Recommended Tools for Joint Chronic Graft-Versus-Host Disease: Results From the Chronic Gvhd Consortium

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 464-464
Author(s):  
Yoshihiro Inamoto ◽  
Xiaoyu Chai ◽  
Brenda Kurland ◽  
Daniel J. Weisdorf ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Symptom Burden ◽  
Assessment Tools ◽  
The Other ◽  
Joint Involvement ◽  
High Dose ◽  
Symptom Scale ◽  
Multicenter Observational Study

Abstract Abstract 464 Background: Assessing joint chronic GVHD needs to be accomplished reliably, simply and in a clinically meaningful way. To determine the optimal tool for assessing joint GVHD, we evaluated 2 NIH recommended joint tools (Table), a photographic range of motion (P-ROM) scale, and 7 other NIH recommended tools (Lee symptom scale, 10-point overall symptoms, FACT-G, SF36, Human Activities Profile, walk test and grip test). Methods: Patients ≥ age 2 with systemically treated chronic GVHD ≤ 3 years after hematopoietic cell transplantation were eligible for a prospective multicenter observational study. Incident and prevalent cases were included. At follow-up visits every 3–6 months, the clinician (MD) and patient (PT) rated separately their perception of change in joint GVHD on an 8-pt scale, which was collapsed into improved, stable or worse categories. Linear mixed models were used to correlate change in each tool with MD or PT-perceived change (improved vs. stable or worse vs. stable) in joint GVHD status. Results: Nine sites in the Consortium enrolled 567 participants through December 2011. Joint involvement, as defined by NIH joint/fascia score ≥1, was present at enrollment in 164 (29%) patients and included wrists (64%), ankles (47%), shoulders (35%) and elbows (30%). Joint involvement at enrollment was associated with longer duration of chronic GVHD, high-dose total body irradiation, higher symptom burden, lower quality of life (QOL), similar activity profile and similar physical function, compared to those without joint involvement. Change in joint GVHD status was examined for 652 paired visits when joint involvement was documented in the previous or current visit. In the later visits, both MDs and PTs more often reported improvement (44% and 45%) than worsening (5% and 11%). Tools that correlated with both MD and PT-perceived joint improvement were NIH joint/fascia score, Hopkins fascia score and SF36-PCS. Tools that correlated with both MD and PT-perceived joint worsening were P-ROM total score, NIH joint/fascia score, Hopkins fascia score, Lee muscle/joint subscale, Lee symptom overall score, 10-point overall symptoms and FACT-G. Among the 3 joint/fascia tools (Figure), for MD-perceived improvement, estimated change in the NIH score and P-ROM score was slightly larger than in the Hopkins score. For PT-perceived improvement, estimated change was similar for NIH and Hopkins scores. In contrast, for both MD and PT-perceived worsening, estimated change for the P-ROM score was significantly larger than in the other tools. Conclusion: Joint involvement with chronic GVHD is frequent and associated with increased symptom burden and decreased QOL. Our results support the combined use of NIH joint/fascia score and P-ROM scale to assess joint GVHD. The NIH score better reflects joint improvement and the P-ROM scale better reflects joint worsening. The more objective P-ROM scale is insensitive to PT-perceived joint improvement possibly because unlike the other two joint assessment tools, it does not incorporate tightness with or without activities of daily living. Disclosures: No relevant conflicts of interest to declare.

