Candidates For Stem Cell Transplantation Research Articles

Gastrointestinal Primary Light Chain Amyloidosis (AL): Safety and Utility of Endoscopic Evaluation and Management of GI Bleeding

Introduction: Multiple reports have cited the potential for GIB in patients with AL. We report 2 cases demonstrating the utility and risks of endoscopy in this setting. Case 1: A 50yo F with multiple myeloma (MM) presented with recurrent hematemesis. Multiple gastric mucosal ulcers and submucosal hematomas (SMH) were found during initial EGD [1a]; biopsies confirmed AL. Repeat exam was performed prior to consideration of stem cell transplant (SCT) one year later. On scope insertion, patchy areas of scar with mottled mucosal discoloration were noted [1b]. On scope withdrawal, spontaneous development of multiple enlarging SMHs and mucosal tears were found in the gastric body related to scope +/- barotrauma not amenable to endotherapy [1c]. Clotting parameters were normal. Although no intervention was required, the patient was deemed not to be a candidate for SCT given high bleeding risk and was continued on lenalidomide. Case 2: A 69yo M with MM s/p SCT on therapy for relapse presented with recurrent hematochezia. During colonoscopy, multiple SMHs and ulcers were found with normal intervening mucosa [2]. Although negative on 3 prior occasions, repeat biopsies confirmed AL. Selective APC and endoclips had been tried without success. Bleeding continued and ultimately total colectomy was performed; unfortunately he passed soon after with complications from systemic amyloidosis. Discussion: AL results in abnormal extracellular protein deposition in various organs including the GI tract and is commonly associated with MM (>15%). Overt GIB may occur in ˜40%. Amyloid infiltration of submucosal vessels induces ischemic change and increases vascular fragility as well as rigidity of the intestinal wall, which can lead to tearing with hemorrhage. Common endoscopic findings include diffuse mucosal erosions, ulcerations, and SMHs, which can be massive. SMHs are highly suggestive of AL in the proper clinical setting, although biopsy is still required to confirm diagnosis, which can be challenging. In most reported cases, SMHs were identified on endoscope insertion and were not thought to have resulted from scope-induced trauma or shear forces associated with scope manipulation. However our experience shows that endoscopy can be traumatic and should be considered high risk. Treatment is often difficult and of limited utility. Conclusion: Guidelines for endoscopy in the setting of GI amyloidosis and GIB are lacking and these patients should be approached with caution.Figure 1Figure 2

Emerging Advances in the Management of Cardiac Amyloidosis

Amyloidosis is a disease in which proteins misfold, aggregate into fibrils, and deposit extracellularly disrupting organ architecture and function. There are two main types which affect the heart: light chain (AL) amyloidosis and transthyretin cardiac amyloidosis (ATTR). There is a misconception that cardiac amyloidosis has no effective treatment options. However, over the past decade, there has been extensive research and drug development. Outcomes are improving in AL amyloidosis with evolving chemotherapeutic regimens and novel monoclonal antibodies. In ATTR, therapies that decrease protein production, prevent dissociation, and promote clearance have the potential to slow or even halt a disease which is uniformly fatal. Selected patients may be candidates for heart and/or stem cell transplant and should be promptly referred to an experienced amyloid program. Herein, we discuss the emerging advances for the treatment of cardiac amyloidosis.

OR46 Using all your tools: Myelodysplastic syndrome (MDS) patient and potential donors HLA-C ambiguity guide us to explore outside of the exons coding the peptide binding domain of HLA-C

Aim An MDS patient has become a candidate for allogeneic hematopoietic stem cell transplantation (HSCT). Samples from patient and five donors were received for HLA typing. HLA-C results were ambiguous in the presence of HLA-C*02:06. We investigated the reason for the variation observed. Methods HLA-Class I high resolution typing was performed by SBT using the group specific strategy (Protrans®S3 HLA-C), allowing most of the alleles to be amplified individually and sequenced as hemizygous. The S3 HLA-C kit sequences the complete exons 2 and 3 of all HLA-C alleles and exon 4 of some. The kit has a locus specific reaction including “all alleles” that we always sequence, since it provides useful data to resolve several relevant ambiguities within exon 4; with the exception of the alleles not having exon 4 data available. This case was unique because some family members were assigned as HLA-C*02:06, 07: AAGAJ (07:01/07:06/07:18/07:343), and others, including the patient, were HLA-C*02:06, 07: ADCTY (07:01/07:06/07:18/07:166/07:343). Upon data review, it was noticed that the multiple NMDP codes referring to the same allele were confusing the clinicians needing to make decisions based on the HLA typing results. We re-sequenced one SBT HLA-C reaction from patient and potential donors to obtain hemizygous data of HLA-C*02:06 exon 4. Results Lack of exon 4 data of HLA-C*02:06 has caused nucleotide position 623 to be ambiguous since only the HLA-C*07:01+ alleles had exon 4 data available. Position 623 was heterozygous on “all alleles” sequencing data of exon 4. We submitted the re-sequenced exon 4 data to IMGT/HLA for review. The submission, HWS 10025170, was confirmed by the WHO Nomenclature Committee for Factors of the HLA System on 02/28/2015. Upon having HLA-C*02:06 exon 4 sequencing data confirmed, we edited the HLA typing reports, the clinicians acknowledged our effort to reduce ambiguities, facilitating their donor selection process; and we made a contribution to the HLA community making exon 4 data of HLA-C*02:06 available at the IMGT/HLA. Conclusions Ambiguities, such as this one, caused by incomplete data of HLA alleles may be prevented when all HLA alleles have complete sequences available, until then, we will keep generating the best resolution results possible using wisely the methods and tools we have available.

