Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplant for Patients with Multiple Myeloma: Long-Term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial.

Allogeneic hematopoietic cell transplant (HCT) may improve long-term multiple myeloma (MM) control through the graft-versus-myeloma effect. The Blood and Marrow Transplant Clinical Trials Network 0102 trial was a biologic assignment trial comparing tandem autologous transplant (auto-auto) versus autologous followed by reduced-intensity allogeneic (auto-allo) transplant in patients with newly diagnosed MM with standard-risk (n = 625) or high-risk (n = 85; ß2-microglobulin at diagnosis ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) disease. Although the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of the graft-versus-myeloma effect. Median follow-up of survivors was over 10 years. Among standard-risk patients there was no difference in PFS (hazard ratio [HR], 1.11; 95% confidence interval [CI], .93 to 1.35; P = .25) or OS (HR, 1.03; 95% CI, .82 to 1.28; P = .82). The 6-year PFS was 25% in the auto-auto arm versus 22% in the auto-allo arm (P = .32), and 6-year overall survival (OS) was 60% and 59%, respectively (P = .85). In the high-risk group, although there was no statistically significant difference in PFS (HR, .66; 95% CI, .41 to 1.07; P = .07) and OS (HR, 1.01; 95% CI, .60 to 1.71; P = .96), a reduction in 6-year risk of relapse of 77% versus 47% (P = .005) was reflected in better PFS of 13% versus 31% (P = .05) but similar OS, at 47% versus 51% (P = .69). Allogeneic HCT can lead to long-term disease control in patients with high-risk MM and needs to be explored in the context of modern therapy.

The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia.

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.

Outcomes in patients with cardiac amyloidosis and implantable cardioverter-defibrillator.

AIMS: Cardiac amyloidosis (CA) is associated with increased mortality due to arrhythmias, heart failure, and electromechanical dissociation. However, the role of an implantable cardioverter-defibrillator (ICD) remains unclear. We conducted case-control study to assess survival in CA patients with and without a primary prevention ICD and compared outcomes to an age, sex, and device implant year-matched non-CA group with primary prevention ICD. METHODS AND RESULTS: There were 91 subjects with CA [mean age= 71.2 ± 10.2, female 22.0%, 49 AL with Mayo Stage 2.9 ± 1.0, 41 transthyretin amyloidosis (ATTR), 1 other] followed by Vanderbilt Amyloidosis centre. Patients with ICD (n = 23) were compared with those without (n = 68) and a non-amyloid group with ICD (n = 46). All subjects with ICD had implantation for primary prevention. Mean left ventricular ejection fraction was 36.2% ± 14.4% in CA with ICD, 41.0% ± 10.6% in CA without ICD, and 33.5% ± 14.4% in non-CA patients. Over 3.5 ± 3.1 years, 6 (26.1%) CA, and 12 (26.1%) non-CA subjects received ICD therapies (P = 0.71). Patients with CA had a significantly higher mortality (43.9% vs. 17.4%, P = 0.002) compared with the non-CA group. Mean time from device implantation to death was 21.8 months in AL and 22.8 months in ATTR patients. There was no significant difference in mortality between CA patients who did and did not receive an ICD (39.0% vs. 46.0%, P = 0.59). CONCLUSIONS: Despite comparable event rates patients with CA had a significantly higher mortality and ICDs were not associated with longer survival. With the emergence of effective therapy for AL amyloidosis, further study of ICD is needed in this group.

Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count.

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P = .03). For low recipient ALC (10th percentile, or .56 × 102/µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 102/µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing.

Outcomes from Autologous Hematopoietic Cell Transplantation versus Chemotherapy Alone for the Management of Light Chain Amyloidosis.

Light chain amyloidosis (AL) results in tissue deposition of misfolded proteins, causing organ dysfunction. In an era of modern therapies, such as bortezomib, reassessment of the benefit of autologous hematopoietic cell transplantation (AHCT) should be considered. In this study, we compared outcomes between patients with AL receiving chemotherapy alone (CT) and those undergoing AHCT. Seventy-four patients with AL were analyzed retrospectively. Two cohorts of patients were studied, those receiving CT (n = 31) and those undergoing AHCT (n = 43). Of the 43 patients in the AHCT cohort, 29 received induction chemotherapy before AHCT, whereas 14 proceeded straight to AHCT without induction therapy. Compared with the CT cohort, patients in the AHCT cohort were younger and had higher ejection fractions, lower brain natriuretic peptide levels, and more severe proteinuria. The majority (87%) of patients in the CT cohort received bortezomib-based treatment. Transplantation-related mortality (TRM) was 7%. Patients receiving AHCT were more likely to achieve complete or very good partial response (P = .048). The median progression-free survival (PFS) and overall survival (OS) were superior in the AHCT cohort (not reached versus 9 months; P < .01 and 74 months versus 8 months; P = .03, respectively). Multivariable analysis demonstrated that improved PFS (hazard ratio, 3.86; 95% confidence interval [CI] 1.3 to 11.5; P = .02) and OS (hazard ratio, 5.6; 95% CI, 1.9 to 16; P < .001) were associated with use of AHCT compared with CT. Patients in the AHCT cohort had deeper and longer durations of response, with superior PFS and OS, compared with those in the CT cohort. Despite the limitations of this study, AHCT should be considered for eligible patients with AL at experienced transplantation centers that can offer this therapy with a low risk of TRM.

Metabolic Complications Precede Alloreactivity and Are Characterized by Changes in Suppression of Tumorigenicity 2 Signaling.

New-onset post-transplantation diabetes mellitus (PTDM) occurs commonly after allogeneic hematopoietic cell transplantation (HCT) and is associated with inferior survival. We hypothesize that PTDM and nonrelapse mortality (NRM) are related to IL-33/suppression of tumorigenicity 2 (ST2) signaling and that soluble ST2 (sST2) levels will predict PTDM diagnosis. sST2 was measured at engraftment and day +30 in 36 euglycemic HCT recipients followed prospectively for PTDM (cohort 1). Results were confirmed in a validation cohort of 26 patients without pre-existing diabetes analyzed retrospectively for PTDM (cohort 2). Twelve patients with established diabetes before HCT were analyzed in cohort 3. When compared with recipients without PTDM, patients developing PTDM (n = 24) from cohort 1 had elevated sST2 levels at engraftment (P = .02) and at day +30 (P < .01). Cohort 2 confirmed this finding at engraftment (P = .01). Cohort 3 patients with pretransplantation diabetes had higher sST2 at engraftment than patients maintaining euglycemia after HCT from cohort 2 (P = .03). Multivariate analysis of cohorts 1 and 2 showed high engraftment sST2 predicted increased PTDM and NRM risk, independent of conditioning and grades 3 to 4 acute graft-versus-host-disease. sST2 was elevated in PTDM, indicating a relationship between glucose homeostasis and the IL-33/ST2 axis after transplantation. Correction of metabolic complications may decrease sST2 and improve NRM.

Current Concepts of Cardiac Amyloidosis: Diagnosis, Clinical Management, and the Need for Collaboration.

Cardiac amyloidosis is a complex and vexing clinical condition that requires a high degree of suspicion for the diagnosis with a substantial amount of discipline to discern the extent of disease and the best available therapy. There is a complex interplay between multiple organ systems, and the clinical presentation may involve a myriad of confusing clinical symptoms. The diagnosis of cardiac amyloidosis can be confirmed with a combination of physical findings, cardiac biomarkers, noninvasive testing, and, if necessary, myocardial biopsy. Genetic testing is critical to establish the type of amyloidosis.

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.

Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

New allergies after cord blood transplantation.

BACKGROUND AIMS: Umbilical cord blood transplantation (CBT) is an effective treatment for benign and malignant diseases. Late effects of CBT are not well described in the literature. In the present study, we present our experience of new-onset allergies in long-term survivors after CBT. METHODS: After an initial patient had a severe peanut allergic reaction after CBT, all CBT patients were prospectively followed for new allergy development. Fifty patients received CBT between March 2006 and June 2011. RESULTS: The median follow-up after CBT was 447 days (range, 12-2022). At the time of analysis, 30 patients were alive, with 3-year survival of 55.5%; median follow-up of surviving patients was 910 days (range, 68-2022). The allergic syndrome developed in five patients, with the cumulative incidence of new allergies at 2 years of 18.4% (95% confidence interval, 10.8-26). The median time to onset of new allergy after transplantation was 298 days (range, 250-809). CONCLUSIONS: Allergy development has been linked to a delayed maturation of the immune system in several studies. We present the first case series of patients who had new allergies after CBT. Further study of this novel complication as well as counseling of patients after CBT would be important.

Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT. METHODS: In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1:1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and ß2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829. FINDINGS: Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0·671); overall survival also did not differ at 3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0·191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group). INTERPRETATION: Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach. FUNDING: US National Heart, Lung, and Blood Institute and the National Cancer Institute.

Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response.

Patients with follicular lymphoma (FL) typically experience an indolent course; however, the disease is rarely curable with conventional chemotherapy. Autologous hematopoietic cell transplantation (HCT) can extend progression-free survival (PFS) and overall survival (OS), but relapse is the primary cause of failure. Allogeneic HCT confers lower relapse rates due to a graft-versus-lymphoma effect. Reduced-intensity conditioning (RIC) allows the performance of allogeneic HCT with lower toxicity. The Blood and Marrow Transplant Clinical Trials Network conducted a prospective multicenter trial comparing these two strategies in patients with relapsed, chemotherapy-sensitive FL. Patients were assigned to a treatment arm based on the availability of an HLA-matched sibling donor (MSD). Those with an MSD underwent allogeneic HCT (n = 8) with the FCR preparative regimen (fludarabine, cyclophosphamide [Cy], rituximab [RTX]) and received tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Those without an MSD (n = 22) underwent mobilization with Cy, RTX, and filgrastim and received a conditioning regimen of either CBV (Cy, carmustine, Etoposide [VP16]) or total body irradiation with Cy and VP16. Patients undergoing autologous HCT received 4 doses of weekly maintenance RTX (375 mg/m²) starting on day +42 post-HCT. Sixteen patients were in complete remission, 10 patients were in partial remission, and 1 patient had stable disease after salvage therapy and before HCT. Median follow-up was 36 months (range, 1-51 months). OS was 73% in autologous HCT versus 100% in allogeneic HCT, and PFS was 63% in autologous HCT versus 86% in allogeneic HCT. No patient had grade II-IV acute GVHD; two patients developed extensive chronic GVHD. Three autologous recipients died from nonrelapse causes. This trial closed early because of slow accrual. We show that the FCR regimen is well tolerated, and that both allogeneic and autologous HCT result in promising 3-year OS and PFS in patients with relapsed FL.

Early lymphocyte reconstitution is associated with improved transplant outcome after cord blood transplantation.

BACKGROUND AIMS: Previous studies have shown that rapid recovery of the absolute lymphocyte count (ALC) is associated with improved transplant outcomes after related and unrelated donor allogeneic stem cell transplantation (allo-SCT). No consistent association has been reported between lymphocyte recovery and transplant outcome after cord blood transplantation (CBT). METHODS: We reviewed the records of 40 consecutive CBT patients at our institution to determine the impact of lymphocyte recovery on transplant outcome. RESULTS: The majority of patients (83%) received CBT for hematologic malignancies. Patients with ALC ≥150/µL at 30 days post-CBT had decreased non-relapse mortality (NRM) (P = 0.011) and improved survival (P = 0.013) compared with ALC <150/µL. Patients with ALC <100/µL at 30 days post-CBT had a significantly higher rate of graft failure than those with ALC ≥100/µL (four of 10 versus one of 29; P = 0.011). ALC was positively correlated with the nucleated cell dose and inversely correlated with the patient's age. There was no relationship between disease risk, type of conditioning regimen, anti-thymocyte globulin and number of cord units on ALC recovery. CONCLUSIONS: Our results indicate that ALC 30 days post-CBT is a surrogate for engraftment, and that low ALC (<150/µL) identifies an 'at-risk' population of patients after CBT. Studies are needed to determine ways to increase ALC cell numbers post-CBT, including ex vivo-expanded natural killer cells using adoptive immunotherapy, which might improve outcome after CBT.

Bortezomib-Based Induction Is Associated with Superior Outcomes in Light Chain Amyloidosis Patients Treated with Autologous Hematopoietic Cell Transplantation Regardless of Plasma Cell Burden.