Allogeneic and Syngeneic Hematopoietic Cell Transplants in Patients with AL-Amyloidosis: A Report from the European Group for Blood and Marrow Transplantation (EBMT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5133-5133 ◽  
Author(s):  
Stefan O. Schoenland ◽  
Michel Baccarani ◽  
Andrew Campbell ◽  
Enric Carreras ◽  
Catherine Cordonnier ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Hematopoietic Cell ◽  
The Other ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Autologous Hct

Abstract AL amyloidosis is caused by a plasma cell dyscrasia in which clonal immunoglobulin light chains deposited in tissues leads to organ failure and death. Treatment with high dose melphalan and autologous PBSC rescue produces hematologic remissions in approximately 40% of evaluable patients and improvements in organ disease and quality of life. For a subgroup of patients, an allogeneic hematopoietic cell transplantation (HCT) may be useful. There is little experience with this procedure in patients with AL amyloidosis. We report the patients (pts) who were registered within the EBMT database. Eleven pts (median age 45 years, range 30–63; 3 female) with AL amyloidosis (n=10) or with multiple myeloma plus AL amyloidosis (n=1) underwent allogeneic (n=8) or syngeneic ( n=3) HCT during 1987–2002, 7 of them before 2000. Donors of allogeneic transplants were matched related siblings. Main organ manifestations were kidney, heart and liver. Indications for allogeneic HCT were young age, relapse after autologous HCT (n=2) and progressive or refractory disease. Conditioning regimen was ablative in 4 pts and reduced-intensity conditioning (RIC) was used in the other 4 pts. Three pts had T cell depletion as graft-versus-host-disease (GvHD) prophylaxis. Engraftment was evaluable in 7/8 pts, 2 pts rejected their grafts and 5 pts had durable engraftment. One out of 5 evaluable pts developed acute GvHD (grade IV), and 1 of 3 evaluable pts developed chronic GvHD (limited disease). Five pts (62,5%) died at a median of 51 (range 25 – 83) days after HCT, all before day +100. From 4 of these 5 pts causes of death are known: 1 pt died of a cerebral aspergillosis (day +54) and 3 pts died of amyloidosis. Three pts remain alive (median observation 27 months, range 12–79) after HCT. Best hematological responses after HCT in surviving pts were immunofixation-negative CR in 1 pt (with cGvHD), PR in 1 pt and SD in the third pt. One of the 3 pts with syngeneic HCT is alive about 60 months after the procedure, the other 2 pts. died of TRM day +7 and +18, respectively. In summary, a very high day +100 mortality was observed. Main problem was cardiac failure due to amyloidosis in the very early phase after HCT. Half of the pts survived RIC and ablative conditioning, respectively. We conclude that a very restrictive patient selection is necessary to decrease mortality as it has been shown for high-dose chemotherapy with autologous HCT. Whether RIC plays an more important role for this patient group in the future remains to be defined.

Haploidentical Transplantation As Salvage Therapy For Disease Relapse After Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2084-2084
Author(s):  
Christiane Dorn ◽  
Sebastian P. Haen ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Median Time ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
The Other ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Allogeneic Hct

Abstract Introduction Therapeutic options and outcome for patients with relapse after allogeneic hematopoietic cell transplantation (HCT) are poor. For individual patients, a second or even third allogeneic HCT can be considered with curative intention. However, treatment-related mortality (TRM) and the risk of relapse after secondary allogeneic HCT are high. Therefore, the use of a haploidentical graft allowing for profound NK- and T-cell-alloreactivity after a reduced-intensity conditioning regimen (RIC) may optimize disease control by enabling potent graft versus leukemia effects and reduction of TRM. Methods We here retrospectively evaluated 26 consecutive patients undergoing haploidentical HCT as second (n=24) or third (n=2) allogeneic HCT at our center between 2003-2012. Diagnoses comprised relapse of AML (n=17) or ALL (n=7), blast crisis of CML (n=1) and transplant failure (n=1). There were 16 male and 9 female patients with a median age of 36 years (range 18-59). Results For RIC, fludarabin, thiotepa and melphalan were used in 16 patients, clofarabin, thiotepa and melphalan in 6 patients and other regimens containing variable combinations of cyclophosphamide, busulfan, TBI and treosulfan in 4 patients. Grafts were manipulated by CD3/CD19 depletion (n=19), TCRαβ depletion (n=1) or CD34 selection (n=6) and consisted of a median of 7.71 x 106 CD34+cells/kg bodyweight. The median interval from first HCT to second HCT was 18 months (range 5-145), and 10 and 16 months from second HCT to third HCT in the two patients undergoing a third HCT. Only 35% (n=9) of the patients receiving a second HCT were in complete remission (CR), while 65% (n=16) were in partial remission (PR). Among the patients receiving a third HCT, one had active disease, while the other was in CR. All patients achieved engraftment of the neutrophils at a median time of 11 days (range 8-26) and platelet engraftment was reached at a median time of 15 days (range 9-35, except one patient at day 375). At present, 5 patients (19%) are alive and in CR with a median follow-up of 1870 days (range 281-3941), while 35% (n=9) died from relapse; non-relapse-mortality was 46% (n=12). Kaplan-Meier estimated overall survival for all patients at 1 year was 33% (52% for patients in CR versus 18% in PR) and at 3 years 17% (26% for patients in CR versus 12% in PR). Causes of death in patients with second HCT included severe infections (n=8), organ failure (n=1), haemorrhage (n=1) and progressive multifocal leukoencephalopathy (n=2). Of the patients with third HCT, one died from respiratory insufficiency due to pulmonary haemorrhage, the other is still alive and in CR. Acute graft versus host disease (GVHD) occurred in 11 patients with predominantly mild presentation (grade 1: n=9, grade 2: n=2), limited chronic GVHD was apparent in 5 patients with no case of extensive GVHD. Conclusion Haploidentical HCT is a feasible salvage concept for patients with relapse after HCT with promising results even in patients not in CR. Disclosures: No relevant conflicts of interest to declare.

Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

2018 ◽  
Vol 141 (1) ◽  
pp. 19-22
Author(s):  
Liat Shargian-Alon ◽  
Pia Raanani ◽  
Uri Rozovski ◽  
Tali Siegal ◽  
Shlomit Yust-Katz ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cerebellar Atrophy ◽  
Acid Decarboxylase ◽  
High Dose ◽  
Host Disease ◽  
Graft Versus Host ◽  
Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

Sustained Graft-Versus-Lymphoma Effect among Patients (pts) with Mantle Cell Lymphoma (MCL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2147-2147 ◽  
Author(s):  
Mohamed L. Sorror ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Thomas Chauncey ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Median Number ◽  
Therapeutic Modality ◽  
High Dose ◽  
Duration Of Treatment ◽  
Autologous Hct

Abstract We previously reported 2-year overall survival (OS) of 65% among 33 pts with MCL given nonmyeloablative HCT (Blood2004; 104: 3535). Here, we update our results on the initial 33 pts with median follow up of 63 months and report on 20 additional pts with emphasis on: long-term disease control and resolution of chronic GVHD. Pts were conditioned with 2Gy TBI with or without fludarabine (90 mg/m2). Median age for all pts was 56 (range 33–75) years and median number of prior regimens was 4. Forty percent of pts had failed high-dose autologous HCT and an additional 11% had planned autologous HCT before allograft (4 pts had refractory disease and 2 were in PR). Comorbidity scores of ≥3 were found among 40% of pts. Forty percent of pts were not in CR/PR at HCT and 26% and 21% had marrow infiltration and lymph node size ≥5 cm, respectively. Donors were related (n=28) or unrelated (n=25). After HCT, incidences of grades II, III, and IV acute GVHD were 25%, 13%, and 9% respectively, and chronic extensive GVHD was 53%. Complete (CR) and partial remissions (PR) were seen in 71% and 3% of pts with measurable disease at HCT, respectively. Estimated 5-year rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 27%, 22%, 58%, and 52%, respectively (Table 1). Among 19 pts in CR at HCT, 11 are alive and in CR, 7 died in CR, and one relapsed (now in CR after Rituximab and donor lymphocyte infusion). Among 13 in PR at HCT, 10 achieved CR and are alive, one died in PR, and 2 died from relapse. Among 21 pts with refractory/relapsed disease at HCT, 12 achieved CR and are alive, 2 have stable disease and are alive, and 7 relapsed (2 are alive in CR and PR after further treatment). At 5-years, 44% and 14% were alive without or with chronic GVHD requiring immunosuppression (Figure); and median duration of treatment for chronic GVHD was 33 months. Outcomes were comparable among related and unrelated recipients. Relapse rates were 47% vs. 14% among pts with vs. without LN size of ≥5 cm (p=0.02) and NRM was 41% vs.17% (p=0.05) among pts with HCT-CI scores of ≥3 vs. 0–2, respectively. Nonmyeloablative HCT is a potentially curative therapeutic modality for pts with advanced MCL, including patients who were chemotherapy-refractory, with a median PFS beyond 5 years. Sustained remissions and continuing resolution of chronic GVHD were observed with extended follow up. Pts with bulky LN might benefit from further debulking strategies before HCT. Table: Outcomes by donor type Donor Related (n = 28) Unrelated (n = 25) % % Grades III–IV non-hematological toxicities 39/18 38/26 Acute GVHD, grades II/ III/ IV 22/14/7 28/12/12 Chronic GVHD 50 55 CR 73 67 5-year NRM 26 28 5-year Progression/relapse 22 21 5-year PFS 53 51 5-year OS 59 56 5-year Pts alive with chronic GVHD requiring immunosuppression 14 7 Figure Figure

