Clinical Characteristics, Treatment Pattern and Outcome of Histologic Transformed Lymphoma, a Single Institution Experience

Article Information

Bolanle Gbadamosi1*, Yifan Pang2, Daniel Ezekwudo1, David Macari1, John Khoury1, Anish Konde1, Nwabundo Anusim1, Michael Stender1, Ishmael Jaiyesimi1, Susanna Gaikazian1

1Department of Hematology and Oncology, Beaumont Hospital Oakland University School of Medicine, Royal Oak, MI, USA

2Department of Internal Medicine, Beaumont Hospital Oakland University School of Medicine, Royal Oak, MI, USA

*Corresponding Author: Dr. Bolanle Gbadamosi, Department of Hematology and Oncology, Beaumont Hospital Oakland University School of Medicine, Royal Oak, MI, USA

Received: 24 July 2019, Accepted: 05 August 2019, Published: 14 August 2019

Citation: Gbadamosi B, Pang Y, Ezekwudo D, Macari D, Khoury J, Konde A, Anusim N, Stender M, Jaiyesimi I, Gaikazian S. Clinical Characteristics, Treatment Pattern and Outcome of Histologic Transformed Lymphoma, A Single Institution Experience. Journal of Cancer Science and Clinical Therapeutics 3 (2019): 114-130

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Indolent lymphomas may transform into intermediate or high-grade lymphoma, a diagnosis that is usually made reached by tissue biopsy, with unfavorable prognosis. A retrospective study was performed of the clinical characteristics, treatment patterns and outcomes of 73 patients with histologic transformed lymphoma originating as follicular lymphoma (FL), chronic lymphocytic leukemia/small cell leukemia (CLL/SCL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), or low grade B cell lymphoma not otherwise specified (NOS). The median time to transformation was 55 months (range 1-258) and Diffuse Large B Cell Lymphoma (DLBCL) constituted the majority of HTL diagnosis diagnoses. There was a statistically significant longer time to the development of HTL in patients with CLL and LPL compared to other indolent lymphoma types (FL, MZL and low-grade B cell lymphoma NOS); however, overall survival (OS) at histologic transformation was similar regardless of the indolent lymphoma type preceding HTL. Treatment with Rituximab-containing regimens have increased overall survival in HTL compared with the pre-rituximab era. In the 63 treated cases of HTL, PET showed complete remission (CR) in the majority of patients (55%) with 15% achieving partial remission (PR) and 15% having progressive disease (PD). OS at two years was approximately 60%, and 41% of patients remained alive at 5 years. Univariate analysis identified that treatment with RCHOP conferred better OS when compared to regimens with less or greater intensity than RCHOP, p=0.001. Multivariate analysis confirmed that achievement of CR and LDH level within the normal range statistically predicted better OS. On-going clinical trials may suggest novel therapeutics and provide for more evidence-based management of HTL.


Lymphoma; Histological transformation; Chemotherapy; Overall survival; Rituximab; Clinical trials

Lymphoma articles, Histological transformation articles, Chemotherapy articles, Overall survival articles, Rituximab articles, Clinical trials articles

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Article Details

1. Introduction

Despite the known favorable prognosis of indolent lymphomas (IL), histologic transformation (HT) to intermediate or high-grade lymphoma is a potential and significant event. Histologic transformed lymphoma (HTL) is rarely an end point in trials of indolent lymphomas and most of the transformations are to Diffuse Large B Cell Lymphoma (DLBCL). The PRIMA trial reported a 4.1% risk of HTL at six years in follicular lymphoma patients with high tumor burden [1]; there is paucity of data on HT in other types of indolent lymphomas. Diagnosis of HTL is ideally made by tissue biopsy, cellular morphology and immunohistochemistry with or without cytogenetics [2]. Others have defined HTL using clinical criteria [3] such as rapid progression of adenopathy, laboratory abnormalities and/or new onset of constitutional symptoms. Radiographic evidence, especially positron emission tomography (PET) scan, may be used in situations where adequate tissue diagnosis is not feasible. Current information on and the management of HTL are mostly extrapolated from retrospective studies of HTL or from prospective trials of DLBCL, despite known heterogeneity of DLBCL and exclusion of HTL patients from most trials of DLBCL [4]. Our study aims to contribute to the existing literature on the clinical characteristics, treatment pattern and outcomes of patients with HTL.