The benefits of pre-transplant induction chemotherapy in light chain (AL) amyloidosis, a low burden plasma cell (PC) neoplasm associated with multiorgan dysfunction, is debatable, although with the availability of bortezomib, this approach is being increasingly pursued. We analyzed the outcomes of AL amyloidosis patients undergoing autologous hematopoietic cell transplant between 2014 and 2018 that were reported to the Center for International Blood and Marrow Transplant Research database. Of 440 patients, 294 received bortezomib-based induction, and 146 received no induction. Patients receiving induction had greater PC burden compared to no induction (PC 10% or more, 39% versus 11%; P < .01). At 2 years, the induction group compared to no induction had lower relapse/progression: 13% (9% to 18%) versus 23% (16% to 32%) (P = .02); better progression-free survival (PFS): 82% (77% to 87%) versus 69% (61% to 77%) (P < .01); and similar overall survival (OS): 92% (88% to 95%) versus 89% (84% to 94%) (P = .22), findings that were confirmed on multivariate analysis. A subset analysis limited to patients with <10% PC also showed superior relapse/progression (hazard ratio [HR], .43; 95% confidence interval [CI], .24 to .78; P < .01) and PFS (HR, .43; 95% CI, .26 to .72; P < .01) for induction compared to no induction. Thus, we conclude that pre-transplant bortezomib-based induction was associated with improved relapse/progression and PFS in AL amyloidosis. Longer survival follow-up is warranted, as OS was excellent in both cohorts at 2 years.

Can routine posttransplant HPV vaccination prevent commonly occurring epithelial cancers after allogeneic stem cell transplantation?

The association between squamous cell carcinoma (SCC) of the oral cavity, female genital tract, and skin with human papilloma virus (HPV) subtypes is well established in the general population and in solid organ transplant recipients, but no consistent link has been reported between HPV infection and SCC after allogeneic stem cell transplantation (allo-SCT). Studies are needed to determine if SCC, the most common secondary malignancy after allo-SCT, which is linked to chronic graft versus host disease and immunosuppressive therapy, is HPV related. Consideration should be given to assessing pretransplant HPV antibodies to identify patients at risk for HPV reactivation. If a strong relationship between HPV and second malignancies after SCT exists, studies to evaluate the immunogenicity and efficacy of quadrivalent HPV vaccine (subtypes 6, 11, 16, and 18) should be considered in both male and female long-term survivors after allo-SCT.

New-onset post-transplant diabetes mellitus after haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose≥ 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose ≥ 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.

Minimal residual disease negativity and lenalidomide maintenance therapy are associated with superior survival outcomes in multiple myeloma.

Modern combinations of therapies for multiple myeloma have led to improvement in survival outcomes with near 100% overall response rate and 25% complete response rates, particularly with autologous hematopoietic cell transplant (AHCT). Minimal residual disease (MRD) assessment with multiparameter flow cytometry is a valid prognostic biomarker for progression-free survival (PFS) and overall survival (OS). However, few data exist regarding whether MRD positivity or negativity will meaningfully influence treatment decisions. We evaluated 433 patients who received induction therapy, followed by AHCT. Participants had MRD assessment by multiparameter flow cytometry before and at days +100 and +365 following AHCT. They also received either lenalidomide, bortezomib, or no maintenance therapy following AHCT. Maintenance treatment with lenalidomide improved MRD negativity at day +365 compared to bortezomib (92.9% vs 41.6%, p = 0.01), or no maintenance therapy (92.9% vs 24.4%, p = 0.012). The median PFS for patients who were MRD negative at day + 365 was 42 vs 17.5 months (p < 0.001) and median OS was 80.6 vs 59 months (p = 0.02). Maintenance therapy following AHCT for multiple myeloma improves the depth of response as assessed by MRD.

Prolonged chronic graft-versus-host disease is a risk factor for thyroid failure in long-term survivors after matched sibling donor stem cell transplantation for hematologic malignancies.

We studied thyroid function in 81 long-term survivors of allogeneic stem cell transplantation (allo-SCT), with a median follow-up of 84 months (range, 45 to 166 months). Median age at transplantation was 35 years (range, 6 to 66). Seventy-two of the patients received a total body irradiation (TBI)-containing conditioning regimen (n = 23, 12 Gy; n = 49, 13 Gy). Twenty-one of the patients (25.9%) had subclinical hypothyroidism, and 9 (11.1%) developed overt hypothyroidism at a median of 28 months (range, 3 to 78 months) after allo-SCT. Multivariate logistic regression analysis demonstrated that prolonged immunosuppressive therapy (IST) was significantly associated with subclinical hypothyroidism (odds ratio [OR] = 3.8) and overt hypothyroidism (OR = 2.6). Antithyroglobulin and thyroid peroxidase antibody were detected in 12 of 60 patients tested (20%). No correlation was found between the occurrence of thyroid antibodies and hypothyroidism (P = .13) or chronic graft-versus-host disease (cGVHD) (P = .55). In conclusion, thyroid dysfunction is relatively common after allo-SCT and is more likely to occur in patients receiving prolonged IST for cGVHD; however, thyroid dysfunction does not appear to be related to an antibody-mediated autoimmune process.