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Can Induce Durable Remission in Heavily Pretreated Relapsed Hodgkin Lymphoma. (HL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1192-1192
Author(s):  
Robert Chen ◽  
Joycelynne Palmer ◽  
Leslie Popplewell ◽  
Jessica Shen ◽  
Eileen Smith ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Heavily Pretreated

Abstract Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Disclosures: No relevant conflicts of interest to declare.

Vaccine Response In Recipients of HLA Mismatched Unrelated Double Unit Cord Blood Transplantation (CBT).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1247-1247 ◽  
Author(s):  
Trudy N Small ◽  
Christine Scura Iovino ◽  
Michelle Abboud ◽  
Marissa Lubin ◽  
Esperanza Papadopoulos ◽  
...  
Keyword(s):  
Hepatitis B ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Optimal Schedule ◽  
High Dose ◽  
Vaccine Response ◽  
Post Transplant ◽  
History Of

Abstract Abstract 1247 The use of CBT has increased steadily over the last decade, with recent studies showing long-term progression-free survival similar to that of unrelated volunteer donor transplant recipients. The ability of CBT survivors to respond to post-transplant immunizations may differ from other allogeneic transplant populations due to the lack of transfer of memory T- and B-cells with the graft. Limited data have been reported on vaccine responses following this treatment modality. We, therefore, analyzed responses to immunizations in 23 double-unit CB recipients (17 adults, 6 children) transplanted at our center from 10/05-12/08. Patients were transplanted at a median age of 34 years (range 7–61) for the treatment of acute leukemia (n=13), or lymphoma/CLL (n=8/2). They received high-dose myeloablative (n=11), reduced intensity myeloablative (n=5), or non-myeloablative (n=7) conditioning according to diagnosis, age, prior therapy, and co-morbidities. GVHD prophylaxis consisted of a calcineurin inhibitor and mycophenolate mofetil. No patient received ATG. The study patients had sustained engraftment with a 5/6 (n=12) or 4/6 (n=11) HLA-matched unit. Seven recipients received rituximab (median 4 doses, range: 4–8) as planned post-transplant therapy for B-cell malignancies (n=6) or treatment of an autoimmune hemolytic anemia (n=1). Eleven patients had a history of grade II-IV acute GVHD and 5 had ongoing late acute or chronic GVHD prior to vaccination. Criteria for vaccination were: CD4 cell count of at least 200 cells/ul, PHA of greater than 60% lower limit of normal and serum IgG level >500 mg/dl at least 6 weeks following the last dose of IVIG. The median time to vaccination was 1.26 years post-CBT; this time was significantly longer in patients treated with Rituximab compared to those who were not (1.6 years versus 1.2 years, p=0.02), due to delayed normalization of B-cell numbers in the former group (449 days vs 108 days, p=0.004).Pre-vaccination titers obtained at a median of 1 year post-CBT demonstrated that over 85% of patients lacked protection against Pneumococcus, H. influenzae, and Pertussis, and at least 50% lacked immunity against tetanus, measles, and mumps. Seroconversion or >3- fold rise in titer was observed in response to tetanus, diphtheria, H. influenzae, and Pneumococcus in 90% (18/20), 81% (13/16), 80% (16/20)and 90% (18/20) of patients and was not significantly different in patients with or without a history of acute or chronic GVHD. Whereas 90% (5/6) of patients without a history of GVHD responded to a series of Hepatitis B immunizations, only 22% (2/9) of those with prior acute and/or chronic GVHD did so (p=0.03). No patient was protected against pertussis following a single TDaP (n=14) and only 1 of 5 patients responded to the protein conjugated meningococcal vaccine. Immunization with a live attenuated vaccine was initiated in 7 seronegative patients, including all 6 children, at a median of 2.25 years (range 1.5–3.6) post-CBT (MMR, n=7, Varivax, n=3). Seroconversion against measles, mumps, rubella, or chickenpox was observed in 3/7, 2/7, 6/7, and 1/3 patients, respectively. There were no serious reactions to any vaccine. These data suggest that CBT recipients are capable of responding to tetanus, diphtheria, H. Influenza and pneumococcal vaccines similar to other transplant groups. Nonetheless, the sub-optimal response to pathogens associated with outbreaks in the community (Hepatitis B, Pertussis, meningococcus, measles, mumps, varicella) highlight the need to obtain pre- and post-vaccination titers to document response, as well as define the optimal schedule of post-transplant immunizations specifically in this transplant population. Disclosures: No relevant conflicts of interest to declare.

Treatment of Recurrent or Persistent AML/MDS After Allogeneic Hematopoietic Cell Transplantation with Azacitidine.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1288-1288
Author(s):  
Jennifer Vaughn ◽  
Barry Storer ◽  
Marco Mielcarek ◽  
Edus H. Warren ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Case Series ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Persistent Disease ◽  
Relapsed Disease

