Photochemotherapy and Graft-versus-leukemia in Acute-leukemia

AML Clinical Trial

Official title:

Photochemotherapy of Acute Graft-versus-host Disease (aGVHD) of the Skin - is Graft-versus-leukemia Preserved in Patients Transplanted for Acute Leukemia?

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02631993
• Other study ID #: TIM Photochem 2
• Status: Completed
• Phase: N/A
• First received: September 8, 2015
• Last updated: December 11, 2015
• Start date: October 2014
• Est. completion date: December 2014

Study information

• Verified date: December 2015
• Source: Karolinska University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Regional Ethical Review Board
• Study type: Observational

Clinical Trial Summary

Cure of leukemia after hematopoietic stem cell transplantation (HSCT) is sustained by the anti-leukemic effect of the grafted cells (graft-versus-leukemia (GVL)). However, it is not known whether the tumor-immunity is affected by photochemotherapy (psoralene photosensitization and ultraviolet light radiation) administered to attenuate graft-versus host disease (GVHD).

The present study aim to investigate what happens to the GVL after photochemotherapy of aGVHD in a predominantly retrospective setting with 10-years follow-up after HSCT

Description:

This is a 10-year follow-up of patients with Acute-myeloid-leukemia (AML) or acute-lymphatic-leukemia (ALL). AML is diagnosed by the French-American-British criteria (FAB-criteria) and ALL is separated into chief forms by immunohistological methods. All patients underwent myeloablative Hematopoietic Stem Cell Transplantation (HSCT) between 1985 and 2005 at the center for allogeneic stem cell transplantation (CAST) at Karolinska University Hospital. All patient receive GVHD-prophylaxis.

The risk for relapse after HSCT is graded into low-risk if the disease is in first complete remission before HSCT, all other disease states are classified as high-risk.

Eligible patients received photochemotherapy (Ultraviolet radiation type A on skin photosensitized by oral 8-methoxypsoralen) for acute graft-versus-host disease (GVHD within 100-days after HSCT). Photochemotherapy may be given as primary or later aGVHD therapy. Patients with aGVHD after booster doses of stem-cells or donor-lymphocyte-infusions are not included.

Additional treatment are registered where present. Methotrexate is not considered as an additional GVHD treatment as intravenous methotrexate a part of the governing GVHD prophylaxis and as the effects of methotrexate as a secondary aGVHD treatment is weak.

At the start, the end, at maximum and up until two weeks after end of PUVA-therapy the GVHD is diagnosed in accordance with Glucksberg and indexed by CIBMTR.

Relapse is diagnosed when leukemic cells is present extra medullary or with a bone marrow biopsy with ≥ 30% blasts. Early relapse is diagnosed when the medulla contain 5 - 30% blasts

The primary outcome is GVL i.e. abscence of relapse in malignant disease or minimal residual disease (MRD) i.e. threatening relapse in malignant disease demanding donor lymphocyte infusion (DLI).

Primary predictor: Time-to-treatment by photochemotherapy at day 0 - 7 vs. start at day 8 ≤ of aGVHD.

Continuous secondary predictor: Time-to-treatment by photochemotherapy as a continuous variable (days after start of aGVHD).

Binary secondary predictors: Risk (Low/High), Sibling donor-recipient (Yes/No), Mismatched related (Yes/No), Unrelated donor (Yes/No), (Male recipients of female grafts (Yes/No), T-cell depletion or Anti-Thymocyte Globulin (Yes/No).

Categorical secondary predictors: AGVHD organ disease stage and disease grade; Skin (+, ++, +++, ++++), Liver (+, ++, +++, ++++), Gastro-intestinal (+, ++, +++, ++++), Center for International Blood and Marrow Transplant Research CIBMTR index (A, B, C, D) respectively.

Statistical analysis:

Cox proportional Hazards ratio is used to conduct a univariate data analysis of all adequate variables in patient characteristics and disease towards the primary outcome. In the analysis, death, DLI or retransplantation due to graft-failure was treated as a competing event. The primary predictor (binary) and all binary or categorical covariates identified from the patient and disease characteristics are to be included in a multivariate forward regression analysis, controlled for with backward regression based on the log-likelihood method. P=0.05 is considered as significant and p=0.10 as a trend. StatSoft, Inc. (2013). STATISTICA (data analysis software system), version 12. www.statsoft.com. are used for statistical computation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 2014
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Eligible patients received photochemotherapy (Ultraviolet radiation type A on skin photosensitized by oral 8-methoxypsoralen) for acute graft-versus-host disease (GVHD within 100-days after HSCT). Photochemotherapy may be given as primary or later aGVHD therapy.

Exclusion Criteria:

• Patients with aGVHD after booster doses of stem-cells or donor-lymphocyte-infusions are not included.

Study Design

Observational Model: Cohort, Time Perspective: Retrospective

Related Conditions & MeSH terms

• Acute GVHD
• ALL
• AML
• Tumor Immunity

Intervention

Radiation:
• Photochemotherapy
Oral 8-Methoxypsoralene (8-MOP), (0.4-0.8 mg/kg), are given 1.5-2 hours before phototherapy. Ultraviolet light type A (UVA, 320-400 nm) is administered in a Waldmann UV1000 supine unit through 26 100-W fluorescent PUVA lamps (Waldmann F85), if needed, UVA is given in a half body unit with 15 100-W PUVA-lamps (Waldmann F85), (Waldmann UV3003K), (Waldmann, Villingen-Schwenningen, Germany). Eye protection is applied during 24 h after oral 8-MOP and the genital area are shielded in males during therapy.The UVA is initiated at 0.2-1.5 J/cm2 and is amplified by 0.25-0.5 J/cm2 after two treatments if photo toxicity is absent. PUVA is given to the patients 3-5 times each week.

Locations

Country	Name	City	State
Sweden	Department of Dermatology, Karolinska University Hospital Huddinge	Stockholm

Sponsors (1)

Lead Sponsor	Collaborator
Karolinska University Hospital

Country where clinical trial is conducted

Sweden, 

References & Publications (12)

Alyea EP, DeAngelo DJ, Moldrem J, Pagel JM, Przepiorka D, Sadelin M, Young JW, Giralt S, Bishop M, Riddell S. NCI First International Workshop on The Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: report from the committee on prevention of relapse following allogeneic cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2010 Aug;16(8):1037-69. doi: 10.1016/j.bbmt.2010.05.005. Epub 2010 May 24. Review. — View Citation

Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974 Oct;18(4):295-304. — View Citation

Hari P, Logan B, Drobyski WR. Temporal discordance between graft-versus-leukemia and graft-versus-host responses: a strategy for the separation of graft-versus-leukemia/graft-versus-host reactivity? Biol Blood Marrow Transplant. 2004 Nov;10(11):743-7. — View Citation

Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringdén O, Rozman C, Speck B, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990 Feb 1;75(3):555-62. — View Citation

Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974 Dec 5;291(23):1207-11. — View Citation

Ringdén O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol. 2009 Dec;147(5):614-33. doi: 10.1111/j.1365-2141.2009.07886.x. Epub 2009 Sep 4. Review. — View Citation

Ringdén O, Labopin M, Solders M, Beelen D, Arnold R, Ehninger G, Milpied N, Niederwieser D, Hamladji RM, Kyrcz-Krzemien S, Ganser A, Socié G, Stelljes M, Volin L, Craddock C, Mohty M; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Who is the best hematopoietic stem-cell donor for a male patient with acute leukemia? Transplantation. 2014 Sep 15;98(5):569-77. doi: 10.1097/TP.0000000000000102. — View Citation

Ringdén O, Sundberg B, Lönnqvist B, Tollemar J, Gahrton G, Nilsson B. Allogeneic bone marrow transplantation for leukemia: factors of importance for long-term survival and relapse. Bone Marrow Transplant. 1988 Jul;3(4):281-90. — View Citation

Ringden O, Witherspoon RP, Storb R, Ekelund E, Thomas ED. Increased in vitro B-cell IgG secretion during acute graft-versus-host disease and infection. Observations in 50 human marrow transplant recipients. Blood. 1980 Feb;55(2):179-86. — View Citation

Strauss GH, Bridges BA, Greaves M, Hall-Smith P, Price M, Vella-Briffa D. Inhibition of delayed hypersensitivity reaction in skin (DNCB test) by 8-methoxypsoralen photochemotherapy. Possible basis for pseudo-promoting action in skin carcinogenesis? Lancet. 1980 Sep 13;2(8194):556-9. — View Citation

Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975 Apr 17;292(16):832-43. Review. — View Citation

Wolf P, Nghiem DX, Walterscheid JP, Byrne S, Matsumura Y, Matsumura Y, Bucana C, Ananthaswamy HN, Ullrich SE. Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis. Am J Pathol. 2006 Sep;169(3):795-805. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Graft-versus-leukemia (GVL)	i.e. abscence of relapse in malignant disease or minimal residual disease (MRD) i.e. threatening relapse in malignant disease demanding donor lymphocyte infusion (DLI).	10-years after HSCT (2005 - 2015)	No
Secondary	Death	Competing event	10-years after HSCT (2005 - 2015)	No
Secondary	Retransplantation	Competing event	10-years after HSCT (2005 - 2015)	No
Secondary	Donor Lymphocyte Infusion (DLI)	Competing event	10-years after HSCT (2005 - 2015)	No