Publications by authors named "Dipenkumar Modi"

26 Publications

  • Page 1 of 1

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
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http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Impact of pre-transplant induction therapy on outcomes of patients who undergo autologous stem cell transplantation for mantle cell lymphoma in first complete remission.

Hematol Oncol Stem Cell Ther 2021 Aug 17. Epub 2021 Aug 17.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.

Mantle cell lymphoma is a rare subtype of non-Hodgkin's lymphoma with poor prognosis and continue to be challenging to treat. The choice of first line induction regimen remains a topic of debate due paucity of clinical trials. We retrospectively evaluated 66 patients diagnosed with mantle cell lymphoma who achieved first complete response after induction chemotherapy followed by autologous stem cell transplant. Treatment groups were divided into low-intensity versus high-intensity regimens. Our data showed the intensity of induction regimen does not impact posttransplant outcomes of mantle cell lymphoma who underwent autologous stem cell transplant in first complete response.
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http://dx.doi.org/10.1016/j.hemonc.2021.07.005DOI Listing
August 2021

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis.

Blood 2021 07;138(3):273-282

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
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http://dx.doi.org/10.1182/blood.2021011281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310426PMC
July 2021

Post-transplant Cyclophosphamide Versus Thymoglobulin in HLA-Mismatched Unrelated Donor Transplant for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

Transplant Cell Ther 2021 09 23;27(9):760-767. Epub 2021 Jun 23.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in mismatched unrelated donor (MMUD) transplants. We retrospectively compared outcomes of 76 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who underwent 7/8 HLA-MMUD transplantation and received either PTcy (50 mg/kg on day 3 and 4) or thymoglobulin (total dose 4.5 mg/kg) for GVHD prophylaxis. In addition, tacrolimus and mycophenolate were used in both groups. Propensity score-based multivariable analyses (PSCA) were performed to adjust confounding effects of patient characteristics between both groups. Between January 2006 and June 2019, 25 patients received PTcy, and 51 received thymoglobulin. Median age of the population was 57 years, 78% of patients had AML, most common graft source was peripheral blood (96%), and 46% received myeloablative conditioning regimens. Median time to neutrophil (15 versus 11 days, P < .001) and platelet engraftment (21 versus 15 days, P = .002) was prolonged in the PTcy group. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (12% versus 19.6%, P = .38), whereas chronic GVHD at 1 year was lower with PTcy compared to thymoglobulin (16% versus 49%, P = .006). Using PSCA, no difference in survival, relapse, relapse-free survival, and GVHD-free relapse-free survival was seen between groups. However, thymoglobulin was associated with higher incidence of acute (hazard ratio [HR] = 2.63, P = .01) and chronic GVHD (HR = 4.43, P = .03), and non-relapse mortality (HR 3.38, P = .04) compared to PTcy. Our study demonstrated that PTcy resulted in significantly lower rates of acute and chronic GVHD and non-relapse mortality compared to thymoglobulin in 7/8 HLA-MMUD transplants for AML and MDS.
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http://dx.doi.org/10.1016/j.jtct.2021.06.018DOI Listing
September 2021

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation.

Transplant Cell Ther 2021 08 12;27(8):665.e1-665.e7. Epub 2021 May 12.

Department of Oncology, Blood & Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

