M A Gertz

Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis

This study sought to develop selection guidelines to determine the eligibility for SCT of patients with light-chain amyloidosis. Patients with biopsy-confirmed lightchain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011 were reviewed in two cohorts by date of transplantation: between 8 March 1996 and 30 June 2009 (n=410) and between 1 July 2009 and 31 December 2011 (n=89). Also evaluated were patients who died before post-transplant day 100 to determine the features predictive of early death. After 1 July 2009, fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before post-transplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) >5000u2009pg/mL died by 10.3 months. When serum troponin T was >0.06u2009ng/mL, 25% died at 3.7 months. The Mayo staging system is predictive for OS but not useful for selecting transplant recipients. Patients with serum troponin T >0.06u2009ng/mL or NT-proBNP >5000u2009pg/mL (not on dialysis) should not be considered candidates for SCT because of early mortality.

Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.

We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using CY and growth factor (n=370) or growth factor alone (n=346) before SCT. Patients receiving CY had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, two vs four sessions, respectively (P=0.001)). However, patients treated with CY required more time for engraftment of platelets and neutrophils (P<0.001 for both). For patients receiving CY, 75% achieved engraftment (defined as a platelet count of 50 × 109/l) by day 39, whereas 75% of patients not receiving CY achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with CY had a higher incidence of post transplant nonstaphylococcal bacteremia. For CY-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session. Our data suggested that CY damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment.

Monoclonal plasma cells in the blood stem cell harvest from patients with multiple myeloma are associated with shortened relapse-free survival after transplantation

We sought to determine whether circulating tumor cells in the blood stem cell harvest from patients with multiple myeloma are associated with a shortened disease-free survival. Prospective analysis was performed in 33 patients of blood obtained at leukapheresis for future transplantation. An immunofluorescence microscopy procedure identified the tumor cells by their morphology and monotypic light chain staining. Eighteen patients had increased (⩾0.2u2009×u2009106/l) monoclonal plasma cells circulating in the blood at stem cell harvest. Fifteen of the 18 have relapsed, with a median relapse-free survival of 6.2 months. Of 15 patients with <0.2u2009×u2009106 cells/l, seven have relapsed, with a median relapse-free survival of 22.5 months (P = 0.008). Patients with circulating plasma cells showed a trend toward shorter overall survival (P = 0.078). In a multivariate analysis using the bone marrow plasma cell labeling index and β2-microglobulin, the absolute number of plasma cells in the stem cell harvest achieved borderline significance for predicting relapse-free survival (P = 0.057). In conclusion, increased monoclonal plasma cells in the blood stem cell harvest are associated with a shortened relapse-free survival. This does not necessarily indicate that the circulating plasma cells were responsible for relapse. These results, however, have implications with regard to the timing of obtaining blood stem cells for patients who are candidates for ablative chemotherapy.

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy

Summary:Autologous stem cell transplant (SCT) improves survival in multiple myeloma (MM) and remains the standard of care for eligible patients. Nearly a third of patients with newly diagnosed MM fail initial therapy aimed at reducing tumor burden preceding SCT (primary refractory). It is unclear if an initial response is important for successful SCT. We evaluated our experience with SCT in 50 patients with primary refractory MM and compared it to 101 patients with chemosensitive disease receiving SCT. The study cohort had a median age of 56 years (range 29–72) consisting of 87 males (58%). A total of 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group had a response to transplant (50% or greater reduction in the M-protein). In all, 10 refractory patients (20%) and 35 (35%) in the chemosensitive group achieved a CR (P=0.06). The 1-year estimated progresion-free survival from the time of transplant for the refractory group was 70% compared to 83% for the chemosensitive group (P=0.65). The lack of response to initial induction therapy does not appear to preclude a good response to SCT. We recommend that patients with primary refractory MM be offered early SCT.

Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: A status report

Stem cell transplantation has been incorporated in the treatment of primary systemic amyloidosis for 5 years. Results reported to date suggest that the response rates are substantially better than those for patients treated with low-dose traditional melphalan and prednisone chemotherapy. Unexpectedly high mortality rates have, however, been reported with stem cell transplantation, reaching 40% in some series. This unexpectedly high mortality appears to be related to multiorgan failure of tissues infiltrated with amyloid deposits. Deaths have been reported from gastrointestinal tract hemorrhage, gastrointestinal tract perforation, sudden cardiac death, and renal failure. The best patient for transplantation appears to have single organ involvement, an age <55 years, the absence of renal insufficiency, and no symptomatic cardiac dysfunction. Patients eligible to receive stem cell transplant represent a highly selected population, and before conclusions about the efficacy of transplantation are drawn, comparison with a matched control group is necessary. Amyloidosis should be considered an indication for stem cell transplantation in the context of a clinical trial so that results can be compiled and reported for an accurate assessment of response rate, survival, relapse rates and treatment-related toxicities. Bone Marrow Transplantation (2000) 25, 465–470.

Successful treatment of POEMS syndrome with autologous hematopoietic progenitor cell transplantation

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a plasma cell dyscrasia that differs substantially from classic multiple myeloma. It is often associated with disabling polyneuropathy in younger patients. Current therapeutic approaches are frequently inadequate and leave many patients wheelchair-bound with significant deterioration in quality and length of life. We present the case of a young man with progressive disease despite conventional therapeutic approaches. We describe a novel approach to treatment with a bone-seeking radiopharmaceutical, samarium-153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell reconstitution. This approach resulted in regression of the organomegaly and skin changes and in neurologic improvement both clinically and electrophysiologically. The patient progressed from being wheelchair-bound to independent ambulation. An aggressive approach should be considered in patients with POEMS syndrome in whom standard therapeutic measures fail. Bone Marrow Transplantation (2001) 28, 305–309.

Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy.

Summary:Bone marrow (BM) angiogenesis is increased in multiple myeloma and is an important prognostic factor. However, prior studies were mainly done on patients receiving conventional chemotherapy and there is limited data on its prognostic value in patients undergoing high-dose therapy (HDT) as initial therapy. We studied BM angiogenesis in terms of microvessel density (MVD) in 88 newly diagnosed patients, who were uniformly treated, with 3–4 cycles of induction chemotherapy followed by HDT. We examined if MVD at diagnosis was predictive of response to induction therapy or to subsequent HDT. In addition, we also examined its prognostic value in these patients. The median MVD for primary refractory patients was 28 (range, 2–84) compared to 27 (range, 2–99) for responding patients (P=0.7). The median progression-free survival (PFS) was 21 months for those with high-grade angiogenesis compared to 42 months for those with low-grade angiogenesis, P=0.017. The median overall-survival (OS) from diagnosis was 40 months for those with high-grade angiogenesis and not yet reached, for those with low-grade angiogenesis, P=0.007. BM MVD at the time of initial diagnosis is an important prognostic factor for OS and PFS in patients undergoing autologous transplantation as frontline therapy for myeloma.

Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma

High-dose chemotherapy in conjunction with auto-SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 to 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was ‘optimal’ (⩾5 × 106) in 53%, ‘low’ (⩾2–5 × 106) in 25%, ‘poor’ (<2 × 106) in 10%, and ‘failed’ (<10 CD34+ cells/μl) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. This usually unappreciated resource utilization associated with stem cell mobilization failure highlights the need for more effective mobilization strategies.

Predicting PBSC harvest failure using circulating CD34 levels: developing target-based cutoff points for early intervention

PBSCs are usually mobilized using G-CSF with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and September 2008 with multiple myeloma (565; 36%), non-Hodgkins lymphoma (NHL) (562; 36%), amyloidosis (345; 22%) or Hodgkins disease (94; 6%), who were initially mobilized with single agent G-CSF. Sensitivity and specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cutoff points that predicted successful collection. In patients with plasma cell disorders, a PB-CD34 count of 11, 17, 21 and 28/μL by day 4 or 5 was required to collect a target of 2, 4, 8 or 12 million cells/kg, respectively. A CD34 yield of <0.8 million cells/kg on first apheresis also predicted for <2 million CD34 cells/kg. For patients with NHL or Hodgkins disease, a PB-CD34 count of <6 and <15/μL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million cells/kg, respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and to prevent collection failures.

Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma

Summary:Secondary myelodysplastic syndrome (sMDS) and acute myelogenous leukemia (AML) have been recognized with increasing frequency following autologous stem cell transplantation (ASCT). A retrospective analysis of 230 consecutive patients with Hodgkins lymphoma (HL, 64) and non-Hodgkins lymphoma (NHL, 166) who underwent ASCT was conducted to assess the incidence and risk factors for the development of sMDS/AML. At a median follow up of 41 months (range 0.1–177 months), 10 of 230 patients (4.3%) developed sMDS/AML. The 5-year-actuarial incidence of sMDS/AML was 13.1% and 5-year cumulative incidence by competing risk analysis was 4.2%. The median time to development of sMDS/AML was 39.9 months from the time of ASCT (range 12.1–62.0 months). Complex karyotypes at diagnosis of sMDS/AML included structural anomalies and/or loss of chromosome 5 (eight patients), 7 (five patients), 17 (two patients) and 20 (two patients). All patients subsequently died, at a median of 6.8 months (range 0–39.9) from diagnosis of sMDS/AML. Fluorescent in situ hybridization (FISH) analysis for −5/5q- and −7/7q- were normal in all six patients whose pre-ASCT bone marrow was available for testing. Five of the six had samples available for testing at diagnosis of sMDS/AML and all had abnormal FISH results. By univariate statistical analysis, male gender (P=0.01), prior alkylating agents (mechlorethamine for HL, P=0.001 and cyclophosphamide for NHL, P=0.05) and the number of prior treatment regimens (P=0.04) were significantly associated with the development of sMDS/AML. Given the relatively low incidence rate of sMDS/AML, these analyses are primarily exploratory in nature but provide some insight into relevant risk factors and illustrate the risk of developing sMDS/AML after myeloablative conditioning and ASCT for lymphoma.