Abstract Abstract 1288 Recurrence or persistence of disease after hematopoietic cell transplantation (HCT) remains a significant obstacle in the treatment of patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndromes (MDS). Standard therapies for relapsed disease include withdrawal of immunosuppression (WIS), donor lymphocyte infusion, induction chemotherapy, and in selected patients, a second HCT. Regardless of the intervention chosen, survival for post-transplant relapse has been dismal. Effective therapies without significant toxicity are needed. Azacitidine, a DNA demethylating agent, is the only non-HCT therapy shown to prolong survival in patients with MDS. It has also shown efficacy in patients with AML when used alone as induction or consolidation therapy or in combination with the anti CD-33 antibody gemtuzumab. Its use following HCT was inspired by the discovery of the drug's potential to enhance the graft-versus-leukemia effect through demethylation of the KIR regions on donor NK cells and by enhancing HLA-DR2 expression on leukemic blasts. It has also been shown to modulate T-cells post-engraftment and may result in lower rates of GVHD without impairing the GVL effect. Several small case series have been published evaluating azacitidine as therapy for treatment of relapse following HCT and have demonstrated improvement in disease status. None of these studies have examined azacitidine in the setting of persistent disease, which has become more relevant with the use of lower intensity conditioning regimens and the use of new methods to detect the presence of disease at extremely low levels. In this retrospective study, we determined the outcomes of patients treated with azacitidine (75 mg/m2/day for 7 days +/− gemtuzumab (3mg/m2) on day 9, every 4 weeks) for post-HCT recurrence or persistence of AML/MDS. Azacitidine treatment was initiated following HCT if there was evidence of recurrent or persistent disease (defined as any recurrent abnormal blasts detected by flow on peripheral blood or marrow or recurrent cytogenetic abnormalities). Seventeen (74%) of the patients had AML while 6 (26%) had MDS. FAB subtypes of the latter included RAEB (3), RA (1), CMML (1) and unclassified (1). Eighteen (78%) patients underwent conventional high dose conditioning, and 5 (22%) patients underwent nonmyeloablative conditioning prior to HCT. Eleven (48%) of patients had low risk cytogenetics, 3 (13%) had intermediate risk, and 9 (39%) had high risk cytogenetics. Seventeen (74%), 0 (0%) and 6 (26%) of patients were diagnosed with persistent or relapsed disease within 100, 100–200 and > 200 days following HCT. Patients began azacitidine 0–242 (median: 17) days from time of relapse and completed a median of 2 azacitidine cycles (range 1–8). Overall 6-month survival from the day of relapse was 57% and from start of azacitidine therapy was 48%. Among the 18 patients who started azacitidine within 2 months of documented relapse the 6-month survival was 50%. Blast count at time of relapse was not significantly associated with survival (> 1% vs ≤ 1%, HR=1.26, p=0.63), nor was survival after initial treatment with azacitidine affected by longer time intervals prior to first administration (> 28 days vs ≤ 28 days, HR=0.85, p=0.76). There were 12 patients who received gemtuzumab with azacitidine, and the addition of gemtuzumab made no difference in survival (HR with gemtuzumab = 0.81 (0.3-2.1), p=0.66). The 6-month survival with azacitidine is superior to that observed with induction chemotherapy (20%) or WIS (10%). Azacitidine therapy may be superior to standard therapies for recurrent/persistent disease following HCT and warrants further study. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4566-4566
Author(s):  
Yoo Jin Lee ◽  
Joon Ho Moon ◽  
In Hee Lee ◽  
Jae-Ho Yoon ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Killer Cell ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells

Abstract Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p<0.001), severe aGVHD (HR 3.851, p<0.001), and cGVHD (HR 0.321, p<0.001) were identified as variables affecting the OS. The following variables adversely affected on TRM: permissive MM and KIR-L-MM group (HR 2.699, p=0.007), severe aGVDH (HR 2.204, p=0.001), and cGVHD (HR 2.052, p<0.001). Non-permissive MM (HR 7.487, p=0.001) and CD34+ cells >6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

2015 ◽  
pp. e375-e380 ◽  
Author(s):  
H. Joachim Deeg
Keyword(s):  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Scoring System ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
World Health ◽  
International Prognostic Scoring System ◽  
Small Subset ◽  
High Dose

Although high-dose chemotherapy may cure a small subset of patients with myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (HCT) is the only currently available modality that is curative in a large proportion of patients. Approximately 30% to 40% of patients with high-risk MDS and 60% to 80% of patients with low-risk MDS survive long-term in remission. Disease classification and risk assessment schemes, such as the World Health Organization (WHO) Prognostic Scoring System (WPSS), the Revised International Prognostic Scoring System (IPSS-R), and patient characteristics as assessed by the HCT Comorbidity Index (HCT-CI) or other scores, provide guidance for patient management. First, by defining the prognosis of patients without HCT, these tools help physicians decide who should and who should not be transplanted. Second, they predict at least in part how successful a transplant is likely to be. Pretransplant cytogenetics and marrow myeloblast count are the strongest risk factors for post-transplant relapse. The HCT-CI allows physicians to estimate the probability of nonrelapse mortality after HCT; recent data suggest that there is also a relationship to the development of graft-versus-host disease (GVHD). In general, the emphasis has shifted from high-dose therapy, aimed at maximum tumor-cell kill, to reduced-intensity conditioning (RIC), relying on the donor cell-mediated graft-versus-tumor (GVT) effects to eradicate the disease. GVT effects are most prominent in patients who also develop GVHD, especially chronic GVHD. Thus, ongoing work is directed at reducing GVHD while maintaining potent GVT effects and at exploiting the growing knowledge of somatic mutations for the development of targeted therapies.

