Effect of melphalan 140 mg/m(2) vs 200 mg/m(2) on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation-a single center experience.

Although melphalan at a dose of 140 mg/m(2) (MEL140) is an acceptable conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients, very few studies compared it to the most commonly used dose of 200 mg/m(2) (MEL200). A retrospective review of records of MM patients (2001-2010) identified 33 patients who received MEL140 and 96 patients who received MEL200. As expected, significantly higher percentage of patients in the MEL140 arm were >65 years or had cardiac ejection fraction <50%, had Karnofsky score <80, or had creatinine >2 at the time of ASCT (P≤.01). There were no significant differences in incidence of treatment related mortality and morbidity. At a median follow-up of 74 months from ASCT, there were no significant differences in relapse free survival (RFS) and overall survival (OS) between the two groups. Similar proportion had myeloma status improve to ≥VGPR at 3 months post-ASCT. Usage of post-ASCT maintenance was similar. In multivariate cox proportional hazards model, only disease status of ≥VGPR at the time of ASCT significantly improved RFS (P=.024), but not OS (P=.104). In conclusion, MM patients who received MEL140 had similar long-term outcomes to MEL200 patients despite their older age and co-morbidities.

Waldenström's macroglobulinemia associated with serum amyloid A protein amyloidosis: pitfalls in diagnosis and successful treatment with melphalan-based autologous stem cell transplant.

Waldenström's macroglobulinemia (WM) is increasingly being associated with amyloidosis particularly of the amyloid light-chain variety. We report on one of the few cases of WM associated with serum amyloid A protein (AA) amyloidosis. Autologous stem cell transplant (ASCT) is now being increasingly used for the treatment of amyloidosis, but most studies are small case series. Traditionally AA amyloid is associated with connective tissue disorders and periodic fever syndromes and has been treated by addressing the underlying condition. We present the first case of serum amyloid A being treated with melphalan-based ASCT to deal with the underlying WM and thereby control the amyloid, thus demonstrating the viability of this novel approach for the treatment of this disorder.

Aldehyde dehydrogenase as an alternative to enumeration of total and viable CD34(+) cells in autologous hematopoietic progenitor cell transplantation.

We validated the correlation of aldehyde dehydrogenase ALDH(br) cells with total and viable CD34(+) cells in fresh and thawed hematopoietic progenitor cell (HPC) products, and looked for a correlation with time to white blood cell (WBC) and platelet engraftment after autologous transplantation, using simple linear regression analyzes. We found a significant correlation between pre-freeze ALDH(br) cell numbers and pre-freeze total CD34(+) (P < 0.001), viable CD34(+) (P < 0.001) and post-thaw viable CD34(+) (P < 0.001) cell numbers. We suggest that ALDH(br) may be substituted for CD34(+) cell numbers when evaluating HPC. As post-thaw viability testing apparently adds no significant information, we suggest that it may not be necessary. Finally, neither marker correlated with time to engraftment in our patients, supporting previous data suggesting the existence of a threshold dose for timely engraftment around 2.5 × 10(6) cells/kg.

Minimal residual disease by either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell transplant is associated with poor outcome in acute myeloid leukemia.

Relapsed acute myeloid leukemia (AML) is a significant challenge after allogeneic hematopoietic cell transplant (HCT). Multiparameter flow cytometry (MFC), conventional cytogenetics (CG), and fluorescence in situ hybridization (FISH) are routinely performed on bone marrow specimens prior to HCT to assess disease status. We questioned the extent by which pre-HCT evidence of minimal residual disease (MRD) detected by these standard assays, corresponded with post-HCT relapse. We conducted a single center, retrospective study of 166 AML patients who underwent HCT. Thirty-eight of one hundred sixty-six (23%) patients in complete remission (CR) or CR with incomplete count recovery (CRi) had MRD detectable by MFC, CG, or FISH. MRD was more frequently seen in patients with poor risk karyotype at diagnosis (P = 0.011). MRD-negative patients (MRDneg) had significantly longer overall survival (OS) and relapse-free survival than patients who were MRD positive (MRDpos) (P = 0.002 and 0.013, respectively). In patients with MRDpos prior to HCT, the presence of acute graft vs. host disease (GVHD) (grade ≥ 2) or chronic GVHD significantly improved progression free survival (PFS) (hazard ratio (HR) = 0.053 (95% confidence interval (CI): 0.01-0.279), P = 0.0005) and OS (HR = 0.211 (95% CI: 0.081-0.547), P = 0.0014).

A new model to predict remission status in AML patients based on day 14 bone marrow biopsy.

