Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

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Busulfan (Bu) Plus Cyclophosphamide (Cy) Versus TBI Plus Cy Conditioning for Allogeneic Stem Cell Transplantation (alloSCT) From Matched Unrelated Donors (MUD) In Adult Patients with AML in First Relapse: A Survey From the Acute Leukemia Working Party of EBMT

Blood ◽

10.1182/blood.v118.21.161.161 ◽

2011 ◽

Vol 118 (21) ◽

pp. 161-161 ◽

Cited By ~ 1

Author(s):

Arnon Nagler ◽

Myriam Labopin ◽

Avichai Shimoni ◽

Jürgen Finke ◽

Dietrich Beelen ◽

...

Keyword(s):

Acute Gvhd ◽

Conflicts Of Interest ◽

Working Party ◽

Risk Groups ◽

Adult Patients ◽

Free Survival ◽

Unrelated Donors ◽

Conditioning Regimens ◽

First Relapse

Abstract Abstract 161 TBY/Cy and Bu/Cy are the standard myeloablative conditioning regimens for alloSCT in adults with AML. Whether, one is associated with better outcomes compared to the other in the setting of relapsed AML is not well described. We therefore compared TBI/Cy to Bu/Cy conditioning prior to alloSCT in 158 adult patients (pts) with AML in first relapse (Rel 1) that underwent alloSCT from HLA matched (6/6) unrelated donors. 83 patients were given TBI/Cy and 75 Bu/Cy. The median age was 38 years (range, 19–62) in the TBI/Cy vs. 42 years (19–72) in the Bu/Cy group (P<0.012). FAB classifications, cytogenetic risk, time from diagnosis to alloSCT, donor gender and CMV serostatus were not different between the 2 groups. Median year of alloSCT was 2004 vs. 2007 (P<0.0001) for the TBI/Cy vs. Bu/Cy groups, respectively. Conditioning included ATG in 31% vs. 67% in the TBI/Cy and Bu/Cy groups, respectively (P<0.001). 78% of the Bu/Cy group and 80% of the TBI/Cy group, received PBSC grafts, while 22% and 20% received BM grafts, respectively (P=0.8). Median follow-up was, 23 months (range, 1–125) in TBI/Cy and 21 months (1–119) in Bu/Cy. The engraftment rate was similar between both groups with ANC>500/μL achieved at a median of 17 (10–33) and 16 (6–31) days in the TBI/Cy and Bu/Cy groups, respectively (P=0.23). Similarly, acute GVHD (≥Gr II) incidence did not differ between the 2 groups: 33% vs. 37% for the TBI/Cy vs. Bu/Cy, respectively. Death before day 100 occurred in 38% vs. 25% with TBI/Cy vs. Bu/Cy, respectively (P=0.25). 2- year NRM was similar between the 2 groups, 31±5% vs. 21±5%, respectively (P=0.15). In addition, the 2-year relapse rate did not differ between the 2 groups: 50±4% vs. 50±6%, respectively (P=0.93). Leukemia-free survival (LFS) at 2 years, was also similar between the TBI/Cy vs. Bu/Cy groups: 18 ± 5% vs. 29 ± 6 %, respectively (P=0.10). However, overall survival (OS) was significantly higher with Bu/Cy vs. TBI/Cy 38±6% vs. 21±4%, respectively (P=0.02). The main cause of death was disease relapse: 53% and 60%, with TBI/Cy vs. Bu/Cy, respectively (p=0.49). Of note, there were no differences in death from organ toxicities including VOD between the 2 groups. The rate of infection-related deaths did not differ between the groups, as well, 19% vs. 11% (p=0.25). In multivariate analysis, age, cytogenetic risk groups, use of ATG and interval from diagnosis to alloSCT were not significant prognostic factors for survival. In all, these results suggest that in AML patients in Rel 1 undergoing myeloablative alloSCT, Bu/Cy and TBI/Cy conditioning regimens can lead to similar outcomes including GVHD, NRM, disease progression and LFS. However, in terms of OS, there is a suggestion for an advantage in favor of the Bu/Cy regimen possibly due to a lower overall toxicity and improved capacity for salvage therapy. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Stem Cell Transplantation as a Promising Treatment for Natural Killer-Cell Neoplasms.

Blood ◽

10.1182/blood.v104.11.3331.3331 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3331-3331

Author(s):

Naoko Murashige ◽

Masahiro Kami ◽

Yukiko Kishi ◽

Sung-Won Kim ◽

Masami Takeuchi ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Nk Cell ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Stem Cell Source ◽

Promising Treatment

Abstract The efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for NK-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. A hematopathologist reclassified the pathological diagnoses according to the WHO classification. Of 345 patients from 76 hospitals who underwent allo-HSCT for malignant lymphoma, 32 had NK-cell neoplasms: extranodal NK/T-cell lymphoma (n=27), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukemia (n=2). Fifteen were chemosensitive and 17 chemorefractory. Nine were in CR at the time of allo-HSCT. Twenty-five had matched related donors, 3 mismatched related, 2 matched unrelated, and 1 mismatched unrelated donors. Stem-cell source was bone marrow in 11 and mobilized peripheral blood in 21. Conditioning regimens were myeloablative (n=26) and non-myeloablative (n=6). Total body irradiation was given to 23 patients. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin and short-term methotrexate in 27 patients. Grade 2–4 acute GVHD and chronic GVHD developed in 13 and 9, respectively. Nine died of disease progression, 4 of infection, 2 of veno-occlusive disease, 2 of acute GVHD, 1 of interstitial pneumonitis, and 1 of thrombotic microangiopathy. Two-year progression-free and overall survivals were 33% and 38%, respectively (median follow-up, 32 months). All patients who did not relapse/progress within 10 months achieved progression-free survival during the follow-up. In multivariate analysis, stem cell source (BM vs. PB; relative risk 3.33) and acute GVHD (grade 2–4 vs. grade 0–1; relative risk 2.56) significantly affected progression-free survival. Allo-HSCT is a promising treatment for NK-cell neoplasms. Figure Figure

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Haploidentical Stem Cell Transplantation after Myeloabaltive Conditioning Is a Valid and Safe Option for Young Patients with Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma: A Study Compared with HLA-Matched Transplant

Blood ◽

10.1182/blood.v128.22.5849.5849 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5849-5849

Author(s):

Haiwen Huang ◽

Xiaofang Xiao ◽

Jia Chen ◽

Zhengming Jin ◽

Xiaowen Tang ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Young Patients ◽