2. Methods and Statistical Analysis

Electronic medical records at Beaumont Hospital were retrospectively queried for patients with a diagnosis of intermediate or high-grade non-Hodgkin’s lymphoma which includes DLBCL, Mantle cell lymphoma (MCL), Burkitt Lymphoma, or High-grade B cell lymphoma, type not otherwise specified (NOS) [5] from January 2007 to December 2015. This Study was approved by the William Beaumont Hospital Institutional Review Board and a waiver of individual informed consent was granted for this retrospective review. Patients having a tissue diagnosis of HTL were then identified for analysis. Baseline characteristics were reported as median (range) or mean (standard deviation) for continuous variables as appropriate, whereas categorical variables were reported as frequency (%). The Shapiro-Wilk test was used to assess the normality of continuous variables. Baseline characteristics of the different indolent lymphoma types were compared using the Kruskal-Wallis H-test for continuous data, and Chi-square test for categorical data. Survival was estimated using the Kaplan-Meier method. Univariate analysis of overall survival (OS) was performed with the log-rank test. A multivariate Cox proportional hazard model was constructed for OS using a limited backward elimination process. Candidate predictors for multivariate analysis were chosen to have a P < 0.20 in univariate analysis. The statistical significance level (P) was set at less than 0.05 for a two-tailed test. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) version 22.0.

3. Results

Among the 617 patients identified with a diagnosis of intermediate or high-grade non-Hodgkin’s lymphoma, 82 (13%) had pathologic diagnosis of HTL during the study period. Seventy-three patients had sufficient data to be included for analysis. Fifty-four of the 73 patients had diagnosis of HTL that was preceded by a period of indolent lymphoma diagnosis, while the remaining 19 patients were diagnosed with HTL based on tissue pathology showing intermediate or high-grade lymphoma at the same time as the initial diagnosis of indolent lymphoma. All patients had the tissue diagnosis confirmed by a hematopathologist.

The median age at diagnosis of HTL was 71 years (range 35-90); 34 (47%) patients were male and 39 (53%) were female. The majority of patients, 65 of 73 (89%), were Caucasian; 3 (4%) were African American and 5 (7%) were identified as other races. The types of indolent lymphoma diagnosed were: grade 1-2 follicular lymphoma (FL) in 33 patients (45%), Chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) in 17 patients (23%), marginal zone lymphoma (MZL) in 10 patients (14%), lymphoplasmacytic lymphoma (LPL) in 8 patients (11%), low grade B cell lymphoma NOS in 5 patients (7%). The median time to transformation was 55 months (range 1-258) in the fifty-four patients whose diagnosis of HTL had been preceded by a period of indolent lymphoma. DLBCL constituted the majority of HTL diagnoses 70 (96%); there were 2 (3%) cases of mantle cell lymphoma and 1 (1%) case of Burkitt lymphoma (Table 1).

