Keren Osman

Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation.

Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus, the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review, we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document, we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem autologous HCT, post-HCT maintenance therapy, and the role of allogeneic HCT for patients with MM.

Cardiac magnetic resonance evaluation of left ventricular remodelling distribution in cardiac amyloidosis

Background Cardiac amyloidosis (CA) is associated with typical morphological features on echocardiography, including concentric LV hypertrophy (LVH). Cardiac magnetic resonance (CMR) can accurately depict anatomy in different cardiomyopathies. Our aim was to describe the morphological features and remodelling patterns of CA with CMR, and establish their diagnostic accuracy, as well as the value of traditional diagnostic criteria derived from echocardiography and electrocardiography. Methods Consecutive patients referred for CMR for possible CA were retrospectively evaluated. The diagnosis of CA was established in the presence of a positive cardiac biopsy and/or a typical pattern of myocardial late gadolinium enhancement. Morphological parameters were obtained from standard cine sequences. The presence and distribution of LVH, relative wall thickness (RWT) and LV remodelling patterns were determined. Results 130 patients (92 males (70.8%), age 64±13 years) were included. CA was diagnosed in 51 (39.2%). Patients with CA had increased LV wall thickness and LV mass index. An LV remodelling pattern different from concentric LVH was found in 42% of patients with CA, and asymmetric LVH was noted in 68.6%. A model including RWT, asymmetric LVH, and LVMI showed diagnostic accuracy of 88%, sensitivity of 67% and specificity of 86% for CA detection. Traditional diagnostic criteria for CA showed high specificity but poor sensitivity. Conclusions Asymmetric LVH and remodelling patterns different from concentric LVH are common in CA. Increased LV mass index, increased RWT, and asymmetric LVH are independently associated with the diagnosis. Traditional diagnostic criteria show poor sensitivity.

Safety and Efficacy of Triplet Regimens in Newly Diagnosed Light Chain Amyloidosis

BACKGROUND The prognosis of patients with systemic light chain (AL) amyloidosis, particularly cardiac, is poor. Treatments have been derived from multiple myeloma, but there are few studies that use triplet regimens in AL amyloidosis because of concern of greater toxicity than seen in myeloma. PATIENTS AND METHODS We conducted a retrospective review of patients with newly diagnosed AL amyloidosis who were initially treated with a triplet regimen. RESULTS For the 9 patients included, the median age was 64 years, and 8 were ineligible for stem cell transplantation. At least 2 organs were involved in 4 patients, including 7 with kidney and 4 with heart involvement, 2 of whom had New York Heart Association class 3 heart failure. All the patients received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. With a median follow-up of 13 months, 8 of 9 patients had a hematologic response, including 2 who achieved complete response, with a median time to response of 2.7 months. An organ response was seen in 7 of 9 patients, including all 4 patients with cardiac involvement. There were no deaths, and only 1 patient had progressive disease. The major toxicity observed was fluid overload and syncope, seen only in patients with heart failure, who eventually achieved a partial or complete response. CONCLUSIONS Dose-attenuated triplet regimens achieved rapid hematologic responses with manageable and reversible toxicity in patients with newly diagnosed AL amyloidosis.