Although bone marrow evaluation on day 14 after initiation of induction chemotherapy (D14 BM) is a widely accepted practice in patients with acute myeloid leukemia (AML), it has suboptimal predictive value for predicting complete remission. We retrospectively analyzed pretreatment characteristics and post-induction response in a cohort of AML patients to determine if adding clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Among 297 patients treated for AML at the single institution 183 patients (61%) had leukemia-positive D14 BM. Of those, 94 were given reinduction chemotherapy and 89 were not. Of the 89 patients who did not receive reinduction, 32 (36%) subsequently achieved complete remission (CR) or complete remission with incomplete count recovery (CRi), and 57 (64%) had persistent disease. Persistent disease after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, a history of relapsed disease before induction, and higher risk disease compared to patients who subsequently achieved CR. Age, diagnostic white blood cell count, and the D14 BM cellularity did not influence the subsequent likelihood of achieving remission in patients with a positive D14 BM. A new mathematical equation was created and resulted in a positive predictive value of 83%, negative predictive value 90% and accuracy 88% for correctly identifying remission status after positive D14 BM in AML. The accuracy of predicting response using these additional parameters was significantly higher than without (0.88 vs. 0.80, P=0.002). Our new model provides better accuracy for predicting the likelihood of achieving remission and if validated in future studies may be useful for managing AML patients.

Steps to diagnosis of a case of surreptitious intake of one of the newer direct oral anticoagulants: a case report and literature review.

Little is known about the effects of newer oral anticoagulants on various coagulation factors. When presented with a case of intentional or suspected overdose with an abnormal coagulation profile, it is imperative to have a working diagnostic algorithm to narrow the cause to a specific drug or drug class. This may become more crucial and time sensitive when dealing with a case of acute hemorrhage. Here we discuss the first reported case of what appears to be a surreptitious intake of newer oral anticoagulants and the steps leading to the diagnosis.

Outcomes of patients with myelodysplatic syndrome and chronic myelomonocytic leukemia post clofarabine failure.

BACKGROUND: The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post clofarabine is unknown. METHODS: We reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53%) patients received salvage therapy after clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments. RESULTS: Eight patients achieved complete remission (CR) and three had stable disease for an overall response rate of 19%. With a median follow-up of 3 months from clofarabine failure, 12 patients (11%) remained alive, 5 remain in CR, 4 of them after ASCT. The median overall survival post clofarabine failure was 4 months with a 1-year survival rate of 23%. CONCLUSIONS: This outcome is predictable, with patients with high-risk disease at the time of clofarabine failure having the worse survival. To date, patients with MDS continue to have a short survival after failure of all available therapies. Ultimately, patients who are candidates for additional treatments should be offered novel approaches. In conclusion, the outcome of patients with MDS and CMML post clofarabine failure is poor. The pattern is similar to patients with MDS post hypomethylating agent failure and predictable using University of Texas M. D. Anderson Cancer Center global scoring system.

XIAP antisense therapy with AEG 35156 in acute myeloid leukemia.

INTRODUCTION: AEG 35156 is an antisense oligonucleotide to X-linked inhibitor of apoptosis protein (XIAP). Overexpression of XIAP is common in acute myeloid leukemia (AML) and other cancers and is thought to cause resistance to cancer therapy. Effective treatment options for patients with relapsed or refractory AML are limited and survival continues to be poor. Targeting resistance mechanisms is expected to improve results in relapsed as well as front-line settings. AREAS COVERED: Role of XIAP in apoptosis pathways, structure of AEG 35156, mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy and review of clinical trials in AML. EXPERT OPINION: AEG 35156 in combination with standard chemotherapy was generally very well-tolerated and had shown some evidence of anti-leukemic activity in AML. The target knock down was transient and has not always correlated with response. Future studies may be done with variations in dose scheduling and with more emphasis on comprehensive pharmacodynamic studies simultaneously analyzing other inhibitor of apoptosis proteins (IAPs) and various XIAP regulators. Use of small molecule mimetics of second mitochondria derived activator of caspases (Smac) simultaneously targeting other IAPs appears to be an attractive option.

Rituximab and intravenous immunoglobulin (IVIG) for the management of acquired factor VIII inhibitor in multiple myeloma: case report and review of literature.

Acquired factor VIII inhibitor (AFI) is a rare disorder and is even more uncommon in multiple myeloma patients, with only five cases reported in literature. Solid and hematologic malignancies, autoimmune conditions, drugs, and infections are the conditions commonly associated with the development of this condition, with mucocutaneous bleeding being the most common presenting sign. Diagnosis is usually made with the laboratory finding of an elevated partial thromboplastin time aPTT that cannot be corrected by plasma mixing, and further confirmed by low factor VIII activity/antigen levels along with elevated factor VIII inhibitor levels using the Bethesda assay. Treatment is usually based on the clinical picture with factor VIII inhibitor bypass activity (FEIBA) and recombinant factor VIIa (rFVIIa) employed to control acute bleeding; steroids and cyclophosphamide to suppress the inhibitor with Rituximab, in combination with other immunosuppressants in cases not suitable for steroids, and finally wherever possible, to remove the offending drug or control the underlying pathology that might predispose to the development of this condition. This case report highlights the successful management of a myeloma patient who presented with life-threatening hemorrhagic pericardial effusion and hemarthrosis. The patient was treated with FEIBA to control the acute bleeding and then received Rituximab in combination with intravenous immunoglobulin to suppress the AFI.