Characteristic n =73
Male 34 (46.6)
Age, years* 71 (35, 90)
Time to HTL, months* 19 (0, 258)
Ki67, %* 72.5 (10, 95)
LDH, U/L* 281 (107, 5403)
Uric acid, mg/dL* 5.6 (2.0-11.3)
Albumin, g/dL* 3.8 (1.9, 4.7)
WBC, bil/L* 6.7 (0.9, 81.8)
Hb, g/dL* 11.6 (4.6, 71.5)
Plt, bil/L* 201 (13, 627)
Low grade lymphoma treatment  
Observation 17 (23.3)
Treatment 37 (50.7)
Concurrent diagnosis with HTL 19 (26.0)
HTL treatment  
RCHOP 43 (58.9)
Rituximab + Bendamustine (BR) 4 (5.5)
Rituximab + Reduced Dose CHOP (R-mini-CHOP) 4 (5.5)
Rituximab + Cyclophosphamide, Vincristine,
and Prednisone (R-CVP)
1 (1.4)
Rituximab only 1 (1.4)
Splenectomy only 1 (1.4)
RCHOP + high dose therapy followed by
 autologous stem cell transplant (HDT-ASCT)
1 (1.4)
Rituximab, Ifosfomide, Cyclophosphamide and
 Etoposide (R-ICE)
4 (5.5)
Rituximab, Etoposide, Prednisolone, Vincristine,
Cyclophosphamide, Doxorubicin (R-EPOCH)
1 (1.4)
Rituximab, hyper fractionated Cyclophosphamide,
Vincristine, Doxorubicin and Dexamethasone
alternating with high dose methotrexate
2 (2.7)
Rituximab + high dose methotrexate 1 (1.4)
Supportive only 8 (11.0)
Unknown 2 (2.7)
HTL response to treatment (n=63)  
CR 40 (54.8)
PR 11 (15.1)
PD 11 (15.1)
Unknown 1 (1.4)
Data are presented as n (%) or *median (range). Abbreviations: HTL, histologically transformed lymphoma; LDH,
 lactate dehydrogenase; WBC, white blood cell count; Hb, hemoglobin; PLT, platelet count; R-CHOP, Rituximab,
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone; CR, complete remission; PR, partial response; PD,
progressive disease.

Table 1: Baseline characteristics of patients with histologically transformed lymphoma.

Among the 54 patients in whom diagnosis of indolent lymphoma preceded diagnosis of HTL, management of indolent lymphoma was by observation only in 17 (31.5%) patients and active treatment was prescribed for the remaining 37 (68.5%) patients (Table 1). Treatment strategies included: Rituximab only in 2 (3.7%) patients, 1-4 lines of a rituximab-containing regimen in 22 (40.7%) patients that included Bendamustine (BR); Fludarabine (FR); Fludarabine and Cyclophosphamide (FCR); or Chlorambucil (CR), Cyclophosphamide, Vincristine, and Prednisone (RCVP); non- rituximab containing systemic therapy in 3 (5.6%) patients (2 Chlorambucil and 1 ibrutinib); radiation therapy alone in 4 (7.4%) patients, and splenectomy only in 3 (5.6%) patients . Details of indolent lymphoma treatment were not available for the remaining 3 patients.

Treatment following diagnosis of HTL included Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone (R-CHOP) in the majority of patients. Eleven (15.1%) patients were treated with a less intense regimen than R-CHOP (R-CHOP) (See Table 1 for treatment details). Eight (11%) patients received supportive care only as they were not suitable candidates for treatment with chemotherapy, and treatment information was not available for the remaining 2 (2.7%) patients. In the 63 treated cases of HTL, PET showed complete remission (CR) in the majority of patients (55%) with 15% achieving partial remission (PR) and 15% having progressive disease (PD). No details of response were available for one patient.

Of the two patients diagnosed with double-hit DLBCL, the original diagnosis of both was follicular lymphoma and they both had elevated proliferative index Ki67 of 80% and 90%. One of the patients had progressive disease with RCHOP and received second line R-Hyper-CVAD without a durable response and died of progressive disease 18 months after diagnosis of HTL. The second patient had initial CR to first line R-CHOP but unfortunately developed CNS relapse shortly after and died of progressive disease 7 months after diagnosis of HTL.

Patient laboratory characteristics included median (range)levels of: lactate dehydrogenase (LDH) at 281 U/L (range: 107-5403 U/L); uric acid 5.6 mg/dL (range: 2.0-11.3 mg/dL), albumin 3.8 g/dL (range 1.9-4.7g/dL), white blood cell count 6.7 bil/L(0.9-81.8 bil/L), hemoglobin 11.5 g/dL (4.6-17.5 g/dL), and platelet count 201 bil/L (13- 627 bil/L). Proliferative index (Ki67) was reported in 64 patients; the median was 72.5% (range: 10-95) and 54 (84.3%) of these had a proliferative index of 50% or greater. Of the 34 patients that had cytogenetics and fluorescent in situ hybridization (FISH) performed, 2 (6%) met criteria for double-hit DLBCL, chromosomal rearrangement involving translocation of the c-myc gene located on chromosome 8q24 with the BCL2 and/or BCL6 genes ( t 14:18) [5]. Extranodal involvement was present in 58 (79%) patients at the time of HTL diagnosis, with the number of extranodal sites being 1 site in 38 patients and 2 sites in 14 patients; 6 patients had 3 or more extranodal site involvement. At the time of diagnosis of HTL, the age of the patient, sex, Ki67, LDH, albumin, number of extranodal sites, response to treatment and OS were similar regardless of the type of indolent lymphoma. However, patients with Richter’s transformation tended to have more leukocytosis and thrombocytopenia while those with HTL from MZL were more likely to have normal hemoglobin at diagnosis relative to others. There was a statistically significant difference in the median (range) time in months to transformation among the different indolent lymphoma histologies, with FL, MZL and low-grade lymphoma NOS progressing in a shorter time period than CLL and LPL; p=0.035 (Table 2).


CLL n=17

FL n=33

LPL n=8

MZL n=10

NOS n=5


Age, years*








M 10, F 7

M 14, F 19

M 4, F 4

M4, F 6

M2, F3


Time to HTL, months†

(22.1-97.0), max 258

(15.0-43.5), max 129

(33.8-135.5), max 223

(1.1-49.7), max 85

(0.0 -83.7), max 110


IDL treatment

Treat: 7

Treat: 14

Treat: 8

Treat: 6

Treat: 2


Median Ki67, %*

63.85% (10%-90%)






Extranodal involvement


Yes: 26


No: 3










Alb, g/dL







WBC, bill/L





(3.9 -55.3)


Hb, g/dL

(7.4 -14.9)






Plt, bill/L








CR 8, PR 2, SD/PD 3

CR 21, PR 5, SD/PD 5

CR 3, PR 2, SD/PD 2

CR 5, PR 2, SD/PD 1

CR 3, PR 0, SD/PD 0


HTL survival time, months*







Data are presented as n (%);*median (full range); or †median (25th, 75th percentiles), maximum.

Abbreviations: HTL, histologically transformed lymphoma; M, male; F, female; IDL, indolent lymphoma; Obs, observation; Treat, treatment; LDH, lactate dehydrogenase; Alb, albumin; WBC, white blood cell count; Hb, hemoglobin; Plt, platelet count; CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.

Table 2: Clinical characteristics of indolent lymphoma types in patients with HTL.

The median OS in the entire cohort of 73 patients from the time HTL was diagnosed was 31.0 months (range: 6.3 to 55.7 months). Survival at two years was approximately 60%, and about 41% of patients remained alive at 5 years (Figure 1). Univariate analysis identified that treatment with RCHOP conferred better OS when compared to regimens with less or greater intensity than RCHOP, p=0.001. Age less than 70 years (p=0.004), attainment of CR (p=0.001), LDH less than 422 U/L (p=0.001), albumin greater than 3.7g/dl (p=0.041) and hemoglobin greater than 11.5g/dl (p=0.001) also conferred better OS by univariate analysis (Table 3). Multivariate analysis confirmed attainment of CR and LDH within normal range (100-238 U/L) to have a statistically significant association with superior OS. Prior treatment with rituximab or other anti-CD 20 monoclonal antibody as indolent lymphoma had no statistically significant association with OS after diagnosis of HTL, p=0.65.

Figure 1: Kaplan Meier Curve of Overall Survival (OS) in the entire patient cohort with histologic transformed lymphoma. OS at two years was approximately 60%, and about 41% of patients remain alive at 5 years.




Indolent lymphoma type






Indolent treated or observation



HTL treatment


RCHOP is better than RCHOP

Extranodal presence or absence



Response to treatment: CR, PR, SD/PD


CR the best

age <70 vs ≥70


<70 is better

Time to develop HTL



Ki67, %





LDH<422 better

Alb, g/dl


Alb>3.7 is better

WBC, bil/L



Hb, g/dl


Hb>11.5 is better

Plt, bil/L



Abbreviations: HTL, histologically transformed lymphoma; CR, complete remission; PR, partial response; SD, stable disease;
 PD, progressive disease; LDH, lactate dehydrogenase; WBC, white blood cells; Hb, hemoglobin; Plt, platelets.

Table 3: Univariate analysis of variables associated with overall survival.

4. Discussion

Despite the favorable clinical course of most indolent lymphomas, histologic transformation to aggressive lymphoma remains a significant adverse event and in the pre-rituximab era was historically associated with worse outcome compared to patients with de novo aggressive lymphoma [2]. Published retrospective cohorts of HTL patients treated with chemotherapy alone without rituximab showed 5-year OS rates of 20% to 30%, and median OS ranging between 1 and 2 years [3, 6]. A more favorable prognosis has been shown for HTL since the introduction of rituximab. A study by Ban-Hoefen et al. reported 2-year OS of 68% [7], while 5-year OS survival of transformed lymphoma ranged from 40-70% [6-8]. These results are comparable to our study findings of 60% 2-year OS and 41% 5-year OS (Figure 1). However, a retrospective study of transformed DLBCL without prior RCHOP chemotherapy treatment for indolent lymphoma compared to de novo DLBCL treated with RCHOP showed no statistically significant difference in CR rate, PFS or OS between the de novo and transformed groups [8].

Follicular lymphoma is the most common subtype of indolent lymphoma and constitutes the most common indolent lymphoma to transform to aggressive lymphoma in the literature [3, 9, 10]. There are reports of HTL in other indolent lymphoma types such as CLL/SLL, MZL, and LPL [11-15]. Our institutional retrospective data also identified follicular lymphoma as the most common indolent lymphomas with HTL followed by CLL. Time to histologic transformation also varies among different types of indolent lymphoma; reported time to Richter’s transformation in CLL ranged from 1.8 years to 4 years [16-18], from 2.75 years to 3.3 years in follicular lymphoma [2, 19], and 1.9 years to 2.6 years for marginal zone lymphoma [14]. Our study showed a statistically significant longer time to HTL in LPL and CLL compared to FL, MZL and low grade lymphoma NOS. Evaluating all indolent lymphomas with HTL, Villa et al reported a median time to transformation of 3.7 years in a retrospective study [20] similar to our findings of 3.4 years in the entire patient cohort.

Survival has also been reported to be different in transformed lymphoma depending on the type of indolent lymphoma [12, 21]; contrary to this, we found no statistically significant different in OS following histologic transformation between the types of indolent lymphoma in our study. Treatment of low-grade lymphoma was thought to have affected outcome at histologic transformation. Yuen et al. showed better outcome at transformation in patients with indolent lymphoma managed with observation [22] in a retrospective study. Another report by Montoto et al. found a higher risk of transformation of indolent lymphoma with expectant management [23, 24] while the GELA trial did not find differing transformation risk between indolent lymphoma managed with expectant management or early treatment [25]. Our study did not find a statistically significant difference between OS after diagnosis of HTL and choice of indolent lymphoma treatment, i.e., observation or systemic therapy. Prior treatment of indolent lymphoma with rituximab or any anti CD-20 monoclonal antibody has not been reported to have any statistically significant relationship with patients’ outcomes after histologic transformation [26], also consistent with our study findings.

