Table 3

Summary of patient characteristics, causes of discontinuation, and outcomes of patients after discontinuing ibrutinib (n = 33)

PatientsPatient characteristicsCause of discontinuationOutcome of patients after ibrutinib
Age, yearsZap-70 Statusβ2 M (mg/L)IGHV mutation statusFluorescence in situ hybridizationNumber of prior therapiesDuration of ibrutinib, monthsSurvival statusSurvival post-ibrutinib, months
Patients who transformed (n = 7)            
 1‡ 57 + 6.8 UM del11q + del13q 5 13.1 Dead 0.0 Histiocytic sarcoma transformation Died on study 
 2 52 ND 6 UM del13q 4 4.5 Dead 0.9 Richter transformation Died 
 3‡ 72 + 4 UM del17p 3 21.9 Alive 2+ Richter transformation On small molecule clinical trial 
 4 73 + 12 UM del17p 1 2 Dead 2.1 Richter transformation Chemoimmunotherapy ×1* 
 5 60 + 10 UM del11q 2 13.1 Dead 2.6 Richter transformation R-MP (1 course) 
 6 65 + 2.1 UM del17p 0 10 Dead 3.1 Richter transformation Chemoimmunotherapy* 
 7 63 + 2 UM del17p + 11q + 13q 4 9.4 Dead 15.0 Richter transformation Chemoimmunotherapy×1* 
Patients who progressed not transformed (n = 7)            
 1‡ 73 + 4 UM del17p 1 14.2 Dead 1.6 Progressive disease Chronic obstructive pulmonary disease, infections, no further treatment of CLL 
 2‡ 78 — 5.2 UM del17p 2 22.5 Alive 1.8+ Progressive disease Ofatumumab 
 3‡ 52 + 3 UM del13q 2 21.4 Alive 1.9+ Progressive disease On small molecule clinical trial 
 4‡ 36 — 5.9 UM del11q 2 6.9 Dead 2.1 Progressive disease Infections, pneumonia, no further treatment of CLL 
 5 63 + 5.1 UM del11q + 13q 5 38.7 Dead 2.8 Progressive disease Pneumonia 
 6 56 + 4.1 ND del17p + 13q 2 33.1 Alive 11.5+ Progressive disease R-MP (4 infusions, PR), on small molecule clinical trial 
 7 83 — 10.8 UM del17p, +12, 13q 4 18.5 Alive 14.4+ Progressive disease Ofatumumab 
Patients who discontinued because of stem cell transplantation (n = 3)            
 1 61 + 2.3 UM del17p + del 11q 3 11.7 Dead 0.1 Stem cell transplantation Died of graft vs host disease 
 2‡ 64 — 2.4 UM Negative 3 12.9 Dead 4.2 Stem cell transplantation Complications of transplant 
 3‡ 63 + 5.1 UM Del17p 1 11.9 Alive 11+ Stem cell transplantation Remission post-SCT 
Patients who discontinued because of adverse events or sudden death (n = 14)            
 1‡ 61 + 5.1 UM Del17p 1 11 Dead 0 Pseudomonas sepsis and bronchiectasis No further treatment 
 2 64 + 10.8 ND Del13q 3 20 Dead 0 Recurrent fungal pneumonia, altered mental status No further treatment, died on study 
 3 50 ND 3.7 UM Negative 1 6 Dead 0 Sudden death† Died on study 
 4 64 + 3 UM Trisomy 12 0 6.2 Dead 0 Suicide Died on study 
 5‡ 67 — 2.6 UM Del11q 1 16.4 Dead 0 Sudden death† Died on study 
 6‡ 76 + 6 UM Del17p 2 2.1 Dead 0.2 Extensive aspergillosis Multifocal aspergillosis, no further treatment of CLL 
 7‡ 68 — 3.9 UM del11q 2 21.5 Alive 0.3+ Diarrhea, subdural hematoma, Plan to restart ibrutinib 
 8 68 — 6 M del17p + del11q + del13q 5 31.9 Dead 1 Diarrhea and pneumonia with DIC No treatment 
 9‡ 62 + 5.4 UM Del17p 0 17 Dead 1.8 Recurrent ear bleeding, past history of cancer oropharynx Died on study, but off ibrutinib 
 10‡ 82 + 4.1 UM Del17p 1 8.4 Dead 4 Comorbidities and recurrent infections, chronic obstructive pulmonary disease No further treatment 
 11 66 ND 4.3 UM del17p +12 del13q 7 3.9 Dead 5 Gastrointestinal bleeding, acquired von Willebrand disease, accelerated CLL Hyper-CVAD with ofatumumab 
 12‡ 57 + 3.2 M Del17p 3 6 Dead 12.8 Recurrent oral ulcers, intolerance OFAR1 cycle, ibrutinib restarted 
 13 50 ND 2.2 UM del13q 3 16.1 Alive 24.1+ Diarrhea, colitis Ofatumumab and MP, progressed with ascites and C1 OFAR-2 again on ibrutinib 
 14 68 + 3.4 UM del13q 4 1.9 Dead 41.8 Subdural hematoma, atrial fibrillation Metastatic cancer of jejunum 
Patients who discontinued because of miscellaneous causes (n = 2)            
 1 55 ND 5.1 UM del17p + del11q + del13q 6 27.4 Dead 1.1 Therapy-related myelodysplasia, cytopenias Died because of therapy-related myelodysplasia 
 2 54 + 4.2 UM Del17p 2 17 Dead 1.4 Patient choice No further treatment 
PatientsPatient characteristicsCause of discontinuationOutcome of patients after ibrutinib
Age, yearsZap-70 Statusβ2 M (mg/L)IGHV mutation statusFluorescence in situ hybridizationNumber of prior therapiesDuration of ibrutinib, monthsSurvival statusSurvival post-ibrutinib, months