Fludarabine 30 mg/m/d × 5 and melphalan 140 mg/m × 1 (Flu-Mel140) is a commonly used reduced-intensity conditioning regimen. We hypothesized that addition of 200cGy total body irradiation (TBI) to Flu-Mel140 may improve antitumor activity and transplant outcomes. Primary objectives was overall survival (OS) at 3 years. Secondary objectives were to assess the cumulative incidences of acute and chronic GVHD, relapse-free survival (RFS), relapse rate, and nonrelapse mortality (NRM). We retrospectively evaluated outcomes of patients receiving Flu-Mel140-TBI followed by HLA-matched donor allogeneic hematopoietic stem cell transplantation (alloSCT) using peripheral blood stem cells. Eighty-one patients (median age, 58 years) underwent alloSCT between January 2008 and December 2018. Thirty-one percent of patients had a prior transplant, 32% had high or very-high disease risk index, and the donor was unrelated in 70% of patients. Grade 3 to 4 regimen-related toxicities were mucositis (37%), cardiac toxicity (17%), and renal toxicity (10%). The cumulative incidence of grade III to IV acute GVHD at day +100 was 24.7% and chronic GVHD at 1 year was 51.3%. Median follow-up for survival was 6.1 years. At 3 years, OS was 39.81%, RFS was 31.47%, and relapse rate was 30.5%. One-year NRM was 29.9%. Patients undergoing first transplantation experienced improved OS compared with second or beyond (63.08% versus 42.31%, P = .02). After adjusting for disease subtypes, age (≤55 versus 55), comorbidity index (CI), number of transplant and GVHD prophylaxis, multivariable analysis did not demonstrate any survival difference among disease subtypes. High CI (≥3) was predictive of adverse OS and NRM, whereas older age (>55 years) was associated with high NRM. Our study shows that Flu-Mel140-TBI seems feasible and provides durable disease control. Addition of TBI did not appear to improve outcomes compared to previously published reports of Flu-Mel140. Considerable NRM could result from the inclusion of patients with older age and prior transplants.
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http://dx.doi.org/10.1016/j.jtct.2021.04.029DOI Listing
August 2021

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Blood Adv 2021 03;5(6):1648-1659

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993097PMC
March 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 09 3;35(9):2672-2683. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
September 2021

Grade 3-4 cytokine release syndrome is associated with poor survival in haploidentical peripheral blood stem cell transplantation.

Leuk Lymphoma 2021 08 24;62(8):1982-1989. Epub 2021 Feb 24.

Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

The information on the impact of cytokine release syndrome (CRS) on haploidentical donor peripheral blood stem cell transplant (haploPBSCT) outcomes is limited. We retrospectively evaluated 98 patients who underwent haploPBSCT between June 2012 and June 2019 for the onset and severity of CRS per the ASTCT guidelines. The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%, <.001), inferior relapse-free survival (64.0% vs. 20%, <.001), and higher non-relapse mortality (NRM) (16.4% vs. 60%, <.001) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71, =.04), and higher NRM (SHR 4.51, =.006) with grade 3-4 CRS. Our study shows that grade 3-4 CRS was adversely associated with survival. Therefore, early identification and preventive strategies are warranted.
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http://dx.doi.org/10.1080/10428194.2021.1891231DOI Listing
August 2021

Comparison of myeloablative and reduced intensity conditioning unrelated donor allogeneic peripheral blood stem cell transplant outcomes for AML using thymoglobulin for GVHD prophylaxis.

Ann Hematol 2021 Apr 16;100(4):969-978. Epub 2021 Feb 16.

Department of Oncology, Karmanos Cancer Institute/Wayne State University, 4100 John R, HW04H0, Detroit, MI, 48201, USA.

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.
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http://dx.doi.org/10.1007/s00277-021-04445-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366386PMC
April 2021

Comparison of myeloablative and reduced intensity conditioning regimens in haploidentical peripheral blood stem cell transplantation.

Bone Marrow Transplant 2021 03 16;56(3):741-744. Epub 2020 Oct 16.

Department of Oncology, Barbara Ann Karmanos Cancer Institute/Wayne State University, 4100 John R, HW04H0, Detroit, MI, 48201, USA.

Limited information is available on the impact of intensity of conditioning regimens in haploidentical peripheral blood stem cell transplant (haploPBSCT) with post-transplant cyclophosphamide (PTcy). We retrospectively compared outcomes of haplo-PBSCT between myeloablative (MAC) (n = 24) and reduced intensity conditioning (RIC) regimens (n = 65). Propensity score-based multivariable analyses were performed to adjust confounding effects of baseline characteristics between both groups. Eighty-nine patients underwent haplo-PBSCT between January 2012 and June 2019. For MAC and RIC, the cumulative incidences of grade III--IV acute GVHD were 4.2% and 3.1%, respectively (p = 0.92), and chronic GVHD were 18.9% and 36.5%, respectively (p = 0.08). Median follow-up for overall survival (OS) after MAC and RIC was 1.86 and 2.2 years, respectively. For MAC and RIC, one-year OS was 68.8% and 67.4%, respectively (p = 0.85); one-year relapse rate was 22.4% and 18.3%, respectively (p = 0.74); one-year relapse-free survival (RFS) was 56% and 59.7%, respectively (p = 0.87); and one-year non-relapse mortality (NRM) was 22% and 21.9%, respectively (p = 0.58). Using propensity score-based multivariable analyses, no difference in OS (HR 0.72, p = 0.51), relapse (SHR 0.63, p = 0.42), RFS (HR 0.74, p = 0.49) and NRM (SHR 1.11, p = 0.87) was noted between RIC and MAC. Our study shows no difference in outcomes between MAC and RIC regimens in haplo-PBSCT.
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http://dx.doi.org/10.1038/s41409-020-01079-8DOI Listing
March 2021

Absolute lymphocyte count on the first day of thymoglobulin predicts relapse-free survival in matched unrelated peripheral blood stem cell transplantation.

Leuk Lymphoma 2020 12 11;61(13):3137-3145. Epub 2020 Aug 11.

Biostatistics Core, Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI, USA.

Anti-thymocyte globulin (ATG) targets in-vivo T lymphocytes. Variations in the recipient absolute lymphocyte count (ALC) might result in a variable exposure of ATG. We hypothesized that recipient ALC on the first day of ATG might predict transplant outcomes. We evaluated 217 patients undergoing 8/8 HLA-matched unrelated donor (MUD) peripheral blood stem cell transplant (PBSCT) between January 2005 and December 2017, and receiving rabbit ATG (Thymoglobulin, total dose 4.5 mg/kg) on days -3, -2 and -1. With a median follow up of 3.68 years for survival (OS), one-year OS, relapse rate, non-relapse mortality (NRM), and relapse-free survival (RFS) were 64.7%, 15.9%, 25.8%, and 58.4%, respectively. Multivariable analysis revealed that ALC > 100 k/mm was associated with superior RFS (HR 0.64,  = .03). Our study indicates that ALC on the first day of thymoglobulin affects relapse-free survival in MUD PBSCT when weight-based thymoglobulin is used.
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http://dx.doi.org/10.1080/10428194.2020.1805114DOI Listing
December 2020

Lenalidomide maintenance after second autologous stem cell transplant improves overall survival in multiple myeloma.

Leuk Lymphoma 2020 08 9;61(8):1877-1884. Epub 2020 Apr 9.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

Maintenance therapy after first autologous transplant (autoSCT) improves progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). However, efficacy of maintenance therapy after second autoSCT is unknown. We retrospectively evaluated outcomes of 111 adult MM patients who underwent second autoSCT between January 2000 and December 2018. Lenalidomide up to 15 mg daily or subcutaneous bortezomib 1.3 mg/m every 2 weeks was considered maintenance therapy. Outcomes were compared among three groups: no-maintenance ( = 73), lenalidomide ( = 23), and bortezomib maintenance ( = 15). At a median follow-up of 58 months from second autoSCT for survival, 3-year PFS and OS for no-maintenance, lenalidomide, and bortezomib maintenance were 11.2%, 29.9%, and 0%, respectively; and 58.5%, 83.3%, and 67.5% respectively. Lenalidomide maintenance was associated with improved PFS (HR 0.46,  = 0.009) and OS (HR 0.25,  = 0.009) compared to no-maintenance. Lenalidomide maintenance therapy after second autoSCT appears to prolong PFS and OS.
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http://dx.doi.org/10.1080/10428194.2020.1749603DOI Listing
August 2020

Poor outcomes for double-hit lymphoma patients treated with curative-intent second-line immunochemotherapy following failure of intensive front-line immunochemotherapy.

Br J Haematol 2020 04 5;189(2):313-317. Epub 2019 Dec 5.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.
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http://dx.doi.org/10.1111/bjh.16319DOI Listing
April 2020

R-BEAM versus Reduced-Intensity Conditioning Regimens in Patients Undergoing Allogeneic Stem Cell Transplantation for Relapsed Refractory Diffuse Large B Cell Lymphoma.

Biol Blood Marrow Transplant 2020 04 1;26(4):683-690. Epub 2019 Nov 1.

Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.

Allogeneic stem cell transplant (alloSCT) is considered in diffuse large B cell lymphoma (DLBCL) patients with chemorefractory disease or who have relapsed after autologous SCT. Here we present the first report of alloSCT using the R-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan) conditioning regimen in DLBCL patients. We retrospectively compared long-term alloSCT outcomes of DLBCL patients who received either R-BEAM (n = 47) or reduced-intensity conditioning (RIC) regimens (n = 23). Seventy patients (median age, 53 years) with DLBCL received alloSCT between January 2005 and December 2017. The median number of pretransplant therapies was 3, and 17 patients (24%) received prior autologous SCT. All received rituximab as a frontline or salvage therapy before alloSCT. The donor was unrelated in 42 patients (60%), and peripheral blood stem cells were commonly used (96%). The 6-month cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) was 36.2% and 8.7% for R-BEAM and RIC, respectively (P = .03). Median follow-up of surviving patients after R-BEAM and RIC was 3.1 and 5.5 years, respectively. Three-year overall survival (OS) after R-BEAM and RIC was 34.4% and 43.4%, respectively (P = .48). At 3 years, R-BEAM was associated with a similar relapse rate (25.5% versus 26.1%, P = .96), nonrelapse mortality (NRM; 39.7% versus 39.1%, P = .98), and relapse-free survival (RFS; 34.8% versus 34.7%, P = .75) compared with RIC. In multivariable analysis lower Karnofsky performance score was associated with lower OS (hazard ratio, .96; P = .05), whereas chemorefractory disease was associated with a higher relapse risk (hazard ratio, 8.8; P = .04). No difference in OS, relapse, NRM, or RFS was noticed between R-BEAM and RIC. R-BEAM regimen seems to be feasible and results in equivalent rates of long-term OS, relapse, NRM, and RFS compared with RIC. However, a significantly higher rate of severe acute GVHD was noticed.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192775PMC
April 2020

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

Cancer 2020 01 30;126(2):293-303. Epub 2019 Sep 30.

Center for Lymphoid Malignancies, Department of Medicine, and Department of Pathology and Cell Biology, Columbia University Medical Center , New York.

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown.

Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy.

Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy.

Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
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http://dx.doi.org/10.1002/cncr.32526DOI Listing
January 2020

Liver Graft-Versus-Host Disease is associated with poor survival among allogeneic hematopoietic stem cell transplant recipients.

Am J Hematol 2019 10 29;94(10):1072-1080. Epub 2019 Jul 29.

Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.

Liver Graft-versus-host disease (GVHD) is common in patients with post-transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post-transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a "non-liver GVHD" group, which consisted of other etiologies of post-transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post-transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the "non-liver GVHD" group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time-varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non-relapse mortality, and adverse relapse-free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting.
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http://dx.doi.org/10.1002/ajh.25575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422561PMC
October 2019

Allogeneic stem cell transplant provides durable response in peripheral T-cell lymphoma.

Leuk Res 2019 08 15;83:106171. Epub 2019 Jun 15.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, 4100 John R, HW04H0, Detroit, MI, 48201, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2019.106171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849390PMC
August 2019

Pre-transplant hypomethylating agents do not influence post-transplant survival in myelodysplastic syndrome.

Leuk Lymphoma 2019 11 23;60(11):2762-2770. Epub 2019 Apr 23.

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

Information on the use of hypomethylating agents (HMAs) as a pre-transplant cytoreductive therapy in MDS is limited. We retrospectively evaluated outcomes of 172 adult MDS patients, who underwent allogeneic hematopoietic stem cell transplantation between January 2000 and December 2016. Patients were divided into three groups: group 1 - pre-transplant blasts <5% with HMA ( = 42), group 2 - pre-transplant blasts ≥5% with HMA ( = 38), group 3 - no HMA ( = 92). With a median follow up of 4.08 years, 1-year survival and relapse rates for groups 1, 2, and 3 were 75%, 40.2%, and 60.71%, respectively; and 17.6%, 26.6%, and 9.8%, respectively. Multivariate analysis revealed adverse relapse (HR 3.54;  = .03) in group 2 compared to groups 1 and 3, while no difference in overall survival was noticed. Our study shows no survival association with pre-transplant HMA; although, higher relapse rate was observed in the non-responding patients indicating possible chemotherapy resistant disease.
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http://dx.doi.org/10.1080/10428194.2019.1605070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865062PMC
November 2019

Multistate Models on Pleural Effusion after Allogeneic Hematopoietic Stem Cell Transplantation.

Open Access Med Stat 2017 15;7:15-26. Epub 2017 Apr 15.

Biostatistics Core, Karmanos Cancer Institute, Detroit, Michigan 48201, United States of America.

A multistate model is more complicated than competing risk models and composed of finite number of states and transitions between states. Unlike competing risk models, this model has the ability to assess the effect of occurrence order of time-to-event data. Pleural effusion (PE) is a severe complication that often occurs after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients develop pleural effusion during the first 100 days after allogeneic HSCT and graft-versus-host disease (GVHD) occurs either before or after the development of PE, implying that the occurrence order of PE and GVHD (i.e., PE after GVHD vs. GVHD after PE) would influence on the incidence, risk factors and mortality of pleural effusion. One can use either Cox proportional models or competing risk models to evaluate these values, but neither method is able to incorporate the occurrence order of incidence into the model. To resolve this difficulty, we developed a multistate model describing several possible events and event-related dependences and applied to a retrospective study of 606 patients, including eight covariates.
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http://dx.doi.org/10.2147/OAMS.S125465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394937PMC
April 2017

Fluoroquinolone prophylaxis in autologous hematopoietic stem cell transplant recipients.

Support Care Cancer 2017 08 2;25(8):2593-2601. Epub 2017 Apr 2.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, 4100 John R, 4 HW04H0, Detroit, MI, 48201, USA.

Purpose: Although fluoroquinolone prophylaxis is frequently utilized in autologous hematopoietic stem cell transplant (AHSCT) patients, its impact on morbidity and mortality is uncertain. This study investigates the role of quinolone prophylaxis after AHSCT in recent years.

Methods: We conducted a retrospective review of 291 consecutive adult patients who underwent AHSCT for malignant disorders, between June 2013 and January 2015. Outcomes were compared between patients who received norfloxacin prophylaxis and those who did not. The endpoints were mortality during prophylaxis and at 100 days after transplant, frequency of ICU admissions, and incidence and type of bacteremia.

Results: Of 291 patients, 252 patients received norfloxacin prophylaxis and 39 patients did not. The mortality during prophylaxis and at 100 days as well as the median number of days of hospitalization following AHSCT did not differ between the two groups. No differences were noted in the frequency of ICU admission, incidence of septic shock, and duration of ICU stay. Patients who did not receive prophylaxis had a significantly higher rate of neutropenic fever (97%) than patients who received prophylaxis (77%) (p = 0.005). The patients with prophylaxis demonstrated a significantly higher rate of gram-positive bacteremia as compared to those without prophylaxis (p = 0.002). Frequency of Clostridium difficile infection was similar during and post-prophylaxis. More antibiotic use was noted among patients without prophylaxis [97%; median 9 (range, 5-24) days] compared to patients with prophylaxis [79%; median 7 (range, 3-36) days, p = 0.04].

