Background:
Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is currently ongoing to answer the question if a 2nd generation TKI (2G‐TKI), i.e. dasatinib (DA), should be used for ...retreatment for 2nd attempt of treatment‐free remission (TFR2) after failing the first TFR attempt (TFR1) with imatinib (IM) discontinuation.
Aims:
In our previous report (ASH 2018), the estimated TFR2 rate was 21.5% at 6 months. Also, rapid relapsing pattern after IM discontinuation correlated with a higher failure after DA discontinuation. It prompted us to revisit evaluating the correlation of doubling time (DT) after TFR1 attempt with TFR2 rate.
Methods:
This prospective clinical trial (BMS CA180–543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. DA 100 mg once daily was started if loss of molecular response is confirmed. DA is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The study was designed to reject our null hypothesis if > 28% of pts (15 out of 54 pts) remain in TFR2 after DA discontinuation.
Doubling time (DT) has been calculated based on the BCR‐ABL1 qPCR value taken monthly in the first 6 months after IM discontinuation. The baseline qPCR level prior to IM discontinuation was referenced. We decided to apply DT measured at 2 months after TFR1 attempt for further analysis based on the previous result (EHA 2018).
Results:
As of Feb 21, 2019, 42 (32.%) of 131 pts are still ongoing. Of the 57 pts who lost molecular response after TFR1 attempt, 55 pts (96%) received DA and reachieved molecular response. 28/55 pts (51%) receiving DA attained MR4.5 for 12 months or longer, and discontinued it for TFR2. 21/28 (75%) of these pts lost molecular response at 3.7 months after TFR2 attempt. TFR2 rate was 20.2% at 6 months (7.4–37.5%), thus not allowing to reject our null hypothesis. 7 pts are still on DA discontinuation phase without losing molecular response (range 27–607 days).
In the risk factor analyses for TFR2, following variables were analyzed but did not show any association with TFR2: Sokal risk score (p = 0.599), total IM duration prior to TFR1 attempt (p = 0.09), MR4 duration with IM (p = 0.866), or time to MR4 achievement with IM (p = 0.09).However, shorter time to molecular relapse after TFR1 attempt (p = 0.001, HR 0.523 per month, 0.350–0.782) and rapid molecular relapse after TFR1 attempt (HR 4.003 for MMR loss, 1.397–11.48) were confirmed to correlate with TFR2 failure.
Next, we have evaluated the DT at 2 months after TFR1 attempt. In the group with DT ≤zero (n = 7), TFR2 rate was 50.0% at 6 months. It was 16.7% in those with DT ≥ 14 days (n = 7), while it was 7.9% in those with DT <14 days (n = 15; p = 0.04).
TFR2 rate at 6 months was significantly higher at 33.3% in low risk (i.e. those with DT ≤zero or ≥ 14 days, n = 14) vs 7.9% in the high risk (i.e. those with DT<14 days, n = 15; p = 0.01, HR 2.902, 1.199–7.026). The TFR2 rate in the low risk group (i.e. 33.3%) is above our pre‐determined criteria to reject our null hypothesis (i.e. 28%), suggesting that this group can be a good candidate for TFR2 attempt.
Summary/Conclusion:
1) Our result suggests that switch to 2G‐TKI after failing TFR1 attempt may not improve TFR2 rate.
2) However, seeing a DT at 2 months after TFR1 attempt seems helpful to identify the subgroup having more benefit from the switch to 2G‐TKI for TFR2 attempt.
Relapsed disease remains a major obstacle following autologous haematopoietic SCT (HSCT) for non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Studies regarding the importance of detectable ...tumour cells in PBSC collections have been inconclusive. Patients undergoing autologous HSCT for NHL and MM between 2001 and 2006 were enrolled (n=158). PBSC grafts were assessed for clonal IgH CDR3 gene rearrangements using qualitative semi-nested PCR. In comparison to patients with PCR-positive PBSC grafts, patients negative for detectable disease had no improvement in overall survival (OS) or PFS for MM (P=0.91 and 0.91) or NHL (P=0.82 and 0.85). Further, no significant difference in OS was observed between patients with PCR-positive compared with PCR-negative PBSC grafts with aggressive NHL histology (P=0.74) or indolent disease (P=0.29). Patients with contaminating tumour cells in autologous PBSCs do not have worsened OS or PFS in MM or NHL. Tumour cells detected by sensitive molecular methods in PBSC collections may be distinct from cells contaminating marrow and appear to have limited utility in identifying patients with MM and B-cell NHL who would benefit from purging strategies.
The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose ...chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL).
Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM).
From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio HR, 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance.
Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.
Summary Background Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or ...refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov , number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio HR 0·203, 95% CI 0·150–0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73–83) in the ibrutinib group and 24% (18–31) in the placebo group (HR 0·203, 95% CI 0·150–0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3–4 events; the most common grade 3–4 adverse events in both groups were neutropenia (154 54% in the ibrutinib group vs 145 51% in the placebo group) and thrombocytopenia (43 15% in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding Janssen Research & Development.
The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively ...mediates host effector functions and is itself less immunogenic than are murine antibodies.
This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses.
From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient.
The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.
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