Progression Free Survival ◽

Hematopoietic Stem ◽

Free Survival

Abstract Purpose: The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) therapy for refractory or relapsed (R/R) aggressive non-Hodgkin lymphoma (NHL) patients was still unknown. In this study, we aimed to explore the clinical outcome of R/R aggressive NHL patients received haplo-HSCT treatment. Patients and Methods: 23 R/R aggressive NHL patients who had undergone haplo-HSCT in our center between February 2006 and October 2015 were retrospectively analyzed, and 25 R/R aggressive NHL patients who received HLA-matched HSCT at the same period were also involved in this study. All patients received myeloablative conditioning (MAC) regimen, and antithymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. 12 patients had experienced autologous HSCT prior to allo-HSCT. Results: The median age of the total 48 patients was 33 (16-58) years old, and there were 33 males and 15 females in the total cohorts. The diagonosis were as following: 16 (33%) diffuse large B cell lymphoma and 22 (46%) peripheral T cell lymphoma. There were no difference in sex, age at transplantation, histologic diagnosis, aaIPI score, previous ASCT and conditioning regime between HLA-matched HSCT and Haplo-hsct groups. 44 patients had achieved engrafment, and the median times to neutrophil and platelet recovery were 12 and 15 days, respectively. Incidences of grade 3-4 acute GVHD were 18.3% in haplo-HSCT group and 16.7% in HLA-matched HSCT groups(p=0.87), while 2 years cumulative incidences of chronic GVHD in these two groups were 43.5% and 36.7% (P=0.68). For 16 patients who had chemoresistant disease at transplantation in haplo-HSCT group, four patients achieved complete remission, and ten patients achieved partial remission, while the other two patients experienced disease progression at 21 days and 37 days, respectively. With a median follow-up of 25 months, 12 patients experienced disease recurrence or progression in haplo-HSCT. And four patients died of transplantation related mortality: infection (n=2); acute GVHD (n=1) and multi-organ failure (n=1). There were no differences in overall survival (OS) rate at 2 years (52.8% vs 57.0%, P=0.85) and 2 years progress free survival (PFS) rate (52.7% vs 56.9%, p=0.73) between the haplo-SCT and HLA-matched SCT groups. Multivariate analyses suggested that old age (>45 years)(p=0.02), primarychemorefractory (p=0.04)and occurrence of grade3-4 aGVHD (p=0.01) may contribute to poor prognosis. Conclusion: Haploidentical hematopoietic stem cell transplantation withmyeloablative conditioning regimenachieved satisfactory outcome with acceptable side-effects. This approachcan be a feasible and acceptabletherapy for young patients withR/R NHLwho have no access to a HLA-matched donor. Figure Comparison of outcomes after haplo-SCT and HLA-matched SCT. (a) Overall survival, (b) Progression-free survival, (c) Cumulative incidences of grade3-4 acute GVHD, (d) cumulative incidences of chronic GVHD, (e) cumulative incidences of relapse, (f) cumulative incidences of non-relapse mortality. Figure. Comparison of outcomes after haplo-SCT and HLA-matched SCT. (a) Overall survival, (b) Progression-free survival, (c) Cumulative incidences of grade3-4 acute GVHD, (d) cumulative incidences of chronic GVHD, (e) cumulative incidences of relapse, (f) cumulative incidences of non-relapse mortality. Disclosures No relevant conflicts of interest to declare.

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Long-term follow-up of adult hematopoietic stem cell transplant recipients diagnosed with COVID-19.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19028 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19028-e19028

Author(s):

Stephanie Hoffman ◽

Pavan Reddy ◽

John Martin Magenau ◽

Attaphol Pawarode ◽

Brian Parkin ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Acute Gvhd ◽

Stem Cell Transplant ◽

Chronic Gvhd ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Long Term Follow Up

e19028 Background: Long-term complications of COVID-19 in hematopoietic stem cell transplant (HCT) recipients are unknown. Recent studies have described short term outcomes of COVID-19 infection post allogeneic (allo) and autologous (auto) HCT. In this study we provide long term follow-up of the outcomes of COVID-19 infection in allo and auto HCT recipients. Methods: We performed a retrospective study of adult patients who have received allo or auto HCT and were subsequently diagnosed with COVID-19 infection between March-December 2020. We summarized patient characteristics, laboratory and treatment data related to COVID-19 infection in these patients. Results: In this study, we provide long-term follow-up of over 7 months. Fifteen patients were identified for inclusion (allo n = 12, auto n = 3). Median follow-up was 7.8 months (range 1.9-10.7) for surviving patients. Median age at COVID-19 diagnosis was 55 years (range 24-77). Most patients were > 1 year out from transplant (allo n = 10, auto n = 1, 73%). Two patients (allo n = 1, auto n = 1, 13%) had undergone transplant within the preceding month. Most allo patients (n = 11, 73%) had received myeloablative conditioning. At the time of COVID-19 diagnosis, 9 allo patients (75%) were on immunosuppression (IS) (n = 7 for chronic graft-versus-host-disease (GVHD); n = 2 for GVHD prophylaxis). Eleven patients (73%) required hospitalization (allo n = 9, auto n = 2). Per the National Institutes of Health definitions of COVID-19 illness severity, 3 patients had critical disease (allo n = 2, auto n = 1, 20%), 5 severe (allo n = 5, 33%), 3 moderate (allo n = 2, auto n = 1, 20%), and 4 mild (allo n = 3, auto n = 1, 27%). All patients with chronic GVHD required hospitalization. Two patients died (allo n = 1, auto n = 1, 13%)—both had critical COVID-19 infections, were > 65 years old, > 3 years out from transplant, and had significant comorbidities. The allo patient was receiving prednisone < 1 mg/kg for chronic lung GVHD at COVID-19 diagnosis. Two allo patients developed either acute GVHD or chronic GVHD exacerbation within 3 months of their infection. One patient developed biopsy-proven acute GVHD (max grade III) 3 weeks after her infection and another patient developed a severe exacerbation of chronic GVHD within 3 months—both continue to require multi-modal IS. The remaining 7 patients with chronic GVHD have been maintained on either stable or tapered IS. Conclusions: Given the effect of COVID-19 infection, its impact on HCT recipients is important to define. The majority of HCT patients who contracted moderate-critical COVID-19 infections in our study were either on IS or had significant comorbidities. Our observational data points to the importance of long-term follow-up in HCT patients. Future studies are needed to delineate whether there is a relationship between COVID-19 infection and GVHD development or exacerbation. The role of vaccination in HCT recipients remains to be explored.

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Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽

10.46765/2675-374x.2020v1n1p53-66 ◽

2020 ◽

Vol 1 (1) ◽

pp. 53-66

Author(s):

Vaneuza A. M. Funke ◽

Maria Claudia Rodrigues Moreira ◽

Afonso Celso Vigorito

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Primary Therapy ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, involving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

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Allo-HSCT in transplant-naïve patients with Hodgkin lymphoma: a single-arm, multicenter study

Blood Advances ◽

10.1182/bloodadvances.2019001016 ◽

2019 ◽

Vol 3 (24) ◽

pp. 4264-4270 ◽

Cited By ~ 1

Author(s):

Emma Das-Gupta ◽

Kirsty J. Thomson ◽

Adrian J. C. Bloor ◽

Andrew D. Clark ◽

Stephen Mackinnon ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Complete Response ◽

Primary Objective ◽

Mixed Chimerism ◽

Hematopoietic Stem ◽

Positron Emission ◽

Computed Tomography Scanning ◽

Unrelated Donors

Abstract We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.

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Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.5.1089 ◽

1995 ◽

Vol 13 (5) ◽

pp. 1089-1095 ◽

Cited By ~ 8

Author(s):

W P Vaughan ◽

E Kris ◽

J Vose ◽

P J Bierman ◽

P Gwilt ◽

...

Keyword(s):

Phase I ◽

Continuous Infusion ◽

Progression Free Survival ◽

High Dose Chemotherapy ◽

Rank Test ◽

High Dose ◽

Hematopoietic Stem ◽

Free Survival ◽

Stem Cell Rescue

PURPOSE A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.

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Nonmyeloablative Conditioning and Hematopoietic Cell Transplantation (HCT) from HLA-Matched Related or Unrelated Donors for Chemotherapy-Refractory Chronic Lymphocytic Leukemia (CLL).

Blood ◽

10.1182/blood.v104.11.2323.2323 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2323-2323

Author(s):

Mohamed Sorror ◽

Michael Maris ◽

Barry Storer ◽

Brenda Sandmaier ◽

Monic Stuart ◽

...

Keyword(s):

Overall Survival ◽

Acute Gvhd ◽

Disease Free Survival ◽

Cerebral Stroke ◽

Phase Ii Trials ◽

Free Survival ◽

Increased Risk ◽

Unrelated Donors ◽

Disease Free

Abstract Sixty-four patients (pts) with chemotherapy-refractory CLL who were ineligible for ablative allogeneic HCT due to age and/or comorbidities were given nonablative-HCT from related (n=44) or unrelated donors (n=20) between 1997-2003 (Table). Median pt age was 56 (range 44–69) years, interval from diagnosis to HCT was 4.4 (3–25) years, and number of prior regimens was 4 (range 1–12). Sixty-one pts were refractory to at least 1 regimen, 56 to fludarabine (FLU), 19 to alkylating agents, 14 to rituxumab and 4 to CAMPATH, and 2 had failed autologous HCT. Twenty-three pts (36%) had disease responsive to last chemotherapy [28% partial (PR) and 8% complete remission (CR)] while 34 were nonresponsive and 7 had untested relapse. Conditioning for HCT consisted of 2 Gy TBI alone (n=11) or combined with FLU (n=53), 90 mg/m2. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Pts received G-CSF mobilized peripheral blood mononuclear cells. After HCT, pts became neutropenic for a median of 11 days. Forty-four percent of pts had thrombocytopenia (<20,000 cells/ul). Three pts had graft rejection; 1 died with aplasia and 2 are alive with disease relapse. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic GVHD was 50% at 2-years. With median follow up of 24 (range 2.8–62.8) months, the overall response rate was 67% (50% in CR). URD-pts had significantly higher CR rate than MRD-pts. All 11 responding patients tested had molecular eradication of their disease. Overall, 39 patients are alive; 25 in CR, 5 in PR, 2 with stable disease, and 7 with relapse/progression. Twenty-five pts died, 10 from progression, 10 from infections ± GVHD, 2 from cardiac causes, 1 from metastatic lung cancer, 1 from cerebral stroke and 1 from rejection and aplasia. Estimated 2-year rates of non-relapse mortality, disease free survival, and overall survival were 22%, 52%, and 60% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher non-relapse mortality and worse survival while bulky lymphadenopathy predicted increased risk of progression. CLL appears susceptible to graft-versus-leukemia effects particularly after URD grafts and nonablative-HCT should be explored in phase II trials in pts with FLU-refractory CLL. Table: Results Related (n = 44) Unrelated (n = 20) P Acute GVHD grade II, III, and IV 39%, 11%, and 2% 40%, 20%, and 0% 0.41 2-year chronic extensive GVHD 44% 69% 0.56 Median follow up (range) 31 (3–63) months 12 (3–39) months CR at 2-years 42% 78% 0.005 Relapse/progression at 2 years 34% 5% 0.08 Surviving pts 13 CR, 3 PR, 2 stable, 5 progression, 1 relapse 12 CR, 2 PR, 1 relapse 2-year non-relapse mortality 22% 20% 0.75 2-year disease free survival 44% 75% 0.15 2-year overall survival 56% 74% 0.33

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Immunologic Recovery after Autologous Transplant in Multiple Myeloma and Progression Free Survival

Blood ◽

10.1182/blood.v112.11.4444.4444 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4444-4444

Author(s):

Fernanda Maria Rodrigues Trigo-Miranda ◽

Rui Cordeiro Bergantim ◽

Ricardo Moreira Pinto ◽

Patricia Guimarães ◽

Jose E. Guimaraes

Keyword(s):

Multiple Myeloma ◽

Progression Free Survival ◽

Response To Treatment ◽

Cell Transplant ◽

Haematopoietic Progenitor Cell ◽

Free Survival ◽

Post Transplant ◽

Historical Comparison ◽

Significant Difference

Abstract Several factors influencing disease progression and survival have been identified in multiple myeloma (MM). We analysed a series of 49 consecutive patients with MM that underwent autologous haematopoietic progenitor cell transplant (HPCT) in one center regarding the following variables: use of G-CSF for haematopoietic recovery post-transplant; recovery of normal IgM levels at day +100 post-transplant; levels of lymphocytes namely of the CD4+ and CD8+ subsets also at day +100. Before 2006, all patients had G-CSF starting 24 hours after the cell infusion until neutrophil > 500×10^9/L in two consecutive days; in the years 2006–2008, no G-CSF was given to transplanted patients. A historical comparison was done and at the time of this study no significant difference in progression free survival (Kaplan-Meyer analysis), was detected between the two groups, possibly due to the shorter follow-up of the “no G-CSF” (n=19) group; nevertheless median progression free survival (PFS) in the “G-CSF” group was 12 months while median PFS was not attained in the “no G-CSF” group (median follow-up = 7 months). Post transplant IgM levels were also determined in 39 patients. Eighteen patients recovered normal IgM levels at day +100 (46.8 %) and 21 (53.8 %) did not. Comparison of Kaplan-Meyer curves for the two groups did not show any statistically significant difference but there is a sharp difference between median PFS of the “low IgM” (10 months) and the “normal IgM” (27 months) groups. CD4/CD8 ratio was determined in 18 patients at day +100. The ratio varied between 0 and 0.63 (median – 0.305). No correlation was found between post-transplant IgM recovery and CD4/CD8 ratio. In conclusion, in our series of MM patients treated with autologous HPCT we could not find a definite relationship between immunologic recovery and response to treatment although there is a trend to a better outlook of the patients which recover normal IgM levels. It is also uncertain whether use of G-CSF in the post-transplant period would have any effect on disease behaviour.