Pre-Transplant 5-Azacitidine (Vidaza®) May Improve Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3664-3664 ◽  
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Melissa Alsina ◽  
Ernesto Ayala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
High Dose ◽  
Unrelated Donor ◽  
Conditioning Treatment ◽  
Risk Of Relapse ◽  
Related Mortality

Abstract Most patients with MDS are older than 60 yrs and, because of age, many have previously been excluded from HCT due to the high risk of transplant related mortality. Reduced intensity conditioning has decreased regimen related mortality in HCT and has increased the age of patients for whom this treatment is offered. There remains substantial risk of relapse after HCT especially in patients with > Int-1 MDS who benefit the most from immediate HCT. One strategy to suppress leukemia burden and potentially decrease the risk of relapse is pre-transplant treatment with 5-azacitidine (Vidaza®). This DNA hypomethylating drug is FDA approved for the treatment of MDS. We analyzed the outcome for 34 MDS patients who received a myeloablative HCT from an HLA compatible sibling or unrelated donor from July 2004 through June of 2006, to investigate the potential impact of pre-transplant 5-azacitidine on response and post-transplant relapse. Fourteen of thirty-four patients received a median of 2 (1–7) cycles of 5-azacitidine prior to HCT. Median age was 59 (49 – 69) yrs. Diagnosis and IPSS category included MDS (8) [Int-1 (1) and Int-2 (7)], MDS-AML (5) and CMML (1). Two patients had induction chemotherapy with residual MDS prior to 5-azacitidine. Subsequent to 5-azacitidine: ten responded [CR (2), PR (1) improvement (7)] three progressed and one was not evaluable. The IPSS category after 5-azacitidine treatment and prior to HCT was Int-2(1), Int-1 (4), and Low (5; 3 in CR) in addition to AML (2) and CMML (1). One was unable to assess. The median follow-up in the survivors is 191 (47 – 524) days. Of the fourteen 5-azacitidine treated patients, none have relapsed post-HCT including patients who progressed on 5-azacitidine. Four have died from non-Hodgkins lymphoma (1), DAH (1), adenovirus pneumonia (1) and chronic GVHD (1). Ten are alive in remission, two for greater than one year. Twenty patients did not receive 5-azacitidine. Diagnosis and IPSS category included MDS (9) [Int-1 (3) and Int-2 (6)], MDS-AML (9) and CMML (1) and one not determined due to lack of cytogenetics. Their median age was 53 (33 – 68) yrs. Treatment included supportive care, induction chemotherapy (9) and SCIO-469 (1). IPSS distribution prior to HCT was Int-2 (7), Int-1 (5) Low (5; 4 in CR); in addition to AML (1) and CMML (1). One was unable to assess. The median follow-up in the survivors is 420 (21 – 742) days. Ten of twenty are alive without relapse and eight have relapsed. Five have died, with relapse (3), fungal pneumonia (1) or multi-organ failure (1). The 1 year K-M estimates of overall and progression free survivals are 64% (SEM 15%) and 64% (SEM 15%), respectively for 5-azacitidine group and 70% (SEM 11%) and 51% (SEM 13%) for non-5-azacytidine group. We conclude from this preliminary analysis that pre-HCT conditioning treatment with 5-azacitidine may reduce the risk for MDS relapse after allogeneic transplant in higher risk patients. In addition to its direct anti-tumor effect, 5-azacitidine may sensitize neoplastic cells to the effects of high dose chemotherapy or promote the expression of antigens critical to effective graft-vs-tumor response. This treatment strategy will be evaluated in a prospective trial to investigate the role of pre-transplant 5-azacitidine on transplant outcomes in patients with higher risk MDS.

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