OR40 Site of HLA-B/C recombination identified by STR analysis and sequencing

Recombination events have been reported between HLA-A/C, HLA-B/DRB1 and HLA-DQB1/DPB1. To our knowledge no proven recombination event between HLA-B and -C has ever been found. In a sibling of a stem cell transplant candidate, the candidate and 3 siblings were typed and a pedigree with 4 different haplotypes could be established, but with very rare B-C segregation patterns (B*35∼C*05, B*44∼C*04). We performed STR analysis (Identifiler, ABI) to confirm sib relationship amongst the 4 individuals. If common HLA-B ∼C associations (B*35∼C*04, B*44∼C*05) were considered, 3 haplotypes could be identified and segregation patterns revealed one common haplotype for all individuals and the occurrence of a C/B recombination in one of the individuals. To investigate this possibility STR analysis was performed with informative markers D6S2838, D6S2851 (telomeric of HLA-A), D6S510, D6S265, D6S2931 (between HLA-A and -C), D6S2811, D6S2928 (between HLA-C and -B), MIB, D6S2792, D6S2787, D6S2920, D6S2894, D6S2883 (between HLA-B and -DRB1), D6S1666 and G51152 (centromeric of HLA-DQB1). The individual with the possible recombination event showed STR markers identical to one sibling with the same HLA-A and -C typing up to marker D6S2928, whereas the markers between HLA-B and -DRB1 and telomeric of DQB1 were identical to the other two siblings with identical HLA-B, -DRB1 and -DQB1 typing results. The region of the recombination was further narrowed by sequencing the area between HLA-B and D6S2928. This showed the recombination event to have taken place in the highly conserved sequence between 847 and 1228 bases after the HLA-B STOP codon. In conclusion, this is the first report confirming a recombination event between HLA-B and -C identified in a family of a stem cell transplant candidate.

Significance of the detection of paroxysmal nocturnal hemoglobinuria clones in patients with multiple myeloma undergoing autologous stem cell transplantation

There are reports about the presence of paroxysmal nocturnal hemoglobinuria (PNH) clones in multiple myeloma (MM), but these have been demonstrated only in red blood cells (RBCs) and the previous reports utilized an obsolete diagnostic method. We carried out a study to identify the clones by flow cytometry (FC) and to understand their clinical significance. A prospective study on consecutive patients with newly diagnosed MM who were candidates for autologous stem cell transplantation (ASCT) from 2008 to 2012. We screened peripheral blood samples by FC for CD55- and/or CD59-deficient RBC, neutrophils, and monocytes. PNH testing was carried out at diagnosis, before ASCT and 3 months after ASCT, as well as sporadically during MM remission and at disease relapse. A total of 31 patients were included in the study. PNH clones reaching a median size of 10.8% (range 4.0-18.7%) were found in 10 patients (32.3%). Clones were detected at diagnosis in nine patients and 3 months after ASCT in one patient. A correlation between the presence of the clones and subclinical hemolysis was observed. Nevertheless, the presence of the clones did not influence the overall management and prognosis of the patients. We confirmed findings of previous reports with current diagnostic guidelines and showed that although the size of the clones may be relatively large, their presence is probably not detrimental. The clinical significance of these clones and the possible mechanisms underlying their expansion in MM must be a subject of further investigation.