Patients who transformed (n = 7)            
 1‡ 57 + 6.8 UM del11q + del13q 5 13.1 Dead 0.0 Histiocytic sarcoma transformation Died on study 
 2 52 ND 6 UM del13q 4 4.5 Dead 0.9 Richter transformation Died 
 3‡ 72 + 4 UM del17p 3 21.9 Alive 2+ Richter transformation On small molecule clinical trial 
 4 73 + 12 UM del17p 1 2 Dead 2.1 Richter transformation Chemoimmunotherapy ×1* 
 5 60 + 10 UM del11q 2 13.1 Dead 2.6 Richter transformation R-MP (1 course) 
 6 65 + 2.1 UM del17p 0 10 Dead 3.1 Richter transformation Chemoimmunotherapy* 
 7 63 + 2 UM del17p + 11q + 13q 4 9.4 Dead 15.0 Richter transformation Chemoimmunotherapy×1* 
Patients who progressed not transformed (n = 7)            
 1‡ 73 + 4 UM del17p 1 14.2 Dead 1.6 Progressive disease Chronic obstructive pulmonary disease, infections, no further treatment of CLL 
 2‡ 78 — 5.2 UM del17p 2 22.5 Alive 1.8+ Progressive disease Ofatumumab 
 3‡ 52 + 3 UM del13q 2 21.4 Alive 1.9+ Progressive disease On small molecule clinical trial 
 4‡ 36 — 5.9 UM del11q 2 6.9 Dead 2.1 Progressive disease Infections, pneumonia, no further treatment of CLL 
 5 63 + 5.1 UM del11q + 13q 5 38.7 Dead 2.8 Progressive disease Pneumonia 
 6 56 + 4.1 ND del17p + 13q 2 33.1 Alive 11.5+ Progressive disease R-MP (4 infusions, PR), on small molecule clinical trial 
 7 83 — 10.8 UM del17p, +12, 13q 4 18.5 Alive 14.4+ Progressive disease Ofatumumab 
Patients who discontinued because of stem cell transplantation (n = 3)            
 1 61 + 2.3 UM del17p + del 11q 3 11.7 Dead 0.1 Stem cell transplantation Died of graft vs host disease 
 2‡ 64 — 2.4 UM Negative 3 12.9 Dead 4.2 Stem cell transplantation Complications of transplant 
 3‡ 63 + 5.1 UM Del17p 1 11.9 Alive 11+ Stem cell transplantation Remission post-SCT 
Patients who discontinued because of adverse events or sudden death (n = 14)            
 1‡ 61 + 5.1 UM Del17p 1 11 Dead 0 Pseudomonas sepsis and bronchiectasis No further treatment 
 2 64 + 10.8 ND Del13q 3 20 Dead 0 Recurrent fungal pneumonia, altered mental status No further treatment, died on study 
 3 50 ND 3.7 UM Negative 1 6 Dead 0 Sudden death† Died on study 
 4 64 + 3 UM Trisomy 12 0 6.2 Dead 0 Suicide Died on study 
 5‡ 67 — 2.6 UM Del11q 1 16.4 Dead 0 Sudden death† Died on study 
 6‡ 76 + 6 UM Del17p 2 2.1 Dead 0.2 Extensive aspergillosis Multifocal aspergillosis, no further treatment of CLL 
 7‡ 68 — 3.9 UM del11q 2 21.5 Alive 0.3+ Diarrhea, subdural hematoma, Plan to restart ibrutinib 
 8 68 — 6 M del17p + del11q + del13q 5 31.9 Dead 1 Diarrhea and pneumonia with DIC No treatment 
 9‡ 62 + 5.4 UM Del17p 0 17 Dead 1.8 Recurrent ear bleeding, past history of cancer oropharynx Died on study, but off ibrutinib 
 10‡ 82 + 4.1 UM Del17p 1 8.4 Dead 4 Comorbidities and recurrent infections, chronic obstructive pulmonary disease No further treatment 
 11 66 ND 4.3 UM del17p +12 del13q 7 3.9 Dead 5 Gastrointestinal bleeding, acquired von Willebrand disease, accelerated CLL Hyper-CVAD with ofatumumab 
 12‡ 57 + 3.2 M Del17p 3 6 Dead 12.8 Recurrent oral ulcers, intolerance OFAR1 cycle, ibrutinib restarted 
 13 50 ND 2.2 UM del13q 3 16.1 Alive 24.1+ Diarrhea, colitis Ofatumumab and MP, progressed with ascites and C1 OFAR-2 again on ibrutinib 
 14 68 + 3.4 UM del13q 4 1.9 Dead 41.8 Subdural hematoma, atrial fibrillation Metastatic cancer of jejunum 
Patients who discontinued because of miscellaneous causes (n = 2)            
 1 55 ND 5.1 UM del17p + del11q + del13q 6 27.4 Dead 1.1 Therapy-related myelodysplasia, cytopenias Died because of therapy-related myelodysplasia 
 2 54 + 4.2 UM Del17p 2 17 Dead 1.4 Patient choice No further treatment 

ara-C, rituximab; CVAD, cyclophosphamide, vincristine, adriamycin (doxorubicin) and dexamethasone; DIC, disseminated intravascular coagulation; M, mutated; MP, methylprednisolone; OFAR, oxaliplatin, fludarabine; R-MP, rituximab with methylprednisolone; UM, unmutated.

*

Chemoimmunotherapy - OFAR- Oxaliplatin, fludarabine, ara-C, Rituximab.

+

Patients who are alive.

†

Cause of sudden death in these 2 patients was unknown (autopsies not performed), 1 patient had no prior cardiac history and another had prior hypertension but no arrhythmias.

‡

Patients treated with ibrutinib and rituximab.

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