Study Title Study design Status Intervention Population
NCT03837873 DLCL002 Protocol for Patients
 with High Risk Aggressive
B-cell Lymphoma
Phase 2 Recruiting R-DA-EPOCH + ASCT
or R-DA-EPOCH then
Transformed lymphoma no prior treatment
NCT02343536 Open-label Trial of Oral
Azacitidine (CC-486) Plus
 RCHOP in Subjects with
 Large B-Cell Lymphoma
or Follicular Lymphoma or
 Transformed Lymphoma
Phase 1 Active, not
Oral Azacytidine + R-CHOP Transformed lymphoma allowed
NCT03352765 Rituximab, Bendamustine and
Melphalan Chemo-immunotherapy
 Followed by Reinfusion of One's
 Own Stem Cell for Treatment
of B-cell Lymphoma in Elderly Patients
Phase 1,2 Recruiting Rituximab, Bendamustine
 & melphalan and ASCT
Transformed lymphoma allowed
NCT02051257 Memory Enriched T Cells Following
 Stem Cell Transplant in Treating
Patients with Recurrent B-Cell Non-Hodgkin Lymphoma
Phase 1 Active, not recruiting CD19CAR-CD28-CD3zeta-
EGFRt-expressing TCM-enriched
T cells
Transformed recurrent non-Hodgkin lymphoma
NCT01665768 Maintenance Rituximab With mTor
Inhibition After High-dose
Consolidative Therapy in Lymphoma
Phase 2 Active, not recruiting Everolimus and Rituximab Transformed lymphoma allowed
NCT03133221 1630GCC: Zydelig Maintenance in
 B-Cell Non-Hodgkin's
Lymphoma After Autologous Stem Cell Transplantation
Phase 2 Recruiting Zydelig Transformed after ASCT
NCT03147885 Selinexor Plus Combination
 Chemotherapy in Treating Patients
with Advanced B Cell Non-Hodgkin
Phase 1,2 Recruiting Selinexor Transformed recurrent non-Hodgkin lymphoma
NCT02652715 Salvia Hispanica Seed in Reducing Risk
of Disease Recurrence in
Patients with Non-Hodgkin Lymphoma
N/A (Pilot) Active, not recruiting Dietary Supplement:
Salvia Hispanica Seed
Transformed recurrent non-Hodgkin lymphoma
NCT02924402 Study to Evaluate Safety and Tolerability of XmAb13676 in Patients
with CD20-expressing Hematologic
Phase 1 Recruiting XmAb13676 Transformed lymphoma allowed
NCT03349450 DPX-Survivac and Checkpoint
Inhibitor in DLBCL (SPiReL)
Phase 2 Recruiting DPX-Survivac vaccine,
Pembrolizumab and
Transformed lymphoma allowed
NCT02207062 Ibrutinib in Treating Patients
with Relapsed or Refractory
Transformed Indolent B-cell
Non-Hodgkin Lymphoma
N/A (pilot) Active, not recruiting Ibrutinib Transformed lymphoma allowed
NCT03321643 Atezolizumab, Gemcitabine,
Oxaliplatin, and Rituximab in Treating
Patients with Relapsed or Refractory
Transformed Diffuse Large
B-Cell Lymphoma
Phase 1 Recruiting Atezolizumab, Gemcitabine,
Oxaliplatin, and Rituximab
Recurrent transformed non-Hodgkin lymphoma
NCT03884998 Copanlisib and Nivolumab in
 Treating Participants with
 Richter's Transformation or
 Transformed Indolent Non-Hodgkin's
Phase 1 Recruiting Copanilisib in Combination
With PD-1 Antagonist
Richter's transformation or transformed indolent non-Hodgkin's lymphoma
NCT00924326 CAR T Cell Receptor Immunotherapy
for Patients With B-cell Lymphoma
Phase 1, 2 Active, not recruiting.
 Has results
Fludarabine, Cyclophosphamide,
 Anti-cluster of differentiation
19 (CD19)-CAR , Aldesleukin
Transformed follicular lymphoma
NCT02348216 Safety and Efficacy of KTE-C19 in
Adults with Refractory Aggressive
Non-Hodgkin Lymphoma (ZUMA-1)
Phase 1,2 Recruiting Axicabtagene Ciloleucel
(KTE-C19), Fludarabine,
Transformed follicular lymphoma
NCT02420912 Nivolumab and Ibrutinib in Treating
