ASH Clinical News August 2017 v3 | Page 31

CLINICAL NEWS

Patients in the quadruplet arm ( n = 526 ) received induction therapy in 28-day cycles , consisting of :

• carfilzomib 36 mg / m 2 intravenously on days 1 , 2 , 8 , 9 , 15 , and 16

• cyclophosphamide 500 mg orally on days 1 and 8

• lenalidomide 25 mg orally on days 1-21

• dexamethasone 40 mg orally on days 1-4 , 8 , 9 , 15 , and 16

Patients in the triplet arm ( n = 2,042 ) received 28-day cycles of :

• cyclophosphamide 500 mg orally on days 1 and 8

• lenalidomide 25 mg orally ( n = 1,021 ) or thalidomide 100-200 mg orally ( n = 1,021 ) daily on days 1-21

• dexamethasone 40 mg orally on days 1-4 and 12-15

Patients in the triplet arm who experienced a very good partial response ( VGPR ) or complete response proceeded directly to autologous hematopoietic cell transplantation ( AHCT ). Suboptimal responders ( patients who achieved partial response or minimal response or had stable or progressive disease ) received additional , sequential , pre-transplant consolidation therapy with cyclophosphamide ( 500 mg on days 1 , 8 , and 15 ), bortezomib ( 1.3 mg / m 2 on days 1 , 4 , 8 , and 11 ), and dexamethasone ( 20 mg on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , and 12 ).

All patients in the analysis received a minimum of four cycles of initial induction therapy and continued therapy until maximum response . At 100 days post-AHCT , patients were randomized to maintenance therapy with either lenalidomide or observation .

At the time of data cutoff , all enrolled patients had completed induction therapy and more than half of the patients in each treatment arm had follow-up data through 100 days after AHCT ( see TABLE ).

Overall , patients received a median of five treatment cycles ( ranges not provided ) in all treatment groups .

“ Grade ≥3 hematologic toxicities differed between the groups ,” the authors reported , although p values were not provided . Rates of grade ≥3 neutropenia appeared to be highest in the lenalidomide triplet group ( 22 %), compared with the thalidomide triplet and quadruplet groups ( 12 % and 16 %, respectively ).

Grade ≥3 thrombocytopenia and anemia appeared to be more common adverse events in the quadruplet group ( 8.1 % and 10 %, respectively ) than in the triplet groups ( 3.4 % and 6.7 % for thalidomide triplet ; 4.5 % and 9.6 % for lenalidomide triplet ). But , the authors added , “ there was no statistically significant difference in rates of investigator-reported , all-grade , thromboembolic events between regimens ( 11.8 % for thalidomide triplet , 11.1 % for lenalidomide triplet , and 14.7 % for quadruplet ).”

Grade ≥2 neurologic toxicity was greater with the thalidomide-containing regimen ( 9.5 %), compared with the lenalidomide triplet ( 3.4 %) and the quadruplet ( 2.3 %) regimens ( p values not provided ).

Follow-up data indicated that patients in the quadruplet arm experienced deeper responses than the triplet arm , “ with an impressive response rate ( VGPR or better ) of 92 percent [ at 100 days post-transplant ],” compared with 77 percent and 82 percent in the triplet groups , the authors reported ( see TABLE ). This was evident at the end of first induction regimen and persisted through 100 days after AHCT ( p < 0.0001 for both ). “ These differences were observed despite the use of randomized pre-transplant consolidation for suboptimal responders to triplet immunomodulatory therapy ,” they added .

Longer-term follow-up is needed to confirm the durability of response and survival outcomes , as well as the effect of maintenance therapy . Variations among the participating centers may have limited the study ’ s findings .

Dr . Pawlyn reports financial relationships with Celgene and Takeda Oncology .

REFERENCE

Pawlyn C , Davies F , Cairns D , et al . Quadruplet vs sequential triplet induction therapy for myeloma patients : results of the Myeloma XI study . Abstract # S407 . Presented at the 22nd Congress of the European Hematology Association , June 24 , 2017 ; Madrid , Spain .

TABLE . Responses Observed in the Myeloma XI Trial According to Treatment Arm

CR 20.9 % 23.7 % 34.9 % VGPR 56.1 % 58.5 % 57.5 % PR 16.1 % 14.4 % 4.8 % AHCT = autologous hematopoietic cell transplantation

Hematopoietic cell transplantation ( HCT ) is associated with a disease-free survival rate of 90 percent at five years in patients with beta-thalassemia , when the transplant is performed during childhood with a human leukocyte antigen-identical sibling . However , long-term data on toxicity and chronic complications following HCT are limited . In a French retrospective study spanning 27 years and presented at the 22nd Congress of the European Hematology Association , Ilhem Rahal , from the Hôpital de la Timone in Marseille , France , and colleagues found that endocrinologic complications were frequent after allogeneic HCT ( alloHCT ). Fertility can be partially preserved , “ but this result has to be re-evaluated with the more recent use of intravenous busulfan ” as part of the conditioning regimen , they wrote .

The researchers identified 134 patients from a French national registry of patients with beta-thalassemia and the French Medical Society of Bone and Marrow Transplantation and Stem Cell Therapy . The analysis included 107 patients who received alloHCT between 1985 and 2012 and were alive at least two years following transplant .

The investigators assessed medical examination results , long-term treatments , and laboratory tests ( including serum ferritin , hemoglobin , liver enzymes , creatinine , and thyroid evaluation ) to determine long-term effects of alloHCT in 99 evaluable patients . Six patients were not evaluable , and two died of chronic graft-versus-host disease .

The median age at the time of alloHCT was 5.9 years ( range = 8 months to 26 years ). Most patients received bone marrow ( 85 %) from a matched sibling donor ( 90 %), and most underwent a conditioning regimen of busulfan and cyclophosphamide ( 85 %, including oral busulfan in 52 % of patients ). The median age at last visit was 19 years ( range not provided ).

Following alloHCT , patients had a median hemoglobin value of 12.5 g / dL ( range = 86-165 g / dL ) at a mean of 18 years of age ( range not provided ). Age , donor sex , and the presence of donor thalassemia trait significantly influenced hemoglobin values , the authors reported .

Chronic complications occurred in 12 percent of patients , including hypothyroidism ( n = 7 ), diabetes ( n = 5 ), and heart failure ( n = 2 ). These were “ similar to those observed in patients treated with transfusion and chelation therapy ,” the researchers noted . Two patients also experienced chronic respiratory failure related to transplant .

At the last evaluation , gonadal dysfunction was observed in 60 percent of women who were > 13 years old ; however , 12 of 27 women > 20 years old experienced at least one successful pregnancy following alloHCT . At least half of patients were receiving a long-term hormonal treatment or antibiotic prophylaxis at the time of the last visit .

After two years , most patients ( n = 93 ) had stopped their immunosuppressive treatment , and 37 patients were being treated with iron chelation therapy and / or phlebotomies .

“ A comprehensive and regular long-term follow-up should be established for all patients receiving alloHCT for beta-thalassemia major ,” the authors concluded .

The study ’ s findings are limited by its retrospective design . Treatment developments for beta-thalassemia may also limit the study ’ s implications .

The study authors report no relevant conflicts of interest .

REFERENCE

Rahal I , Galambrun C , Bertrand Y , et al . Long-term health status after HSC transplantation for thalassemia : the French experience . Abstract # S131 . Presented at the 22nd Congress of the European Hematology Association , June 23 , 2017 ; Madrid , Spain .

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