Organ transplantation in AL Amyloidosis Andrea Havasi, MD Boston - PowerPoint PPT Presentation

Organ transplantation in AL Amyloidosis Andrea Havasi, MD Boston University Renal Section

Disclosure of Conflict of Interest I do not have a relationship with a for-profit and/or a not-for- profit organization to disclose

Renal Involvement in AL amyloidosis • Over 70-78% of patients present with renal involvement • Up to 40% require renal replacement therapy (RRT) Gertz MA et al. Kidney Int. 2002. Gertz MA et al. Nephrol Dial Transplant. 2009. Havasi A et al. Am J Hematol. 2016. Palladini G et al. Blood. 2014. Sidiqi MH et al. Bone Marrow Transplant. 2019

Overall survival from diagnosis 1990’s Today • HDM/SCT BU cohort with renal involvement: 8.2 years • 12-18 • HDM/SCT Mayo cohort with or months without renal involvement: 11.2 years • All patients Pavia cohort: 3.9 years • All patients Heidelberg cohort: 4.5 years Kyle RA et al. N Engl J Med 1997. Gertz MA et al. Nephrol Dial Transplant. 2009. Havasi A et al. Am J Hematol. 2016. Palladini G et al. Blood. 2014. Sidiqi MH et al. Bone Marrow Transplant. 2019

More patients with ESRD

Median overall survival on dialysis 1990’s Today • 8.2 months • 24-39 months; regardless of treatment modality After starting dialysis mortality is mainly driven by ESRD!! (but OS 5.8 years if ESRD was reached before HDM/SCT; 6% became dialysis-independent after achieving CR and 33% had kidney transplantation) Gertz et al. Arch Intern Med. 1992. Havasi A et al. Am J Hematol. 2016. Palladini G et al. Blood. 2014. Sidiqi MH et al. Bone Marrow Transplant. 2019. Batalini F at al. Biol Blood Marrow Transplant. 2018.

Renal transplantation in AL amyloidosis?? • Concerns about recurrence in the graft • Lack of data regarding overall survival and renal transplant outcomes • No clear guidelines regarding renal transplant eligibility Limited referral or acceptance for renal transplantation

49 AL amyloidosis pts Boston University Amyloidosis Center 1987-2017 Median follow up 7.2 years (0-19) Angel-Korman A et al. KI. 2019.

Clinical features at diagnosis Feature Median (range) Age (years) 53.7 (26.4-73.8) Gender Male: 82% Race White 98% Lambda 61% Light chain clonality Kappa 37% Creatinine 2 mg/dL (0.4-12) 36 mL/min/1.73m 2 (2-117) eGFR Proteinuria 7.2 g/24 hr (0.1-42) Renal only 20%, Cardiac 33%, Organ involvement ≥3 organs 43% OS from diagnosis 15.4 years (1-20.7)

Renal transplant characteristics Feature Median (range) 60.1 years (30.7-73.2) Age at renal transplantation pre-emptive 18% ESRD status post RRT 82% Living donor 65% Transplant type Deceased donor 20% Unknown 15% Time from diagnosis to ESRD 1.5 years (0-10.3) Time from diagnosis to renal 4 years (-5.7-12) transplantation Time from ESRD to renal 1.9 years (0.2-11.3) transplantation Time from hematologic response to 2.4 years (0.4-10.4) renal transplantation

Number of transplants per decade Angel-Korman A et al. KI. 2019.

Overall survival after renal transplant improved over the last decade OS from diagnosis OS from transplant Angel-Korman A et al. KI. 2019.

Graft survival and recurrence rate after renal transplant improved over the last decade Graft survival Recurrence in the graft Angel-Korman A et al. KI. 2019.

Renal transplant outcomes – Overall survival UK USRDS All types of >65 yrs DM Our National (cadaveric/ Mayo amyloid (cadaveric/ (cadaveric cohort amyloidosi living) clinic 2011 patients living) /living) (AL s center (All (AL only) USRDS (All (All only) 2010 etiologies) 2017 etiologies) etiologies) (AL only) Number of 49 22 19 576 patients Overall Survival Media 10.5 6.5 Not (years N/A 5.8 N/A N/A n (1-20.3) (0.2-13.3) reached from renal Tx) 1 yr 97%/98.7% 96% 95% N/A 91% 94.2%/96% 96%/97% 3 yrs N/A 91% N/A N/A N/A 86%/89.5% 89%/93% 5 yrs 86%/93% 86% 67% N/A 70% 74%/82% 83%/87% Angel-Korman A et al. KI. 2019.

Renal transplant outcomes – Overall survival UK USRDS All types of >65 yrs DM Our National (cadaveric/ Mayo amyloid (cadaveric/ (cadaveric cohort amyloidosi living) clinic 2011 patients living) /living) (AL s center (All (AL only) USRDS (All (All only) 2010 etiologies) 2017 etiologies) etiologies) (AL only) Number of 49 22 19 576 patients Overall Survival Media 10.5 6.5 Not (years N/A 5.8 N/A N/A n (1-20.3) (0.2-13.3) reached from renal Tx) 1 yr 97%/98.7% 96% 95% N/A 91% 94.2%/96% 96%/97% 3 yrs N/A 91% N/A N/A N/A 86%/89.5% 89%/93% 5 yrs 86%/93% 86% 67% N/A 70% 74%/82% 83%/87% Adapted from Angel-Korman A et al. KI. 2019.

