Hematopoietic Cell Transplant Reduces Rate of Relapse in Patients With Waldenström Macroglobulinemia

Both autologous hematopoietic cell transplantation (AHCT) and allogeneic hematopoietic cell transplantation (allo-HCT) appeared to be effective for the treatment of patients with Waldenström macroglobulinemia (WM), inducing a 2-fold lower relapse rate in a systematic review and meta-analysis published in Clinical Lymphoma, Myeloma, & Leukemia.

“Given that the majority of the data analyzed in the study came from patients with relapsed/refractory disease, both AHCT and allo-HCT afford relatively high complete response (CR) rates when compared with established chemo-immunotherapy regimens and novel agents,” the study authors wrote. “Allo-HCT affords a circa 2-fold lower relapse rate, which is offset by a 7-fold higher nonrelapse mortality. HCT affords a shorter duration of treatment, is more cost-effective, and in the case of allo-HCT, is a potentially curative treatment modality compared with some novel agents, many of which require continuous treatment.”

Overall, 385 studies were identified for the analysis from the Medline and EMBASE databases, which included 13 manuscripts of 15 studies that met the inclusion criteria. Of these studies, 8 used AHCT in patients (n = 278) and 7 used allo-HCT (n = 311). The median age for patients who received AHCT ranged from 49 to 60 years, while the median age ranged from 43 to 57 for recipients of allo-HCT. All patients in the allo-HCT studies had relapsed/refractory disease compared with all but 2 studies in the AHCT group.

Data were collected from a comprehensive search of published literature, and there were no exclusions based on language, country of origin, or type of study. Data on clinical outcomes, such as overall survival (OS), progression-free survival (PFS), and overall response rate (ORR), as well as harms from treatment were extracted and assessed independently by 3 authors.

Overall, 58% of patients in the AHCT arm received melphalan conditioning while 41% received BEAM conditioning. In the allo-HCT arm, 48.4% of patients received myeloablative conditioning, 67% received hematopoietic stem cells from a matched sibling donor, and 81% received peripheral blood stem cells. Additionally, 9.6% of patients in the allo-HCT arm had previously undergone an AHCT. At the time of transplant, 10% in the AHCT and 33% in the allo-HCT arm were chemotherapy-refractory. The median follow-up was 20.5 months in the allo-HCT arm and 11.3 months in the AHCT arm.

Both OS and PFS were reported on in 8 AHCT studies (n = 278) and 7 allo-HCT studies (n = 311). The pooled OS rate among the AHCT arm was 76% (95% CI, 65%-86%) compared with 57% in the allo-HCT arm (95% CI, 50%-65%). In the OS analysis, the AHCT arm had moderate heterogeneity (I2 = 58.7%) compared with low heterogeneity in the allo-HCT arm (I2 = 19%). The PFS rate was 55% in the AHCT arm (95% CI, 42%-68%) with moderate heterogeneity (I2 = 67.8%), and the PFS rate was 49% in the allo-HCT arm (95% CI, 42%-56%) with low heterogeneity (I2 = 15%).

The ORR was reported in 6 studies of AHCT (n = 257) and 4 studies of allo-HCT (n = 136). The pooled ORR in the AHCT arm was 85% (95% CI, 72%-94%) with moderate heterogeneity (I2 = 71.4%), while the pooled ORR in the allo-HCT arm was 81% (95% CI, 69%-91%) with moderate heterogeneity (I2 = 46.8%). The CR rate was 22% in the AHCT arm (95% CI, 17%-28%) with low heterogeneity (I2 = 0%) and 26% in the allo-HCT arm (95% CI, 7%-50%) with high heterogeneity (I2 = 82.8%). The partial response (PR) rate was 58% in the AHCT arm (95% CI, 45%-70%) with moderate heterogeneity (I2 = 60.9%) and 50% in the allo-HCT arm (95% CI, 22%-78%) with high heterogeneity (I2 = 87.9%).

The CR rates observed in this study are impressive, according to the study authors, as CR rates greater than 10% do not typically occur with either chemotherapy or novel agents in this setting.

Among 7 AHCT studies (n = 250) and 7 allo-HCT studies (n = 311), the relapse rate was 42% (95% CI, 30%-55%) with moderate heterogeneity (I2 = 55.3%) and 23% (95% CI, 18%-28%) with low heterogeneity (I2 = 0%), respectively. The nonrelapse mortality rate was also reported on, which led to a 4% nonrelapse mortality rate in the AHCT arm (95% CI, 1%-7%) and 29% among patients in the allo-HCT arm (95% CI, 23%-34%) with low heterogeneity in both groups (I2 = 0%, each).

“The near 30% nonrelapse mortality associated with allo-HCT in our analysis raises the question of the wider applicability of allo-HCT for WM,” the study authors wrote. “However, improved patient and conditioning regimen selection as well as improvements in supportive care have allowed us to improve the outcomes of patients, especially elderly patients, undergoing both allo-HCT and AHCT.”

Allo-HCT, for example, utilizing melphalan-based reduced-intensity conditioning compared with busulfan-based or low-dose total body irradiation-based regimens has proven to be well-tolerated in elderly patients with lower relapse rates and similar survival outcomes with a variety of hematologic malignancies, which includes WM.

The rate of acute graft-versus-host-disease (GVHD) was 71% (95% CI, 54%-87%) among 5 allo-HCT studies (n = 141), which led to moderate heterogeneity (I2 = 65.8%). The rate of grade I to II acute GVHD was also observed in 4 allo-HCT studies (n = 55), which occurred in 68% of patients (95% CI, 54%-80%) with low heterogeneity (I2 = 0%). Grade III to IV acute GVHD was observed in 3 of these studies as well (n = 45), which led to a rate of 10% (95% CI, 2%-22%) with low heterogeneity as well (I2 = 0%).

Chronic GVHD was observed in 5 allo-HCT studies (n = 141), which led to a chronic GVHD rate of 51% (95% CI, 33%-68%) with moderate heterogeneity (I2 = 62.4%). Limited chronic GVHD was observed in 2 of the allo-HCT studies (n = 35), which had a rate of 28% (95% CI, 14%-45%) with low heterogeneity (I2 = 0%). Extensive chronic GVHD was observed in 3 of the allo-HCT studies ( n = 50), which led to a rate of 36% (95% CI, 19%-53%) with moderate heterogeneity (I2 = 31.2%).

WM is a rate and indolent IgM-producing lymphoproliferative disorder that is considered incurable. It is highly responsive to chemoimmunotherapy, but most patients relapse overtime. Patients with high-risk WM, in particular, have a shortened OS compared with patients considered to have low- or intermediate-risk disease. Based on this analysis, either allo-HCT or AHCT can potentially be curative in this patient population.

_Reference

_{Parrondo RD, Reljic T, Iqbal M, et al. Efficacy of autologous and allogeneic hematopoietic cell transplantation in waldenström macroglobulinemia: a systematic review and meta-analysis. Clin Lymphoma, Myeloma & Leuk. 2020. 2:(20); 30267-6; S2152-2650. doi: 10.1016/j.clml.2020.05.021}