Patients with Relapsed, Refractory,
or High-Risk Untreated Chronic
Lymphocytic Leukemia,
Small Lymphocytic Lymphoma,
or Richter Transformation
Phase 2 Active, not recruiting Nivolumab, Ibrutinib Richter syndrome
NCT02747732 Study of Ibrutinib in Combination
 with Bendamustine and Rituximab
for Patients with Relapsed/Refractory
 Aggressive BCL
Phase 2 Recruiting Ibrutinib, Bendamustine,
Transformed indolent lymphoma
NCT03277729 A Phase I/II Study to Evaluate the
 Safety of Cellular Immunotherapy
Using Autologous T Cells Engineered to
 Express a CD20-Specific
Chimeric Antigen Receptor for
Patients with Relapsed or Refractory
B Cell Non-Hodgkin Lymphomas
Phase 2 Recruiting CD20 CAR T cell IV Recurrent/refractory transformed B-cell non-Hodgkin lymphoma
NCT02499003 GOAL: GA101 Plus Pixantrone for
 Relapsed Aggressive Lymphoma
Phase 2 Active, not recruiting Obinutuzumab, Pixantrone Transformed indolent non-Hodgkin's lymphoma
NCT02628405 R-ICE and Lenalidomide in Treating
Patients with First Relapse/Primary
Refractory Diffuse Large B-Cell Lymphoma
Phase 1,2 Recruiting R-ICE and Lenalidomide Recurrent/ refractory transformed non-Hodgkin lymphoma
NCT01897571 Open-Label, Multicenter study of
Tazemetostat (EZH2 Histone Methyl
Transferase [HMT] Inhibitor) as a
Single Agent in Subjects with Adv.
Solid Tumors or With B-cell Lymphomas
 and Tazemetostat in
Combination With Prednisolone in
 Subjects With DLBCL
Phase 1,2 Active, not recruiting Tazemetostat Transformed follicular lymphoma
NCT02572453 Onalespib in Treating Patients with
Relapsed or Refractory
Anaplastic Large Cell Lymphoma,
 Mantle Cell Lymphoma,
or Diffuse Large B-Cell Lymphoma
Phase 2 Recruiting Onalespib Recurrent/ refractory transformed non-Hodgkin lymphoma
NCT03440567 Avelumab, Utomilumab, Rituximab,
 Ibrutinib, and Combination
Chemotherapy in Treating Patients
 with Relapsed or Refractory
 Diffuse Large B-Cell Lymphoma or
Mantle Cell Lymphoma
Phase 1 Recruiting Avelumab, Utomilumab,
Rituximab, Ibrutinib,
and Combination Chemotherapy
Transformed follicular lymphoma to diffuse large B-cell lymphoma
NCT03583424 Venetoclax, Carmustine, Etoposide,
Cytarabine, and Melphalan
Before Stem Cell Transplant in
Treating Participants with Relapsed
or Refractory Non-Hodgkin Lymphoma
Phase 1,2 Recruiting Venetoclax, Carmustine,
Etoposide, Cytarabine
, and Melphalan
Refractory transformed indolent non-Hodgkin lymphoma
NCT03103971 huJCAR014 CAR-T Cells in
Treating Adult Patients with
Relapsed or Refractory B-Cell
Non-Hodgkin Lymphoma
or Acute Lymphoblastic Leukemia
Phase 1 Recruiting Autologous Human
CD4+/CD8+ T-lymphocytes,
Cyclophosphamide, Fludarabine
Recurrent transformed non-Hodgkin lymphoma
NCT03704714 Nivolumab and Combination
Chemotherapy in Treating
Participants with Diffuse Large
B-Cell Lymphoma
Phase 1,2 Recruiting Cyclophosphamide, Doxorubicin ,
Hydrochloride, Nivolumab,
Prednisone, Rituximab,
Vincristine Sulfate
Transformed follicular lymphoma to diffuse large B-cell lymphoma
NCT03484702 Trial to Determine the Efficacy
and Safety of JCAR017 in
Adult Subjects with Aggressive
B-Cell Non-Hodgkin Lymphoma (TRANSCENDWORLD)
Phase 2 Recruiting JCAR017 Transplant-ineligible transformed follicular lymphoma
NCT03833180 A Phase 1 Dose-Escalation and
Cohort-Expansion of
VLS-101 in Hematologic
Phase 1 Recruiting VLS-101 Richter transformation lymphoma

Abbreviations: N/A, not applicable.

Search performed on on 7/10/2019, using search criteria of transformed lymphoma, interventional studies, adult patients 18 and above, recruiting or active but not currently recruiting, available in all countries, all funders included. (Search algorithm) . Thirty-one results were generated but three studies are not included in the above table (one excluded transformed lymphoma, another only included CD30 expressing-lymphoma utilizing brentuximab vedotin, while the third is a study of topical treatment in CD30 positive lymphoma).

Table 4: Clinical Trials of Histologic Transformed Lymphoma.

Double hit DLBCL is historically known to be resistant to chemoimmunotherapy and has a higher incidence of CNS disease. Aside from its occurrence in de novo DLBCL, it has also been reported in HTL, particularly when t (14;18) in follicular lymphoma acquires c-myc translocation [27], as also identified in our study. Jonathan W. Friedberg proposed considering dose-adjusted R-EPOCH similar to what is prescribed for de novo double-hit lymphoma, for those patients with double-hit lymphoma in the setting of transformed follicular lymphoma without prior anthracycline exposure or salvage chemotherapy followed by ASCT in those with prior anthracycline treatment [28].

Treatment and survival of patients with HTL continues to evolve particularly in the era of targeted therapies. Data on timing and role of HDT-ASCT in HTL continues to be debated in the rituximab era, with some studies suggesting better outcome with HDT-ASCT in CR-1 [29-31] and others finding no significant impact on survival [26]. Silvia Montoto proposed that consolidation with HDT-ASCR may be considered in patients with transformed lymphoma who received lines of chemotherapy for indolent lymphoma and treatment with R-CHOP at transformation, or for those who received RCHOP prior to HTL, required salvage chemotherapy at the time of transformation, and had good response and performance status [7]. Only one of our study patients received ASCT in CR-1.

There are a number of on-going clinical trials of DLBCL enrolling patients with HTL that are evaluating the role of targeted therapies upfront and in the relapsed-refractory setting, and utilizing novel therapies such as immunomodulatory drugs (IMiDs), Bruton's tyrosine kinase (BTK) inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, Programmed T cell death-1 (PD-1) inhibitors, HDT-ASCT, and Chimeric Antigen Receptors T cell (CAR-T) therapy (Table 4). Many of these studies are in early stages and thus optimal treatments for DLBCL HTL will likely remain unresolved for the foreseeable future.

5. Conclusion

Despite improved outcome in the rituximab era, the outcome of HTL particularly in the relapsed-refractory setting remains unsatisfactory. Our retrospective study identified achievement of CR and LDH level within the normal range to statistically predict better OS. We found a statistically significant longer time to the development of HTL in patients with CLL and LPL compared to other indolent lymphoma types (FL, MZL and low-grade B cell lymphoma NOS; however, OS at histologic transformation was similar regardless of the indolent lymphoma type preceding HTL. Future directions will depend on the outcome of on-going clinical trials, the results of which will suggest novel therapeutics and provide for more evidence-based management of HTL

Conflicts of Interest

All authors declare no conflict of interest.


Special thanks to Rose Callahan for detailed editing of the manuscript.


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