INN:

Chlorambucil CAS Number: 305‐03‐3 Current Sponsor code: Chlorambucil Other descriptive name: Chlorambucil Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐

CONDITION:

Chronic Lymphocytic Leukemia ; MedDRA version: 19.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04]

PRIMARY OUTCOME:

Main Objective: To establish that the combination of ublituximab + TGR‐1202 is superior to the combination of obinutuzumab + chlorambucil as measured by Progression‐Free Survival (PFS) in patients with CLL Primary end point(s): Progression‐free survival (PFS); PFS is defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause.; Definitive disease progression based on standard criteria (Hallek et al. 2008) and occurring for any reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease‐related symptoms) other than lymphocytosis.; ; Overall response rate (ORR); ORR is defined as sum of CR and PR rates.; ; Complete Response (CR) Rate; CR rate is defined as the proportion of patients who achieve a CR.; ; Minimal Residual Disease (MRD) Negativity Rate; MRD negativity rate is defined as the proportion of patients who are MRD negative.; ; Duration of response (DOR); DOR is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. Secondary Objective: To establish that the combination of ublituximab + TGR‐1202 provides clinical benefit over both ublituximab alone and TGR‐1202 alone; To evaluate and compare the combination of ublituximab + TGR‐1202 to the combination of obinutuzumab + chlorambucil with respect to overall response rate in patients with CLL Timepoint(s) of evaluation of this end point: Each primary end points will be evaluated every three months

SECONDARY OUTCOME:

Secondary end point(s): Efficacy Timepoint(s) of evaluation of this end point: Efficacy will be evaluated every three months

INCLUSION CRITERIA:

1. B‐cell CLL (treatment naïve or previously treated) that warrants treatment consistent with accepted IWCLL criteria for initiation of therapy. Any of the following conditions constitute CLL that warrants treatment: a. Evidence of progressive marrow failure as manifested by the onset or worsening of anemia and/or thrombocytopenia, or b. Massive (i.e., lower edge of spleen = 6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or c. Massive (i.e., = 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or d. Progressive lymphocytosis in the absence of infection, with an increase in blood absolute lymphocyte count (ALC) >50% over a 2‐month period or lymphocyte doubling time of <6 months (as long as initial ALC was =30,000/L), or e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or f. Constitutional symptoms, defined as any one or mo

Introducción: Los pacientes con leucemia linfocítica crónica (LLC) de alto riesgo tienen tasas de respuesta más bajas, un curso clínico más agresivo y resistencia a la quimioterapia estándar, lo que representa un desafío para el tratamiento. En estos casos se pueden utilizar los inhibidores de la tirosina quinasa de Bruton (BTK - ibrutinib y acalabrutinib) y el inhibidor de BCL-2 (venetoclax). Objetivo:Identificar y evaluar estudios sobre la eficacia y seguridad del uso de ibrutinib, acalabrutinib y venetoclax en el tratamiento de primera línea en pacientes con LLC de alto riesgo. Método: Revisión sistemática de ensayos clínicos aleatorios que evaluaron pacientes adultos con LLC, portadores de deleción 17p o mutación TP53 y sin tratamiento previo. Se realizaron búsquedas en las bases de datos PubMed, EMBASE, LILACS y Cochrane Library y se evaluó el riesgo de sesgo mediante la herramienta Cochrane RoB 2 y la calidad de la evidencia se evaluó mediante GRADE. Resultados: En el metaanálisis en red para la supervivencia libre de progresión (SSP) venetoclax + obinutuzumab (RR: 0,62; IC 95% 0,41-0,95; valor de p 0,027) y acalabrutinib + obinutuzumab (RR: 0,74; IC 95%). 0,55-0,99; valor de p 0,043) presentaron un menor riesgo de progresión o muerte, con una significación considerada límite. Ibrutinib + obinutuzumab (RR: 0,93; IC del 95 %: 0,86-1,00; valor de p 0,054) no mostró una diferencia significativa en la SSP para pacientes con LLC de alto riesgo. Conclusión: El tratamiento de primera línea con inhibidores de BTK (ibrutinib y acalabrutinib) y el inhibidor de BCL-2 (venetoclax), asociados con agentes monoclonales anti-CD20, especialmente obinutuzumab, se ha propuesto como estándar para la mayoría de los pacientes con LLC. Sin embargo, según los resultados de esta revisión con metaanálisis en red, no fue posible confirmar esta recomendación

Effective new treatments are now available for patients with hematologic malignancies. However, their propensity to cause tumor lysis syndrome (TLS) has not been systematically examined. A literature search identified published Phase I-III clinical trials of monoclonal antibodies (otlertuzumab, brentuximab, obinutuzumab, ibritumomab, ofatumumab); tyrosine kinase inhibitors (alvocidib [flavopiridol], dinaciclib, ibrutinib, nilotinib, dasatinib, idelalisib, venetoclax [ABT-199]); proteasome inhibitors (oprozomib, carfilzomib); chimeric antigen receptor (CAR) T cells; and the proapoptotic agent lenalidomide. Abstracts from major congresses were also reviewed. Idelalisib and ofatumumab had no reported TLS. TLS incidence was ≤5 % with brentuximab vedotin (for anaplastic large-cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies). TLS incidences were 8.3 and 8.9 % in two trials of venetoclax (for chronic lymphocytic leukemia [CLL]) and 10 % in trials of CAR T cells (for B-cell malignancies) and obinutuzumab (for non-Hodgkin lymphoma). TLS rates of 15 % with dinaciclib and 42 and 53 % with alvocidib (with sequential cytarabine and mitoxantrone) were seen in trials of acute leukemias. TLS mitigation was employed routinely in clinical trials of alvocidib and lenalidomide. However, TLS mitigation strategies were not mentioned or stated only in general terms for many studies of other agents. The risk of TLS persists in the current era of novel and targeted therapy for hematologic malignancies and was seen to some extent with most agents. Our findings underscore the importance of continued awareness, risk assessment, and prevention to reduce this serious potential complication of effective anticancer therapy.

Background: A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL). Methods: We compared available therapies for treatment-naive, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis. Results: In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75. months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70. months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60. months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90. months for fludarabine, RClb, chlorambucil and GClb, respectively. Conclusions: Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS.