Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 8, 2017
Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been... more Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. In spite of recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM prior to ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in t...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasm... more Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, r...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 15, 2016
Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of t... more Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transpl...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 2, 2016
Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a hig... more Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a high-risk multiple myeloma (HRM) population characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma with FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (< 45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 (17.5%) HRM patients, induction with bortezomib and immunomodulatory agents (imid) was higher compared to non-HRM (56% vs 43%, p <0.001) with similar pre-transplant complete response (CR) (14% vs 16%, p 0.1). At day-100 post-transplant, ≥ very good partial response was 59% in HRM and 61% in non-HRM (p=0.6). More HRM pat...
Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progeni... more Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months. Median age was 66 (18-72) and all had intermediate, high, or very-high risk disease. Less than 20% UCB chimerism in the CD33 lineage was associated with an increased rate of disease recurrence (54% versus 11% p < 0.0001) and decrease in one year progression-free (20% versus 55%, p = 0.004) and overall survival (30% versus 62%, p = 0.02). Less than 100% UCB chimerism in the CD3 lineage was associated with increas...
Clinical lymphoma, myeloma & leukemia, Jan 18, 2016
Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (... more Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (MF) at our institution. The median age at the time of transplant was 49 (range, 18-68) years, 74% of patients had advanced Dynamic International Prognostic Scoring System (DIPSS) scores, and 83% received reduced-intensity conditioning. With a long follow-up of our patients, we analyzed disease and transplant variables that contributed to engraftment and outcomes. Neutrophil engraftment was achieved in 27 patients (90%) at a median time of 15 (range, 10-44) days, and 19 patients (63%) achieved platelet recovery at a median time of 18 (range, 8-100) days. Splenomegaly was associated with poor neutrophil engraftment (subdistributional hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.21-0.83; P = .01) and platelet engraftment (SHR, 0.18; 95% CI, 0.07-0.48; P < .001). Increased levels of lactate dehydrogenase (LDH) was associated with poor platelet engraftment (SHR, 0.39; 95% CI, ...
Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histo... more Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDAC) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor which exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines. We performed a phase 2 trial of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment consisted of romidepsin (13 mg/m2) given as a 4 hour IV infusion on days 1, 8, and 15 every 28 days. Thirteen patients received a median of 2 cycles of therapy (range 1–7 cycles). Although no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia. We conclude that romidepsin, as a single agent, is unlikely to be associated with response rate of 30% or higher in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy.
... References: Knight R, IMiDs: a novel class of immunomodulators, Semin Oncol, 2005;32:S24–30. ... more ... References: Knight R, IMiDs: a novel class of immunomodulators, Semin Oncol, 2005;32:S24–30. Bartlett JB, Dredge K, Dalgleish AG, The evolution of thalidomide and its IMiD derivatives as anticancer agents, Nat Rev Cancer, 2004;4:314–22. ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 14, 2015
Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chai... more 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. 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). Mortality at 30 and 100 days progressi...
The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup ... more The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;poor mobilizers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; with granulocyte-colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. Significant differences (p ≤ 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.
Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different moda... more Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different modalities have been used to treat this condition. The efficacy of these agents in patients with aVWD secondary to cardiac assist devices is not fully understood. A case is reported of a patient with two risk factors for aVWD, multiple myeloma and ventricular assist device (VAD), who was successfully treated with von Willebrand factor (VWF)/Factor VIII concentrate (Humate-P, CSL Behring) during the bridge to VAD replacement. Although continued absence of high-molecular-weight VWF persisted after VWF replacement with Humate-P, the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s VWF antigen and activity increased and clinical hemostasis was achieved. The VAD clotted on a few occasions, despite a continuous heparin infusion; however, these events were resolved with temporarily holding the Humate-P. A VAD exchange was performed and the patient was successfully bridged to heart transplant. The treatment of VAD-associated aVWD may be augmented with Humate-P, and successful treatment can allow a bridge to heart transplantation. However, careful monitoring for thrombosis in the VAD circuit must be undertaken.
Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment wi... more Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.
The novel agents bortezomib and lenalidomide improve outcomes in multiple myeloma, yet most patie... more The novel agents bortezomib and lenalidomide improve outcomes in multiple myeloma, yet most patients will relapse after exhausting treatment. Management of relapsed and refractory multiple myeloma (RRMM) is challenging owing to disease-, patient- and treatment-related factors, and new therapies for these patients are required. Pomalidomide (POM) is an immunomodulatory compound that has been recently approved in the USA for the treatment of RRMM after two prior therapies, including lenalidomide and bortezomib. POM has several potential mechanisms of action and has a unique pharmacokinetic profile. Several trials demonstrate the efficacy and safety of POM in RRMM, including subjects refractory to lenalidomide and bortezomib. Herein, POM is reviewed as a clinically active new treatment option for RRMM.
Non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more Non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma and multiple myeloma are often incurable and respond to a limited set of treatment options. The selective expression of CD74, the invariant chain of the MHC class II molecule, in these malignancies provides an attractive target for antibody-based therapy. This review evaluates the preclinical data for milatuzumab, a humanized antibody targeting CD74, as a treatment for non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphomas and multiple myeloma. A review of the literature was carried out using PubMed. Current Phase I protocols using milatuzumab are summarized. Milatuzumab is cytotoxic to lymphoma and multiple myeloma cell lines and mouse-human xenografts. The efficacy dramatically increases when milatuzumab is attached to a toxin or a radioactive agent. Phase I trials of milatuzumab are now underway in human subjects with lymphoma and multiple myeloma.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 8, 2017
Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been... more Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. In spite of recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM prior to ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in t...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasm... more Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, r...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 15, 2016
Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of t... more Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transpl...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 2, 2016
Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a hig... more Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a high-risk multiple myeloma (HRM) population characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma with FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (< 45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 (17.5%) HRM patients, induction with bortezomib and immunomodulatory agents (imid) was higher compared to non-HRM (56% vs 43%, p <0.001) with similar pre-transplant complete response (CR) (14% vs 16%, p 0.1). At day-100 post-transplant, ≥ very good partial response was 59% in HRM and 61% in non-HRM (p=0.6). More HRM pat...
Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progeni... more Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months. Median age was 66 (18-72) and all had intermediate, high, or very-high risk disease. Less than 20% UCB chimerism in the CD33 lineage was associated with an increased rate of disease recurrence (54% versus 11% p < 0.0001) and decrease in one year progression-free (20% versus 55%, p = 0.004) and overall survival (30% versus 62%, p = 0.02). Less than 100% UCB chimerism in the CD3 lineage was associated with increas...
Clinical lymphoma, myeloma & leukemia, Jan 18, 2016
Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (... more Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (MF) at our institution. The median age at the time of transplant was 49 (range, 18-68) years, 74% of patients had advanced Dynamic International Prognostic Scoring System (DIPSS) scores, and 83% received reduced-intensity conditioning. With a long follow-up of our patients, we analyzed disease and transplant variables that contributed to engraftment and outcomes. Neutrophil engraftment was achieved in 27 patients (90%) at a median time of 15 (range, 10-44) days, and 19 patients (63%) achieved platelet recovery at a median time of 18 (range, 8-100) days. Splenomegaly was associated with poor neutrophil engraftment (subdistributional hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.21-0.83; P = .01) and platelet engraftment (SHR, 0.18; 95% CI, 0.07-0.48; P < .001). Increased levels of lactate dehydrogenase (LDH) was associated with poor platelet engraftment (SHR, 0.39; 95% CI, ...
Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histo... more Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDAC) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor which exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines. We performed a phase 2 trial of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment consisted of romidepsin (13 mg/m2) given as a 4 hour IV infusion on days 1, 8, and 15 every 28 days. Thirteen patients received a median of 2 cycles of therapy (range 1–7 cycles). Although no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia. We conclude that romidepsin, as a single agent, is unlikely to be associated with response rate of 30% or higher in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy.
... References: Knight R, IMiDs: a novel class of immunomodulators, Semin Oncol, 2005;32:S24–30. ... more ... References: Knight R, IMiDs: a novel class of immunomodulators, Semin Oncol, 2005;32:S24–30. Bartlett JB, Dredge K, Dalgleish AG, The evolution of thalidomide and its IMiD derivatives as anticancer agents, Nat Rev Cancer, 2004;4:314–22. ...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 14, 2015
Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chai... more 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. 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). Mortality at 30 and 100 days progressi...
The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup ... more The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;poor mobilizers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; with granulocyte-colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. Significant differences (p ≤ 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.
Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different moda... more Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different modalities have been used to treat this condition. The efficacy of these agents in patients with aVWD secondary to cardiac assist devices is not fully understood. A case is reported of a patient with two risk factors for aVWD, multiple myeloma and ventricular assist device (VAD), who was successfully treated with von Willebrand factor (VWF)/Factor VIII concentrate (Humate-P, CSL Behring) during the bridge to VAD replacement. Although continued absence of high-molecular-weight VWF persisted after VWF replacement with Humate-P, the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s VWF antigen and activity increased and clinical hemostasis was achieved. The VAD clotted on a few occasions, despite a continuous heparin infusion; however, these events were resolved with temporarily holding the Humate-P. A VAD exchange was performed and the patient was successfully bridged to heart transplant. The treatment of VAD-associated aVWD may be augmented with Humate-P, and successful treatment can allow a bridge to heart transplantation. However, careful monitoring for thrombosis in the VAD circuit must be undertaken.
Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment wi... more Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.
The novel agents bortezomib and lenalidomide improve outcomes in multiple myeloma, yet most patie... more The novel agents bortezomib and lenalidomide improve outcomes in multiple myeloma, yet most patients will relapse after exhausting treatment. Management of relapsed and refractory multiple myeloma (RRMM) is challenging owing to disease-, patient- and treatment-related factors, and new therapies for these patients are required. Pomalidomide (POM) is an immunomodulatory compound that has been recently approved in the USA for the treatment of RRMM after two prior therapies, including lenalidomide and bortezomib. POM has several potential mechanisms of action and has a unique pharmacokinetic profile. Several trials demonstrate the efficacy and safety of POM in RRMM, including subjects refractory to lenalidomide and bortezomib. Herein, POM is reviewed as a clinically active new treatment option for RRMM.
Non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more Non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma and multiple myeloma are often incurable and respond to a limited set of treatment options. The selective expression of CD74, the invariant chain of the MHC class II molecule, in these malignancies provides an attractive target for antibody-based therapy. This review evaluates the preclinical data for milatuzumab, a humanized antibody targeting CD74, as a treatment for non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphomas and multiple myeloma. A review of the literature was carried out using PubMed. Current Phase I protocols using milatuzumab are summarized. Milatuzumab is cytotoxic to lymphoma and multiple myeloma cell lines and mouse-human xenografts. The efficacy dramatically increases when milatuzumab is attached to a toxin or a radioactive agent. Phase I trials of milatuzumab are now underway in human subjects with lymphoma and multiple myeloma.
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