WM

Dexamethasone, rituximab, and cyclophosphamide regimen demonstrates efficacy and tolerability in newly diagnosed as well as relapsed/refractory patients with WM

On 8th August 2017, in the British Journal of Haematology, Jonas Paludo from the Mayo Clinic, Rochester, MN, USA, and colleagues published results of dexamethasone, rituximab, and cyclophosphamide (DRC) as upfront and salvage therapy (mainly focusing on Relapsed/Refractory [R/R] patients requiring salvage treatment) in patients with Waldenström Macroglobulinemia (WM). The group also evaluated with impact of MYD88 mutational status on outcomes with DRC.

The medical records of consecutive WM patients seen at Mayo Clinic Rochester, Arizona, and Florida from January 2007 to December 2014 were reviewed and patients who had received one or more cycles of DRC were included in the final analysis (first-line, n=50; R/R, n=50). The regimen was usually made available to patients with symptomatic or bulky disease, WM-associated hemolytic anemia, or cytopenias.

Key Highlights:
Patients and treatment:
  • DRC given for up to six 21-day cycles: dexamethasone 20mg IV day 1, rituximab 375mg/m2 IV day 1, cyclophosphamide 100mg/m2 PO daily days 1–5
  • Median age = 68 years (range, 37–95)
  • In R/R pts, median number of prior lines of therapy = 1 (range, 1–7)
  • Forty percent of R/R pts were refractory to their prior chemotherapy regimen before DRC
  • Constitutional symptoms = 36%; lymphadenopathy = 26%; splenomegaly = 10%; hyperviscosity symptoms = 6%
DRC as salvage therapy:
  • DRC was second-line or later (range, 2–8) in 58% of R/R WM pts
  • Median number of cycles administered = 6 (range, 2–6); nearly three-quarters (71%) of pts completed 6 cycles
  • Median IgM levels dropped from 38.71g/l to 18.46g/l (P = 0.0001)
  • Median M-spike dropped from 28g/l to 11g/l at best response
  • Median time-to-best-response = 6.8 months (range, 0.5–28.0 months)
  • In R/R pts, ORR = 87%; with Very Good Partial Response (VGPR) of 4%, PR of 64%, Minimal Response (MR) or 19%, SD of 9%, and PD of 4%
  • Similar ORRs were observed in pts who had only received prior single-agent rituximab (95%) versus pts who have received other regimens (81%; P = 0.22)
  • In pts refractory to rituximab (n=6), ORR = 83%
  • Median follow-up = 51 months (95% CI, 38–55)
  • Median PFS = 32 months (95% CI, 15–51); 2-year PFS = 54%; 4-year PFS = 34%
  • Median Time-To-Next-Treatment (TTNT) = 50 months (95% CI, 35–60); 2-year TTNT = 87%; 4-year TTNT = 68%
  • A trend to longer PFS (40 months vs 20 months; P = 0.11) and TTNT (52 months vs 36 months; P = 0.10) was observed in pts who had only received prior single-agent rituximab compared to pts who had received other regimens
  • A trend to longer median PFS was observed in relapsed pts (50 months) vs refractory pts (20 months; P = 0.5)
  • Sixteen deaths reported (32%); of these, 11 were due to PD
  • Median Disease-Specific Survival (DSS) = Not Reached (NR); 2-year DSS = 81%; 4-year DSS = 74%
DRC as front-line therapy:
  • Median number of cycles administered = 6 (range, 2–6); 93% of pts completed 6 cycles
  • Median IgM levels dropped from 41.3g/l to 12.5g/l (P = 0.0001)
  • Median M-spike dropped from 21g/l to 11g/l (P = 0.0001) at best response
  • Median time-to-best-response = 11 months (range, 0.6–47.0 months)
  • In newly diagnosed pts, ORR = 96%; with VGPR of 17%, PR of 70%, MR of 9%, and SD of 4%
  • Median follow-up = 30 months (95% CI, 21–36)
  • Median PFS = 34 months (95% CI, 23–NR); 2-year PFS = 67%; 4-year PFS = 47%
  • Median TTNT = NR (95% CI, 37 months–NR); 2-year TTNT = 79%; 4-year TTNT = 67%
  • Seven death reported (14%); of these, 4 were due to PD
  • Median DSS = NR (95% CI, NR–NR); 2-year DSS = 95%; 4-year DSS = 82%
MYD88 status:
  • Status available for 29 pts (first-line, n=10; R/R, n=19)
  • MYD88L265P observed in 25 pts (first-line, n=8; R/R, n=17)
  • ORR in MYD88L265P pts was 92% versus 100% in MYD88WT pts (P = 1.0)
  • Median PFS in MYD88L265P pts was 41 months (95% CI, 16–59) versus 34 months (95% CI, 15–34) in MYD88WT pts (P = 0.45)
  • Median TTNT in MYD88L265P pts was 56 months (95% CI, 38–NR) versus 37 months (95% CI, 20–37) in MYD88WT pts (P = 0.23)
Safety:
  • Grade 3 or worse AEs for all pts were neutropenia (20%), thrombocytopenia (7%), and infections (3%)
  • One newly diagnosed patient had a stroke after one cycle of DRC, leading to treatment discontinuation; not deemed treatment related
  • Treatment was shortened due to toxicity in 11% of pts (n=7; all R/R)
  • No deaths related to DRC were reported
  • Therapy-related MDS (n=2) and transformation to DLBCL (n=4) reported after a median of 9 months (range, 5–49) after DRC; 5 of these pts had received prior alkylating agent and/or nucleoside analogue

The authors conclude that DRC demonstrated activity and a tolerable safety profile in both the front-line and salvage settings for patients with WM. This data also suggested the regimen is active in patients regardless of MYD88 mutational status. Lastly, they note that the DRC regimen is a “less expensive, limited-duration treatment option” compared to ibrutinib.

Abstract:

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 (95% confidence interval [CI]: 15-51) and 50 (95% CI: 35-60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23-not reached [NR]) and NR (95% CI: 37-NR), respectively. Twenty-five (86%) of 29 genotyped patients harbored MYD88L265P . The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well-tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients' MYD88 status.

References
  1. Paludo J. et al. Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenstrom macroglobulinemia. British Journal of Haematology. 2017 Aug 8. DOI: 10.1111/bjh.14826. [Epub ahead of print].