Adriana C Rossi

BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long term lenalidomide therapy in previously untreated patients with multiple myeloma

The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.

Cord blood chimerism and relapse after haplo-cord transplantation

Abstract Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months. Median age was 66 (18–72) and all had intermediate, high, or very-high risk disease. Less than 20% UCB chimerism in the CD33 lineage was associated with an increased rate of disease recurrence (54% versus 11% p < 0.0001) and decrease in one year progression-free (20% versus 55%, p = 0.004) and overall survival (30% versus 62%, p = 0.02). Less than 100% UCB chimerism in the CD3 lineage was associated with increase rate of disease recurrence (46% versus 12%, p = 0.007). Persistent haplo-chimerism in the CD3 lineage was associated with an increased rate of disease recurrence (40% versus 15%, p = 0.009) Chimerism did not predict for treatment related mortality. The cumulative incidence of acute GVHD by day 100 was 43%. The cumulative incidence of moderate/severe chronic GVHD was only 5%. Engraftment of the umbilical cord blood grafts provides powerful graft-versus-leukemia (GVL) effects which protect against disease recurrence and is associated with low risk of chronic GVHD. Engraftment of CD34 selected haplo-identical cells can lead to rapid development of circulating T-cells, but when these cells dominate, GVL-effects are limited and rates of disease recurrence are high.

Haplo-cord transplant: HLA-matching determines graft dominance

Haplo-cord transplantation combines the infusion of CD34 selected third party cells from a haplo-identical donor, with an umbilical cord blood (UCB) graft from an unrelated donor.[1–5] In a majority of the cases, initial engraftment from the haplo-identical donor is superseded by dominance of the UCB graft. But in some cases, only the haplo-graft persists. In previous studies, we found that patients who received very high CD34 doses from the haplo-identical donor had impaired/delayed UCB engraftment.[6] More recently, we have limited the cell dose of the haplo-graft to 3–5 10 CD34/kgrec. But occasional cases of haplo-dominance continue to occur. Here we attempted to determine the additional graft and conditioning characteristics that influence the interaction between haplo-graft and cord blood graft and the eventual long-term dominance of one graft over the other. All the patients were enrolled in a prospective study of reduced intensity conditioning and haplo-cord transplantation. The study was approved by the Institutional Review Board of Weill Cornell Medical College and all patients and donors provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and registered on clinical trials.gov (NCT01810588). Cord blood units (CBUs) were selected based on human leukocyte antigen (HLA) typing and cell count. As of mid-2012, we utilized high-resolution HLA typing for HLA-A, B, C, and DR for cord graft selection.[7] In contrast with common practice, we prioritized matching over cell dose and established a minimum cell count of 1.2 10 nucleated cells/kg of the recipient’s body. After collection and prior to cryopreservation, haploidentical grafts were T-cell depleted using the Miltenyi CliniMACS device under an Investigational New Device (IND) permit from the United States Food and Drug Agency. The infused cell dose of the haplo-graft was fixed at a minimum of 3 10 CD34 cells/kg and a maximum of 5 10 CD34 cells/kg of recipient weight. Patients received fludarabine 30mg/m/d iv for 5 consecutive days (days 7, 6, 5, 4, 3), rabbit antithymocyte globulin (thymoglobulin, r-ATG) at 1.5mg/kg every other day for 3 or 4 doses, and melphalan 140mg/m/d for 1 dose on day 2.[8] Thirteen patients were also given a 400 cGray, usually because of concern over disease recurrence. One patient received TBI 600 cGray. The haplo-identical cells were infused on day 0 followed by cord blood later the same day or on day 1. Posttransplant GVHD prophylaxis consisted of tacrolimus on day 2 until day 180 and mycophenolate mofetil 1 g per oral (po) three times a day (TID) until day 28. CD3 and CD33 chimerism was studied as previously described.[9] Univariate regression models were used to analyze the relation between continuous variables and chimerism. T-tests or ANOVA were used for categorical variables. All p values are two-sided. Factors examined include (1) degree of CBU HLA-match to recipient dichotomized as 4-5-6 out of 8 HLA match vs. 7 or 8 out of 8 HLA match, (2) UCB graft CD34/kgrec collected, (3) UCB TNC/kgrec infused, (4) presence of donor-specific antibodies (DSA) against UCB graft, (5) UCB viability at the time of infusion – as defined by >90% Trypan blue exclusion vs. <90%, (6) degree of haplo-graft HLA-match to recipient HLA-dichotomized as 4–5 out of 8 HLA match vs. 6–7 out of 8 HLA match, (7) presence of DSA against haplograft, (8) use of TBI in conditioning, (9) CIBMTR Disease Risk index, (10) degree of HLA match between CBU and recipient, (11) degree of HLA match between haplo-graft and recipient, and (12) degree of HLA match between CBU graft and haplo-graft. Eighty-three patients with hematologic malignancies were enrolled between January 2012 and February 2015. Four died prior to engraftment including one due to infection, one from multi-organ failure, and two from VOD/SOS. Of the remaining 79 patients, three (4%) had complete graft failure with autologous reconstitution. Seventeen additional patients were excluded from the

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma

Abstract We studied T-BiRD (thalidomide [Thalomid®], clarithromycin [Biaxin®], lenalidomide [Revlimid®] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1–28; lenalidomide 25 mg/day on days 1–21; and thalidomide 100 mg/day (50 mg/day on days 1–7 of cycle 1 only) on days 1–28. Twenty-six patients received a median of 6 cycles (range 0–41). Overall response rate (ORR) was 80% for the group and 100% in 11 patients who underwent autologous stem cell transplantation as part of first-line therapy. The 4-year overall survival rate was 74.9%, and the median progression-free survival was 35.6 months. Eight patients discontinued due to regimen toxicity. Grade 3 non hematologic toxicity affected 12 patients (46.2%). T-BiRD is a highly active regimen with potential toxicity limitations. ClinicalTrials.gov identifier: NCT00538733

Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physicians discretion, 6% (n = 3) started after day +12 at the physicians discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.

Comparison of time to engraftment between autologous patients receiving washed versus non-washed cryopreserved peripheral blood stem cell products

Abstract Washing cryopreserved peripheral blood stem cell (PBSC) products can decrease infusion-related adverse reactions but can also result in cell loss and reduced cell viability. To assess the risk and benefit of washing products, we compared the time to neutrophil and platelet engraftment between autologous patients that received washed products (n = 201) and non-washed products (n = 89). The effect of the other variables, including age, gender, diagnosis, transplant dose, method of stem cell mobilization, and growth factor support regimen post-transplant, was assessed. In multivariate analysis, direct thaw and infusion of non-washed products resulted in significantly faster neutrophil engraftment (p = .003) and platelet engraftment (p = .017) than washed products. The mean neutrophil and platelet engraftment times were 1.07 days faster and 2.27 days faster, respectively. In conclusion, direct thaw and infusion of cryopreserved PBSC without washing results in significantly shorter time to recovery of neutrophils and platelets after autologous transplantation.

Cellular Proliferation by Multiplex Immunohistochemistry Identifies High-Risk Multiple Myeloma in Newly Diagnosed, Treatment-Naive Patients

Micro‐Abstract The plasma cell labeling index (PCLI) prognosticates survival in multiple myeloma (MM) yet is underutilized as a result of its technical difficulty. We retrospectively evaluated multiplex immunohistochemistry (mIHC) in 151 newly diagnosed patients as a clinically feasible alternative to PCLI. The mIHC correlated with PCLI results and was predictive of overall survival for MM. Introduction: Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Patients and Methods: Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell–specific marker, and Ki‐67. Myeloma cells (CD138+) were counted as proliferating if coexpressing Ki‐67. Retrospective analysis was performed on 151 newly diagnosed, treatment‐naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Results: Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high‐risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty‐three (36%) of the 64 patients with low‐risk disease (ISS stage 1, without high‐risk cytogenetics) were uniquely reidentified as high risk by PCPI. Conclusion: PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.