Robert F. Cornell

Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study

PURPOSE Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. PATIENTS AND METHODS Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). RESULTS Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m(2) or greater were associated with worsened OS. CONCLUSION Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial

BACKGROUND In the era of widespread rituximab use for Waldenströms macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenströms macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenströms macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenströms macroglobulinaemia. FUNDING Pharmacyclics LLC, an AbbVie Company.

Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity

The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.

Adult acute leukemia.

Hematological malignancies account for approximately 7% of new ancers annually. AML is the most common acute leukemia in adults. In 010, there were an estimated 12,330 new cases and 8950 deaths from ML. It accounts for about 80% of acute leukemias in adults. ALL had n estimated 5330 new cases and 1420 deaths in 2010. The total incidence f all forms of leukemia is 9.6 per 100,000. The annual incidence of AML s 2.7 per 100,000 and ALL is 1.5 per 100,000 population. Both occur lightly more frequently in men and people of European ancestry. ALL as a bimodal distribution with an early peak age of 4-5 years followed y a second peak around age 50. ALL accounts for only about 20% of dult acute leukemias, but accounts for 80% of pediatric acute leukemias.

Cardio-Oncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 109/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 109/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38–48) in GF and 40% (95% CI 35–45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78–86) vs 80% (95% CI 75–84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54–68) vs 60% (95% CI 52–67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation

Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.

Minimal residual disease testing after stem cell transplantation for multiple myeloma

Increased use of novel agents and autologous stem cell transplantation has led to a significant improvement in PFS and overall survival in patients with multiple myeloma. Despite improved treatment strategies, most patients eventually relapse due to persistent low levels of disease in the bone marrow. Increasingly sensitive methods to measure or detect such disease have been evaluated, including multi-parametric flow cytometry, PCR, next-generation sequencing and imaging modalities. The following literature review examines current methods for detecting and monitoring minimal or measurable residual disease (MRD) in the post-transplant setting. Improved methods for detecting MRD will refine the current definitions of remission and could guide treatment approaches.

Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach.

Engraftment syndrome (ES) encompasses a continuum of periengraftment complications after autologous hematopoietic stem cell transplantation. ES may include noninfectious fever, skin rash, diarrhea, hepatic dysfunction, renal dysfunction, transient encephalopathy, and capillary leak features, such as noncardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication.

Divergent Effects of Novel Immunomodulatory Agents and Cyclophosphamide on the Risk of Engraftment Syndrome after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

Engraftment syndrome (ES) is an increasingly observed and occasionally fatal complication after autologous peripheral blood stem cell transplantation (PBSCT). In this study, we demonstrate that the incidence of ES is significantly increased in patients undergoing autologous PBSCT for multiple myeloma in comparison to patients with non-Hodgkin lymphoma or Hodgkin lymphoma. Multivariate analysis revealed that age > 60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12 to 2.62; P = .013) and transplantation for multiple myeloma (HR, 2.80; 95% CI, 1.60 to 4.90; P = .0003) were associated with an increased risk of this complication. When stratified for myeloma patients only, age > 60 (HR, 1.80; 95% CI, 1.13 to 2.87; P = .013) and prior treatment with both lenalidomide and bortezomib (HR, 1.83; 95% CI, 1.11 to 3.04; P = .0001) were associated with an increased incidence of ES. Conversely, lack of exposure to cyclophosphamide from either chemomobilization or as a component of the pretransplantation therapeutic regimen increased the risk of this complication (HR, 3.05; 95% CI, 1.91 to 4.87; P <.0001). These studies demonstrate that the pretransplantation exposure of multiple myeloma patients to novel immunomodulatory agents and cyclophosphamide significantly affects the subsequent risk of developing ES.