A case report of secondary autograft failure due to Gaucher disease

To the Editor: Recently, Mistry et al. [1] suggested that diagnostic delays in Gaucher disease (GD) resulted in severe disease manifestations. We present a case where the delayed treatment of known GD after transplant led to secondary engraftment failure. A 69-year-old Ashkenazi male with a history of asymptomatic GD underwent autologous stem cell transplant (ASCT) for relapsed non-Hodgkin’s lymphoma (NHL) lymphoma. His GD was diagnosed with his initial presentation of lymphoma with Gaucher cells in bone marrow. His initial lymphoma was treated with rituximab, cyclophosphamide, doxorubicin, prednisolone (R-CHOP) and achieved complete remission for 3 years. Reoccurence was detected on routine positron emission tomography (PET) and he was referred for ASCT. Prior to transplant, his CBC showed a white blood cell (WBC) count of 8.9 10/L, hemoglobin of 14.1 g/dL, and platelets of 142 10/L. No positron emission tomography and computerized tomography (PETCT) was available. He received rituximab, ifosfamide, carboplatin, etoposide (R-ICE) followed by carmustine, etoposide, cytarabine, melphalan (BEAM) and ASCT. Neutrophil engraftment occurred on day þ12 but was followed by an absolute neutroprhil count (ANC) nadir of 0.85 10/L on day þ93 requiring filgrastim. Platelet engraftment occurred on day þ35, but platelets were never >45 10/L. His average hemoglobin was 9.1 g/dL despite blood transfusions and weekly epoetin alpha administration. At þ90 days, a bone marrow biopsy (see Fig. 1) showed infiltrates of Gaucher cells but no evidence of lymphoma, and GD evaluation was initiated. GD was confirmed by enzyme studies. Mutational analysis showed homozygosity for the N370S (1226G) mutation. Evaluation revealed diffuse infiltration of the femurs with increased marrow activity, mild splenomegaly (seen on PETCT with cranial–caudate measurement of 13.2 cm, normal <12 cm), osteopenia (seen on dual-energy x-ray absorptiometry (DEXA) scan with a hip bone density of 1.18), and an elevated chitotriosidase level (448 mol/mL, normal <300). The patient refused to have an MRI; therefore, liver and spleen volumes are unavailable. Enzyme replacement therapy (ERT) with imiglucerase at 60 U/kg IV every 2 weeks was started on day þ153. Peripheral counts have improved after ERT during these past 8 months. Prior to ERT, his platelets were >45 10/L, but after ERT, they have increased to >70 10/L. He has not required blood transfusions, and epoetin alpha was last needed 42 days after ERT. At 1 year posttransplant, his CBC showed an ANC of 2.07 10/L, hemoglobin of 11.4 g/dL, and platelets of 73 10/L, and a PETCT found NHL remission with a normal spleen (cranial–caudate measurement of 11.4 cm) with DEXA pending. Prior to transplant, he was asymptomatic with mild thrombocytopenia. After transplant he was pancytopenic requiring transfusion and growth factor support until the initiation of ERT. Gaucher cells were resistant to chemotherapy and may have contributed to secondary graft failure. It is interesting to speculate whether the chemotherapy, transplant, or growth factor support may have accelerated the GD phenotype by causing accelerated bone marrow turnover and increased substrate loading. In summary, patients with GD should be carefully evaluated in anticipation of high-dose chemotherapy and ASCT. ERT may be indicated in anticipation after ASCT to avoid secondary graft failure.

Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment

BackgroundThe mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells.MethodsWe used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence.ResultsWe report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21CIP1 upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78high/CD138+ MM cells from patients suggested that high levels correlated with progressive disease.ConclusionsWe conclude that Bz-surviving MM cells display a GRP78HIGH/p21HIGH/CDK6LOW/P-RbLOW profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability.

Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin.

Background. We previously showed that antithymocyte globulin (ATG) given with total body irradiation (TBI) 200 cGy and fludarabine results in high rate of donor engraftment. Its influence on acute and chronic graft versus host disease (GVHD) and on graft versus tumor effect is less known. Methods. Sixty-five patients underwent nonmyeloablative stem cell transplant with ATG, TBI 200 cGy, and fludarabine. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Forty-two patients (pts) (65%) had match related donors, 18 (27%) match unrelated, 1 (1.5%) mismatch related, and 4 (6%) mismatch unrelated donors. Results. At a median follow-up of 862 days, 24 patients (37%) developed GVHD. The median age of the patients with and without GVHD was 56 years respectively. Acute GVHD grade II-IV developed in 19 pts (29%). Fatal GVHD of liver and/or gut occurred in nine pts (14%). Forty-one pts survived more than 100 days. Five pts (12%) had chronic GVHD, two had extensive, and three had limited involvement. Relapsed disease was observed in 22 pts (34%). Infections occurred in 15 pts (23%) and were fatal in 13 (20%). Conclusions. The addition of ATG to TBI 200cGy and fludarabine resulted in a modest incidence of GVHD. The best transplant outcomes were observed in pts with lymphoid malignancies.

Myocardial Amyloid Quantification with Look-Locker Magnetic Resonance Sequence in Cardiac Amyloidosis. Diagnostic Accuracy in Clinical Practice and Histological Validation

BACKGROUND Cardiac magnetic resonance (CMR) has demonstrated its utility in the noninvasive diagnosis of cardiac amyloidosis (CA). Our aim was to evaluate the ability of standard Look-Locker sequences to quantify amyloid deposition in CA. METHODS AND RESULTS Consecutive patients referred for CMR for possible CA were retrospectively evaluated. Positive cardiac biopsy and/or typical pattern of late gadolinium enhancement were required for the diagnosis of CA. Postcontrast T1 values were obtained from Look-Locker sequences and correlated with markers of severity of disease and major events. When cardiac biopsies were available, histological validation was determined. A total of 174 patients were included. A final diagnosis of CA was reached in 37.4%. Myocardial and endocardial T1 times, as well as the respective ratios with blood and skeletal muscle, were lower among patients with CA and demonstrated good diagnostic performance. The best parameters were myocardial/blood (area under the curve  0.83; P < .001) and endocardial/blood (area under the curve 0.84; P < .001) T1 ratios. Among patients with CA, no associations were found between T1 ratios either with markers of amyloid burden or with prognostic variables. However, all T1 indexes showed significant correlations with histological quantification of amyloid deposition. CONCLUSIONS Look-Looker derived postcontrast T1 shows good diagnostic accuracy to detect CA and correlation with histological amyloid burden.