Overview of Pediatric Extracranial Germ Cell Tumors

Germ cell tumors the designation given to neoplasm arising from the cells of the germline, the cells that are destined to become either the egg or the sperm. These tumors have a number of unique features that includes bimodal and wide age distribution, remarkable phenotypic diversity, and varying biologic behavior. During infancy, sacrococcygeal locations predominate with either teratomas in neonates or endodermal sinus tumors in infants above three months. After puberty, non-germinomatous germ cell tumors predominate with gonadal, mediastinal or intracranial tumor. Specific subtypes of germ cell tumors secrete proteins as tumor markers. Surgical resection of the tumor is necessary to establish the diagnosis and for staging of the extent of tumor spread. Except for teratoma, germ cell tumors are highly sensitive to chemotherapy in particular cisplatin. The most commonly used chemotherapy regimen for malignant germ cell tumors is PEB (cisplatin, etoposide and bleomycin). Prognosis is good even in metastatic diseases. Patients with relapsed or recurrent disease may be candidates for high dose chemotherapy and autologous hematopoietic stem cell transplantation. pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2015.22.1.30 Clin Pediatr Hematol Oncol 2015;22:30∼37

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

AbstractBecause a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome–negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10−3 (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

Yttrium-90 Ibritumomab Tiuxetan Followed by Rituximab Maintenance as Treatment for Patients with Diffuse Large B-Cell Lymphoma Are Not Candidates for Autologous Stem Cell Transplant

Background: Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. ⁹⁰Y ibritumomab tiuxetan (⁹⁰Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. Methods: This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with ⁹⁰Y-IT (0.4 or 0.3 mCi ⁹⁰Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. Results: 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. Conclusion: The ORR of 36% with ⁹⁰Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.

Unrelated cord blood compared with haploidentical grafts in patients with hematological malignancies.

Alternative donors, such as unrelated umbilical cord blood (UCB) and related haploidentical (haplo) donors, are more and more frequently searched for and used for patients who are candidates for allogeneic hematopoietic stem cell transplantation but are without a suitable related or unrelated donor. The aim of the current retrospective study was to compare the outcome of patients after haplo and UCB grafts prepared using a nonmyeloablative conditioning regimen. A total of 150 adult patients with high-risk hematologic diseases who underwent allogeneic hematopoietic stem cell transplantation from alternative donors at 2 centers (Paoli-Calmettes Institute [Marseille, France] and Humanitas Cancer Center [Milan, Italy]) were analyzed. Sixty-nine patients had haplo donors and 81 patients had UCB donors. The cumulative incidence of nonrecurrence mortality at 1 year was 23% in the UCB group versus 17% in the haplo group (P = .39). The incidence of grade 2 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease in the UCB group versus the haplo group was 52% versus 29% (P = .05) and 12% versus 6% (P<.0001), respectively. The overall survival rate at 2 years was 45% in the UCB group (95% confidence interval [95% CI], 34%-56%) versus 69% in the haplo group (95% CI, 58%-80%) (P = .10). The progression-free survival rate at 2 years was 36% in the UCB group (95% CI, 25%-47%) versus 65% in the haplo group (95% CI, 53%-77%) (P = .01). The results of the current study suggest that for patients with high-risk hematological diseases without a related or unrelated donor, haploidentical transplants are a promising alternative option that deserves further investigation.

Serum Soluble CD25 and CD30 Levels as a Biomarker in Adult T-Cell Leukemia/Lymphoma Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Adult T-cell leukemia/lymphoma (ATL) is one of the incurable mature T-cell malignancies. Recently, younger survivors after chemotherapy are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). We compared the clinical value of soluble CD30 (sCD30) levels with soluble interleukin 2 receptor α chain (sCD25) levels in 24 ATL patients underwent HSCT at National Hospital Organization Kumamoto Medical Center. In univariate analysis of prognostic factor in patients underwent HSCT, both sCD25 (p=0.041) and sCD30 levels (p=0.0003) levels were significant predictor of overall survival in HSCT. Furthermore, sCD30 levels before the conditioning therapy turns out to predict more patients with early death (7 of 11) than were predicted by sCD25 levels (4 of 11). In addition, regarding graft-versus-host disease (GVHD), no acute GVHD or severe acute GVHD (grade III or IV) (n=10) was associated with unfavorable prognosis in contrast to the favorable prognosis associated with grade I and II (n=14) (hazard ratios=8.2, 95% confidence intervals 2.4–28, p=0.0007). It is thought that sCD30 is a useful biomarker to predict the risks involved with HSCT.

Successful Stem Cell Mobilization with High-Dose Cytarabine Plus G-CSF after Lenalidomide Therapy for Multiple Myeloma - a Series of Four Cases

Of late years, newly developed agents, such as bortezomib, lenalidomide, thalidomide, are widely used for treatment against multiple myeloma. After induction therapy, candidates for autologous stem cell transplantation are supposed to be followed by stem cell harvesting. There are several reports showing lenalidomide has a negative impact on stem cell mobilization. This opinion tends to let us refrain from using lenalidomide on the myeloma patients who are eligible for transplantation, even lenalidomide is expected promising. We experienced a series of three clinical cases presenting that stem cells were poorly mobilized with cyclophosphamide (CY) plus G-CSF after lenalidomide treatment, but sequential stem cell mobilization was incredibly improved with high-dose cytarabine plus G-CSF. One additional case who was treated with lenalidomide also presented successful stem cell mobilization with high-dose cytarabine plus G-CSF. Here we show all four cases in detail.Case 1: 66 years old male, symptomatic myeloma after smoldering period. After three course of bortezomib induction, the response was insufficient. Sequentially he was treated with lenalidomide (25mg/day, every day for three weeks with one week rest period) and dexamethasone (Dex) (40mg/day, weekly) for two courses, and finally achieved Partial response (PR). First peripheral blood stem cell harvesting was attempted with high-dose CY (2.0 g/m2, day1-2) + lenograstim (5mg/kg daily, on days 7 until leukapheresis), but mobilization was unsuccessful so harvesting was not performed. For subsequent mobilization, high-dose cytarabine was administered at a dose of 2.0 g/m2 twice daily (day1-2) + lenograstim. Second mobilization was markedly improved, and finally 33.0 x 106/kg CD34+ cells were obtained.Case 2: 63 years old male, symptomatic myeloma, IgG type. This patient was treated with bortezomib, CY and Dex but resulted in disease progression. As an alternative therapy, lenalidomide (10mg/day, daily for three weeks with one week rest) and Dex (40mg, weekly) were used for three cycles. The dose of lenalidomide was reduced due to renal dysfunction. PR was obtained, then first harvesting was attempted with high-dose CY + lenograstim, as case 1, and 0.088 x 106/kg of CD34+ cells were collected, which was not sufficient for transplantation. Second mobilization was performed with high-dose cytarabine as case 1, and consequently we could obtain 60.1 x 106/kg of CD34+ cells; the yield was dramatically improved.Case 3: 41 years old female, symptomatic myeloma after one year course of smoldering myeloma. As an induction therapy, bortezomib, CY and Dex were selected, but finally she could not achieved PR after three cycles. We gave up bortezomib-based induction, and then lenalidomide (15-25 mg on day1-21 with 1 week rest) and Dex (40 mg, weekly) were administrated for five courses, followed by PR. As previous two cases, the first peripheral stem cell collection was initiated with high-dose CY + lenograstim, and it was not sufficient (0.059 x 106/kg of CD34+ cells). And the second mobilization with high-dose cytarabine with lenograstim recovered the yield of stem cell up to 6.90 x 106/kg.Case 4: 63 years old male, symptomatic myeloma. He was treated with bortezomib, Dex with/without CY, but this regimen was not very effectual, and CY caused elevation of aminotransferase (CTCAE grade 3). Then lenalidomide (10-15 mg on day 1-21) and Dex (40 mg, weekly) were administrated for four courses, and the patient achieved PR. Due to the adverse effect of liver dysfunction, we could not use high-dose CY for mobilization. For this case, high-dose cytarabine was selected for first mobilization, and it was very successful, 50.2 x 106/kg of CD34+ cells were harvested. The yields of PBSC from all four cases are summarized on Table 1.These four cases suggest mobilization with high-dose cytarabine could be an alternative option for poor mobilizer of myeloma patient treated with lenalidomide-based induction. This fact may enable us to choose lenalidomide, not only bortezomib, for induction even for transplant-eligible cases. [Display omitted] DisclosuresIshiko:Celgene: Honoraria.

Relevance of a One-Year Maintenance Therapy with Interleukin-2 in the Treatment of Childhood Acute Myeloid Leukemia: Results from the French Multicenter, Phase III, Randomized Controlled Sfce Trial, ELAM02

▪Background: Childhood acute myeloid leukemia (AML) remains a challenging disease as the outcome is still poor despite major improvement over the past decades; current survival rates are around 70% but event free survival (EFS) is only about 50%. No benefit of standard maintenance chemotherapy has been proven after intensive induction/consolidation chemotherapy.Objective: To determine whether the addition of a one-year maintenance therapy using interleukin-2 (IL-2), known to stimulate antitumor immunity, decreases the risk of relapse and improves EFS in pediatric AML.Methods: ELAM02 trial was designed to recruit patients aged from 0 to 18 years, diagnosed with primary AML. Children with acute promyelocytic leukemia and Down Syndrome were not included. The treatment consisted of one induction course (cytarabine and mitoxantrone) and three consolidation courses (course 1 and 3 with high dose cytarabine); all children without t(8;21) were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 courses of consolidation if a geno-identical donor was available; children with poor-prognosis karyotype were also candidates for HSCT with pheno-identical donor.The patients not receiving HSCT and in continuous CR after the third course of consolidation were eligible for randomization for a one-year maintenance therapy consisting in monthly courses of IL-2. IL-2 (Proleukin®, Chiron, Novartis) was given subcutaneously at 2.5 MUI/m² on day 1 and at 5 MUI/m² from day 2 to 5. Cycles were planned to be given monthly for up to 12 cycles. In case of side effects such as severe (grade ≥ 3) clinical toxicities (fever >40°C, hypotension requiring IV fluids) and/or severe biological toxicities (thrombocytopenia (grade ≥ 3), renal dysfunction (grade ≥ 2), liver dysfunction (grade ≥ 3)) doses of IL-2 was lowered of 50%. In case of persistent side effects, treatment was discontinued. The control group received no maintenance treatment.Results: The 28 French SFCE centers participated to the study, leading to the enrollment of 441 patients from March 2005 to December 2011. Among the 441 enrolled patients, 3 patients were excluded due to non-conformity of inclusion criteria; 392/438 (89%) were in CR after the first consolidation course and 116 (30%) were allografted in CR1. Out of the 241 eligible patients for randomization, i.e. still in CR after the third course of consolidation, 154 (64%) were actually randomized for maintenance therapy; causes for non-randomization were either parents refusal (n=50, 21%) or medical decision (n=37, 15%). Median follow-up is 5 years. The characteristics of the randomized patients at diagnosis were as follows: [Display omitted] Median number of IL-2 cycles administered was 12 [5-12], the mean being 8.6 ± 4.2. Among the 77 patients receiving maintenance therapy, IL-2 was stopped before cycle 6 in 20 patients (26%) and after cycle 6 in 18 (23%); 39 patients (51%) received 12 cycles. Treatment was stopped because of relapse occurrence (n=15), severe persistent toxicities (n=6) or parents or medical decision (n=17). The most frequent toxicities related to IL-2 treatment were fever, chills, and cytolytic hepatitis; no toxic death related to IL-2 therapy was observed. Incidence of relapses in IL2+ group and IL2- group were 36% (n=28) and 38% (n=29) respectively. The 5-year disease free survival (DFS) was 62 % (95% CI 51-73) for the IL2- group vs. 64% (95% CI 53-75) for the IL2+ group (p=0.74). Among the CBF population, a trend in favor of the IL-2 treatment was observed as the 5-year DFS was 57% (95% CI 43-71) for the IL2- group vs. 78% (95% CI 63-94) for the IL-2+ group (p=0.08).Conclusion: A prolonged administration of IL-2 as maintenance therapy after intensive chemotherapy is feasible in pediatric AML patients in first CR but did not improve DFS in this study. DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Lenalidomide in Combination with Low-Dose Dexamethasone in Japanese Transplantation-Ineligible Newly-Diagnosed Multiple Myeloma Patients

Introduction: Lenalidomide (LEN) plus low-dose dexamethasone (Rd) has been shown to be effective and to have a manageable safety profile in non-Japanese patients (pts) with newly diagnosed multiple myeloma (NDMM) (Rajkumar, Lancet Oncol 2010). Recently, the FIRST trial showed prolonged progression-free survival (PFS) and favorable overall survival (OS) benefits for pts who were administered continuous Rd until progressive disease (PD) vs. the standard of care melphalan-prednisolone-thalidomide (Facon, Blood 2013). In Japan, the combination of melphalan- prednisolone -Velcade®(MPV) is the current standard of care for transplant-ineligible NDMM pts. However, prolonged treatment (Tx) with MPV is associated with increased toxicity including peripheral neuropathy (PN) and bone marrow suppression. Consequently, continuous Tx with MPV may have limited benefits due to toxicity and related Tx discontinuation. MM-025 is a phase 2, multicenter, open-label, registration, single-arm trial. It aimed to evaluate the efficacy and safety of the continuous Rd regimen in Japanese NDMM pts who are transplant-ineligible.Methods: The study enrolled Japanese NDMM pts who were aged ≥ 65 years (yrs), or were not candidates for hematopoietic stem cell transplantation. Pts with an ECOG performance status (PS) score > 2 or with grade ≥ 2 PN were excluded from the study. Tx consisted of LEN (25 mg once daily on days 1–21 of each 28-day cycle) and dexamethasone (40 mg for pts aged ≤ 75 yrs or 20 mg for pts aged > 75 yrs, once daily on days 1, 8, 15, and 22 of each 28-day cycle) until PD or discontinuation. The dose of LEN was adjusted according to baseline renal function: 25 mg/day for pts with normal or mild renal impairment (RI) (creatinine clearance [CrCl] ≥ 60 mL/min); 10 mg/day for moderate RI (CrCl ≥ 30 to < 60 mL/min); and 15 mg every other day for those with severe RI (CrCl < 30 mL/min, not requiring dialysis). Pts who discontinued Tx were followed up every 2 months (mos) for ≥ 5 yrs from the start of Tx. The primary endpoint was overall response rate (ORR; defined as complete response [CR] + very good partial response [VGPR] + partial response [PR]) based on the IMWG criteria. The secondary endpoints included time to response (TTR), duration of response (DOR), PFS, OS, and safety. Statistical analyses included the one-sample binomial test for ORR and Kaplan-Meier analysis for DOR, PFS, and OS. The data cutoff date for this analysis was November 2013.Results: A total of 26 pts were enrolled. Of these, 46.2% of pts (n = 12) were aged > 75 yrs, 50.0% (n = 13) were male, 19.2% (n = 5) had ISS stage III disease, 23.1% (n = 6) had an ECOG PS score of 2, and 7.7% (n = 2) had severe RI (CrCl < 30 mL/min). With a median follow-up of 7.4 mos, the median Tx duration was 6.4 mos. The ORR was 83.3%, including VGPRs (12.5%) (n=3) and PRs (70.8%) (n=17). The median TTR was 2.0 mos. Due to the short follow-up DOR, PFS, and OS were not reached at data cutoff. The most common grade 3–4 adverse events (AEs; reported in > 10% of pts) were anemia (19.2%), neutropenia (15.4%), and rash (11.5%). The most frequently reported AEs (≥ 20% incidence) were rash, constipation, anemia, nasopharyngitis, and insomnia. A total of 8 pts (30.8%) discontinued the study: 4 due to AEs, 3 through the investigator’s decision and 1 due to protocol deviation. No deaths, thromboembolic events, or second primary malignancies were reported.Conclusion: Continuous Rd was effective and well tolerated by Japanese transplant-ineligible NDMM pts. These findings are consistent with those reported in the FIRST trial (Facon, Blood 2013) and support the use of the Rd combination regimen as a first-line Tx for this pt group. DisclosuresOff Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Taniwaki:Celgene Corporation: Honoraria, Research Funding. Iida:Celgene K.K.: Honoraria, Research Funding. Matsumura:Celgene: Honoraria. Ogaki:Celgene K.K.: Employment. Midorikawa:Celgene K.K.: Employment. Houck:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.

Assessment of Incidence Toxoplasma Gondii Infection and Outcomes in Allogeneic Stem Cell Patients

BackgroundToxoplasma gondii infection is a catastrophic infectious complication with a high rate of mortality in immune compromised patients and particularly stem cell transplant (SCT) recipients. Incidence of infection is variable from 0.1 % to 6% and higher in Europe and Latin America compared to US. Mortality rate is 60-90% in SCT patients compared to 30% in AIDS patients (Clin Infect Dis 2005;40:67–68). Most cases of toxoplasmosis among SCT recipients are due to disease reactivation from previously acquired infection. Per ASBMT guidelines of 2009, incidence of clinical reactivation is 2-6% of seropositive recipients, and cord blood recipients are at highest risk. Allogeneic SCT candidates should be tested for toxoplasma IgG antibody and patients who are seropositive should be treated empirically if develop CNS or pulmonary lesions. The introduction of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis (Br J Haematol 2002;117:370–386) has led to a decrease of toxoplasmosis, however patients can still develop infection while on TMP/SMX. This is a rare infectious complication in recipients of allogeneic SCT, and can be difficult to diagnose.MethodsWe retrospectively reviewed patients who received an allogeneic (allo) SCT at MD Anderson from 1994 to 2013. In period from 1994-2009 routine serologic testing for toxoplasma was not done and from 2010 – 2013 SCT patients were routinely tested for toxoplasma IgG antibody. Diagnosis made in first cohort by: autopsy (3), brain biopsy (4), PCR CSF and cytopathology (1), PCR blood (1). Diagnosis in second cohort was made by PCR blood (5), PCR CSF (5), autopsy (1), characteristic findings on imaging + improvement on therapy (1).ResultsFrom 1994-2009 nine of 3623 allo SCT patients had a clinical toxoplasma infection, of which 4 were international patients and 5 were from the US; total incidence of 0.25%; 4/246 international patients: 1.6% and 5/3380 US patients 0.15% (p=0.002). In time period from 2010-2013 of 1047 transplanted patients, 9 cases of toxoplasma diagnosed of which 3 patients from high incidence countries. Time to presentation is bimodal; early (1 month) and late (3-6 months) post transplant.From 1994-2009, 9 patients presented with toxoplasma infection of which 8 died - 3 presented with disseminated infection/pulmonary symptoms while 6 had neurologic symptoms. Type of donor: matched related donor (MRD) (6), matched unrelated donor (MUD) (1), haploidentical donor (2).In the 2nd cohort 2 cases didn’t have serology done but serology in entire patient population revealed toxoplasma IgG (+) equaled 97/1047 (9.2%), clinical cases of all tested patients, 7/1047 (0.7%) and all clinical cases with positive toxoplasma IgG pretransplant 7/97 for an incidence of 7.2%.From 2010-2013, 9 patients presented with toxoplasma infection, 4 died of toxoplasmosis while 5 survived of which 1 died of relapse. Five patients presented with sepsis, 2 with pneumonia and 1 with myocarditis, while 8 patients had CNS symptoms including meningoencephalitis and classic presentation of brain lesions. Six patients had concomitant CMV reactivation and 3 were on corticosteroids. Remaining patients had no other predisposing conditions. Type of donor: MRD (1), MUD (5), haploidentical (2), cord blood (1). Three cases were second transplants and all those patients died. The 5 patients who survived all received treatment within 6 days of presentation. (Table 1)ConclusionsThe most common presentations of toxoplasma infection in SCT patients are meningoencephalitis and sepsis. Only 2 patients in our most recent patient population had classic brain disease. Five of nine survived in our more recent cohort compared to 1/9 in previous time period. It appears that delayed treatment (³6 days) may be related to increased mortality. Although toxoplasma infection in SCT patients carries a high mortality, identifying patients at higher risk and early treatment may improve outcomes.TABLE 1Type of transplantSCT to illnessSite of infectionDays to TreatmentPrimary Cause of DeathMUDSCT33Sepsis/Pneumonia6Protozoal infectionMUDSCT (2nd)94Brain4MUDSCT100Meningoencephalitis2MUDSCT166BrainUNKHAPLO34Sepsis/CNS4HAPLO (2nd)165Sepsis/CNSNO TXAutopsy: Cardiac/Lung/CNS ToxoMUDSCT13Sepsis/ meningoencephalitis6Autopsy: Recurrence/persistence of diseaseCord30Sepsis/Meningitis7Protozoal infectionAlloMRD (2nd)10Meningoencephalitis8Protozoal infection DisclosuresNo relevant conflicts of interest to declare.

