Racquel Innis-Shelton

Safety of repeated un-manipulated peripheral blood stem cell haploidentical transplant for graft failure

Safety of repeated un-manipulated peripheral blood stem cell haploidentical transplant for graft failure

Abstract 1299: Effect of family history of cancer on the risk of multiple myeloma: Differences by ancestry and age of onset

Background. Multiple myeloma (MM) is the most common hematologic malignancy affecting African Americans, with a younger age of onset and standardized incidence and mortality rates that are twofold higher compared to European Americans despite the presence of clinical features, which are consistent with milder clinical course. The basis for this paradox remains poorly understood. However, evidence suggests a shared genetic susceptibility. Methods. Using 720 participants (259 confirmed MM cases; 461 age-, sex-, ancestry-matched controls) enrolled in the Molecular and Genetic Epidemiology (iMAGE) study of myeloma, we examined the risk of MM associated with a positive family history of cancer and the excess risk observed among AA patients. Family history of cancer was obtained from structured interviews and risk estimates were calculated using odds ratios (OR) and corresponding 95% confidence intervals (CI) from logistic regression stratified by ancestry and median age of MM onset (65 years). Results. Of the total participants included (42% African American), the majority reported a positive family history of cancer (80%), including solid tumors (75%), hematologic malignancies (17%) and MM (4%). A positive family history of any cancer in any relative was strongly associated with an increased risk of MM overall (OR=1.73, 95% CI 1.14-2.60; P=0.008), as well as among African Americans (P=0.03) and participants less than 65 years of age (P=0.0005). MM risk was markedly increased for participants who reported any relative with MM overall (OR=3.06, 95% CI 1.42-6.58; P=0.004) and among participants less than 65 years of age (OR=4.06, 95% CI 1.44-11.5; P=0.005). The magnitude of this effect was greater in African Americans (OR=18.6, 95% CI 2.32-148; P=0.0002) compared to European Americans, and was notable among first-degree relatives (OR=9.90, 95% CI 1.14-85.9; P=0.01). In contrast, MM risk was not significantly elevated for participants who reported relatives with any hematologic malignancy other than MM (OR=1.47, 95% CI 0.96-2.27; p=0.08) nor a positive family history of solid tumors (OR=1.36, 95% CI 0.95-1.95; P=0.09), and these estimates did not differ by ancestry, age of onset or degree of relative. Conclusions. Our observations suggest that the excess risk of MM observed among African Americans and among those with early age of onset may be attributed to shared susceptibility including underlying heritable genetic and environmental factors. Future studies are warranted to examine the relationship between family history of MM with clinical and cytogenetic factors, which are known to differ by ancestry. Citation Format: Gwendolyn I. Pruitt, Howard W. Weiner, Racquel D. Innis-Shelton, Donna Salzman, Kelly N. Godby, Vishnu B. Reddy, Fady M. Mikhail, Andrew J. Carroll, Elizabeth E. Brown. Effect of family history of cancer on the risk of multiple myeloma: Differences by ancestry and age of onset. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2014-1299

Impact of high-dose steroid premedication on the outcome of myeloablative T-cell replete haploidentical peripheral blood stem cell transplant

Haploidentical hematopoietic stem cell transplant (haplo HCT) with post-transplant cyclophosphamide (PTCy) is increasingly used for patients who lack human leukocyte antigen (HLA)-matched donors [1]. PTCy was initially used with bone marrow (BM) product [1], and subsequently with peripheral blood stem cell (PBSC) product [2, 3]. PTCy is believed to deplete the donor allo-reactive T cells that are culprit for Graft versus host disease (GVHD) [4]. Administration of corticosteroids with product infusion and PTCy is believed to interfere with proliferation of the allo-reactive T cells diminishing the anti-GVHD effect of PTCy [5]. When we started haplo PBSC transplant with PTCy in our institution in 2012, we opted to keep our standard of care administration of methylprednisolone prior to product infusion to mitigate the risk of febrile reaction. Later, we decided to change our practice and eliminate steroid premedication given the consistent practice across USA. We present a retrospective analysis of patients who received (n= 15) and did not receive (n= 14) steroid premedication with myeloablative haplo PBSC transplant and PTCy. We used fludarabine/busulfan ±TBI (2 Gy) for myeloid malignancy and either fludarabine/total body irradiation (TBI) 8 Gy or fludarabine/TBI 12 Gy for lymphoid malignancy (Fig. 1 supplementary). A total of 14 patients (48%) were African American, and 14 patients (48%) had comorbidity index (HCT-CI) ≥ 3. All patients had hematological malignancy (except one patient with severe aplastic anemia) with 12 patients (41%) not in complete remission. Disease risk index was high/very high in 12 (41%) and intermediate in 14 (48%). Patients received PTCy/tacrolimus/mycophenolate mofetil as has been previously described [1], and supportive care including prophylactic antibiotic and weekly viral surveillance. Chimerism analysis was performed on T-cell and myeloid populations. Immune reconstitution was evaluated by flow cytometric analysis of absolute count of CD3, CD4, CD8, CD16/56, and CD19-positive cells in peripheral blood on Day+ 30,+ 60,+ 100 and+ 180,+ 365. Patient characteristics are described in supplementary table 1. The median duration of follow-up of surviving patients was 36 months. Median time for neutrophil engraftment in the steroid and non-steroid groups were 14 (range 6–18) and 17 (12–55) days (P= 0.09), respectively. CI of neutrophil engraftment on day+ 28 was 93% (95% CI: 43–99) and 79% (95% CI: 43–93), respectively, which is comparable to previously reported data [6]. Median time for platelet engraftment in the steroid and non-steroid groups were 16 (range 12–40) and 22 (13–97) days (P= 0.3), respectively. CI of platelet engraftment ( ≥ 20,000/μL) on day+ 56 was 90% (95% CI: 32–99) and 79% (95% CI: 43–93), respectively. Primary engraftment failure was observed in three patients; one in steroid and two in non-steroid. These patients received fludarabine/ busulfan ± TBI (2 Gy) with two of them surviving after repeated haplo HCT as published before [7]. No primary engraftment failure noted with myeloablative TBI (8 or 12 Gy) (n= 9). All patients achieved full donor chimerism in CD3+ and CD15+ compartments at day+ 30. CI of aGVHD GII–IV on day+ 100 was 27% (95% CI: 8–51%) and 21% (95% CI: 5–46%) (P= 0.8) in the steroid and nonsteroid groups, respectively. CI of aGVHD GIII–IV on day These authors contributed equally: Ayman Saad, Alankrita Taneja.

Phase 1/2 Trial of Carfilzomib Plus High-Dose Melphalan Preparative Regimen for Salvage Autologous Hematopoietic Cell Transplantation Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma

We performed a phase 1/2 trial to investigate the safety and activity of the second-generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2 (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36 mg/m2 days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). The patients had received a median of 3 previous lines of therapy, 56% had undergone previous AHCT, and 51% had received previous K therapy. During phase 1 (n = 15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27 mg/m2 (on day -3) and 56 mg/m2 (on day -2) was used in phase 2. The rate of very good partial response after K-MEL therapy (n = 44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n = 27), 12-month progression-free survival was 66.7% and 12-month overall survival was 88.1%. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in patients with MM.

Mobilization of Hematopoietic Progenitor Cells for Autologous Transplantation Using Pegfilgrastim and Plerixafor: Efficacy and Cost Implications

Filgrastim (FIL) is the most common growth factor combined with plerixafor for autologous hematopoietic progenitor cell mobilization, but requires daily, multi-injection administration. We adopted a standardized mobilization regimen with pegfilgrastim (PEG) and upfront plerixafor, allowing for a single injection given the long half-life and slow elimination of PEG. Between 2015 and 2017, a total of 235 patients with lymphoma or plasma cell dyscrasias underwent mobilization with PEG 6 mg on day 1 and upfront plerixafor 24 mg on day 3, followed by apheresis on day 4 regardless of peripheral blood CD34+ cells. The median CD34+ cells/mm3 in peripheral blood on first day of collection was 48 and median collection yield was 7.27 × 106 CD34+ cells/kg (range, 0.32 to 39.6 × 106 CD34+ cells/kg) after a mean of 1.6 apheresis collections. Overall, 83% of patients achieved the mobilization target, and 95% reached the minimum necessary CD34+ cell yield to proceed with transplantation (2 × 106 CD34+ cells/kg). Because FIL is weight-based and dosed daily, the cost comparison with PEG is influenced by patient weight and number of apheresis sessions required. A cost simulation using actual patient data indicates that PEG is associated with lower cost than FIL for the majority of patients. Autologous hematopoietic progenitor cell mobilization with PEG and plerixafor is practical, effective, and not associated with increased cost compared with FIL mobilization.

Paradigm shifts in the management of poor-risk chronic lymphocytic leukemia

Abstract With the growing complexity of treatment options for chronic lymphocytic leukemia (CLL) and variables that influence the underlying biology of this disease, providing allogeneic stem cell transplant (alloSCT) to appropriate candidates poses a challenge for transplant physicians. Novel small molecule inhibitors hold unprecedented promise for poor-risk subgroups, which will likely alter decision-making and referral patterns for transplant. In this review, we analyze what is known and may still remain true about indications for transplant based on outcomes reported in the literature recently and over the last decade.

Telomere Length in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: Is It Ready for “Prime Time”?

Severe aplastic anemia is a heterogeneous bone marrow failure syndrome, characterized by peripheral blood pancytopenia and bone marrow aplasia. The disease affects both children and young adults. The incidence is estimated at 2per 1millionannally.1-3Early treatmentmaydeterminepatientoutcomes, thusdevelopingbetter treatments for this condition could have an important clinical implications. Immunosuppressionanduseof somenewerdrugshavebeen shown tobeeffective.4-6However, allogeneichematopoietic stemcell transplant (HSCT) canbecurative for severeaplastic anemia.7-9 Although the survival results of HLA-matched related donor andHLA-matchedunrelateddonorHSCT in leukemiaare comparable, this is not the case in severe aplastic anemia.10 The results of matched unrelated donor HSCT for severe aplastic anemiahavebeensuboptimal.Comparedwith80%to90%expected long-term survival withmatched related donorHSCT, that ofmatchedunrelateddonorHSCThasbeen39%to64%.10 Thus, further improvement of the survival results inmatched unrelateddonorHSCT insevereaplastic anemia is critically important; thus, risk factors associatedwith improved outcome need to be identified. The article by Gadalla et al11 in this issue of JAMA evaluated the association between leukocyte telomere length and outcomes inmatchedunrelateddonorHSCT for severe aplastic anemia. A telomere is a noncoding region of repetitive nucleotide at each end of the chromatid that becomes progressively shorterwith serial cellularmitosis, thus protecting telomeric (terminally located) genes during mitosis. Telomeres become shorter with cellular aging (genomic senescence).12 Based on donor telomere length distribution, the authors classified recipient and donor leukocyte telomere length as long (third tertile) and short (first and second tertiles combined) and examined the associationwith overall survival, neutrophil recovery, and acute and chronic graft-vshostdiseaseduring follow-up toMarch2013.Longerdonor leukocyte telomere lengthwasassociatedwithhigheroverall survivalaftermatchedunrelateddonorHSCT;amongpatientswho received HCT from donors with longer telomeres (third tertile,n = 113)vs shorter telomeres (first andsecond tertiles combined, n = 217), the survival probabilities were 60%vs 50% at 1 year, 58% vs 44% at 3 years, and 56% vs 40% at 5 years. Although the outcomeofmatchedunrelateddonorHSCT has been shown to be betterwith younger donors,13 the study by Gadalla et al showed that shorter donor leukocyte telomere length is an independent risk factor fromdonor age. Importantly, the authors found that recipient leukocyte telomere length was not associated with outcome after matched unrelated donor HSCT, although recipient leukocyte telomere lengthhas been shown tobe associatedwith survival after immunosuppressive therapy alone.14 Although the findings reported by Gadalla et al may help in choosing optimal donors for HSCT, many questions remainunanswered.For instance,whywassurvivalbetteramong patients who received grafts from donors with longer leukocyte telomere length?Asnotedby the authors, leukocyte telomere length is a marker of cellular replicative capacity, cellular senescence, and aging. If leukocyte telomere length were associatedwithengraftmentstatus, itwouldprovideastraightforward explanation. However, leukocyte telomere length is not associated with any engraftment characteristics such as neutrophil andplatelet engraftment or graft failure rate nor is leukocyte telomere length associated with acute or chronic graft-vs-host disease. The authors cited a report showingpossible effect of leukocyte telomere lengthonengraftment in the pediatric population.15However, in the studybyGadalla et al, the engraftment patterns seemed to overlap in the longer and shorter leukocyte telomere length cohorts and did not show any difference. In addition, if engraftment is not the reason for the survival difference,whichmechanisms account for the apparent association between leukocyte telomere length and survival? It thenstands toreasonthat thedifferencemustbeduetotransplant-relatedmortality, although the authors didnot find any relationshipbetweendonor leukocyte telomere lengthandspecific causes of death in this study. Were there less infections or less regimen-related toxicities? If there were fewer infections, is longer leukocyte telomere lengthassociatedwithmore rapid immunereconstitution?Furtherdataareneededtoclarify these issues. This observational report by Gadalla et al11 provides potentially important data and may mark the beginning of other new findings to come. Another question iswhether leukocyte telomere length is an independent risk factor for transplant outcome, particularly in any other transplant populations. The authors analyzed the outcome of matched unrelated donor HSCT for severeaplastic anemiaamongrelativelyyoungpatientsprimarily using bone marrow graft. Would similar findings occur with different type of grafts, such as peripheral blood stem cells or Related article page 594 Opinion