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Administration of Rituximab 375 Mg/m2 on Days +1 and +8 after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT) Regimens for Patients with Advanced CD20+ Lymphoid Malignancies

Blood ◽

10.1182/blood.v112.11.4323.4323 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4323-4323

Author(s):

Mohamed A Kharfan-Dabaja ◽

Cheryl Tate ◽

Janelle Perkins ◽

Teresa Field ◽

Hugo F. Fernandez ◽

...

Keyword(s):

Chronic Gvhd ◽

Response Rates ◽

Hematopoietic Stem ◽

Lymphoid Malignancies ◽

Gvhd Prophylaxis ◽

Mantle Cell ◽

Conditioning Regimens ◽

Nih Consensus Criteria ◽

Time To Onset

Abstract We evaluated the safety of adding rituximab 375 mg/m2 only on days +1 and +8 following allo-HCT in 18 patients (M=12, F=6), median age 56 (41–66) years, with advanced CD20+ lymphoid malignancies [CLL=9 (CR2=3, PR2=3; ≥PR3=3); Mantle cell lymphoma (MCL)= 5 (CR1=1, PR2=2, ≥PR3=2); follicular (FL)=3 (CR3=2, ≥PR3=1); DLBC NHL=1 (≥PR3=1). Source of stem cells consisted of matched-related (MRD)=11 (61%), matched-unrelated (MUD)=5 (28%), or mismatched-unrelated (MMUD)=2 (11%) donors. Conditioning regimens consisted of fludarabine plus targeted doses of IV busulfan (FLU-BU) (N=11) or 200 cGy TBI (N=4), or cyclophosphamide (FLU-CY) (N=1). ATG was administered on days −3 and −1 in 2 MMUD cases (FLU-BU-ATG). Fifteen patients received rituximab on day +1 (±3) and all on day +8 (±3). GVHD prophylaxis was tacrolimus plus mycophenolate mofetil (N=11) or methotrexate (N=7). Non-relapse mortality at 100 days was 6%. Median time to neutrophils and platelets engraftment was 15 (6–27) days and 12.5 (9–18) days, respectively. Eight patients never dropped platelets below 20,000/uL. Median CD3 and CD33 chimerisms at day +90 (±10) were 89% (50%–100%) and 100% (15%–100%), respectively. DLI was required in 2 patients (FLU-BU=1, FLU-TBI=1) due to poor CD3 engraftment. Response rates after 90 days post allo-HCT, according to diagnosis, were as follows: CLL (evaluable=8/9; CR=7/8; PR=1/8); MCL (evaluable=4/5; CR=4/4); FL (CR=3/3); DLBC (PD=1/1). Twelve (67%) patients remain alive in remission at a median follow up of 9.4 (2.3–42.3) months. The incidence of grade 0,I, II, and III–IV acute GVHD (aGVHD) was 6%, 33%, 50%, and 11%, respectively. Time to onset of aGVHD was 29 (16–77) days. The incidence of chronic GVHD (cGVHD), per NIH consensus criteria, was as follows in 15 evaluable patients: no cGVHD= 27%, mild= 33%, moderate= 13%, and severe=27%. These findings suggest that administration of rituximab 375 mg/m2 only on days +1 and +8 is safe. Response rates are encouraging; but controlled studies will be needed to conclusively determine the effect of post-transplant rituximab on efficacy.

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