O2-4-5 - Bortezomib Combined Chemotherapy for Multiple Myeloma Patients Who are Candidate for Autologous Stem Cell Transplant

Background: Novel agents for multiple myeloma (MM) have been reported to increase complete remission (CR) rates compared with conventional chemotherapy. It is also estimated that deeper remission may improve survival in MM patients. We retrospectively evaluated the efficacy of novel agents combined induction chemotherapy to treat MM patients who are candidate for autologous stem cell transplant (ASCT).Patients and methods: Thirty seven newly diagnosed MM patients who underwent ASCT at our hospital from April 2004 to September 2012 were retrospectively analyzed. The 20 patients who underwent ASCT before July 2009 were treated with conventional induction Chemotherapy: doxorubicin, vincristine, dexamethasone (VAD) or cyclophosphamide plus VAD (C-VAD), and the recent 17 patients were treated with bortezomib and dexamethasone (BD) followed by ASCT.Results: The median age of patients were 61yr (range: 46-70). The median follow up time was 1041 days (range: 25-2804). There were no significant differences in the patient characteristics between those two groups other than the year of transplant. CR rate was significantly higher in BD group compared with conventional treatment group (56.3% vs. 15.0%, p < 0.001). The two-year overall survival is significantly improved in BD group and compared to VAD/C-VAD group (100% vs. 70% p = 005). The same trend is observed in two-year progression free survival (87.5% in BD group vs. 45.0% in VAD/C-VAD group), though it was not statistically significant (p = 0.17). In multivariate analysis, also, BD induction chemotherapy significantly improved CR rate (Odds ratio = 24.1, p < 0.01).Conclusion: Bortezomib combined induction chemotherapy for MM may improve survival by achieving deeper remission in ASCT setting.

P130 : CONFIRMATION OF AN ALLELE DROPOUT DEPENDANT ON DNA SOURCE

Aim Whenever homozygous alleles are encountered by sequence-based typing (SBT), it is our protocol to confirm by another typing method that allele dropouts have not occurred. We present a case where DNA extracted from peripheral blood was homozygous for an HLA-A locus when tested by SBT. This assignment was confirmed by SSP. However, follow-up testing with buccal swab extracted DNA resulted in the detection of an additional HLA-A allele. Methods A patient with T-cell large granular lymphocyte leukemia (TLGL) was initially typed by SBT (Life Technologies SeCore) for HLA-A, B, C, DRB1, DQB1, and DPB1 using DNA extracted from peripheral blood. We subsequently typed six siblings as potential donors by SBT for A, B, and DRB1 loci using buccal swab extractions. Results The typing assignments of sibling donors led us to further investigate the typing of the patient when trying to establish family haplotypes. The recipient was typed as A ∗ 02:05 homozygous, which was confirmed by SSP (Invitrogen). However, the family study suggested that A ∗ 68:01 had dropped out of the recipient. We noticed very low peaks at the positions that assigned A ∗ 68:01 in the SBT software. We ordered a buccal swab on this patient in order to clarify the family study. (Interestingly, this patient’s diagnosis is linked to deletions in chromosome 6.) The buccal swab extracted DNA revealed A ∗ 68:01 in SBT typing, demonstrating that the A ∗ 68:01 had indeed dropped out in the peripheral blood. Conclusion Using buccal swab- extracted DNA is recommended when confirming homozygous assignment and allele dropouts for stem cell transplant candidates who are originally typed by peripheral blood extracted DNA.

Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal.

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

Recent developments in drug therapy for aplastic anemia.

This article reviews recent developments in immunosuppressive therapy (IST) for aplastic anemia (AA) patients who are not candidates for stem cell transplant (SCT); including, front-line, salvage, and novel treatment options with a focus on response rates (RRs) and overall survival (OS). A PubMed literature search was performed from 1977 to June 2014 using the search terms aplastic anemia, horse antithymocyte globulin (hATG), rabbit ATG (rATG), thymoglobulin, and cyclosporine (CSA). Additional references were identified from a review of literature citations. All English-language studies investigating IST for treatment of AA in non-SCT candidates were evaluated. Studies indicate addition of CSA and corticosteroids to hATG for treatment of AA improves RRs, decreases relapse rates, and improves 5-year OS. hATG improved RRs, relapse rates, and OS compared to rATG in the front-line setting. Studies support the use of rATG when front-line IST with hATG fails or when hATG is unavailable. Front-line daclizumab can be considered for nonsevere AA (NAA); however, data is limited. Alemtuzumab or eltrombopag are options for relapsed AA in select patients. hATG with methylprednisolone and CSA is recommended for front-line treatment of AA, whereas rATG is reserved for salvage therapy. Front-line use of daclizumab has been studied in NAA patients, but additional prospective trials are needed before this is adopted into clinical practice. Alemtuzumab and eltrombopag have been studied for treatment of AA; recruiting is ongoing in clinical trials to assess the appropriate dosing strategy and place in therapy.

Indications actuelles de l’allogreffe de cellules souches hématopoïétiques dans le traitement de la leucémie aiguë myéloïde de l’adulte

Allogeneic stem cell transplantation (SCT) is an increasingly important therapeutic option for the treatment of adult patients with acute myeloid leukemia. Here we review the current indications of SCT in this disease. While patients with favorable cytogenetics should receive consolidation chemotherapy, patients with unfavorable karyotype are prime candidates for SCT or new approaches to SCT (which should be done in first complete remission). Patients with intermediate prognoses should also receive SCT in first complete remission. In the absence of a suitable matched related donor, most patients will be able to find an alternative donor to proceed to a potentially curative allogeneic transplantation. The use of reduced-intensity conditioning regimens before SCT has allowed patients in the sixth or seventh decades of life to be routinely transplanted. Despite major differences among transplant centers in the intensity and composition of the conditioning regimen and immunosuppression, choice of graft source, postgraft immune-modulation, and supportive care, there has been a dramatic improvement in terms of tolerance. Although it is presumed to be a curative strategy, major complications of SCT remain graft-versus-host disease, delayed immune recovery, multiple comorbidities, and relapse after transplant.

Noninvasive Measurement of Liver Fibrosis Using Transient Elastography in Pediatric Patients with Major Thalassemia Who Are Candidates for Hematopoietic Stem Cell Transplantation

Although liver biopsy is an invasive procedure, it remains the gold standard technique for the evaluation of hepatic fibrosis in different patients, including those with major thalassemia (MT). Recently, noninvasive imaging techniques, such as transient elastography, have emerged. We investigated the effectiveness of TE, in comparison to liver biopsy, for the evaluation of liver fibrosis in pediatric patients with MT who were candidates for hematopoietic stem cell transplantation (HSCT). Eighty-three pediatric MT patients (48 boys and 35 girls), who were candidates for HSCT, were included in this study. The median age was 8 years. Liver stiffness was assessed for all patients, before transplantation, using both TE, measured in kilopascals (kPa) and liver biopsy, based on the Metavir score. The diagnostic accuracy of TE and liver biopsy were estimated using linear discriminated analysis (the area under the receiver operating characteristic curves [AUROCs]). The median TE score was 4.3 kPa (range, 3.5 to 5.2). The TE value did not differ among patients with different ferritin levels (P = .53). TE increased proportionally to Metavir fibrosis stages (P < .001) and the necro-inflammatory grade (P < .001). The TE score also correlated to liver iron content (P < .001), liver size (P < .003), and Lucarelli risk classification (LRC) (P < .001). ROC curve analysis revealed moderate accuracy of the TE score for the diagnosis of fibrosis (AUROC = 73%) and for distinguishing individuals with a LRC III from those classified as I and II (AUROC = 82%). The TE score was also superior to Fibrosis-4 (AUROC = 61%) for the assessment of liver fibrosis and LRC differentiation. The results of this study demonstrated that TE can be a valuable method for assessing liver fibrosis and differentiating LRC III from the other 2 classes in pediatric patients with MT who have been selected for HSCT.