Renal transplant outcomes – Graft survival All types of >65 yrs DM USRDS Our UK National Mayo clinic amyloid (cadaveric (cadaveric (cadaveric/ cohort amyloidosis 2011 patients /living) /living) living) (AL center 2010 (AL only) USRDS (All (All (All etiologies) only) (AL only) 2017 etiologies) etiologies) Number of 49 22 19 576 patients Median 6.9 Graft Not 9.1 (0.5- 5.8 4.8 Survival reached 18.8) (years) 1 yrs 93.4%/97.2% 94% N/A (74%) N/A N/A/94% 92%/96% 3 yrs N/A 89% N/A N/A N/A N/A/87% 83%/88.5% 5 yrs 72.4%/84.6% 81% N/A (53%) N/A N/A/78% 73%/81.5% Angel-Korman A et al. KI. 2019.

Renal transplant outcomes – Graft survival All types of >65 yrs DM USRDS Our UK National Mayo clinic amyloid (cadaveric (cadaveric (cadaveric/ cohort amyloidosis 2011 patients /living) /living) living) (AL center 2010 (AL only) USRDS (All (All (All etiologies) only) (AL only) 2017 etiologies) etiologies) Number of 49 22 19 576 patients Median 6.9 Graft Not 9.1 (0.5- 5.8 4.8 Survival reached 18.8) (years) 1 yrs 93.4%/97.2% 94% N/A (74%) N/A N/A/94% 92%/96% 3 yrs N/A 89% N/A N/A N/A N/A/87% 83%/88.5% 5 yrs 72.4%/84.6% 81% N/A (53%) N/A N/A/78% 73%/81.5% Angel-Korman A et al. KI. 2019.

Eligibility criteria for renal transplantation?

Overall survival from diagnosis: CR/VGPR vs PR/NR Median OS: 17.9 y vs 9.7 y Angel-Korman A et al. KI. 2019.

Overall survival from renal transplant: CR/VGPR vs PR/NR Median OS: 11.7 y vs 7 y Angel-Korman A et al. KI. 2019.

Graft survival: CR/VGPR vs PR/NR Median time to graft loss: 10.4 y vs 5.5 y Angel-Korman A et al. KI. 2019.

Recurrence of amyloid in the graft • 14 pts (29%) had recurrent amyloidosis in the graft • Median time from renal transplantation to recurrence: 3.7 years (range 1.1-11.9) • 20 pts received treatment for hematologic relapse: graft survival was not different from the pts without relapse (6.9 vs 8.3 years, p=0.35) • 4 pts lost the graft due to amyloidosis • 10 pts were successfully treated • 6 pts HDM/SCT >>> VGPR or CR Angel-Korman A et al. KI. 2019.

Lower recurrence in the graft in CR/VGPR

Time from renal transplantation to recurrence in the graft: CR/VGPR vs PR/NR Angel-Korman A et al. KI. 2019.

Cause of death in kidney transplant recipients Cause of death # of pts Progressive amyloidosis 10/23 Renal failure 2 Treatment related 2 Sepsis 2 Heart failure (non-AL) 1 Surgical complication (unrelated) 1 CVA 1 Unknown 4 Angel-Korman A et al. KI. 2019.

What does not seem to change renal transplant outcome? No difference in OS and graft survival • HDM/SCT vs. chemotherapy (39 vs 10 pts) • Hematologic relapse vs no relapse (20 vs 29 pts) • HDM/SCT before vs after renal transplantation (33 vs 6 pts) • Living vs. cadaveric • Pre-emptive • Number of organs involved • Cardiac involvement at the time of diagnosis • κ vs λ

Immunosuppressive regimens • Standard therapies • No change in regimen while getting treatment for AL amyloidosis • During SCT: mycophenolate on hold • Only 4 acute rejections

Timing of renal transplantation • 4 y (range -5.7-12) from diagnosis • 1.9 y (range 0.2-11.3) from ESRD • 2.4 y (range 0.4-10.4) from hematological response Why? • The time it requires to go through the transplant evaluation (both recipient and donor, if available) • Wait time on the cadaveric transplant list • Patients’ preference regarding the timing of transplantation

Timing of renal transplantation Our recommendation Wait 6-12 months post hematologic response to document the durability of response and to recover from therapy related toxicities

Limitations • Small sample size • Mostly white (98%) perhaps representing under- diagnosis of amyloidosis in other races or ethnicities • Retrospective study • The choice of treatment, the timing of treatment and renal transplantation were physician and patient dependent >>>>> selection bias

Heart transplantation in AL amyloidosis

What did we learn from heart transplants? • Mayo Clinic; 1992-2011; 23 pts; median age 53 • OS: 3.5 years (95%CI: 1.2-8.2) • OS in CR (=7 pts) in response to chemoth or HDM/SCT: 10.8 years • Survival is better in pts with limited extra-cardiac involvement • 5-year survival 43% vs 85% for non-amyloid • Eight patients had rejection at a median of 1.8 months post OHT (range 0.4 to 4.9 mo) Grogan M at al. World J Transplant. 2016. Gray Gilstrap L at al. J Heart Lung Transplant. 2014.