Conclusion: Although fluoroquinolone prophylaxis reduced the incidence of neutropenic fever and antibiotic use in AHSCT, it did not alter mortality or morbidity.
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http://dx.doi.org/10.1007/s00520-017-3670-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886234PMC
August 2017

Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: F-FAU, F-FMAU, and F-FLT.

Cancer Imaging 2016 Oct 17;16(1):34. Epub 2016 Oct 17.

Karmanos Cancer Institute and Oncology, Wayne State University, 4100 John R., HW04HO, Detroit, MI, 48201, USA.

Background: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[F]fluorothymidine (F-FLT), 1-(2'-deoxy-2'-[F]fluoro-β-D-arabinofuranosyl) thymidine (F-FMAU), and 1-(2'-deoxy-2'-[F]fluoro-β-D-arabinofuranosyl) uracil (F-FAU) in patients with advanced cancer.

Methods: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUV) and using kinetic analysis.

Results: Patients imaged with F-FLT showed variable changes in retention and two patients exhibited an increase in SUV of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in F-FMAU retention was 0.2 % (range -24.4 to 23.1) and F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUV but not kinetic measurements.

Conclusions: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. F-FAU and F-FMAU showed little change, on average, after treatment.
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http://dx.doi.org/10.1186/s40644-016-0092-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067904PMC
October 2016

Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation.

Am J Hematol 2016 09 14;91(9):E341-7. Epub 2016 Jul 14.

Department of Oncology, Co-Director, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.

Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852667PMC
September 2016

Radium-223 in Heavily Pretreated Metastatic Castrate-Resistant Prostate Cancer.

Clin Genitourin Cancer 2016 10 10;14(5):373-380.e2. Epub 2016 Mar 10.

Department of Hematology-Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI. Electronic address:

Background: Radium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown.

Patients And Methods: We conducted a retrospective study of 29 patients with mCRPC who received radium-223 at 1 of 3 participating institutions between August 2013 and December 2014. Trend of PSA, radiographic changes, and association of biochemical and clinical variables with PSA trend were measured.

Results: The median age of patients was 70 years, 79% of patients (N = 23) were European Americans, and 17% of patients (N = 5) were African Americans. Twenty patients (69%) had received at least 3 lines of prior therapies. Some 38% of patients (N = 11) received all 6 cycles of radium-223. Twenty patients (69%) had an increase in PSA during radium therapy, and 4 patients (14%) had a decline in PSA levels. Five patients had visceral metastases on computed tomography imaging performed during the course of radium-223.

Conclusions: Radium therapy in mCRPC was associated with an increase in PSA in the majority of these heavily pretreated patients. The development of visceral disease was not uncommon, suggesting a need for follow-up computed tomography monitoring during radium-223 therapy. The significance of early increases in PSA and pain with radium-223 is still uncertain. Although pain and PSA flare have been reported in patients who subsequently have a dramatic response to therapy, we observed that a PSA increase or pain flare correlates to an improvement in bone scans only in a minority of patients.
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http://dx.doi.org/10.1016/j.clgc.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849387PMC
October 2016

Pomalidomide-Induced Pulmonary Toxicity in Multiple Myeloma.

Am J Med Sci 2015 Sep;350(3):241-2

Department of Internal Medicine, Wayne State University, Detroit Medical Center, Detroit, Michigan.

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http://dx.doi.org/10.1097/MAJ.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124277PMC
September 2015

Malignant cause of abdominal pain in leukemia: spontaneous splenic rupture.

Am J Med Sci 2015 Feb;349(2):189-90

Departments of Internal Medicine Wayne State University/Detroit Medical Center Detroit, Michigan.

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http://dx.doi.org/10.1097/MAJ.0000000000000374DOI Listing
February 2015
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