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Five patients discontinued treatment and left the study before a 12-week response assessment . When these patients were excluded from the analysis , the ORR increased to 76 percent .
The investigators observed similar response rates among all patients , regardless of organ involvement .
Of the 28 responders , 20 ( 71 %) had a sustained response for ≥20 weeks ( the study ’ s primary endpoint ). “ This cGVHD
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study is the first to report sustained response as an efficacy endpoint ,” the authors noted . “ This endpoint is clinically relevant because [ patients with ] cGVHD generally require therapy for an extended period and short-term responses do not allow for resolution of disabling symptoms or tapering of corticosteroids .”
Median corticosteroid dose in responders decreased from 0.29 mg / kg / day ( range = 0.06-1.30 mg / kg / day ) at baseline to
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0.12 mg / kg / day ( range = 0.0-0.18 mg / kg / day ) at week 49 . Additionally , five responders could completely discontinue corticosteroids during response to ibrutinib treatment , and 26 patients ( 62 %) tapered down to a corticosteroid dose of < 0.15 mg / kg / day . “ Our results suggest that ibrutinib may have a steroid-sparing effect , which could reduce the morbidity associated with long-term corticosteroid use ,” the authors explained . |
The most common treatment-emergent AEs ( reported in ≥10 % of patients ) included fatigue ( n = 24 ), diarrhea ( n = 15 ), muscle spasms ( n = 12 ), nausea ( n = 11 ), and bruising ( n = 10 ), most of which were grade 1 or 2 . The most common grade ≥3 AEs were pneumonia ( n = 6 ), fatigue ( n = 5 ), and diarrhea ( n = 4 ).
Any-grade infectious complications were reported in 29 patients ( 69 %), including 15 ( 36 %) grade ≥3 events .
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REVLIMID ® [ lenalidomide ] capsules , for oral use
of AML and MDS cases in patients with NDMM treated with REVLIMID in combination with dexamethasone without melphalan was 0.4 %.
In patients receiving REVLIMID maintenance therapy following high dose intravenous melphalan and auto-HSCT , hematologic SPM occurred in 7.5 % of patients compared to 3.3 % in patients receiving placebo . The incidence of hematologic plus solid tumor ( excluding squamous cell carcinoma and basal cell carcinoma ) SPM was 14.9 %, compared to 8.8 % in patients receiving placebo with a median follow-up of 91.5 months . Non-melanoma skin cancer SPM , including squamous cell carcinoma and basal cell carcinoma , occurred in 3.9 % of patients receiving REVLIMID maintenance , compared to 2.6 % in the placebo arm .
In patients with relapsed or refractory MM treated with REVLIMID / dexamethasone , the incidence of hematologic plus solid tumor ( excluding squamous cell carcinoma and basal cell carcinoma ) SPM was 2.3 % versus 0.6 % in the dexamethasone alone arm . Non-melanoma skin cancer SPM , including squamous cell carcinoma and basal cell carcinoma , occurred in 3.1 % of patients receiving REVLIMID / dexamethasone , compared to 0.6 % in the dexamethasone alone arm .
Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms . Monitor patients for the development of second primary malignancies . Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID .
5.7 Hepatotoxicity
Hepatic failure , including fatal cases , has occurred in patients treated with lenalidomide in combination with dexamethasone . In clinical trials , 15 % of patients experienced hepatotoxicity ( with hepatocellular , cholestatic and mixed characteristics ); 2 % of patients with multiple myeloma and 1 % of patients with myelodysplasia had serious hepatotoxicity events . The mechanism of drug-induced hepatotoxicity is unknown . Pre-existing viral liver disease , elevated baseline liver enzymes , and concomitant medications may be risk factors . Monitor liver enzymes periodically . Stop REVLIMID upon elevation of liver enzymes . After return to baseline values , treatment at a lower dose may be considered .
5.8 Allergic Reactions
Angioedema and serious dermatologic reactions including Stevens- Johnson syndrome ( SJS ) and toxic epidermal necrolysis ( TEN ) have been reported . These events can be fatal . Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID . REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash . REVLIMID must be discontinued for angioedema , Grade 4 rash , exfoliative or bullous rash , or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions .
REVLIMID capsules contain lactose . Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance .
5.9 Tumor Lysis Syndrome
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide . The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment . These patients should be monitored closely and appropriate precautions taken .
5.10 Tumor Flare Reaction
Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma , and is characterized by tender lymph node swelling , low grade fever , pain and rash . REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials .
Monitoring and evaluation for tumor flare reaction ( TFR ) is recommended in patients with MCL . Tumor flare reaction may mimic progression of disease ( PD ). In the MCL trial , 13 / 134 ( 10 %) of subjects experienced TFR ; all reports were Grade 1 or 2 in severity . All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11 . Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification , at the physician ’ s discretion . Patients with Grade 1 and 2 TFR may also be treated with corticosteroids , non-steroidal antiinflammatory drugs ( NSAIDs ) and / or narcotic analgesics for management of TFR symptoms . In patients with Grade 3 or 4 TFR , it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1 . Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR .
5.11 Impaired Stem Cell Mobilization
A decrease in the number of CD34 + cells collected after treatment (> 4 cycles ) with REVLIMID has been reported . In patients who are ASCT candidates , referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection . In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34 + cells have been collected with G-CSF alone , G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered .
5.12 Thyroid Disorders
Both hypothyroidism and hyperthyroidism have been reported [ see Adverse Reactions ( 6.2 )]. Measure thyroid function before start of REVLIMID treatment and during therapy .
6 ADVERSE REACTIONS
The following adverse reactions are described in detail in other sections of the prescribing information :
• Embryo-Fetal Toxicity [ see Boxed Warnings , Warnings and Precautions ( 5.1 , 5.2 )]
• Hematologic Toxicity [ see Boxed Warnings , Warnings and Precautions ( 5.3 )]
• Venous and Arterial Thromboembolism [ see Boxed Warnings , Warnings and Precautions ( 5.4 )]
• Increased Mortality in Patients with CLL [ see Warnings and Precautions ( 5.5 )]
• Second Primary Malignancies [ see Warnings and Precautions ( 5.6 )]
• Hepatotoxicity [ see Warnings and Precautions ( 5.7 )]
• Allergic Reactions [ see Warnings and Precautions ( 5.8 )]
• Tumor Lysis Syndrome [ see Warnings and Precautions ( 5.9 )]
• Tumor Flare Reactions [ see Warnings and Precautions ( 5.10 )]
• Impaired Stem Cell Mobilization [ see Warnings and Precautions ( 5.11 )]
• Thyroid Disorders [ see Warnings and Precautions ( 5.12 )]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
Newly Diagnosed MM - REVLIMID Maintenance Therapy Following Auto-HSCT :
Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity . The mean treatment duration for REVLIMID treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 ( overall range across both studies from 0.1 to 108 months ). As of the cut-off date of 1 Mar 2015 , 48 patients ( 21 %) in the Maintenance Study 1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date
The adverse reactions listed from Maintenance Study 1 included events reported post-transplant ( completion of high-dose melphalan / auto-HSCT ), and the maintenance treatment period . In Maintenance Study 2 , the adverse reactions were from the maintenance treatment period only . In general , the most frequently reported adverse reactions ( more than 20 % in the REVLIMID arm ) across both studies were neutropenia , thrombocytopenia , leukopenia , anemia , upper respiratory tract infection , bronchitis , nasopharyngitis , cough , gastroenteritis , diarrhea , rash , fatigue , asthenia , muscle spasm and pyrexia . The most frequently reported Grade 3 or 4 reactions ( more than 20 % in the REVLIMID arm ) included neutropenia , thrombocytopenia , and leukopenia . The serious adverse reactions lung infection and neutropenia ( more than 4.5 %) occurred in the REVLIMID arm .
For REVLIMID , the most common adverse reactions leading to dose interruption were hematologic events ( 29.7 %, data available in Maintenance Study 2 only ). The most common adverse reaction leading to dose reduction of REVLIMID were hematologic events ( 17.7 %, data available in Maintenance Study 2 only ). The most common adverse reactions leading to discontinuation of REVLIMID were thrombocytopenia ( 2.7 %) in Maintenance Study 1 and neutropenia ( 2.4 %) in Maintenance Study 2 .
The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment .
Table 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms .